Objectives. Venous thromboembolism (VTE) is a major potential complication following orthopaedic surgery. Subcutaneously administered enoxaparin has been used as the benchmark to reduce the incidence of VTE. However, concerns have been raised regarding the long-term administration of enoxaparin and its possible negative effects on bone healing and bone density with an increase of the risk of osteoporotic fractures. New oral anticoagulants such as rivaroxaban have recently been introduced, however, there is a lack of information regarding how these drugs affect bone metabolism and post-operative bone healing. Methods. We measured the migration and proliferation capacity of mesenchymal stem cells (MSCs) under enoxaparin or rivaroxaban treatment for three consecutive weeks, and evaluated effects on MSC mRNA expression of markers for stress and osteogenic differentiation. Results. We demonstrate that enoxaparin, but not rivaroxaban, increases the migration potential of MSCs and increases their cell count in line with elevated mRNA expression of C-X-C chemokine receptor type 4 (CXCR4), tumor necrosis factor alpha (TNFα), and alpha-B-crystallin (CryaB). However, a decrease in early osteogenic markers (insulin-like growth factors 1 and 2 (IGF1, IGF2), bone morphogenetic protein2 (BMP2)) indicated inhibitory effects on MSC differentiation into osteoblasts caused by enoxaparin, but not by rivaroxaban. Conclusions. Our findings may explain the adverse effects of enoxaparin treatment on bone healing. Rivaroxaban has no significant impact on MSC metabolism or capacity for osteogenic differentiation in vitro. Cite this article: Dr H. Pilge. Enoxaparin and rivaroxaban have different effects on human mesenchymal stromal cells in the early stages of bone healing. Bone Joint Res 2016;5:95–100. DOI: 10.1302/2046-3758.53.2000595

Aims. The aim of this study was to evaluate the healthcare costs and benefits of enoxaparin compared to aspirin in the prevention of symptomatic venous thromboembolism (VTE) after total hip arthroplasty (THA) or total knee arthroplasty (TKA) using data from the CRISTAL trial. Methods. This trial-based economic analysis reports value for money as incremental cost per quality-adjusted life-year (QALY) gained in 2022 Australian dollars, compared to a single threshold value of AUD$70,000 per QALY. Event costs were estimated based on occurrence of VTEs and bleeds, and on published guidelines for treatment. Unit costs were taken from Australian sources. QALYs were estimated using CRISTAL six-month follow-up data. Sensitivity analyses are presented that vary the cost of VTE treatment, and extend the analyses to two years. Results. The CRISTAL trial found that enoxaparin was more effective than aspirin in preventing symptomatic VTE within 90 days of THA or TKA (risk difference 1.97% (95% confidence interval (CI) 0.54% to 3.41%; p = 0.007)). The additional cost after a THA or TKA was AUD$83 (95% CI 68 to 97) for enoxaparin, and enoxaparin resulted in an additional 0.002 QALYs (95% CI -0.002 to 0.005). Incremental cost per QALY gained was AUD$50,567 (95% CI 15,513, dominated) for enoxaparin. We can be 60% confident that the incremental cost per QALY does not exceed the willingness-to-pay threshold of AUD$70,000. Increasing the cost of VTE treatment and extension of costs and consequences to two years suggested greater confidence that enoxaparin is good value for money (70% and 63% confidence, respectively). Conclusion. This analysis provides strong evidence that enoxaparin thromboprophylaxis following THA or TKA reduced VTEs, but weak evidence of net economic benefits over aspirin. If the value of avoiding VTEs is high, and there is a strong likelihood of VTE-related health impairments, we can be more confident that enoxaparin is cost-effective compared to aspirin. Cite this article: Bone Joint J 2024;106-B(6):589–595

