Introduction: The standard length of hospital stay after total hip arthroplasty (THA) can be as short as 4 days. However, the risk of venous thromboembolism (VTE) extends beyond this period of hospitalization. A pooled analysis of the RECORD1 and RECORD2 studies evaluated the efficacy, safety, and timing of events with rivaroxaban compared with enoxaparin for the prevention of VTE after THA.

Methods: Patients (N=7,050) were randomized to receive oral rivaroxaban 10 mg once daily starting postoperatively (for 31–39 days) or subcutaneous enoxaparin 40 mg once daily starting preoperatively (for 31–39 days in RECORD1, and 10–14 days followed by placebo in RECORD2). The primary efficacy endpoint was the composite of symptomatic VTE and all-cause mortality. The safety endpoints were treatment-emergent major bleeding, major bleeding including surgical-site bleeding, major bleeding plus clinically relevant non-major (CRNM) bleeding, and any bleeding. The primary efficacy endpoint was assessed during treatment. The incidence and timing of the safety endpoints were assessed after the first dose of study medication and up to 2 days after the last dose.

Results: Rivaroxaban significantly reduced the incidence of symptomatic VTE and all-cause mortality compared with enoxaparin regimens (0.44% vs 1.01%, respectively; p=0.006), with no significant differences in major bleeding (0.2% vs 0.09%; p=0.219) or the composite of major plus CRNM bleeding (3.23% vs 2.61%; p=0.141). Of the symptomatic VTE and all-cause mortality events, 73% and 86% occurred after day 4 with the rivaroxaban and enoxaparin regimens, respectively. For the composite of major plus CRNM bleeding, 48% and 33% of events occurred after day 4 with the rivaroxaban and enoxaparin regimens, respectively.

Conclusion: Rivaroxaban significantly reduced symptomatic VTE and all-cause mortality after THA compared with the enoxaparin regimens, with no significant difference in bleeding events. Major plus CRNM bleeding was more likely to occur earlier than day 4, whereas the majority of symptomatic venous thromboembolic events occurred after day 4. These results highlight the relevance of extended duration of thromboprophylaxis after THA as most VTE events occur post-discharge.

Introduction: The risk of venous thromboembolism (VTE) remains a major concern beyond the standard period of hospitalization of about 4 days after total knee arthroplasty (TKA). A pooled analysis of the RECORD3 and RECORD4 studies evaluated the efficacy, safety, and timing of events with rivaroxaban compared with enoxaparin for the prevention of VTE after TKA.

Methods: Patients (N=5,679) were randomized to receive oral rivaroxaban 10 mg once daily starting postoperatively or subcutaneous enoxaparin 40 mg once daily starting preoperatively (European Union regimen; RECORD3) or enoxaparin 30 mg every 12 hours starting postoperatively (North American regimen; RECORD4) for 10–14 days. The primary efficacy endpoint was the composite of symptomatic VTE and all-cause mortality, and this was analyzed over the treatment period. The safety endpoints were treatment-emergent major bleeding, major bleeding including surgical-site bleeding, major bleeding plus clinically relevant non-major (CRNM) bleeding, and any bleeding. The incidence and timing of the safety endpoints were assessed after the first dose of study medication and up to 2 days after the last dose.

Results: Rivaroxaban significantly reduced symptomatic VTE and all-cause mortality compared with enoxaparin regimens (0.73% vs 1.71%, respectively; p=0.001) with no significant differences in major bleeding (0.62% vs 0.36%, p=0.185) or composite of major plus CRNM bleeding (3.13% vs 2.48%, p=0.145). The majority of venous thromboembolic events occurred after day 4 for both regimens (rivaroxaban: 70%; enoxaparin: 68%). For the composite of major plus CRNM bleeding events, 44% occurred after day 4 with rivaroxaban regimens and 38% occurred after day 4 with enoxaparin regimens.

Conclusion: Rivaroxaban significantly reduced symptomatic VTE and all-cause mortality compared with enoxaparin regimens after TKA, with no significant difference in bleeding events between regimens. Major plus CRNM bleeding was more likely to occur before day 4, whereas the majority of symptomatic venous thromboembolic events occurred after day 4. These results highlight the importance of continuing thromboprophylaxis beyond the normal time of hospital discharge for TKA.

