Aims. The aim of this study was to compare the results of 16S/28S rRNA sequencing with the erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) level, and synovial fluid analysis in the diagnosis of prosthetic joint infection (PJI). Patients and Methods. Between September 2015 and August 2016, 214 consecutive patients were enrolled. In the study population, there were 25 patients with a PJI and 189 controls. Of the PJI patients, 14 (56%) were women, and the mean age at the time of diagnosis was 65 years (38 to 83). The ESR and CRP levels were measured, and synovial fluid specimens were collected prospectively. Synovial fluid was subjected to reverse transcription polymerase chain reaction (RT-PCR)/sequence analysis targeting the 16S/28S rRNA, and to conventional culture. Laboratory personnel who were blind to the clinical information performed all tests. The diagnosis of PJI was based on the criteria of the Musculoskeletal Infection Society. Results. A total of 25 patients had a confirmed PJI. In 20 cases of monomicrobial PJI, the PCR products could be perfectly matched with the 16S/28S rRNA genes specific for different species of bacteria provided by sequence analysis. Of the five polymicrobial cases of PJI, 16S/28S rRNA PCR sequence analysis failed to identify the concordant bacteria species. In the 189 control patients, there was one false-positive RT-PCR result. The sensitivity and specificity of the molecular diagnosis method were 100% (95% confidence interval (CI) 85.7 to 100) and 99.5% (95% CI 97.1 to 99.9), respectively, whereas the positive and negative predictive values of PCR were 96.1% (95% CI 79.6 to 99.9) and 100% (95% CI 98.1 to 100), respectively. The PCR results were significantly better than serological diagnostic methods (p = 0.004 and p = 0.010 for ESR and CRP, respectively), the synovial fluid white blood cell (WBC) count (p = 0.036), and percentage of polymorphonuclear cells (PMN%) (p = 0.014). Conclusion. Stepwise RT-PCR and sequence analysis of the 16S/28S rRNA carried out under stringent laboratory conditions achieved highly sensitive and specific results for the differentiation between aseptic and septic joints undergoing arthroplasty. Sequence analysis successfully identified bacterial strains in monomicrobial infections but failed to identify molecular targets in polymicrobial infections. Further refinement of the protocols to identify the bacteria in polymicrobial infections is needed. Cite this article: Bone Joint J 2018;100-B:1345–51

We have assessed the different adhesive properties of some of the most common bacteria associated with periprosthetic joint infection on various types of ultra high molecular Weight Polyethylene (UHMWPE). Quantitative in vitro analysis of the adhesion of biofilm producing strains of Staphylococcus aureus and Escherichia coli to physically and chemically characterised standard UHMWPE (PE), vitamin E blended UHMWPE (VE-PE) and oxidised UHMWPE (OX-PE) was performed using a sonication protocol. A significant decreased bacterial adhesion was registered for both strains on VE-PE, in comparison with that observed on PE, within 48 hours of observation (S. aureus p = 0.024 and E. coli p = 0.008). Since Vitamin E reduces bacterial adhesive ability, VE-stabilised UHMWPE could be valuable in joint replacement by presenting excellent mechanical properties, while reducing bacterial adhesiveness. Cite this article: Bone Joint J 2014;96-B:497–501

