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 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

Post-operative complications after total hip or knee replacement can delay recovery, prolong hospitalisation, increase rates of re-admission and, in the most severe cases, lead to long-term disability or even death. In this analysis of pooled data from four large, randomised, phase III clinical trials that compared the oral, direct Factor Xa inhibitor rivaroxaban with subcutaneous enoxaparin for the prevention of venous thromboembolism after total hip or knee replacement (n = 12 729), the incidence of complications, including bleeding and adverse events related to surgery (such as wound infection, wound dehiscence and haemarthrosis) are reported. Interventions and procedures relating to surgery are also compared between the groups. Bleeding events, including excessive wound haematoma and surgical-site bleeding, occurred at similar rates in the rivaroxaban and enoxaparin groups. Over the total study duration, adverse surgical events occurred at a similar rate in the rivaroxaban group compared with the enoxaparin group after total knee replacement (2.26% vs 2.69%, respectively) and total hip replacement (1.48% vs 1.65%, respectively). Blood loss, wound drainage and transfusion requirements were also similar between the two groups. This analysis shows that the incidence of adverse surgical events with rivaroxaban was similar to enoxaparin

Rivaroxaban has been recommended for routine use as a thromboprophylactic agent in patients undergoing lower-limb arthroplasty. However, trials supporting its use have not fully evaluated the risks of wound complications. This study of 1048 total hip/knee replacements records the rates of return to theatre and infection before and after the change from a low molecular weight heparin (tinzaparin) to rivaroxaban as the agent of chemical thromboprophylaxis in patients undergoing lower-limb arthroplasty. During a period of 13 months, 489 consecutive patients undergoing lower-limb arthroplasty received tinzaparin and the next 559 consecutive patients received rivaroxaban as thromboprophylaxis. Nine patients in the control (tinzaparin) group (1.8%, 95% confidence interval 0.9 to 3.5) returned to theatre with wound complications within 30 days, compared with 22 patients in the rivaroxaban group (3.94%, 95% confidence interval 2.6 to 5.9). This increase was statistically significant (p = 0.046). The proportion of patients who returned to theatre and became infected remained similar (p = 0.10). Our study demonstrates the need for further randomised controlled clinical trials to be conducted to assess the safety and efficacy of rivaroxaban in clinical practice, focusing on the surgical complications as well as the potential prevention of venous thromboembolism

A once-daily dose of rivaroxaban 10 mg, an oral, direct Factor Xa inhibitor, was compared with enoxaparin 40 mg subcutaneously once daily for prevention of venous thromboembolism in three studies of patients undergoing elective hip and knee replacement (RECORD programme). A pooled analysis of data from these studies (n = 9581) showed that rivaroxaban was more effective than enoxaparin in reducing the incidence of the composite of symptomatic venous thromboembolism and all-cause mortality at two weeks (0.4% vs 0.8%, respectively, odds ratio 0.44; 95% confidence interval 0.23 to 0.79; p = 0.005), and at the end of the planned medication period (0.5% vs 1.3%, respectively; odds ratio 0.38; 95% confidence interval 0.22 to 0.62; p < 0.001). The rate of major bleeding was similar at two weeks (0.2% for both) and at the end of the planned medication period (0.3% vs 0.2%). Rivaroxaban started six to eight hours after surgery was more effective than enoxaparin started the previous evening in preventing symptomatic venous thromboembolism and all-cause mortality, without increasing major bleeding

