Purpose: Venous thromboembolism (VTE) after major orthopaedic surgery remains an important clinical problem. Convenient, oral antithrombotic agents that are both effective and safe could improve adherence to guidelines for VTE prophylaxis. Recently, the focus has been on the development of oral agents that target a single step in the coagulation cascade and Factor Xa is a pivotal step. Rivaroxaban is an oral, direct Factor Xa inhibitor. Four international phase III trials (the RECORD programme) were undertaken to investigate the safety and efficacy of once-daily rivaroxaban for thromboprophylaxis after major orthopaedic surgery. The results of RECORD3 showed that rivaroxaban was more effective than enoxaparin 40 mg once daily after total knee replacement (TKR), with a 48% risk reduction in VTE and all cause mortality. RECORD4 was designed to determine the efficacy and safety of 10 mg rivaroxaban od compared to 30 mg bid enoxaparin after total knee replacement (TKR).

Method: This study randomized 3148 patients to either rivaroxaban (10 mg od started 6–8 hours after surgery) or enoxaparin (30 mg bid s.c. started 12–24 hours after surgery) for 10–14 days. The primary efficacy outcome was the composite of asymptomatic deep vein thrombosis (DVT) detected by mandatory, bilateral venography and symptomatic DVT, non-fatal pulmonary embolism (PE), and all-cause mortality up to day 13±4. Secondary outcomes included major VTE (composite of proximal DVT, non-fatal PE, and VTE-related death) and symptomatic VTE. Safety outcomes included on-treatment major and non-major bleeding.

Results: Rivaroxaban provided a 31% relative risk reduction in the incidence of the primary efficacy outcome when compared to enoxaparin (6.9% vs 10.1%, respectively; p=0.012). The corresponding rates for major VTE were 1.2% and 2.0%, respectively (p=0.124) and for symptomatic VTE were 0.7% and 1.2%, respectively (p=0.187). There were no significant differences in bleeding incidence observed between rivaroxaban and enoxaparin (major bleeding: 0.7% vs 0.3%, respectively, p=0.110; clinically relevant non-major bleeding: 2.6% vs 2.0%, respectively, p=0.279).

Conclusion: Rivaroxaban 10 mg od is the first oral thromboprophylactic agent to significantly reduce the incidence of VTE after TKR compared to enoxaparin 30 mg bid, with a similar, low rate of bleeding.

Purpose: Rivaroxaban is a novel, oral, direct Factor Xa inhibitor in advanced clinical development for the prevention and treatment of thromboembolic disorders. RECORD3 was a phase III trial conducted to compare the efficacy and safety of oral rivaroxaban with subcutaneous enoxaparin for the prevention of venous thromboembolism (VTE) in patients undergoing total knee replacement (TKR).

Method: In this randomized, double-blind trial, patients received rivaroxaban 10 mg once daily (od), or enoxaparin 40 mg od. Enoxaparin was initiated the evening before surgery, and rivaroxaban 6–8 hours after surgery; therapy continued for 10–14 days. The primary efficacy outcome was the composite of any deep vein thrombosis (DVT), pulmonary embolism (PE), and all-cause mortality. Secondary efficacy outcomes included major VTE (the composite of proximal DVT, PE, and VTE-related death) and symptomatic VTE. Major bleeding was the primary safety outcome. Other safety outcomes included any on-treatment bleeding and hemorrhagic wound complications (the composite of excessive wound hematoma and surgical-site bleeding).

Results: A total of 2531 patients were randomized; 2459 were eligible for inclusion in the safety population and 1702 for the modified intention-to-treat population. The incidence of the primary efficacy outcome was significantly reduced with rivaroxaban compared with enoxaparin (relative risk reduction 49%, p< 0.001). Major VTE occurred in 1.0% and 2.6% of patients receiving rivaroxaban and enoxaparin, respectively (relative risk reduction 62%, p=0.016). The incidence of symptomatic VTE was significantly lower in the rivaroxaban group than in the enoxaparin group (p=0.005). Major bleeding rates were 0.6% and 0.5% in the rivaroxaban and enoxaparin groups, respectively, and rates of any on-treatment bleeding were 4.9% and 4.8%, respectively. The incidence of hemorrhagic wound complications was 2.1% in the rivaroxaban group and 1.9% in the enoxaparin group.

Conclusion: Rivaroxaban was significantly more effective than enoxaparin for thromboprophylaxis after TKR. Importantly, the incidence of bleeding was low and similar in both groups. This is the first trial to demonstrate the efficacy and safety of a fixed, unmonitored regimen of an oral, direct Factor Xa inhibitor – rivaroxaban – for thromboprophylaxis after TKR.