Rivaroxaban

Major orthopedic surgery is associated with a high risk of venous thromboembolism (VTE). Anticoagulants are recommended to prevent VTE, and recently an oral direct factor Xa inhibitor (FXaI) was approved for this indication. We compared the cost-effectiveness of FXaIs with low-molecular-weight heparin (LMWH) in patients undergoing total hip replacement (THR) or total knee replacement (TKR) surgery. A decision-tree model was developed to compare the cost-effectiveness of oral direct FXaIs (rivaroxaban, apixaban, and edoxaban) to subcutaneous LMWHs (enoxaparin and dalteparin), with separate models for THR and TKR. The analysis was conducted over a 180-day postoperative time horizon from the U.S. Medicare perspective. The model was developed using TreeAge Pro 2011 (TreeAge Software Inc., Williamstown, MA, USA). Efficacy and safety data (probabilities of distal and proximal deep vein thrombosis, symptomatic pulmonary embolism, and major bleeding) were derived from a systematic review and meta-analysis of phase II and III clinical trials. Costs and quality-adjusted life-years (QALYs) are reported. One-way and probabilistic sensitivity analyses were performed to evaluate parameter uncertainty. In the THR model, the average costs per patient for FXaIs and LMWHs were $18,762 and $18,897, respectively, and the QALYs were 0.938 and 0.932. In the TKR model, the average cost per patient for FXaIs and LMWHs were $18,804 and $18,991, respectively, and the QALYs were 0.935 and 0.931. In both models, FXaIs dominated LMWH (less costly and more efficacious). Neither model was sensitive to changes in any of the variables in the one-way sensitivity analyses. Probabilistic sensitivity analysis indicated that FXaIs were cost-effective in more than 99% of iterations in the THR population and in 98% of iterations in the TKR population assuming a willingness-to-pay threshold of $50,000/QALY. Oral direct FXaIs may be an economically dominant strategy compared with LMWHs for VTE prophylaxis in patients undergoing either THR or TKR surgery.

The impact of postoperative venous thromboembolism (VTE) during initial hospitalization for total hip replacement (THR) or total knee replacement (TKR) surgery was assessed. Using Medicare Provider Analysis and Review files, patients who underwent THR, TKR, or hip fracture surgery from 2005 to 2007 were identified using appropriate procedure codes from the International Classification of Diseases, 9th Revision, Clinical Modification. Medicare managed care patients were excluded from the study. Eligible patients were classified as having had deep venous thrombosis (DVT), pulmonary embolism (PE), DVT and PE, or no VTE during their initial hospitalization. Risk adjustment was performed using propensity score matching. Medicare cost, cost to beneficiaries, and cost to primary payers were analyzed to determine risk-adjusted differences in outcome measures, including mortality, rehospitalization, bleeding, length of stay, and total health care expenditures related to VTE events. A total of 170,047 patients were identified. Postoperative VTE events occurred in 3,014 patients (1.77%) during their initial hospitalization. Risk-adjusted mortality rates were three to four times higher for patients with VTE compared with those without VTE. Patients with VTE were more likely to be rehospitalized and experience bleeding within 30 days. Risk-adjusted differences in annual mean cost, including Medicare cost and costs to beneficiaries and primary payers, were significantly greater for patients with VTE. Patients who developed VTE after THR or TKR had a higher likelihood of mortality, bleeding, and rehospitalization; were hospitalized longer; and incurred higher costs to Medicare, Medicare beneficiaries, and private payers compared with patients without VTE.