Newer irreversible oral anticoagulants such as rivaroxaban, a direct factor 10a inhibitor, are increasingly employed to prevent thromboembolic events in atrial fibrillation (AF) patients, and to manage venous thromboembolism (VTE). Unlike warfarin, these agents require no monitoring and involve infrequent dose adjustment. We report the case of a patient treated with rivaroxaban for AF. Patient presented with unprovoked sudden onset right shoulder pain which clinically resembled shoulder haemarthrosis. A single case was anonymised and retrospectively reviewed through examination of clinical and radiographic data. A 70 year old female with known AF presented to Accident and Emergency with sudden onset of right shoulder pain and limited movement, which developed over one hour. The pain was constant, localised to the shoulder and without trauma. Past medical history included severe aortic regurgitation and associated thoracic aortic aneurysm, heart failure, atrial fibrillation and hypertension. Observations were normal upon admission with no haemodynamic compromise or pyrexia. Examining the right shoulder demonstrated distension of shoulder joint capsule, tenderness and a reduced range of movement. Temperature and neurovascular status in the right arm were normal. Investigations upon admission included an INR of 1.2. An anteroposterior right shoulder radiograph showed no evidence of fracture. Patient was managed conservatively with simple oral analgesia. Importantly, rivaroxaban was withheld for 5 days and symptoms resolved. Warfarin therapy was subsequently commenced instead as treatment for AF. Patient was discharged one week later and seen in clinic two weeks post-discharge. A full recovery occurred and with a full range of movement in the right shoulder. In the UK, current National Institute for Health and Care Excellence (NICE) guidelines recommend the use of factor 10a inhibitors, for prevention of stroke in AF patients, and following elective total hip and knee replacement operations to prevent VTE. In turn, rivaroxaban is increasingly prescribed as first line therapy. Whereas warfarin has a documented association with haemarthrosis, there is no primary literature evaluating the incidence of factor 10a therapy associated haemarthrosis. In our case, the unprovoked shoulder haemarthrosis resolved following rivaroxaban cessation. In comparison with warfarin, rivaroxaban is irreversible. With warfarin and a high INR, vitamin K can be used to reverse the anticoagulation. There is no equivalent for rivaroxaban. We suggest further studies into incidence of haemarthrosis associated with oral anticoagulant therapy be undertaken, and treating physicians be aware of such complication

Introduction: Rivaroxaban is a novel, oral, direct Factor Xa inhibitor in advanced clinical development for the prevention and treatment of thromboembolic disorders. In this phase III trial, the efficacy and safety of thromboprophylaxis with rivaroxaban was compared with enoxaparin in patients undergoing total knee replacement (TKR). Methods: In RECORD3 – a randomized, double-blind trial – patients received rivaroxaban 10 mg 6–8 hours after surgery and once daily (od) thereafter, or enoxaparin 40 mg od beginning the evening before surgery; both were continued for 10–14 days. The primary efficacy outcome was the composite of any deep vein thrombosis (DVT), non-fatal pulmonary embolism (PE) and all-cause mortality. Secondary efficacy outcomes included major venous thromboembolism (VTE; the composite of proximal DVT, PE and VTE -related death) and symptomatic VTE. The primary safety outcome was major bleeding, and other safety outcomes included any on-treatment bleeding and haemorrhagic wound complications (the composite of excessive wound haematoma 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 primary efficacy outcome was reported in 9.6% of patients receiving rivaroxaban and 18.9% of patients receiving enoxaparin. This equated to a relative risk reduction of 49% (p< 0.001) with rivaroxaban compared with enoxaparin. The incidence of major VTE was also significantly reduced with rivaroxaban compared with enoxaparin (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 haemorrhagic wound complications was 2.1% in the rivaroxaban group and 1.9% in the enoxaparin group. Conclusions: Rivaroxaban was significantly more effective than enoxaparin for the prevention of VTE after TKR, with a similar safety profile. The oral, direct Factor Xa inhibitor rivaroxaban, given as a fixed, unmonitored dose, may have the potential to change clinical practice for thromboprophylaxis after TKR