Aims. We investigated the efficacy and safety profile of commonly used venous thromboembolism (VTE) prophylaxis agents following hip and knee arthroplasty. Methods. A systematic search of PubMed, Embase, Cochrane Library, Web of Science, and OrthoSearch was performed. Prophylaxis agents investigated were aspirin (< 325 mg and ≥ 325 mg daily), enoxaparin, dalteparin, fondaparinux, unfractionated heparin, warfarin, rivaroxaban, apixaban, and dabigatran. The primary efficacy outcome of interest was the risk of VTE, whereas the primary safety outcomes of interest were the risk of major bleeding events (MBE) and wound complications (WC). VTE was defined as the confirmed diagnosis of any deep vein thrombosis and/or pulmonary embolism. Network meta-analysis combining direct and indirect evidence was performed. Cluster rank analysis using the surface under cumulative ranking (SUCRA) was applied to compare each intervention group, weighing safety and efficacy outcomes. Results. Of 86 studies eligible studies, cluster rank analysis showed that aspirin < 325 mg daily (SUCRA-VTE 89.3%; SUCRA-MBE 75.3%; SUCRA-WC 71.1%), enoxaparin (SUCRA-VTE 55.7%; SUCRA-MBE 49.8%; SUCRA-WC 45.2%), and dabigatran (SUCRA-VTE 44.9%; SUCRA-MBE 52.0%; SUCRA-WC 41.9%) have an overall satisfactory efficacy and safety profile. Conclusion. We recommend the use of either aspirin < 325 mg daily, enoxaparin, or dabigatran for VTE prophylaxis following hip and knee arthroplasty. Cite this article: Bone Joint J 2024;106-B(9):924–934

Without thromboprophalaxis, the recorded incidence of deep venous thrombosis (DVT) in pelvic fracture varies between 35% and 61%. The incidence of pulmonary embolism (PE) is reported to be 2–10% and death subsequently occurs in 0.5–4% of patients. With preventative measures the incidence of clinically significant DVT has been reported as low as 0.5%. The primary aim of this study is to look into the efficacy of Enoxaparin in preventing clinically significant DVT and PE in patients with pelvic and acetabular fracture. The secondary aim is to investigate the effect of prolonged pre-operative exposure to Enoxaparin on operative and post-operative bleeding. Sixty-four patients with pelvic and acetabular fractures were reviewed retrospectively between 2000–2005. Patients with coagulopathies were excluded. 40mg Enoxaparin was administered daily following haemodynamic evaluation and continued thereafter until discharge. Blood loss was measured using 3 indicators: volume of blood transfused, difference in pre and post operative Hb, and amount of blood collected in surgical drains. The incidence of clinically significant DVT was 2.9% (2 cases). There was no confirmed incidence of PE. 47% of patients were operated on within a week of admission (Group A), 40% within 1–2 weeks (Group B) and 13% in over 2 weeks (Group C). The group with the most prolonged pre-operative exposure to Enoxaparin: Group C, required the least transfused blood (A: 4.8units, B: 2.0units C: 1.3units), bled the least into drains (A:310ml, B:253ml and C:212ml) and had the smallest post-operative fall in Hb (A:2.2, B:2.0, C:1.9). The low incidence of clinically detectable DVT in the study confirms that Enoxaparin is an effective method for reducing the incidence of significant thrombotic events. Prolonged pre-operative administration of Enoxaparin does not pre-dispose patients to an increased risk of operative and post-operative bleeding

Introduction. Venous thromboembolism (VTE), including pulmonary embolism (PE) resulting from deep vein thrombosis (DVT), remains a well-known serious complication after femoral fractures. The low molecular heparin is widely used to prevent VTE. This study compared the effectiveness of VTE prevention between dalteparin and enoxaparin. Materials and Methods. From 2013 to 2014, we retrospectively recruited 712 patients who had femoral fractures with operative treatment. All patients receiving VTE chemoprophylaxis with perioperative period using dalateparin in Group 1(N=395) and enoxaparin in Group 2(N=317). The prophylactic dosing was determined using individual product labeling and identified as enoxaparin 40 mg every 12 hours and dalteparin 2500 international unit (IU) once daily, based on clinical practice guidelines. The prophylaxis was started at admission, and maintained during average 8.43.5 days after operation. The outcome including the incidence of clinically significant deep vein thrombosis, pulmonary embolism, perioperative bleeding and cost of drugs were evaluated between two groups. Results. The two study groups did not differ significantly in fracture type, age, gender, ASA score. The overall incidence of VTE is similar between two groups. However, the incidence of fatal PE is significantly lower in patients with dalteparin (Group 1: 4/395(1.00%), Group 2: 10/317(3.15%), p<0.001). And the overall cost of each group is significantly different between two groups (Group 1: average KRW 89,426, Group 2: average KRW 32,188, p<0.001). Conclusion. Both dalteparin and enoxaparin could be safely used without notable complications in VTE prophylaxis. However, dalteparin had more advantages for prevention of fatal PE, compared to enoxaparin in patients with femoral fractures with significant cost effectiveness