This paper presents a summary of the evidence review group (ERG) report into the clinical effectiveness and cost-effectiveness of dabigatran etexilate (DBG) for the prevention of venous thromboembolism (VTE) in patients undergoing elective hip and knee surgery based upon a review of the manufacturer’s submission to the NICE as part of the single technology appraisal (STA) process. The submission’s evidence came from three reasonable-quality trials comparing DBG with enoxaparin, and a comparison of DBG with fondaparinux based on the relative efficacy and safety as derived from a mixed treatment comparison (MTC) meta-analysis. DBG (220 mg and 150 mg once daily) is not inferior to enoxaparin (40 mg once daily and 30 mg twice daily) in terms of major VTE or VTE-related events (secondary outcome). Meta-analysis shows that 220 mg DBG is not inferior to enoxaparin (40 mg once daily or 30 mg twice daily) in reducing total VTE and all-cause mortality (primary outcome) in total hip or knee replacement, whereas there is uncertainty around the clinical effectiveness of 150 mg DBG for this outcome. In the MTC analysis DBG compared favourably with the other interventions, with the exception of extended enoxaparin and fondaparinux. The adverse event profile was not significantly different in those receiving DBG and those receiving enoxaparin. The submitted two-phase economic model compares DBG with enoxaparin and fondaparinux in total hip and knee replacement. The model structure is appropriate and the model assumptions are reasonable. The health states, costs, utilities and recurrence rates used are considered to be appropriate for the required analysis. The model estimated that at the licensed dose of 220 mg once daily DBG dominates enoxaparin in both total hip replacement and total knee replacement and that at the lower dose of 150 mg once daily DBG dominates enoxaparin in total hip replacement and enoxaparin dominates DBG in total knee replacement. DBG is less cost-effective than fondaparinux in total hip replacement at both doses; the cost per quality-adjusted life-year of fondaparinux versus DBG is £11,111 and £6857 for the higher and lower doses of DBG respectively. In total knee replacement, both DBG doses are dominated by fondaparinux. For DBG versus all comparators in all cases the cost-effectiveness results are based on small incremental cost and health benefits. Weaknesses of the submitted evidence include that methods used for screening studies, data extraction and applying quality assessment criteria to included studies, as well as key details of trials included in the MTC, were not adequately described. In addition, some input parameters into the modelling process are incorrect. The ERG was unable to correct all of these mistakes and the impact on the model results is therefore unknown. The National Institute for Health and Clinical Excellence guidance issued as a result of the STA states that DBG is recommended as an option for the primary prevention of VTE events in adults who have undergone elective total hip or knee replacement surgery.

BackgroundVenous thromboembolism (VTE) is an important complication following total hip replacement (THR) and total knee replacement (TKR) surgeries. Aim of this study was to comprehensively compare the clinical outcomes of low-molecular-weight heparin (LMWH) with other anticoagulants in patients who underwent TKR or THR surgery.MethodsMedline, Cochrane, EMBASE, and Google Scholar databases were searched for eligible randomized controlled studies (RCTs) published before June 30, 2017. Meta-analyses of odds ratios were performed along with subgroup and sensitivity analyses.ResultsTwenty-one RCTs were included. In comparison with placebo, LMWH treatment was associated with a lower risk of VTE and deep vein thrombosis (DVT) (P values < 0.001) but similar risk of pulmonary embolism (PE) (P = 0.227) in THR subjects. Compared to factor Xa inhibitors, LMWH treatment was associated with higher risk of VTE in TKR subjects (P < 0.001), and higher DVT risk (P < 0.001) but similar risk of PE and major bleeding in both THR and TKR. The risk of either VTE, DVT, PE, or major bleeding was similar between LMWH and direct thrombin inhibitors in both THR and TKR, but major bleeding was lower with LMWH in patients who underwent THR (P = 0.048).ConclusionIn comparison with factor Xa inhibitors, LMWH may have higher risk of VTE and DVT, whereas compared to direct thrombin inhibitors, LMWH may have lower risk of major bleeding after THR or TKR.

