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: Thromboprophylaxis is recommended for at least 10 days and up to 35 days following total hip replacement (THR). Rivaroxaban is an oral, direct Factor Xa inhibitor in advanced clinical development that showed promise in early clinical trials. The purpose of this randomized, double-blind, double-dummy, phase III study was to compare the efficacy and safety of oral rivaroxaban with subcutaneous enoxaparin for 5 weeks, to prevent venous thromboembolism (VTE) in patients undergoing primary THR.

Method: Patients received 10 mg rivaroxaban orally 6–8 hours after surgery and once daily thereafter, or 40 mg enoxaparin subcutaneously the evening before surgery (restarting 6–8 hours after surgery), and continued once daily. Thromboprophylaxis was administered for 35±4 days, and mandatory, bilateral venography was conducted the next day. The primary efficacy endpoint was the composite of any deep vein thrombosis (DVT), non-fatal pulmonary embolism (PE), and all-cause mortality. The primary efficacy analysis was a test for non-inferiority, followed by a test for superiority. Safety endpoints included major and non-major bleeding during the active treatment period.

Results: A total of 4541 patients were randomized to receive rivaroxaban or enoxaparin. Rivaroxaban significantly reduced the incidence of the composite of DVT, PE, and all-cause mortality compared with enoxaparin (1.1% vs 3.7%, respectively; p< 0.001; relative risk reduction [RRR] 70%). Rivaroxaban also significantly reduced the incidence of major VTE compared with enoxaparin (0.2% vs 2.0%, respectively; p< 0.001; RRR 88%). There were no significant differences in the incidence of major bleeding (0.3% vs 0.1%; p=0.178) or non-major bleeding (5.8% vs 5.8%; p=1.000) between rivaroxaban and enoxaparin, respectively. There was no evidence of cardiac or liver safety issues.

Conclusion: Oral, once-daily rivaroxaban was significantly more effective than subcutaneous, once-daily enoxaparin for extended thromboprophylaxis following THR. Rivaroxaban was not associated with an increased risk of bleeding and had a similar safety profile to enoxaparin. This trial demonstrated the efficacy and safety of a fixed, unmonitored dose of an oral, direct Factor Xa inhibitor – rivaroxaban – for extended thromboprophylaxis after THR.

Purpose: Venous thromboembolism (VTE) is a common, potentially fatal complication of major orthopaedic surgery. Pharmacologic thromboprophylaxis is recommended following total hip replacement (THR) for a minimum of 10 days, and up to 35 days. However, its extended use is not accepted universally – an effective, safe and convenient, oral anticoagulant would improve implementation of these recommendations. This study was conducted to compare short-term thromboprophylaxis with enoxaparin and extended thromboprophylaxis with the novel, oral, direct Factor Xa inhibitor rivaroxaban after THR. This was the largest, prospective, randomized clinical trial conducted to date for the evaluation of the risk/benefit of extended duration thromboprophylaxis.

Method: In this global, double-blind trial, 2509 patients undergoing THR were randomized to receive either subcutaneous enoxaparin 40 mg once daily (od), beginning the evening before surgery and continued for 10–14 days, followed by placebo until day 35±4 (short-term prophylaxis); or oral rivaroxaban 10 mg od beginning 6–8 hours after surgery and continuing for 35±4 days (extended prophylaxis). Mandatory, bilateral venography was conducted on day 36±4. The primary efficacy endpoint was the composite of any deep vein thrombosis (DVT), non-fatal pulmonary embolism (PE), and all-cause mortality. The main secondary efficacy endpoint was major VTE; the composite of proximal DVT, non-fatal PE, and VTE-related death. Safety endpoints included the incidence of major and non-major bleeding.

Results: Extended thromboprophylaxis with rivaroxaban significantly reduced the incidence of both the primary efficacy endpoint (2.0% versus 9.3%, respectively; p< 0.001; relative risk reduction [RRR] 79%) and major VTE (0.6% versus 5.1%, respectively; p< 0.001; RRR 88%), compared with short-term enoxaparin. The incidence of major bleeding was 0.1% in patients receiving either extended or short-term thromboprophylaxis. Non-major bleeding was reported in 6.5% of patients receiving extended prophylaxis with rivaroxaban and 5.5% of those receiving short-term enoxaparin.

Conclusion: Extended duration thromboprophylaxis with rivaroxaban was significantly more effective than short-term enoxaparin for the prevention of VTE in patients undergoing THR. Both regimens were associated with a similar incidence of bleeding. Extended thromboprophylaxis provides substantial benefits for patients undergoing THR and rivaroxaban provides a safe and effective option for this strategy.

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.