Introduction. There is insufficient data on the trends of anticoagulation after total knee arthroplasty (TKA) in the USA, and the efficacy and safety of rivaroxaban, beyond randomized clinical trials and small cohort studies. Patients and Methods. Using the Truven Health MarketScan database, we retrospectively evaluated new anticoagulation prescriptions after elective TKA from 2010 to 2015. The frequency of deep vein thrombosis (DVT), pulmonary embolism (PE), and adverse events, within 90 days, were then evaluated in 24,856 new users of warfarin and 21,398 new users of rivaroxaban in commercially insured patients (COM), and 15,483 new users of warfarin and 8,997 new users of rivaroxaban in Medicare supplement patients (MED). Data was analyzed by odds ratios using logistic regression models with stabilized inverse probability treatment weighting. Results. Warfarin use decreased from approximately 50% to 17% in COM patients and 60% to 25% in MED patients. Rivaroxaban use increased from 0 to 35% in COM patients and from 0 to 39% in MED patients. Older patients, females, a history of DVT, renal impairment, use of antiplatelet agents or surgery performed as an outpatient had lower odds of getting rivaroxaban. Patients in Western region and having surgery in 2015 had higher odds of getting rivaroxaban. COM patients with capitated insurance plans and a history of PE had lower odds of rivaroxaban initiation. MED patients with atrial fibrillation, cardiovascular disease or hyperlipidemia had lower odds of rivaroxaban initiation. Warfarin users had significantly higher odds ratio of DVT (OR 2.06 in COM patients and OR 2.21 in MED patients) and PE (OR 2.03 in COM patients and OR 2.16 in MED patients) than rivaroxaban users. There were no statistically significant differences in the bleeding risk between the two agents, but warfarin users had a significantly higher odds ratio of periprosthetic infection in both COM (1.57) and MED (1.79) patients. Conclusions. There has been an increase in prophylaxis with rivaroxaban, and a decrease in both warfarin and LMWH use after elective TKA over four years. Rivaroxaban had lower odds ratio of both DVT and PE than warfarin, and bleeding risks were similar. For figures, tables, or references, please contact authors directly

Aims. Cementless primary total hip arthroplasty (THA) is associated with risks of bleeding and thromboembolism. Anticoagulants are effective as venous thromboprophylaxis, but with an increased risk of bleeding. Tranexamic acid (TXA) is an efficient antifibrinolytic agent, but the mode and timing of its administration remain controversial. This study aimed to determine whether two intravenous (IV) TXA regimens (a three-hour two-dose (short-TXA) and 11-hour four-dose (long-TXA)) were more effective than placebo in reducing perioperative real blood loss (RBL, between baseline and day 3 postoperatively) in patients undergoing THA who receive rivaroxaban as thromboprophylaxis. The secondary aim was to assess the non-inferiority of the reduction of blood loss of the short protocol versus the long protocol. Patients and Methods. A multicentre, prospective, randomized, double-blind, placebo-controlled trial was undertaken involving 229 patients undergoing primary cementless THA using a posterior approach, whose extended rivaroxaban thromboprophylaxis started on the day of surgery. There were 98 male and 131 female patients, with a mean age of 65.5 years (32 to 91). The primary outcome, perioperative RBL, was evaluated at 72 hours postoperatively. The efficacy of short- and long-TXA protocols in the reduction of perioperative RBL was compared with a placebo group. Results. TXA significantly reduced perioperative blood loss compared with placebo (p < 0.001); the mean differences were 525.3 ml (short-TXA vs placebo) and 550.1 ml (long-TXA vs placebo). No venous or arterial thromboembolic complications were reported. The upper boundary of the 95% confidence interval, when comparing short and long protocols, was below the pre-specified margin of non-inferiority (p = 0.027). Conclusion. In patients undergoing primary cementless THA, using a posterior approach, who are treated with rivaroxaban for thromboembolic prophylaxis, short- and long-TXA IV protocols are significantly more effective than placebo in reducing perioperative RBL, without any thromboembolic complications. Non-inferiority of a short- versus a long-TXA protocol in reducing perioperative RBL was supported in a secondary analysis