Aims. As a proven and comprehensive molecular technique, metagenomic next-generation sequencing (mNGS) has shown its potential in the diagnosis of pathogens in patients with periprosthetic joint infection (PJI), using a single type of specimen. However, the optimal use of mNGS in the management of PJI has not been explored. In this study, we evaluated the diagnostic value of mNGS using three types of specimen with the aim of achieving a better choice of specimen for mNGS in these patients. Methods. In this prospective study, 177 specimens were collected from 59 revision arthroplasties, including periprosthetic tissues, synovial fluid, and prosthetic sonicate fluid. Each specimen was divided into two, one for mNGS and one for culture. The criteria of the Musculoskeletal Infection Society were used to define PJI (40 cases) and aseptic failure (19 cases). Results. The sensitivity and specificity of mNGS in the diagnosis of PJI were 95% and 94.7%, respectively, for all types of specimen. The sensitivity and specificity were 65% and 100%, respectively, for periprosthetic tissues, 87.5% and 94.7%, respectively, for synovial fluid, and 92.5% and 94.7%, respectively, for prosthetic sonicate fluid. The mNGS of prosthetic sonicate fluid outperformed that for other types of specimen in the rates of detection of pathogens (84.6%), sequencing reads (> ten-fold) and the rate of genome coverage (> five-fold). Conclusion. mNGS could serve as an accurate diagnostic tool in the detection of pathogens in patients with a PJI using three types of specimen. Due to its superior perfomance in identifying a pathogen, mNGS of prosthetic sonicate fluid provides the most value and may partly replace traditional tests such as bacteriological culture in these patients. Cite this article: Bone Joint J 2021;103-B(5):923–930

Aims. Use of molecular sequencing methods in periprosthetic joint infection (PJI) diagnosis and organism identification have gained popularity. Next-generation sequencing (NGS) is a potentially powerful tool that is now commercially available. The purpose of this study was to compare the diagnostic accuracy of NGS, polymerase chain reaction (PCR), conventional culture, the Musculoskeletal Infection Society (MSIS) criteria, and the recently proposed criteria by Parvizi et al in the diagnosis of PJI. Methods. In this retrospective study, aspirates or tissue samples were collected in 30 revision and 86 primary arthroplasties for routine diagnostic investigation for PJI and sent to the laboratory for NGS and PCR. Concordance along with statistical differences between diagnostic studies were calculated. Results. Using the MSIS criteria to diagnose PJI as the reference standard, the sensitivity and specificity of NGS were 60.9% and 89.9%, respectively, while culture resulted in sensitivity of 76.9% and specificity of 95.3%. PCR had a low sensitivity of 18.4%. There was no significant difference based on sample collection method (tissue swab or synovial fluid) (p = 0.760). There were 11 samples that were culture-positive and NGS-negative, of which eight met MSIS criteria for diagnosing infection. Conclusion. In our series, NGS did not provide superior sensitivity or specificity results compared to culture. PCR has little utility as a standalone test for PJI diagnosis with a sensitivity of only 18.4%. Currently, several laboratory tests for PJI diagnosis should be obtained along with the overall clinical picture to help guide decision-making for PJI treatment. Cite this article: Bone Joint J 2021;103-B(1):26–31

Aims. Arthrofibrosis is a relatively common complication after joint injuries and surgery, particularly in the knee. The present study used a previously described and validated rabbit model to assess the biomechanical, histopathological, and molecular effects of the mast cell stabilizer ketotifen on surgically induced knee joint contractures in female rabbits. Methods. A group of 12 skeletally mature rabbits were randomly divided into two groups. One group received subcutaneous (SQ) saline, and a second group received SQ ketotifen injections. Biomechanical data were collected at eight, ten, 16, and 24 weeks. At the time of necropsy, posterior capsule tissue was collected for histopathological and gene expression analyses (messenger RNA (mRNA) and protein). Results. At the 24-week timepoint, there was a statistically significant increase in passive extension among rabbits treated with ketotifen compared to those treated with saline (p = 0.03). However, no difference in capsular stiffness was detected. Histopathological data failed to demonstrate a decrease in the density of fibrous tissue or a decrease in α-smooth muscle actin (α-SMA) staining with ketotifen treatment. In contrast, tryptase and α-SMA protein expression in the ketotifen group were decreased when compared to saline controls (p = 0.007 and p = 0.01, respectively). Furthermore, there was a significant decrease in α-SMA (ACTA2) gene expression in the ketotifen group compared to the control group (p < 0.001). Conclusion. Collectively, these data suggest that ketotifen mitigates the severity of contracture formation in a rabbit model of arthrofibrosis. Cite this article: Bone Joint Res 2020;9(6):302–310