The National Institute for Health and Clinical Excellence (NICE) invited Boehringer Ingelheim GmbH, the manufacturer of dabigatran etexilate (DBG), to submit evidence on the clinical and cost effectiveness of this drug for the primary prevention of venous thromboembolism (VTE) in adult patients who have undergone total hip replacement (THR) or total knee replacement (TKR) surgery, as part of NICE's single technology appraisal process. The comparators were enoxaparin and fondaparinux, as identified in the scope issued by NICE. The School of Health and Related Research at the University of Sheffield was commissioned to act as the Evidence Review Group (ERG). This article provides a description of the company submission, the ERG review and NICE's subsequent decisions. Clinical-effectiveness evidence for DBG versus enoxaparin was derived from two randomized, double-blind, noninferiority trials, one for THR and the other for TKR. Clinical-effectiveness evidence for DBG versus fondaparinux was taken from a mixed treatment comparison (MTC) and from one study. The results presented show that DBG at the licensed dose of 220 mg and 150 mg once daily was noninferior to enoxaparin (40 mg once daily) in terms of the primary efficacy outcome of total VTE and all-cause mortality. In the MTC, fondaparinux was found to be more effective than DBG; the level of statistical significance was not reported. The manufacturer's cost-effectiveness model estimated that at a dose of 220 mg once a day, DBG dominated enoxaparin in both THR and TKR. At a dose of 150 mg daily, DBG dominated enoxaparin in THR, while enoxaparin dominated DBG in TKR. At a dose of 220 mg daily, DBG was less cost effective than fondaparinux in THR. The cost per QALY gained for fondaparinux versus DBG was £11,111 (year 2008 values). At a dose of 150 mg daily, DBG was less cost effective than fondaparinux in THR. The cost per QALY gained for fondaparinux versus DBG was £6857 (year 2008 values). In TKR, both DBG doses were dominated by fondaparinux. There was some evidence that DBG was more cost effective than enoxaparin; however, these results were based on only one trial each in THR and TKR. Fondaparinux appeared to be more cost effective than DBG; however, this was based on indirect comparisons. NICE concluded that although there was uncertainty in the evidence base, DBG was very likely to be of equivalent clinical and cost effectiveness to enoxaparin or fondaparinux in the prevention of VTE. The NICE Appraisal Committee (AC) acknowledged that oral administration of DBG, without the need for monitoring, would reduce administration costs and that it may support adherence to treatment. Therefore, the AC concluded that DBG should be recommended as an option in the circumstances in which enoxaparin (or fondaparinux as an alternative) may be offered.

Total hip replacement (THR) and total knee replacement (TKR) surgery are carried out for the relief of hip or knee pain, usually caused by osteoarthritis. This is the first of two articles on THR and TKR. It will outline the different types of replacement used in lower limb joint replacement surgery. Preparation of patients for surgery requires attention to physical, psychological and social factors and these are explored in detail. The organization of services along the patient pathway to ensure comprehensive preparation is considered and the nursing role highlighted. The second article, to be published in the next issue, will discuss recovery and rehabilitation from THR and TKR surgery.

Recent Advances in Venous Thromboembolic Prophylaxis in Major Orthopedic Surgery: A Regional Perspective

Deep vein thrombosis and pulmonary embolism are collectively called venous thromboembolism (VTE) and are a major cause of morbidity and mortality in the United States and Europe. March is deep vein thrombosis awareness month in the United States, and each year Arteriosclerosis, Thrombosis, and Vascular Biology marks this event with a series of reviews on VTE. This year we have 3 excellent articles on (1) mouse models of venous thrombosis, (2) risk factors for VTE in humans, and (3) the new generation of oral anticoagulants that are available to treat VTE. See accompanying articles on pages 556, 563, and 569 The first review, by Diaz et al1 describes how the use of mouse models has increased our understanding of the mechanisms of initiation, propagation, and resolution of venous clots. The obvious advantage of mice is that we can determine the effect of the loss or mutation of any given gene on thrombosis. Indeed, work with P-selectin knockout mice suggested a role for P-selectin in venous thrombosis that was subsequently confirmed in nonhuman primates. It will be interesting to see whether P-selectin inhibitors will be successfully developed as anticoagulant drugs. Mice have several disadvantages, however, including their small size, their resistance to thrombosis, and the surgical challenges of working with small vessels. Diaz et al1 evaluate 4 inferior vena cava (IVC) thrombosis models. The ferric chloride model induces oxidative damage to the vessel wall that produces an occlusive thrombosis. The advantage of this model is that it is …