Introduction: Low-molecular-weight heparin is commonly used for thromboprophylactic therapy post orthopaedic surgery. Studies in the past have suggested that it may have a negative effect on osteoblasts and some have implicated its use with the risk of developing osteoporosis. Recently, Rivaroxaban, an oral Factor Xa inhibitor is gaining impetus for antithrombotic therapy over the last year and has been recommended for licensing by the FDA for this purpose. The effect of Rivaroxa-ban on bone and osteoblasts, if any, remains to be seen. Methods: In a standardized in vitro model, human osteoblasts were cultured and exposed to a range of Enoxaparin and Rivaroxaban concentrations including their therapeutic dose. We evaluated the effects of these drugs on osteoblastic proliferation and activity using CellTiter 96 AQueous non-radioactive cell proliferation (MTS) and alkaline phosphatase assays respectively. Gene expression of Runt-related transcription factor 2 (Runx2), osteocalcin and bone morphogenetic protein 2 (BMP-2) were evaluated using Real time-polymerase chain reaction (RT-PCR) studies. Statistical analyses (t-test) were conducted using Microsoft Excel 2007. Results: Rivaroxaban and Enoxaparin significantly reduced alkaline phosphatase activity (p< 0.05) however, no negative effects on osteoblastic proliferation was seen at all concentrations of both drugs. Rivaroxaban decreased Osteocalcin and Runx2 mRNA expression levels at 24 hours at therapeutic concentrations (p< 0.05). This effect was similarly found at therapeutic levels of Enoxaparin. Both Rivaroxaban and Enoxaparin significantly reduced BMP-2 mRNA expression both at 24 hours and 7 days at therapeutic concentrations. (p< 0.05). Conclusion: Our study suggests that Rivaroxaban has similar negative effects on osteoblasts compared to Enoxaparin in the early stages. The increased duration of recommended Rivaroxaban therapy (2 and 5 weeks) post arthroplasty compared to Enoxaparin therapy (around 1 week) may have a more pronounced effect on bone homeostasis

Introduction. Rivaroxaban, an oral factor Xa inhibitor, has been approved by USFDA for prophylaxis of deep vein thrombosis (DVT) and pulmonary embolism (PE) in hip and knee arthroplasties. Its indication in hip fracture surgery has been recently recommended in Asian venous thromboembolism (VTE) guidelines. Phase II dose-ranging study demonstrated that 5 mg rivaroxaban is as effective as enoxaparin for VTE prophylaxis with lower incidence of bleeding complication than the recommended 10 mg dose. Rivaroxaban is recommended to be given 6–8 hours after operation. However, many surgeons are hesitated to follow this guideline since it might increase post-operative blood loss and wound complication. Elderly patients, such as hip fracture patients, are generally at more risk of bleeding and wound complications. These patients may benefit from using the delayed and reduced-dose regimen. Methods. Since July 2011, all eligible hip fracture patients treated by single group of surgeons were given 5mg daily dose of rivaroxaban for VTE prophylaxis. Initial dose of rivaroxaban was given after drain had been removed (24–36 hours post-operatively) and continued for 14 days. Inclusion criteria are femoral neck fracture or intertrochanteric fracture in patients age 60 and over. Exclusion criteria are pathologic fracture, reoperation for failed fixation, chronic anticoagulant therapy, and allergy to rivaroxaban. Criteria by Aniwan and Rojnackarin were used for clinical diagnosis of DVT and PE. Suspected case of DVT and PE were sent for confirmation with Doppler U/S and Pulmonary Artery CT scan, respectively. All bleeding and wound complications were recorded. Numbers of blood transfusion were also recorded. Patients were followed for at least 6 weeks, all complications were recorded. Results. There were 79 hip fracture patients matching our criteria. They were composed of 54 femoral neck fractures and 25 intertrochanteric fractures. Mean age of patients was 76.3 years. All femoral neck fractures were treated with bipolar hemiarthroplasty and intertrochanteric fractures were treated with short cephalomedullary nail. Two patients (2.6%) were compatible with clinical criteria of DVT. However, Doppler ultrasound examinations do not demonstrate thrombus or intraluminal filling defect. There was no suspected case of PE. There was no major hemorrhagic wound complication requiring reoperation. Minor wound complications include 7 (8.9%) cases of prolong serous oozing and 1 (1.3%) superficial wound infection. Extrasurgical site bleeding includes 1 (1.3%) upper GI bleeding and 2 (2.5%) hematuria. None of the patients received more than 2 units of blood transfusion. Discussion and Conclusion. Delayed and reduced-dose regimen of rivaroxaban is effective for VTE prophylaxis in hip fracture patients. There is no major hemorrhagic wound complication. Nonetheless, extrasurgical site bleeding is frequent. Further randomized comparative study with larger number of patients should be performed to demonstrate whether the benefits of the modified regimen existed or not

