The cost-effectiveness of fondaparinux compared with enoxaparin as prophylaxis against thromboembolism following major orthopedic surgery

Summary.  Background : The selective antithrombotic fondaparinux is more effective than the low-molecular-weight heparin enoxaparin for prevention of venous thromboembolism (deep-vein thrombosis [DVT] or pulmonary embolism) in patients undergoing major orthopedic surgery, but its cost-effectiveness is undetermined. Objectives : To evaluate the cost-effectiveness of fondaparinux relative to enoxaparin as prophylaxis against venous thromboembolism (VTE) for patients undergoing total hip replacement, total knee replacement or hip fracture surgery in the UK. Patients/methods : A decision analysis model was created simulating the impact of fondaparinux and enoxaparin on patient outcomes and costs over various time points up to 5 years following surgery. The main outcome measures were treatment costs per patient and the incidence of clinical VTE and VTE-related deaths. A weighted (combined) cohort reflects the proportion of patients undergoing these procedures in 2000/2001. Results : In the combined cohort, compared with enoxaparin, fondaparinux is expected to produce 20 fewer clinical VTE events and 3.2 fewer VTE-related deaths per 1000 procedures at 5 years. Cost savings at 5 years are £27 per patient with fondaparinux (discounted at 6% per year). In each of the three surgical groups, fondaparinux leads to lower expected costs per patient and to a smaller number of VTE events and VTE-related deaths. Results are sensitive to the price difference between fondaparinux and enoxaparin and variation in the rate of late DVT. The analysis is robust to variations in all other key parameters. Conclusions : Compared with enoxaparin, fondaparinux is more effective and reduces costs to the healthcare system. At current prices, fondaparinux is the recommended strategy in the UK for prophylaxis following major orthopedic surgery.     

Fondaparinux: a new antithrombotic agent

BACKGROUND: Venous thrombosis is usually triggered by a low-flow state, as in prolonged periods of bed rest after hip or knee surgery. Antithrombotic agents are the drugs of choice in such circumstances. The new factor Xa inhibitor fondaparinux has been approved by the US Food and Drug Administration for the prevention of venous thromboembolism in patients undergoing hip fracture surgery, hip replacement surgery, or knee replacement surgery. OBJECTIVE: The aim of this article was to review the clinical pharmacology of fondaparinux and summarize the data from available clinical trials of this agent. METHODS: The terms fondaparinux, SR90107A/ORG31540, and factor Xa were used to search MEDLINE and Current Contents/Clinical Medicine for English-language studies in humans published between 1996 and May 2002. Unpublished data were provided by the manufacturer of fondaparinux, and additional information was obtained from abstracts presented at the 2001 congress of the International Society on Thrombosis and Haemostasis in Paris. RESULTS: Fondaparinux is a synthetic pentasaccharide that selectively binds to antithrombin III, inducing a conformational change that increases anti-factor Xa activity. Phase III studies to date have reported that fondaparinux had greater efficacy compared with enoxaparin in terms of prevention of venous thromboembolism after hip or knee replacement surgery. Preliminary studies have suggested that this agent may have efficacy in the treatment of deep vein thrombosis, as well as in the management of acute coronary syndromes. However, 1 study reported a significant increase in the risk of major bleeding with fondaparinux compared with enoxaparin (2.1% vs 0.2%, respectively; P = 0.006), and another reported a significant increase in the risk of minor bleeding (4.1% vs 2.1%; P = 0.02). CONCLUSIONS: Fondaparinux has shown efficacy in the prevention of venous thromboembolism in patients undergoing hip or knee replacement surgery. Large-scale clinical trials of its potential efficacy in deep vein thrombosis and acute coronary syndromes are ongoing. Use of fondaparinux may be associated with an increased bleeding risk, and patients should be assessed individually to ensure that the possible benefits outweigh the risks. Routine use of fondaparinux as a replacement for low-molecular-weight heparin is not recommended at this time.     