Aims. The primary aim of this study was to compare the wear properties of vitamin E-diffused, highly crosslinked polyethylene (VEPE) and one formulation of moderately crosslinked and mechanically annealed ultra-high molecular weight polyethylene (ModXLPE) in patients five years after primary total hip arthroplasty (THA). The secondary aim was to assess the clinical results of patients treated with VEPE by evaluating patient-reported outcome measures (PROMs), radiological evidence of fixation, and the incidence of mechanical failure. Patients and Methods. A total of 208 patients (221 THAs) from four international centres were recruited into a prospective study involving radiostereometric analysis (RSA) and the assessment of clinical outcomes. A total of 193 hips (87%) were reviewed at the five-year follow-up. Of these, 136 (70%) received VEPE (vs ModXLPE) liners and 68 (35%) received ceramic (vs metal) femoral heads. PROMs and radiographs were collected preoperatively and at one, two, and five years postoperatively. In addition, RSA images were collected to measure PE wear postoperatively and at one, two, and five years after surgery. Results. We observed similar bedding in one year postoperatively and wear two years postoperatively between the two types of liner. However, there was significantly more penetration of the femoral head in the ModXLPE cohort compared with the VEPE cohort five years postoperatively (p < 0.001). The only variables independently predictive of increased wear were ModXLPE (vs VEPE) liner type (β = 0.22, p = 0.010) and metal (vs ceramic) femoral head (β = 0.21, p = 0.013). There was no association between increased wear and the development of radiolucency (p = 0.866) or PROMs. No patient had evidence of osteolysis. Conclusion. Five years postoperatively, patients with VEPE (vs ModXLPE) and ceramic (vs metal) femoral heads had decreased wear. The rates of wear for both liners were very low and have not led to any osteolysis or implant failure due to aseptic loosening

Aims

The outcomes of patients with unexpected positive cultures (UPCs) during revision total hip arthroplasty (THA) and total knee arthroplasty (TKA) remain unknown. The objectives of this study were to establish the prevalence and infection-free implant survival in UPCs during presumed aseptic single-stage revision THA and TKA at mid-term follow-up.

Aims

Fungal and mycobacterial periprosthetic joint infections (PJI) are rare events. Clinicians are wary of missing these diagnoses, often leading to the routine ordering of fungal and mycobacterial cultures on periprosthetic specimens. Our goal was to examine the utility of these cultures and explore a modern bacterial culture technique using bacterial blood culture bottles (BCBs) as an alternative.

Aims. There is uncertainty regarding the optimal means of thromboprophylaxis following total hip and knee arthroplasty (THA, TKA). This systematic review presents the evidence for acetylsalicylic acid (aspirin) as a thromboprophylactic agent in THA and TKA and compares it with other chemoprophylactic agents. Materials and Methods. A search of literature published between 2004 and 2014 was performed in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. A total of 13 studies were eligible for inclusion. Results. Evidence from one good quality randomised controlled trial (RCT) showed no difference in rates of venous thrombo-embolism (VTE) in patients given aspirin or low molecular weight heparin (LMWH) following TKA. There was insufficient evidence from trials with moderate to severe risk of bias being present to suggest aspirin is more or less effective than LMWH, warfarin or dabigatran for the prevention of VTE in TKA or THA. Compared with aspirin, rates of asymptomatic deep vein thrombosis (DVT) in TKA may be reduced with rivaroxaban but insufficient evidence exists to demonstrate an effect on incidence of symptomatic DVT. Compared with aspirin there is evidence of more wound complications following THA and TKA with dabigatran and in TKA with rivaroxaban. Some studies highlighted concerns over bleeding complications and efficacy of aspirin. Conclusion. The results suggest aspirin may be considered a suitable alternative to other thromboprophylactic agents following THA and TKA. Further investigation is required to fully evaluate the safety and efficacy of aspirin. Cite this article: Bone Joint J 2016;98-B:1056–61