Introduction. Our department is responsible specifically for complex cases resulting from trauma. Our experience does not want to add what has been clearly demonstrated by multicenter studies on the efficacy of rivaroxaban but aims to demonstrate how the use of this molecule was effective also in mega-prosthesis and how it has proven to be flexible and safe in dealing with difficulties and surgical complications more common in such difficult cases. Materials and Methods. From January 2010 to date DVT prophylaxis in THR / TKR and revision was routinely performed with rivaroxaban. To date, in addition to first implant/revision in THR/TKR we treated over 30 cases of large segments replacements (large segments+mega-prosthesis) and we have not highlighted complications attributable to rivaroxaban. Discussion. We present in particular the medical and surgical management of three cases with a high risk of bleeding: a case of revision of total femur due to recurrent dislocation, one case of revision for early infection of a TKR and a case of traumatic acetabular revision for pelvicbreakthrough during rehabilitation. Conclusion. The major practical advantages found are: 1) the ability to choose when to start prophylaxis in relation to intraoperative bleeding Vs therapy that begins the previous day, 2) seeking the best prophylaxis for primary prosthetic and complex cases, the single-dose and pharmaco-kinetics/dynamic of rivaroxaban guarantee to be able to easily switch to a traditional prophylaxis in case of a need for further surgey Vs multi-dose of other oral drugs

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

Venous thromboembolism (VTE) is a potentially fatal complication after total hip replacement (THR) and may be associated with a considerable economic burden. In many centres, thromboprophylaxis using a subcutaneous (sc) anticoagulant in patients undergoing THR is restricted to 14 days or less. Rivaroxaban is a once-daily, oral, direct Factor Xa inhibitor in advanced clinical development for thromboprophylaxis after major orthopaedic surgery; it does not require monitoring or dose adjustment. In a phase III study, RECORD2, oral rivaroxaban 10 mg, given once daily for 35±4 days, significantly reduced the incidence of the primary endpoint (deep vein thrombosis, pulmonary embolism and all-cause mortality), compared with 40 mg sc enoxaparin, given for 14 days (2.0% vs 9.3%, respectively; relative risk reduction 79%; p< 0.001). The incidence of bleeding was low and similar in both groups, despite extended thromboprophylaxis with rivaroxaban. This analysis demonstrates the economic impact of extended thromboprophylaxis with oral rivaroxaban. The effect of rivaroxaban on healthcare costs was based on the primary efficacy results, and the associated reduced administration and monitoring costs, and includes non-drug costs only. The cost of symptomatic VTE was taken from published sources in the US and the UK 2007 NICE Guidelines. It was assumed that nurses spent 3 mins/day administering enoxaparin and training patients to self-inject for outpatient use. Hospital duration was 5 days. In the UK, full blood counts should be taken every 3 days when receiving enoxaparin. The total US health-care resource cost was $192/patient for enoxaparin and $39 for rivaroxaban (excluding drug costs). This saving of $153 was driven by reduced hospital costs associated with fewer VTEs when using rivaroxaban. In the UK, the total healthcare cost/patient was £44 with enoxaparin and £2 with rivaroxaban – savings driven equally by reduced hospitalization and monitoring costs with rivaroxaban prophylaxis. The different cost savings in the US and UK are due to higher US hospital costs. The costs of post-thrombotic syndrome (PTS) were excluded in this analysis. PTS has an estimated 5-year rate of 21% after asymptomatic VTE and 30% after symptomatic VTE, at a total cost/patient of more than $11,000 in the US and £4000 in the UK. Given the reduction in all VTE events with rivaroxaban, there are potential further healthcare cost savings due to reduced PTS. The RECORD2 study showed that extended prophylaxis (35 days) with rivaroxaban was significantly more effective than short-term enoxaparin (14 days) for the prevention of VTE, and was not associated with an increased risk of bleeding. This analysis illustrates an additional benefit of once-daily, oral rivaroxaban in the reduction in healthcare costs related to administration and monitoring