Introduction: Venous thromboembolism (VTE) after major orthopaedic surgery remains an important clinical problem. Convenient, oral antithrombotic agents that are both safe and effective could improve adherence to guidelines for VTE prevention. Recently, the focus has been on the development of oral agents that target a single step in the coagulation cascade. Factor Xa is the pivotal point in the coagulation cascade, making it a particularly attractive target for anticoagulant drugs. Rivaroxaban is an oral, direct Factor Xa inhibitor. Four international phase III trials (the RECORD programme) are being 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 is designed to compare rivaroxaban 10mg once daily with enoxaparin 30 mg every 12 hours for thromboprophylaxis following TKR.

Methods: RECORD4 is a prospective, double-blind trial in which approximately 3000 TKR patients worldwide are being studied. Patients are randomized to receive either oral rivaroxaban 10 mg (starting 6–8 hours after surgery and continued once daily), or subcutaneous enoxaparin 30 mg (given every 12 hours and starting 12–24 hours after surgery). Study medication is given for 10–14 days, and mandatory bilateral venography is undertaken the following day. The primary efficacy outcome is a composite of deep vein thrombosis (DVT; symptomatic, or detected by mandatory venography), non-fatal pulmonary embolism (PE), and all-cause mortality. The major secondary efficacy outcome is major VTE (the composite of proximal DVT, PE and VTE-related death). The primary safety outcome is major bleeding. Other safety endpoints include all bleeding events, cardiovascular events and abnormal laboratory parameters.

Results: The final results of this trial will be presented.

Conclusions: The results of this trial will provide valuable data concerning the use of rivaroxaban for thromboprophylaxis after TKR in the North American setting.

Rivaroxaban is an oral, direct Factor Xa inhibitor in clinical development for the prevention of VTE after major orthopaedic surgery. Data from three phase II trials of twice-daily (bid) rivaroxaban in patients undergoing elective, total hip or knee replacement were pooled to determine whether age, gender or weight affected the efficacy or safety of rivaroxaban, and thus whether dose adjustment would be necessary. Patients received 5–9 days of oral rivaroxaban (2.5–30 mg bid, post-operatively), or s.c. enoxaparin. A logistic regression model using total daily dose of rivaroxaban as a covariate, and adjusted for differences between dose groups with respect to study, age and gender, was used to estimate rates of the primary efficacy endpoint (DVT, PE or all-cause mortality; n=1380 intention-to-treat patients) and clinically relevant bleeding (major and non-major clinically relevant bleeding; safety population, n=1854). Rivaroxaban at total daily doses of 5–20 mg had similar efficacy and safety to enoxaparin. Overall, logistic regression showed a positive dose–response relationship with rivaroxaban for clinically relevant bleeding (p< 0.001), and a flat relationship for the primary efficacy endpoint (p=0.115). The risk of VTE increased with age – the efficacy endpoint was estimated to occur in 17.3–9.4%, 18.7–17.3% and 26.6–20.2% of patients aged < 60 yrs, 60–70 yrs and > 70 yrs receiving rivaroxaban (total daily dose 5–60 mg), respectively, in separate regression models. Age was also prognostic for clinically relevant bleeding with rates of 1.4–12.0% (< 60 yrs), 2.7–15.4% (60–70 yrs) and 5.7–15.4% (> 70 yrs). The rates are for a population distributed equally across the studies and genders. Incidences of the efficacy endpoint were higher in females (25.8–20.5%) than males (16.6–10.7%), while clinically relevant bleeding occurred more frequently in males (5.4–16.3%) than in females (1.7–11.6%), after adjustment for age. Weight was not prognostic for the efficacy endpoint or clinically relevant bleeding (p=0.87 and p=0.48, respectively, after adjustment for age, gender and study), nor did it modify the dose–response relationships with rivaroxaban. Incidences of the efficacy endpoint for a population of equal study and gender distribution and of mean patient age were 23.4–15.7% and 19.1–14.6% in patients weighing < 65 kg and ≥90 kg, respectively, with corresponding bleeding rates of 3.3–16.5% and 3.2–17.5%. This analysis indicates that age, gender or weight did not affect the dose–response relationships (or lack thereof) between rivaroxaban and the primary efficacy endpoint or clinically relevant bleeding. As expected, age was prognostic for VTE and bleeding. These findings suggest that rivaroxaban may not require dose adjustment for age, gender or weight in orthopaedic patients.