The National Institute for Clinical Excellence (NICE) produces recommendations on appropriate treatment within the National Health Service (NHS) in England and Wales. The NICE guidelines on prophylaxis for venous thromboembolism in orthopaedic surgery recommend that all patients be offered a low molecular weight heparin (LMWH). The linked hospital episode statistics of 219 602 patients were examined to determine the rates of complications following lower limb arthroplasty for the 12-month periods prior to and following the publication of these guidelines. These were compared with data from the National Joint Registry (England and Wales) regarding the use of LMWH during the same periods. There was a significant increase in the reported use of LMWH (59.5% to 67.6%, p < 0.001) following the publication of the guidelines. However, the 90-day venous thromboembolism events actually increased slightly following total hip replacement (THR, 1.69% to 1.84%, p = 0.06) and remained unchanged following total knee replacement (TKR, 1.99% to 2.04%). Return to theatre in the first 30 days for infection did not show significant changes. There was an increase in the number of patients diagnosed with thrombocytopenia, which was significant following THR (0.11% to 0.16%, p = 0.04). The recommendations from NICE are based on predicted reductions in venous thromboembolism events, reducing morbidity, mortality and costs to the NHS. The early results in orthopaedic patients do not support these predictions, but do show an increase in complications

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

Aims

Metagenomic next-generation sequencing (mNGS) is useful in the diagnosis of infectious disease. However, while it is highly sensitive at identifying bacteria, it does not provide information on the sensitivity of the organisms to antibiotics. The purpose of this study was to determine whether the results of mNGS can be used to guide optimization of culture methods to improve the sensitivity of culture from intraoperative samples.

Aims

Periprosthetic joint infections (PJIs) are among the most devastating complications after joint arthroplasty. There is limited evidence on the efficacy of different antiseptic solutions on reducing biofilm burden. The purpose of the present study was to test the efficacy of different antiseptic solutions against clinically relevant microorganisms in biofilm.

Since the introduction of the National Institute for Health and Care Excellence (NICE) guidelines on thromboprophylaxis and the use of extended thromboprophylaxis with new oral agents, there have been reports of complications arising as a result of their use. We have looked at the incidence of wound complications after the introduction of dabigatran for thromboprophylaxis in our unit. We investigated the rate of venous thromboembolism and wound leakage in 1728 patients undergoing primary joint replacement, both before and after the introduction of dabigatran, and following its subsequent withdrawal from our unit. We found that the use of dabigatran led to a significant increase in post-operative wound leakage (20% with dabigatran, 5% with a multimodal regimen; p < 0.001), which also resulted in an increased duration of hospital stay. The rate of thromboembolism in patients receiving dabigatran was higher (1.3%) than in those receiving the multimodal thromboprophylaxis regimen, including low molecular weight heparin as an inpatient and the extended use of aspirin (0.3%, p = 0.047). We have ceased the use of dabigatran for thromboprophylaxis in these patients. Cite this article: Bone Joint J 2014;96-B:122–6

Aims

Calprotectin (CLP) is produced in neutrophils and monocytes and released into body fluids as a result of inflammation or infection. The aim of this study was to evaluate the utility of blood and synovial CLP in the diagnosis of chronic periprosthetic joint infection (PJI).

Aims

As the first wave of the COVID-19 pandemic began to dip, restarting elective orthopaedics became a challenge. Protocols including surgery at ‘green’ sites, self-isolation for 14 days, and COVID-19 testing were developed to minimize the risk of transmission. In this study, we look at risk effects of 14-day self-isolation on the incidence of venous thromboembolism (VTE) in our green site hospital among patients undergoing total joint replacement (TJR).

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The aim of this study was to develop a single-layer hybrid organic-inorganic sol-gel coating that is capable of a controlled antibiotic release for cementless hydroxyapatite (HA)-coated titanium orthopaedic prostheses.