Rivaroxaban, an oral direct factor Xa inhibitor was introduced for thromboprophylaxis at the Royal Cornwall Hospital for hip and knee arthroplasty surgery in October 2009. Our aim was to investigate how safely Rivaroxaban could be implemented and how quickly its regular use was established. We identified 140 patients from theatre logbooks who underwent elective total hip and knee joint replacements between October 2009 and March 2010. Patient notes, computer and DVT clinic records data were collected to determine the uptake of the new drug and the incidence of post-operative complications. We compared our chemical thromboprophylactic rates to those recorded at discharge in a 4-month period prior to our study in 2009. In addition we quantified the time needed before a newly introduced drug becomes established in clinical practice. Patients were divided into two groups. Those who received Rivaroxaban were in group A (n=78, 55.7%) and those who received alternative or no chemical thromboprophylaxis constituted group B (n=62, 44.3%). All patients were prescribed TEDs stockings. 10.3% [8/78] of patients in group A suffered wound complications compared with 6.6% [4/62] of group B patients. Within group A we found that 41.1% (n=7) of the documented wound complications were wound ooze. DVTs occurred in both groups, 1 in group A and 2 in group B. 4 patients had postoperative haematemesis, 2 in each group. Group A had 17 (22%) documented complications. A similar number (n=15, 24%) of patients in group B had recorded complications. Our complication rates compared favourably to the RECORD 1–3 pooled study. From January to April 2009, prior to introduction of Rivaroxaban, 51% of all elective hip and knee replacement surgery patients were receiving any chemical thromboprophylaxis on discharge. This increased to 83% following introduction of Rivaroxaban. During the first month of introduction of Rivaroxaban at our hospital, following NICE guideline, 28% of patients who qualified to receive the drug did. This improved to 95% by the time it had been in use by 3 months. The data shows that there is no statistical significance in complications in thromboprophylaxis in elective total hip and knee replacement surgery between Group A and Group B (P-value 0.8941). This shows similar complication rates to the RECORD clinical study and concludes a safe introduction of the drug to our District General Hospital. Patients in Group A had a reduced occurrence of thrombotic events, but an increase in cases of wound ooze when compared to group B. Following the introduction of Rivaroxaban, it took 3 months for 95% of eligible patients for the drug to be NICE compliant. This demonstrated a 3 month run in time for the implementation of this new treatment regime in our hospital

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

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

Background. Current treatments for the prevention of thromboembolism include heparin and low-molecular weight heparins (LMWHs). A number of studies have suggested that long term administration of these drugs may adversely affect osteoblasts and therefore, bone metabolism. Xarelto(tm) (Rivaroxaban) is a new anti-thrombotic drug for the prevention of venous thromboembolism in adult patients undergoing elective hip and knee replacement surgery. The aim of this in vitro study was to investigate the possible effects of rivaroxaban on osteoblast proliferation, function, matrix mineralisation and gene expression compared to enoxaparin, a commonly used LMWH. Methods. Primary human osteoblast cultures were treated with varying concentrations of rivaroxaban (0.013, 0.13, 1.3 and 13 μg/ml) or enoxaparin (0.1, 1.0 and 10 international units/ml). The effect of each drug on osteoblast function and matrix mineralisation was evaluated by measuring alkaline phosphatase activity and calcium deposition, respectively. The MTS assay was used to assess the effect of drug treatments on cell proliferation. Changes in osteocalcin, Runx2 and BMP-2 messenger RNA (mRNA) expression following drug treatments were measured by real-time polymerase chain reaction (PCR). Results. Rivaroxaban and enoxaparin treatment did not adversely affect osteoblast proliferation. However, both drugs caused a significant reduction in osteoblast function, as measured by alkaline phosphatase activity, with a moderate reduction in calcium deposition also observed. This reduction in osteoblast function was associated with a reduction in the mRNA expression of the bone marker, osteocalcin, the transcription factor, Runx2, and the osteogenic factor, BMP-2. Conclusion. These data show that rivaroxaban treatment may negatively affect bone through a reduction in osteoblast function. The increased duration of recommended Rivaroxaban therapy (2 and 5 weeks) post-arthroplasty compared to Enoxaparin therapy (average one week) may have a more pronounced effect on bone homeostasis