BackgroundThere are indications of beneficial short-term effect of pre-operative exercise in reducing pain and improving activity of daily living after total hip replacement (THR) and total knee replacement (TKR) surgery. Though, information from studies conducting longer follow-ups and economic evaluations of exercise prior to THR and TKR is needed. The aim of the study was to analyse 12-month clinical effect and cost-utility of supervised neuromuscular exercise prior to THR and TKR surgery.MethodsThe study was conducted alongside a randomised controlled trial including 165 patients scheduled for standard THR or TKR at a hospital located in a rural area of Denmark. The patients were randomised to replacement surgery with or without an 8-week preoperative supervised neuromuscular exercise program (Clinical Trials registration no.: NCT01003756). Clinical effect was measured with Hip disability and Osteoarthritis Outcome Score (HOOS) and Knee injury and Osteoarthritis Outcome Score (KOOS). Quality adjusted life years (QALYs) were based on EQ-5D-3L and Danish preference weights. Resource use was extracted from national registries and valued using standard tariffs (2012-EUR). Incremental net benefit was analysed to estimate the probability for the intervention being cost effective for a range of threshold values. A health care sector perspective was applied.ResultsHOOS/KOOS quality of life [8.25 (95% CI, 0.42 to 16.10)] and QALYs [0.04 (95% CI, 0.01 to 0.07)] were statistically significantly improved. Effect-sizes ranged between 0.09-0.59 for HOOS/KOOS subscales. Despite including an intervention cost of €326 per patient, there was no difference in total cost between groups [€132 (95% CI −3942 to 3679)]. At a threshold of €40,000, preoperative exercise was found to be cost effective at 84% probability.ConclusionPreoperative supervised neuromuscular exercise for 8 weeks was found to be cost-effective in patients scheduled for THR and TKR surgery at conventional thresholds for willingness to pay. One-year clinical effects were small to moderate and favoured the intervention group, but only statistically significant for quality of life measures.Trial registrationClinicalTrials.gov (NCT01003756) October 28, 2009.

Implant costs associated with total hip replacement and total knee replacement procedures account for a large share of total costs and reimbursements to hospitals. Federal policymakers are promoting episode-of-care payment and other value-based delivery and payment reforms in part to encourage physicians and hospitals to cooperate in managing costs for these and other procedures. The present study quantifies the patient, hospital, and market characteristics associated with variation in implant and total procedure costs for hip and knee arthroplasty. Clinical, demographic, and economic data were collected on 10,155 unilateral primary total knee replacement procedures and 5013 unilateral primary total hip replacement procedures from sixty-one hospitals in 2008. Variation in implant costs per procedure was measured within and across hospitals. Multivariate statistical analyses were used to measure the association between patient and hospital characteristics and implant costs and total procedure costs. The average implant cost per case ranged from $1797 to $12,093 for total knee replacement procedures and from $2392 to $12,651 for total hip replacement procedures. For total knee replacement, 2.5% of total variation in device costs was attributable to patient characteristics and 61.0% was attributable to hospital characteristics; the remaining 36.5% of variance was attributable to within-hospital variation not due to patient or hospital characteristics. For total hip replacement, 4.4% of variance was attributed to patient characteristics, 36.1% was attributed to hospital characteristics, and 59.5% was attributed to within-hospital variation not due to patient or hospital characteristics. There are substantial variations in total hip replacement and total knee replacement implant costs within and across hospitals after controlling for patient diagnoses and comorbidities. This variation is responsible for the majority of variation in the overall cost of total hip and knee replacement surgery.

A Specific Inpatient Aquatic Physiotherapy Program Improves Strength After Total Hip or Knee Replacement Surgery: A Randomized Controlled Trial

