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.

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

Aims: The fondaparinux thromboprophylaxis phase III studies database including 7344 patients in orthopaedic surgery provides information regarding patient management according to country specificities. Methods: 4 randomized double-blind trials were conducted in 376 centers in 23 countries comparing fondaparinux to enoxaparin – 1 in major knee surgery (MKS) in North America (NA); 2 in total hip replacement (THR) in NA and in Europe, respectively; and 1 in hip-fracture (HF) surgery worldwide except in NA. The use of regional anesthesia or cement during surgery, use of stockings during hospitalization, or prolonged prophylaxis (PP) after discharge were left to the investigators. Results: In all studies the majority of patients were women, particularly in HF. The median age was 67 years for THR, 69 years for MKS, and 79 years for HF. In THR studies, regional anesthesia was used more frequently in Europe (59%) than in NA (24.4%). The table summarizes investigators’ practice. Conclusions: There are important differences in the management of orthopedic surgery patients according to country specificities and type of surgery. However, fondaparinux is more effective than enoxaparin for thromboprophylaxis irrespective of patient or surgery characteristics.

Aims: To assess whether there was a relationship between the timing of the first administration of fondaparinux and its efficacy and safety in preventing venous thromboembolism (VTE) in orthopaedic surgery. Methods: Overall, 3616 patients received fondaparinux in 4 randomized, double-blind studies in this setting. We performed a post-hoc analysis of the effect of this timing on VTE up to day 11 (primary efficacy) and bleeding with a bleeding index (BI) ≥2, using logistic regression. These 2 parameters were also analyzed according to whether fondaparinux started before 6 hours or at 6 hours or later postoperation. Results: Logistic regression showed that the efficacy of fondaparinux was not affected by the timing of its first administration (p=0.67). However, there was a statistically significant relationship between this timing and bleeding with a BI ≥2 (p=0.008). The table gives the incidence of VTE and bleeding with a BI ≥2 according to the interval between skin closure and the first fondaparinux injection. Conclusions: The efficacy of fondaparinux in preventing VTE in orthopaedic surgery was not related to the timing of its first administration. In addition, a significant reduction in the incidence of bleeding with a BI ≥2 was observed when the first fondaparinux injection took place between 6 and 9 hours after skin closure.

Aims: In major orthopedic surgery, fondaparinux provided a major benefit over enoxaparin, with an overall venous thromboembolsim (VTE) risk reduction of > 50% and similar safety profile regarding clinically relevant bleeding (leading to death or reoperation, or occurring in critical organ). The aim of the present study was to analyze this superior efficacy according to patients and surgery characteristics. Methods: In four phase III trials, the primary efficacy outcome was the VTE incidence up to day 11, defined as deep-vein thrombosis (DVT) detected by mandatory bilateral venography or documented symptomatic DVT or pulmonary embolism. Primary efficacy was further analyzed according to predefined categorical covariates using a logistic regression model. Results: Fondaparinux was more effective than enoxaparin irrespective of age, gender, obesity, the use of cement or surgery duration (odds reduction from −46.9% to −59.7% in favor of fondaparinux. Clinically relevant bleeding did not differ between the two groups according to predefine covariates. Conclusions: For VTE prevention in major orthopaedic surgery, the superiority of fondaparinux over enoxaparin was consistent irrespective of patient or surgery characteristics.

Aims: In orthopedic surgery, the optimal duration of thromboprophylaxis is debated, and very few data are available in hip fracture. We addressed these issues in 5 randomized double-blind clinical trials of fondaparinux. Methods: In four studies in 7344 orthopedic surgery patients, fondaparinux was administered up to 11 days and compared to approved enoxaparin regimens. In the PENTHIFRA-Plus study in 656 hip fracture surgery patients, after an initial treatment with fondaparinux for 7±1 days, patients were randomized to fondaparinux or placebo for additional 21±2 days. In all trials, primary efficacy was venous thromboembolism (VTE), at the end of the treatment period. Results: In the four 11-day prophylaxis studies, fondaparinux reduced the incidence of VTE from 13.7% with enoxaparin to 6.8% (risk reduction [RR]: 55.2%; P< 0.001). Fondaparinux efficacy was significantly influenced by treatment duration (P< 0.001): for instance, the incidence of VTE was lower in patients treated for 9 to11 days (5.2%) than in patients treated for ≤5 days (8.7%, P= 0.038). In the PENTHIFRA-Plus study, the incidence of VTE up to 4 weeks was reduced to 1.4% compared with 35.0% with placebo (relative RR: 95.9%, P< 0.001). The incidence of symptomatic VTE was also significantly lower with fondaparinux (0.3%) than with placebo (2.7%, relative RR: 88.8%, P=0.021). Conclusions: Fondaparinux efficacy in preventing VTE in orthopedic surgery increased significantly with a longer duration of treatment. Hip fracture surgery patients are at high risk of VTE up to 4 weeks after surgery and treatment with fondaparinux for 4 weeks postoperatively provides greater benefit than active treatment for only 1 week.

Aims: To evaluate the inßuence of the type of anesthesia on the superior efþcacy of fondaparinux over enoxaparin in preventing venous thromboembolism (VTE) in orthopedic surgery (RRR > 50%; P< 0.0001). Methods: 4 randomized, double-blind trials were performed: 2 in hip replacement (THR), 1 in North America (NA) and 1 in Europe; 1 in knee surgery (MKS); and 1 in hip-fracture surgery (HF). The choice of anesthesia was left to the investigators. A predeþned covariate analysis according to the type of anesthesia was performed on primary efþcacy.

Conclusions: Fondaparinux once-daily started postoperatively provided superior efþcacy versus enoxaparin in preventing VTE whatever the type of anesthesia and may improve convenience in current practice.

Aims: Whether the use of elastic stockings (ES) on top of pharmacological thromboprophylaxis is beneficial remains debated. In a worldwide phase III program including 7344 patients in major orthopaedic surgery, fondaparinux, the first synthetic selective factor Xa inhibitor, demonstrated a substantial benefit over enoxaparin in preventing venous thromboembolism (VTE); risk reduction > 50% without increasing clinically relevant bleeding. The aim of this study was to evaluate the influence of ES on this superior efficacy of fondaparinux. Methods: In all four randomized, double-blind trials, comparing a once daily 2.5 mg s.c. injection of fondaparinux to enoxaparin, the primary efficacy outcome was VTE up to day 11, defined as deep-vein thrombosis (DVT) detected by mandatory bilateral venography, or documented symptomatic DVT or pulmonary embolism. A post-hoc analysis on primary efficacy was performed according to the use of ES. Results: The table shows VTE incidences by day 11 without and with ES. Conclusions: In major orthopaedic surgery, fondaparinux showed a similar superior efficacy over enoxaparin in patients with and without ES, indicating that ES did not influenced the major benefit of this new agent. An additive effect of ES in enoxaparin-treated patients cannot be excluded but the effect is insufficient compared with fondaparinux alone.