Background. Hitherto, no study has compared blood loss (BL) after different thromoprophylactic regimes (TR). The objective of this study was to quantify and compare BL in total hip arthroplasty (THA) under three different TRs. Methods. Between September 2013 and July 2014, sixty primary, unilateral, same-implant THAs entered a randomised, double-blind clinical trial. The patients were randomised to receive manufacturers' recommended doses of enoxaparin, dabigatran or rivaroxaban. Complete blood counts were obtained preoperatively and on the third day postoperatively. BL was calculated according to the Nadler formula. We also evaluated the occurence of wound healing disturbances (WHDs). All data were analysed using R statistical software. Results. The mean BL and standard deviations were 844 ± 222 ml for enoxaparin, 854 ± 205 ml for dabigatran and 806 ± 227 ml for rivaroxaban. The BL did not significantly differ between groups (Kruskall-Wallis, p=0.92). More WHDs occured in the rivaroxaban group (5/20), compared to enoxaparin (2/20) and dabigatran (3/20). Conclusions. None of the chemical TR is superior to others in terms of reducing the BL. There seems to be more WHDs with the use of oral agents - this finding needs further studies. Level of evidence. 1b (Centre for Evidence Based Medicine, Oxford). Approval. This study was approved by The Medical Centre of Postgraduate Education Ethical Committee. Disclosure. The authors disclose no competing interests

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

Introduction: Rivaroxaban is a novel, oral, direct Factor Xa inhibitor for the prevention of venous thromboembolism (VTE) after total hip and knee arthroplasty (THA, TKA). The pivotal RECORD trials showed that 35 days’ rivaroxaban significantly reduced total VTE following THA versus both 35-day and 14-day enoxaparin regimens. Following TKA, 14 days’ rivaroxaban significantly reduced total and symptomatic VTE versus 14 days enoxaparin. Major bleeding was similar for rivaroxaban and enoxaparin. An economic model was developed based on these results to assess the cost-effectiveness of rivaroxaban relative to enoxaparin in Sweden. Methods: The incidence of clinical events and resulting consequences on resource use and quality of life were modelled for rivaroxaban and enoxaparin over 5 years. VTE incidence during the prophylaxis period was based upon RECORD2 (THA) and RECORD3 (TKA) and extrapolated out to 90 days following surgery based on published epidemiological data. These trials were used because they best reflect the treatment length currently applied in clinical practice in Sweden. Recurrent VTE and post-thrombotic syndrome (PTS) beyond 90 days were modelled from published clinical data. Literature indicates that 10% of enoxaparin patients require visits from a district nurse following hospital discharge to administer subcutaneous (sc) enoxaparin, a cost not incurred with oral rivaroxaban. The cost associated with clinical events (major bleed, VTE and PTS) and home care visit was derived from published Swedish sources and expressed in Swedish kroner (SEK). Rivaroxaban and enoxaparin costs were included. Results: In THA, 35 days’ rivaroxaban produced an additional cost (SEK 119 [€12.59] per patient) versus 14 days enoxaparin. However, rivaroxaban resulted in a gain of quality-adjusted life years (QALYs) and in fewer symptomatic events per patient relative to enoxaparin. This means an extra cost with rivaroxaban of SEK 29,378 (€3,109) per QALY gained and SEK 3,929 (€416) per symptomatic event avoided. Because the cost for treating a VTE range from SEK 12,000 to 30,000, it is less costly to avoid such an event by using rivaroxaban than treating it once it occurs. In TKA, 14 days’ rivaroxaban produced savings of SEK 873 (€92) per patient versus 14 days’ enoxaparin, as well as an improvement in QALYs and a reduction in symptomatic VTE events. Consequently, rivaroxaban was both more effective and less costly. Extensive sensitivity analyses showed that these results persist in a clear majority of situations. Conclusion: The economic analysis showed that by reducing VTE, and providing an oral alternative to sc enoxaparin, oral rivaroxaban has the potential to significantly improve health outcomes in Sweden at a slightly higher (in THA) or lower (in TKA) cost than existing VTE prophylaxis