Aims

The diagnosis of periprosthetic joint infection (PJI) can be difficult. All current diagnostic tests have problems with accuracy and interpretation of results. Many new tests have been proposed, but there is no consensus on the place of many of these in the diagnostic pathway. Previous attempts to develop a definition of PJI have not been universally accepted and there remains no reference standard definition.

We studied 4253 patients undergoing primary joint replacement between November 2002 and November 2007, of whom 4060 received aspirin only as chemical prophylaxis; 46 were mistakenly given low molecular weight heparin initially, which was stopped and changed to aspirin; 136 received no chemoprophylaxis and 11 patients received warfarin because of a previous history of pulmonary embolism. We identified the rate of clinical thromboembolism before and after discharge, and the mortality from pulmonary embolism at 90 days. The overall death rate was 0.31% (13 of 4253) and the rate of fatal pulmonary embolism was 0.07% (3 of 4253). Our data suggest that fatal pulmonary embolism is not common following elective primary joint replacement, and with modern surgical practice elective hip and knee replacement should no longer be considered high-risk procedures

Aims

To develop and validate patient-centred algorithms that estimate individual risk of death over the first year after elective joint arthroplasty surgery for osteoarthritis.

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Preoperative nasal Staphylococcus aureus screening and eradication reduces surgical site infections (SSIs) but its impact on reducing early prosthetic joint infection (PJI) remains controversial. This study aims to assess the effect of preoperative nasal S. aureus screening and eradication on the incidence of early PJI in general and S. aureus-induced early PJI.

Aims

Prosthetic joint infection (PJI) remains a major clinical challenge. Neutrophil CD64 index, Fc-gamma receptor 1 (FcγR1), plays an important role in mediating inflammation of bacterial infections and therefore could be a valuable biomarker for PJI. The aim of this study is to compare the neutrophil CD64 index in synovial and blood diagnostic ability with the standard clinical tests for discrimination PJI and aseptic implant failure.

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The aim of this study was to determine the prevalence and characteristics of C-reactive protein (CRP)-negative prosthetic joint infection (PJI) and evaluate the influence of the type of infecting organism on the CRP level.

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The aim of this study was to establish the diagnostic accuracy of culture of joint aspirate with and without saline injection-reaspiration.

Aims

The aim of this study was to present data on 11 459 patients who underwent total hip (THA), total knee (TKA) or unicompartmental knee arthroplasty (UKA) between November 2002 and April 2014 with aspirin as the primary agent for pharmacological thromboprophylaxis.

We examined the risk of thrombotic and major bleeding events in patients undergoing total hip and knee replacement (THR and TKR) treated with thromboprophylaxis, using nationwide population-based databases. We identified 83 756 primary procedures performed between 1997 and 2011. The outcomes were symptomatic venous thromboembolism (VTE), myocardial infarction (MI), stroke, death and major bleeding requiring hospitalisation within 90 days of surgery.

A total of 1114 (1.3%) and 483 (0.6%) patients experienced VTE and bleeding, respectively. The annual risk of VTE varied between 0.9% and 1.6%, and of bleeding between 0.4% and 0.8%. The risk of VTE and bleeding was unchanged over a 15-year period. A total of 0.7% of patients died within 90 days, with a decrease from 1% in 1997 to 0.6% in 2011 (p < 0.001). A high level of comorbidity and general anaesthesia were strong risk factors for both VTE and bleeding, with no difference between THR and TKR patients. The risk of both MI and stroke was 0.5%, which remained unchanged during the study period.

In this cohort study of patients undergoing THR and TKR patients in routine clinical practice, approximately 3% experienced VTE, MI, stroke or bleeding. These risks did not decline during the 15-year study period, but the risk of dying fell substantially.

Cite this article: Bone Joint J 2014;96-B:479–85.