Routine prophylaxis is recommended to prevent venous thromboembolism (VTE) – manifesting as deep vein thrombosis (DVT) and/or pulmonary embolism (PE) – in patients undergoing major orthopaedic surgery. Rivaroxaban (BAY 59-7939) is a novel, oral, direct Factor Xa inhibitor in development for the prevention and treatment of VTE. The efficacy and safety of 5–9 days’ prophylaxis with rivaroxaban were investigated in three randomized, double-blind, phase IIb trials in patients undergoing elective, total hip or knee replacement (THR or TKR), relative to subcutaneous enoxaparin.

Two trials (one in patients undergoing THR, N=722; and one in patients undergoing TKR, N=621) investigated twice-daily (bid) rivaroxaban (at total daily doses of 5–60 mg); the third (in patients undergoing THR, N=873) investigated once-daily (od) rivaroxaban (at doses of 5, 10, 20, 30 or 40 mg od).

Rivaroxaban – at all doses tested – had similar efficacy to enoxaparin in the bid trials. This promising finding was strengthened by the od trial, in which the observed incidences of the primary efficacy endpoint (DVT, non-fatal PE or all-cause mortality) were lower in patients receiving rivaroxaban 5, 10, 20, 30 and 40 mg od (14.9%, 10.6%, 8.5%, 13.5% and 6.4%, respectively) than enoxaparin (25.2%). Although there was no significant dose–response relationship between rivaroxaban and the primary efficacy endpoint in these trials, there was with major VTE (proximal DVT, PE or VTE-related death; p=0.0072) in the od trial (incidences were 8.5%, 2.7%, 0.9%, 1.9% and 1.1% with rivaroxaban 5, 10, 20, 30 and 40 mg od, respectively, vs 2.8% with enoxaparin).

Significant dose–response relationships between rivaroxaban and major bleeding were observed in all three trials. In the bid trials, major bleeding rates with rivaroxaban were similar to those with enoxaparin at total daily doses of 5–20 mg. In the od trial, major bleeding occurred in 2.3%, 0.7%, 4.3%, 4.9% and 5.1% of patients receiving rivaroxaban 5, 10, 20, 30 and 40 mg od, respectively, and in 1.9% of those receiving enoxaparin.

Rivaroxaban was generally well tolerated in the bid and od trials, and the incidence of nausea and vomiting with early post-operative oral rivaroxaban administration was low for all doses tested.

The bid trials suggest that oral rivaroxaban at total daily doses of 5–20 mg may be a safe and effective alternative to enoxaparin for the prevention of VTE after major orthopaedic surgery. The od trial suggests that the more-convenient od regimen is feasible and that 10 mg od, a dose within the range identified by the bid trials, should be investigated further. As a result, oral rivaroxaban 10 mg od is currently being investigated in four phase III trials for the prevention of VTE after major orthopaedic surgery (the RECORD trials).

Purpose: Thromboembolic events, such as deep vein thrombosis (DVT) and pulmonary embolism (PE), are a serious risk after major orthopaedic surgery. BAY 59-7939 is a novel, 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. This pre-specified analysis combines data from two multicenter, multinational, double-blind, dose-ranging studies; the hip surgery trial was performed in Europe, and the knee surgery trial in North America.

Methods: 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), continuing 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. The primary safety endpoint was major, post-operative bleeding.

Results: The primary efficacy endpoint occurred in 21.6%, 22.9%, 16.1%, 24.4%, and 19.3% of patients receiving BAY 59-7939 2.5, 5, 10, 20, and 30 mg bid, respectively, and 27.8% receiving enoxaparin (n=914). No significant dose–response relationship for efficacy was observed with BAY 59-7939 (P=0.39); 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), which occurred in 0.9%, 1.3%, 2.1%, 3.9%, and 7.0% of patients receiving BAY 59-7939 2.5, 5, 10, 20, and 30 mg bid, respectively, and 1.7% of patients receiving enoxaparin (n=1317).

Conclusions: This analysis showed that BAY 59-7939 has a wide therapeutic window for the prevention of VTE following major orthopaedic surgery, and, at doses of 2.5–10 mg bid, has similar efficacy and safety to the enoxaparin regimens.

Funding : Commerical funding

Funding Parties : This study was sponsored by Bayer HealthCare AG