Introduction: After total hip replacement (THR), thromboprophylaxis for at least 10 days and for up to 35 days is recommended – yet a convenient, oral anticoagulant is not currently available. Rivaroxaban – a once-daily, oral, direct Factor Xa inhibitor with a predictable clinical profile – is in advanced clinical development. RECORD1, a multinational, randomized, double-blind, double-dummy, phase III study, compared once-daily oral rivaroxaban with subcutaneous enoxaparin for 5 weeks following THR. Methods: In total, 4541 patients were randomized to receive oral rivaroxaban 10 mg (6–8 hours after surgery and once daily thereafter), or 40 mg enoxaparin (administered subcutaneously the evening before surgery, resumed 6–8 hours after surgery, and continued once daily). Thromboprophylaxis was administered for 35±4 days; mandatory, bilateral venography was conducted the next day. The primary efficacy endpoint was the composite of any deep vein thrombosis (DVT), nonfatal pulmonary embolism (PE), and all-cause mortality. Safety endpoints included major and non-major bleeding during the active treatment period. Results: The incidence of the composite of DVT, PE, and all-cause mortality was significantly lower for rivaroxaban compared with enoxaparin (1.1% vs 3.7%, respectively; p< 0.001; relative risk reduction [RRR] 70%). The incidence of major VTE was also significantly lower for rivaroxaban 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. Conclusions: Following THR, thromboprophylaxis with once-daily, oral rivaroxaban was shown to be significantly more effective than subcutaneous, once-daily enoxaparin – without an increased risk of bleeding. This trial demonstrates the efficacy and safety of oral rivaroxaban using a fixed, unmonitored, once-daily dose for extended thromboprophylaxis after THR

Introduction. In Japan, edoxaban has been used for the prevention of venous thromboembolism (VTE) after total knee arthroplasty (TKA) since June 2011. Edoxaban is an oral direct factor Xa inhibitor, expected to be more convenient for the postoperative treatment of TKA. Enoxaparin, a II and Xa inhibitor, was approved in Japan for the prevention of VTE in patients undergoing orthopedics surgery from 2008. In this study, the effect for the prevention of VTE after TKA was compared between these two drugs in Japanese patients. Patients and Methods. We studied 42 Japanese patients who underwent TKA from May 2011 to April 2012. The operations were performed under general anesthesia, continuous femoral nerve block, an air tourniquet, and using cements for implant fixation. These patients were divided in two groups, use of 30 mg edoxaban once daily (ED group), and use of 1000 IU of enoxaparin twice daily (EN group). The initial dose was administered between 12 and 21 hours after surgery. We compared the incidence of VTE, bleeding complications, D dimer levels, and hemoglobin (Hb) loss. The screening of VTE was performed by enhanced CT scan screening from the chest to the foot on postoperative day 5 or 6 in all patients. The bleeding complication was divided into major bleeding and minor bleeding with Japanese guideline for the prevention of VTE. D dimer levels and Hb levels were preoperatively and postoperative day 1, 3, 5, 7, and 14. The loss of Hb was calculated from preoperative Hb level minus lowest postoperative Hb level. Results. The following results is showed in the order as ED group, EN group. The incidence of VTE was 45%, 32%, that was higher in ED group (see figure 1). There were almost no differences between both groups about D dimer levels and Hb loss in follow up period (see figure 2, 3). There were no major bleeding in both groups. The incidence of minor bleeding were 20%, 32%, that was higher in EN group (see figure 4). Discussion. We compared the effect of edoxaban and enoxaparin for the prevention of VTE. These two drugs are different way of administration. Edoxaban is administered orally, on the other enoxaparin requires with hypodermic injection. Therefore edoxaban is expected to be more convenient and less complaints than enoxaparin for the prevention of VTE. However our study showed that the use of 30 mg edoxaban once daily was less efficacy than the use of enoxaparin 1000 IU twice daily. The bleeding complication was lower incidence in the edoxaban, thus consideration should be given to the administration dosage of edoxaban to Japanese patients