Prevention of venous thromboembolism in the orthopedic surgery patient

Patients undergoing major orthopedic surgery--hip or knee arthroplasty, or hip fracture repair--are in the highest risk category for venous thromboembolism (VTE) solely on the basis of the orthopedic procedure itself. Despite this, nearly half of patients undergoing these procedures do not receive appropriate prophylaxis against VTE, often due to a disproportionate fear of bleeding complications in this population. Guidelines from the American College of Chest Physicians (ACCP) provide evidence-based recommendations for many aspects of VTE risk reduction in the setting of orthopedic surgery, as detailed in this review. The ACCP recommends the use of either low-molecular-weight heparin (LMWH), fondaparinux, or adjusted-dose warfarin as preferred VTE prophylaxis in patients undergoing either hip or knee arthroplasty. Fondaparinux is the preferred recommendation for patients undergoing hip fracture repair, followed by LMWH, unfractionated heparin, and adjusted-dose warfarin as alternative options. Extended-duration prophylaxis (for 4 to 5 weeks) is now recommended for patients undergoing hip arthroplasty or hip fracture repair. Patients undergoing knee arthroscopy do not require routine pharmacologic VTE prophylaxis.     

Venous thromboembolism prevention with LMWHs in medical and orthopedic surgery patients

OBJECTIVE: 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. DATA SOURCES AND STUDY SELECTION: 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. DATA SYNTHESIS: 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. CONCLUSIONS: 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.     

Recombinant factor VIIa reverses the in vitro and ex vivo anticoagulant and profibrinolytic effects of fondaparinux

Summary.  Background : Fondaparinux is a synthetic pentasaccharide, which selectively inhibits coagulation factor (F) Xa, and is registered for prevention of venous thromboembolism following hip fracture, hip replacement, and knee replacement surgery. Recently, it was shown that recombinant FVIIa (rFVIIa) reverses anticoagulant effects of fondaparinux in healthy volunteers. Objectives : In this study, we have explored the in vitro and ex vivo effects of rFVIIa on clot formation and thrombin-activatable fibrinolysis inhibitor (TAFI)-mediated down-regulation of fibrinolysis after fondaparinux administration. Methods :  In vitro clot lysis assays were performed in pooled normal plasma from healthy volunteers to which fondaparinux was added, and in serial samples from healthy volunteers who received a single bolus dose of fondaparinux, a single bolus dose of rFVIIa, or both. Results and conclusions : Fondaparinux significantly delayed clot formation, and clot lysis was significantly increased due to decreased activation of TAFI. Addition of recombinant FVIIa corrected the inhibited clot formation induced by fondaparinux, and the acceleration of clot lysis was partially reversed. In vivo administration of fondaparinux (10 mg) to healthy volunteers similarly resulted in accelerated plasma clot lysis. Subsequent administration of rFVIIa (90 µg kg⁻¹) normalized the clot lysis time up to 6 h postadministration. rFVIIa might be a good therapeutic option in patients treated with fondaparinux who develop bleeding complications, since both clot formation as well as fibrinolytic resistance are improved.     

Efficacy and safety of rivaroxaban or fondaparinux thromboprophylaxis in major orthopedic surgery: findings from the ORTHO‐TEP registry

Summary. Background: Thromboprophylaxis with rivaroxaban (R) is superior to enoxaparin in patients undergoing major orthopedic surgery (MOS). However, rivaroxaban has never been directly compared with fondaparinux (F), which also shows superior efficacy over enoxaparin. The clinical impact of switching from fondaparinux to rivaroxaban thromboprophylaxis is unclear. Objectives: To evaluate the efficacy and safety of rivaroxaban or fondaparinux thromboprophylaxis in unselected patients undergoing MOS. Patients/Methods: This is a monocentric, retrospective cohort study in 5061 consecutive patients undergoing MOS at our centre, comparing rates of symptomatic VTE, bleeding and surgical complications, length of hospital stay and risk factors for VTE. Results: Rates of symptomatic VTE were 5.6% (F) and 2.1% (R; P < 0.001), with rates for distal DVT being 3.9 vs. 1.1% (P < 0.001). Rates of major VTE were numerically higher with fondaparinux (1.8 vs. 1.1%), but not statistically significant. Rates of severe bleeding (bleeding leading to surgical revision or death, occurring in a critical site, or transfusion of at least two units of packed red blood cells) were statistically lower with rivaroxaban compared with fondaparinux (2.9 vs. 4.9%; P = 0.010). The mean length of hospital stay was significantly shorter in the rivaroxaban group (8.3 days, 95% CI 8.1–8.5 vs. 9.3 days, 9.1–9.5; P < 0.001). Conclusion: Based on an indirect comparison of two consecutive cohorts, our data suggest that thromboprophylaxis with rivaroxaban is associated with less VTE and bleeding events than fondaparinux in unselected patients undergoing MOS. Prospective comparisons are warranted to confirm our findings.     