We performed a meta-analysis of modern total joint replacement (TJR) to determine the post-operative mortality and the cause of death using different thromboprophylactic regimens as follows: 1) no routine chemothromboprophylaxis (NRC); 2) Potent anticoagulation (PA) (unfractionated or low-molecular-weight heparin, ximelagatran, fondaparinux or rivaroxaban); 3) Potent anticoagulation combined (PAC) with regional anaesthesia and/or pneumatic compression devices (PCDs); 4) Warfarin (W); 5) Warfarin combined (WAC) with regional anaesthesia and/or PCD; and 6) Multimodal (MM) prophylaxis, including regional anaesthesia, PCDs and aspirin in low-risk patients. Cause of death was classified as autopsy proven, clinically certain or unknown. Deaths were grouped into cardiopulmonary excluding pulmonary embolism (PE), PE, bleeding-related, gastrointestinal, central nervous system, and others (miscellaneous). Meta-analysis based on fixed effects or random effects models was used for pooling incidence data.

In all, 70 studies were included (99 441 patients; 373 deaths). The mortality was lowest in the MM (0.2%) and WC (0.2%) groups. The most frequent cause of death was cardiopulmonary (47.9%), followed by PE (25.4%) and bleeding (8.9%). The proportion of deaths due to PE was not significantly affected by the thromboprophylaxis regimen (PA, 35.5%; PAC, 28%; MM, 23.2%; and NRC, 16.3%). Fatal bleeding was higher in groups relying on the use of anticoagulation (W, 33.8%; PA, 9.4%; PAC, 10.8%) but the differences were not statistically significant.

Our study demonstrated that the routine use of PA does not reduce the overall mortality or the proportion of deaths due to PE.

Patients who have undergone total hip or knee replacement (THR and TKR, respectively) are at high risk of venous thromboembolism. We aimed to determine the time courses of both the incidence of venous thromboembolism and effective prophylaxis. Patients with elective primary THR and TKR were enrolled in the multi-national Global Orthopaedic Registry. Data on the incidence of venous thromboembolism and prophylaxis were collected from 6639 THR and 8326 TKR patients.

The cumulative incidence of venous thromboembolism within three months of surgery was 1.7% in the THR and 2.3% in the TKR patients. The mean times to venous thromboembolism were 21.5 days (sd 22.5) for THR, and 9.7 days (sd 14.1) for TKR. It occurred after the median time to discharge in 75% of the THR and 57% of the TKA patients who developed venous thromboembolism. Of those who received recommended forms of prophylaxis, approximately one-quarter (26% of THR and 27% of TKR patients) were not receiving it seven days after surgery, the minimum duration recommended at the time of the study.

The risk of venous thromboembolism extends beyond the usual period of hospitalisation, while the duration of prophylaxis is often shorter than this. Practices should be re-assessed to ensure that patients receive appropriate durations of prophylaxis.

This prospective randomised clinical trial evaluated the effect of alternatives for allogeneic blood transfusions after total hip replacement and total knee replacement in patients with pre-operative haemoglobin levels between 10.0 g/dl and 13.0 g/dl. A total of 100 patients were randomly allocated to the Eprex (pre-operative injections of epoetin) or Bellovac groups (post-operative retransfusion of shed blood). Allogeneic blood transfusions were administered according to hospital policy.

In the Eprex group, 4% of the patients (two patients) received at least one allogeneic blood transfusion. In the Bellovac group, where a mean 216 ml (0 to 700) shed blood was retransfused, 28% (14 patients) required the allogeneic transfusion (p = 0.002). When comparing Eprex with Bellovac in total hip replacement, the percentages were 7% (two of 30 patients) and 30% (nine of 30 patients) (p = 0.047) respectively, whereas in total knee replacement, the percentages were 0% (0 of 20 patients) and 25% (five of 20 patients) respectively (p = 0.042).

Pre-operative epoetin injections are more effective but more costly in reducing the need for allogeneic blood transfusions in mildly anaemic patients than post-operative retransfusion of autologous blood.

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.