Purpose:. Starting February 2012, our institution changed from enoxaparin (Lovenox) to the Factor Xa inhibitor, rivaroxaban (Xarelto) for venous thromboembolism prophylaxis after primary total hip (THA) and total knee arthroplasty (TKA). The purpose of our study was to compare rates of venous thromboembolism and rates of major bleeding between these two medications when used for venous thromboembolism prophylaxis after primary THA and TKA. Methods:. A retrospective review was performed on 1795 patients who underwent THA or TKA at our institution between January 1, 2011 and December 31, 2012. Patients were excluded if they had a bilateral procedure, partial arthroplasty (hip hemiarthroplasty, unicompartmental knee arthroplasty), revision surgery, and cases designated as complex. Patients were excluded if they were on other anticoagulants (dabigatran, aspirin, clopidogrel, warfarin, heparin, fondaparinux), or if pre-operative creatinine was 1.2 or greater. After excluding these patients, there were 1089 patients included in the study. Chart review recorded demographics (age, gender), comorbidities (BMI, ASA, creatinine), surgery performed (primary THA or TKA), length of stay (LOS), venous thromboembolic events (deep venous thrombosis [DVT], pulmonary embolus [PE]), post-operative infections, and major bleeding events (stroke, post-operative bleeding requiring transfusion). Periprosthetic infection rates are also currently being reviewed. T-tests were used to compare continuous variables between treatment groups, and Chi-square tests were used to compare categorical variables between treatment groups (α = 0.05). Results:. There were 779 patients (71.5%) who received enoxaparin and 310 patients (28.5%) who received rivaroxaban during the study period. Demographics of the patients are presented in Table 1. A comparison of venous thromboembolism rates. Pre-operative creatinine was higher in the enoxaparin group (0.81 ± 0.19 vs. 0.72 ± 0.18, p < 0.001). With the numbers available for study, there were no demonstrable differences in DVT (p = 0.400, power = 0.125), PE (p = 0.679, power = 0.066), cerebrovascular events (p = 0.913, power = 0.049), or transfusion rates (p = 0.412, power = 0.121). Conclusion:. To our knowledge this is one of, if not the largest non-industry funded studies comparing these two medications. There were no statistically demonstrable differences between the enoxaparin and rivaroxaban groups in terms of venous thromboembolism or major bleeding complications

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

Introduction. Embolism in total arthroplasty or hip fractures, coagulation disorders, such as a variety of ways for the prevention of complications of anticoagulation therapy with medication is being done well. The purpose of this study, a representative of the anticoagulation therapy with enoxaparin and drug rivaroxaban of coagulation tests performed in patients between the two groups was to determine whether statistically significant differences. Methods. 47 patients who underwent arthroscopic surgery were randomly divided into two groups to rivaroxaban and enoxaparin group, and we performed coagulation tests before and 5 days after arthroscopic surgery to two drugs groups in order to investigate about the difference in clotting capacity. Results. Preoperative coagulation tests coagulation tests before the item was not significantly different between the two groups. (p=0.584) 5 days after surgery, the coagulation tests coagulation tests performed on all items, rivaroxaban showed an increase in the anticoagulation activity Between the two groups showed statistically significant difference (p=0.001),. Discussion and Conclusion. Our results indicate that orthopaedic surgery can induce a lot of bleeding will be careful for use of rivaroxaban. Rivaroxaban(Xarelto®) showed more bleeding tendency than Enoxaparin(Clexane®). So we should take more attentions in postoperative care after Total Joint Arthroplasty

RECORD3 was a multicentre, phase III study designed to investigate the efficacy and safety of rivaroxaban – a novel, oral, once-daily, direct Factor Xa inhibitor – compared with subcutaneous enoxaparin for thromboprophylaxis in patients undergoing total knee arthroplasty (TKA). Patients scheduled to undergo TKA (N=2,531) were randomized to receive either rivaroxaban 10 mg once daily (initiated 6–8 hours after surgery) or enoxaparin 40 mg once daily (initiated the evening before surgery, then given 6–8 hours after surgery), and daily thereafter for 10–14 days. The primary efficacy outcome was the composite of any deep vein thrombosis (DVT; symptomatic or asymptomatic detected by mandatory, bilateral venography), non-fatal pulmonary embolism (PE) and all-cause mortality within 13–17 days after surgery. Rivaroxaban significantly reduced the incidence of the primary efficacy outcome compared with enoxaparin (9.6% vs 18.9%, respectively; p< 0.001; relative risk reduction [RRR] 49%). Rivaroxaban significantly reduced the incidence of major VTE (the composite of proximal DVT, non-fatal PE and VTE-related death) compared with enoxaparin (1.0% vs 2.6%, p=0.01; RRR 62%), and the incidence of symptomatic VTE (0.7% vs 2.0%, p=0.005; RRR 66%). The incidence of bleeding events was similar in both groups (major bleeding: 0.6% and 0.5% in the rivaroxaban and enoxaparin groups, respectively; any on-treatment bleeding: 4.9% and 4.8%, respectively; haemorrhagic wound complications [the composite of excessive wound haematoma and surgical-site bleeding]: 2.0% and 1.9%, respectively). There were no deaths or PEs in the rivaroxaban group during the treatment period, and two deaths and four PEs in the enoxaparin group. Rivaroxaban was significantly more effective than enoxaparin for the prevention of VTE after TKA, with a similar rate of bleeding. The oral, direct Factor Xa inhibitor rivaroxaban, given once daily as a fixed, unmonitored dose of 10 mg, has the potential to change clinical practice for thromboprophylaxis after TKA