Purpose. This study investigates the effect of early tourniquet release on range of flexion following total knee replacement, and the influence of anticoagulation with Rivaroxaban and Clexane (Enoxaparin). Method. 78 patients were included in the study, who underwent unilateral primary total knee replacement (TKR) in our department under the care of two specialist knee surgeons over a 12 month period. 27 patients underwent TKR with early release of the tourniquet and haemostasis, prior to closure of quadriceps layer: 22 were anticoagulated with Rivaroxaban (GROUP ER), 15 with the low molecular weight heparin Clexane (GROUP EC). Over the same time period, 41 patients TKR with late release of the tourniquet, following closure and bandaging: 13 were anticoagulated with Rivaroxaban (GROUP LR), 28 with Clexane (GROUP LC). A standardised operative technique was employed, and all patients received an AGC (Biomet) PCL-retaining prostheses. Outcome was assessed with range of flexion at 12 weeks postoperatively. Results. The mean range of flexion at 12 weeks was 106.8° in Group ER, 96.54° in Group LR, 108.33° in Group EC and 101.11° in LC. The mean difference in flexion at 12 weeks between Group EC and LC was 7.2°, and between ER and LR was 10.2°. Conclusion. Our study supports the theory that early tourniquet release and haemostasis has a beneficial effect on the early range of flexion following TKR. This affect appears to be increased when the oral anticoagulant Rivaroxaban is used, when compared with low molecular weight heparin

Hypothesis. Pre-specified pooling of data from the four phase III RECORD studies was conducted to determine whether rivaroxaban significantly reduced the less-frequent clinical endpoint of symptomatic venous thromboembolism (VTE) and all-cause mortality after total hip or knee arthroplasty (THA or TKA, respectively), compared with standard North American and European enoxaparin regimens. Methods and analysis. Patients (n=12,729) received rivaroxaban 10 mg once daily or enoxaparin 40 mg once daily (RECORD1-3) or 30 mg 12-hourly (RECORD4). Thromboprophylaxis was administered for 31-39 days (RECORD1; THA) or 10-14 days (RECORD3 and 4; TKA). RECORD2 (THA) compared 31-39 days' rivaroxaban with 10-14 days' enoxaparin followed by placebo. The pre-specified primary efficacy endpoint in the pooled analysis (composite of symptomatic VTE and all-cause mortality) and adjudicated bleeding events were analysed in the day 12±2 active treatment pool, when all patients had received active drug, and total treatment duration pool, where subgroup analyses were performed. Results. In the day 12±2 active treatment pool, the primary efficacy endpoint occurred in 0.5% of patients receiving rivaroxaban versus 1.0% of patients receiving enoxaparin (p=0.001). Major bleeding occurred in 0.3% versus 0.2% patients respectively (p=0.18) and major plus clinically relevant non-major bleeding occurred in 2.9% versus 2.5% patients respectively (p=0.19). In the total treatment duration pool, rivaroxaban significantly reduced the primary efficacy endpoint compared with enoxaparin regimens 0.6% versus 1.3% patients (p< 0.001) with similar rates of major bleeding. Over the total treatment period, rivaroxaban consistently reduced the primary efficacy endpoint across the pre-specified subgroups (age, gender, body weight, creatinine clearance). Conclusion. Rivaroxaban significantly reduced the composite of clinically important symptomatic VTE and all-cause mortality after THA or TKA compared with subcutaneous enoxaparin regimens in the direct comparison day 12±2 active treatment pool, with no significant differences in bleeding events. These results suggest a positive benefit-risk profile for oral, once-daily rivaroxaban