To discuss the role of low-molecular-weight heparins (LMWHs) in the prevention of venous thromboembolism (VTE) in medical and orthopedic surgery patients. VTE prophylaxis trials in these practice settings establishing the current use of LMWHs marketed in the US are included. An overview is also provided of VTE incidence, risk factors, and prophylaxis consensus guidelines. Clinical trials, review articles, and meta-analyses for Food and Drug Administration-approved LMWHs were identified from a MEDLINE search (1980-March 2002). Search terms included dalteparin, enoxaparin, internal medicine, low-molecular-weight heparin, orthopedic surgery, risk factors, tinzaparin, and venous thromboembolism. Consensus guidelines are useful as an initial guide to appropriate VTE prophylaxis; however, a review of the primary literature is needed to identify optimal agents, regimens, or interventions. LMWHs have demonstrated sound efficacy in VTE prevention; however, the quantity and quality of literature are not always comparable for the available agents. Enoxaparin has demonstrated efficacy and safety in VTE prevention in medical patients, whereas information is limited or lacking for dalteparin and tinzaparin. Total hip replacement (THR) trials have been conducted with all US-marketed LMWHs and have demonstrated the efficacy and safety of each agent. Trials specifically establishing the efficacy of an LMWH in total knee replacement surgery (TKR) have been published for enoxaparin. One combination THR and TKR trial has been published for tinzaparin. These trial outcomes have positioned the LMWHs as key alternatives to adjusted-dose warfarin for VTE prophylaxis in orthopedic surgery. Inherent differences between LMWHs prevent the extrapolation of clinical outcomes from 1 trial to another.

Venous thromboembolism (VTE) is an important complication of major orthopaedic surgery of the lower limbs. Fondaparinux, a synthetic pentasaccharide and highly selective inhibitor of activated Factor Xa, is the first in a new class of antithrombotic agents. To determine the optimal dose in Japanese patients, double-blind, placebo-controlled, dose-ranging studies of fondaparinux were conducted in patients undergoing total knee replacement (TKR) or total hip replacement (THR) surgery. Patients were randomly assigned to receive a once-daily subcutaneous injection of fondaparinux (0.75, 1.5, 2.5, or 3.0 mg) or placebo in Study 1 (TKR) and Study 2 (THR). In Study 1, the incidence of VTE was 65.3% in the placebo group and was 34.2%, 21.3%, 16.2%, and 9.5% in the groups receiving 0.75, 1.5, 2.5, and 3.0 mg fondaparinux respectively. In Study 2, the incidence of VTE was 33.8% in the placebo group and was 24.2%, 4.6%, 7.4%, and 14.4% in the 0.75, 1.5, 2.5, and 3.0 mg fondaparinux groups respectively. Dose-response effects were observed in both studies; however, no statistically significant differences in major bleeding events were found among any groups. Fondaparinux proved to be a potent anticoagulant with a favourable benefit-to-risk ratio in the prevention of VTE in these study patients.

IntroductionIn 2006, our provincial government initiated a program to reduce wait times for total hip or knee replacements by referring patients to a single tertiary-care centre. This program provided an opportunity to identify risk factors for perioperative complications as part of a continuing quality improvement project. We report the risk of postoperative urinary retention after hip and knee replacements and the risk factors associated with this complication.MethodsAfter local Research Ethics Board approval, data were abstracted from charts of patients who underwent elective primary unilateral total hip or knee replacement surgery. The outcome was urinary retention in the first 24 hr after surgery. Risk factors were identified using multivariable logistic regression, and they were expressed as odds ratios (OR) or 95% confidence intervals (CI).ResultsFrom April 1, 2006 to May 31, 2007, 1,440 patients underwent 1,515 elective total hip replacement or total knee replacement. We abstracted data from 1,031 (71.3%) patients: mean age, 62 yr (interquartile range [IQR] 55-70); 53.7% female; 605 total hip replacements; and 426 total knee replacements. The procedures were performed under spinal (81.8%), general (10.2%), or combined spinal and general (8.0%) anesthesia. Patients spent 100 [IQR 90-114] min in the operating room and 3 [IQR 3-4] days in hospital. The 24-hr incidence of urinary retention was 43.3% (446/1031). Male sex (odds ratio [OR] 3.9; 95% CI 3.0 to 5.2), total hip replacement (OR 1.4; 95% CI 1.1 to 1.9), and intrathecal morphine were risk factors.DiscussionPostoperative urinary retention is a common complication after total hip or total knee replacement, especially amongst men and patients receiving intrathecal morphine.

Dose-escalation study of rivaroxaban (BAY 59-7939) – an oral, direct Factor Xa inhibitor – for the prevention of venous thromboembolism in patients undergoing total hip replacement