Aims. This phase II safety study aimed to investigate the bleeding side effect profile in patients treated with Rivaroxaban as a new agent for venous thromboembolism (VTE) prophylaxis following hip or knee arthroplasty. Methods. A retrospective study of complications was conducted in 88 consecutive patients undergoing hip and knee arthroplasty at one centre. Patients received chemical and/or mechanical VTE prophylaxis according to local guidelines. Data was collected from notes and evaluated using Fisher's exact test and t-Test. Significance was determined if p< =0.05. The primary end-point was local wound site oozing or bleeding. Secondary end-points were drop in haemoglobin, drain output and infection. Results. 55 patients were treated with Rivaroxaban, 18 with mechanical prophylaxis only, 10 with Enoxaparin and 5 with aspirin, clopidogrel or warfarin. The Rivaroxaban cohort demonstrated a statistically significant amount of increased major bleeding (24% vs. 0% p=0.03) and wound oozing (27% vs. 0% p=0.02) when compared to patients treated with Enoxaparin. Compared to those treated with other methods of VTE prophylaxis, Rivaroxaban also significantly increased major bleeding (24% vs. 6% p=0.01) and wound oozing (27% vs. 12% p=0.03). The Rivaroxaban cohort demonstrated a significantly larger drop in haemoglobin compared to the combined non-Rivaroxaban group (3.0 vs. 2.4 g/dL p=0.04). There was no significant difference in drain volume or rate of infection between groups. Conclusions. Rivaroxaban appears to cause increased wound site bleeding in comparison to Enoxaparin and other methods of thromboembolism prophylaxis. Further use of Rivaroxaban at this centre was therefore discontinued; however, the small group sizes and retrospective non-randomised design of this study introduce bias and limit the reliability of its findings. Prospective randomised controlled trial focused on wound complications is required to eliminate selection and reporter biases

Rivaroxaban is a novel, oral, once-daily, direct Factor Xa inhibitor in advanced clinical development. RECORD1 was a multinational, randomized, double-blind, double-dummy, phase III study investigating the efficacy and safety of extended thromboprophylaxis with rivaroxaban compared with subcutaneous enoxaparin following THR. Patients (N=4541) were randomized to receive oral rivaroxaban 10 mg (6–8 hours after surgery and once daily thereafter) or subcutaneous enoxaparin 40 mg (administered the evening before surgery, 6–8 hours after surgery, and once daily thereafter) for 35±4 days. The primary efficacy outcome was the composite of deep vein thrombosis (DVT: symptomatic or detected by mandatory, bilateral venography if asymptomatic), non-fatal pulmonary embolism (PE), and all-cause mortality up to day 36±6. Major venous thromboembolism (VTE), the composite of any DVT, non-fatal PE and VTE-related death, was a secondary outcome. Safety endpoints included major and non-major bleeding while receiving study medication. Rivaroxaban significantly reduced the incidence of the primary efficacy outcome 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 liver safety issues associated with rivaroxaban. Thromboprophylaxis with once-daily, oral rivaroxaban was significantly more effective than subcutaneous enoxaparin following THR without an increased risk of bleeding. This trial demonstrates the efficacy and safety of a fixed, unmonitored, once-daily dose of oral rivaroxaban for extended thromboprophylaxis after THR

Aims: To investigate the efficacy and safety of a new dosage regimen of the oral direct thrombin inhibitor ximelagatran, and its subcutaneous (sc) form melagatran, started in close proximity to surgery. Methods: In a randomised, double-blind, parallel-group study, duration 8–11 days, patients undergoing total hip or knee replacement (THR, n= 1856; TKR, n= 908) received either sc melagatran 2 mg immediately before surgery followed by sc 3 mg in the evening after surgery, and then by oral ximelagatran 24 mg bid as a fixed dose (the ximelagatran group), or sc enoxaparin 40 mg od, started the evening before surgery. Bilateral venography was performed on the final day of treatment. Results: The rate of proximal deep vein thrombosis plus pulmonary embolism was 2.3% in the ximelagatran group vs. 6.3% in the enoxaparin group (p< 0.000002; RRR 63.2%). The total rates of venous thromboembolism (VTE) were 20.3% vs. 26.6%, respectively (p< 0.0003; RRR 23.6%). Cases with symptomatic VTE were rare: 8 in the ximelagatran group and 12 in the enoxaparin group. Bleeding events were more common in the ximelagatran group compared with the enoxaparin group (3.3% vs. 1.2%) as were the transfusion rates (66.8% vs. 61.7%). Importantly, there were no differences in fatal bleeding, critical organ bleeding or bleeding requiring re-operation. Conclusion: Pre-operatively initiated sc melagatran followed by oral ximelagatran was superior in efficacy to enoxaparin in preventing VTE in patients undergoing THR or TKR

Aims: We conducted an cost-utility analysis to compare standard (in-hospital) with prolonged (out-of-hospital) enoxaparin prophylaxis after elective total hip and knee replacement. Methods: The perspective was that of a societal healthcare payer, taking Belgium as a case country. The main outcome measure was the incremental cost-utility ratio, reported as the incremental cost per quality-adjusted life year gained (Euro/QALY). Costs for diagnosis and treatment of proximal and distal deep vein thrombosis, pulmonary embolism, postphlebitic syndrome, and major bleeding were obtained from a Delphi panel (orthopaedic surgeons) and the official reimbursement rates (Federal Ministery of Health). QALYs for these health states were based on utility scores as reported in the literature. Results: In the base-case analysis, incremental costs of prolonged prophylaxis amounted 58 Euro and 114 Euro per patient, with an additional gain in QALY of 0.0083 and 0.0018 after total hip and knee replacement, respectively. Thus, a strategy of prolonged enoxaparin prophylaxis was associated with a cost-utility ratio of 6,964 Euro/QALY and 64,907 Euro/QALY after total hip and knee replacement, respectively. Applying a societal willingness-to-pay threshold value of 20,000 Euro/QALY, prolonged enoxaparin prophylaxis is cost-effective after elective total hip replacement. Sensitivity analyses confirmed the general robustness of these findings. Conclusions: After elective total hip or knee replacement, prolonged enoxaparin prophylaxis leads to increased effectiveness at increased cost. Nevertheless, given the additional costs healthcare decision makers in Europe are usually prepared to pay for a gain in effectiveness, prolonged prophylaxis with enoxaparin is cost-effective after total hip replacement

Aims. The aim of this study is to compare the effectiveness and safety of thromboprophylactic treatments in patients undergoing primary total knee arthroplasty (TKA). Methods. Using nationwide medical registries, we identified patients with a primary TKA performed in Denmark between 1 January 2013 and 31 December 2018 who received thromboprophylactic treatment. We examined the 90-day risk of venous thromboembolism (VTE), major bleeding, and all-cause mortality following surgery. We used a Cox regression model to compute hazard ratios (HRs) with 95% confidence intervals (CIs) for each outcome, pairwise comparing treatment with dalteparin or dabigatran with rivaroxaban as the reference. The HRs were both computed using a multivariable and a propensity score matched analysis. Results. We identified 27,736 primary TKA patients who received thromboprophylactic treatment (rivaroxaban (n = 18,846); dalteparin (n = 5,767); dabigatran (n = 1,443); tinzaparin (n = 1,372); and enoxaparin (n = 308)). In the adjusted multivariable analysis and compared with rivaroxaban, treatment with dalteparin (HR 0.68 (95% CI 0.49 to 0.92)) or dabigatran (HR 0.31 (95% CI 0.13 to 0.70)) was associated with a decreased risk of VTE. No statistically significant differences were observed for major bleeding or all-cause mortality. The propensity score matched analysis yielded similar results. Conclusion. Treatment with dalteparin or dabigatran was associated with a decreased 90-day risk of VTE following primary TKA surgery compared with treatment with rivaroxaban. Cite this article: Bone Joint J 2021;103-B(10):1571–1577

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