Results of an economic model to assess the cost-effectiveness of enoxaparin,a low-molecular-weight heparin,versus warfarin for the prophylaxis of deep vein thrombosis and associated long-term complications in total hip replacement surgery in the United States

BACKGROUND: Premature death due to pulmonary embolism is a short-term complication of deep vein thrombosis (DVT). The long-term clinical course after DVT can be further complicated by excess mortality, recurrent venous thromboembolism (VTE), and the post-thrombotic syndrome (PTS), which may produce sizable long-term economic burdens. OBJECTIVE: The goal of this study was to determine the cost-effectiveness of the low-molecular-weight heparin (LMWH) enoxaparin versus warfarin for the universal prophylaxis of DVT and associated long-term complications in US patients undergoing total hip replacement surgery (THRS). METHODS: A model was constructed to assess the long-term cost-effectiveness of the 2 treatments. Patients undergoing THRS were exposed to a short-term risk of developing a DVT. Patients surviving a DVT were exposed to increased risk of long-term complications of DVT, including PTS, recurrent VTE, and increased mortality. Published literature, augmented by expert opinion, served as input for the model's resource use and costs for DVT prophylaxis, clinical diagnosis, and treatment of DVT, VTE, and PTS. RESULTS: When the analysis included only the short-term consequences of DVT, therapy with enoxaparin resulted in a net cost of $133 per patient and a net increase of 0.04 quality-adjusted life-years (QALYs) per patient. Thromboprophylaxis with enoxaparin versus warfarin resulted in $3733 per QALY saved. In contrast, when the long-term consequences of DVT were included, enoxaparin resulted in net lifetime savings of $89 per patient and net QALY benefits of 0.16 per patient. CONCLUSIONS: To the best of our knowledge, this is the first US economic analysis comparing DVT prophylaxis with the LMWH enoxaparin versus warfarin that included the long-term complications of DVT. Our model suggests that use of enoxaparin in patients undergoing THRS reduces the economic burden associated with these long-term complications.     

Fondaparinux: an overview

Fondaparinux is a synthetic pentasaccharide belonging to a new group of anticoagulants that inhibit thrombin formation by inhibiting Factor Xa, which is located at the crossing of both the intrinsic and extrinsic pathways. It has a favorable pharmacokinetic profile, and its effect is predictable and the drug does not need platelet monitoring. Current evidence suggest that fondaparinux is as effective as, if not more than, enoxaparin in the prevention of venous thromboembolism in the postoperative period. It has also been found to have similar effectiveness to enoxaparin and unfractionated heparin in the treatment of venous and pulmonary embolism, respectively. In the field of cardiology, studies have demonstrated that in the setting of acute coronary syndromes, treatment with fondaparinux is not inferior to enoxaparin in preventing major cardiac outcomes, but it is associated with lower risk of bleeding complications, irrespective of the use of percutaneous coronary intervention. During percutaneous coronary intervention, there is a slightly increased risk of catheter thrombosis, which is removed when used along with unfractionated heparin. However, in patients with ST-elevation myocardial infarction, the benefit has been shown in those either receiving thrombolysis or not undergoing any revascularization, but not in subjects undergoing primary percutaneous coronary intervention where unfractionated heparin is still preferred.     

AVE5026, a new hemisynthetic ultra-low-molecular-weight heparin for the prevention of venous thromboembolism in patients after total knee replacement surgery – TREK: a dose-ranging study

Summary.  Background: AVE5026 is a new hemisynthetic ultra-low-molecular-weight heparin, with a novel anti-thrombotic profile resulting from high anti-factor (F)Xa activity and residual anti-FIIa activity. AVE5026 is in clinical development for venous thromboembolism (VTE) prevention, a frequent complication after total knee replacement (TKR) surgery. Objectives: This study evaluated the dose-response of AVE5026 for the prevention of VTE in patients undergoing TKR surgery. Patients/methods: In this parallel-group, double-blind, double-dummy study, 690 patients were randomized, and 678 treated with once-daily doses of AVE5026 (5, 10, 20, 40, or 60 mg) or enoxaparin 40 mg in the calibrator arm. The primary efficacy end point was VTE until post-operative day 11, defined as deep vein thrombosis (DVT) detected by bilateral venography, symptomatic DVT, non-fatal pulmonary embolism (PE) and VTE-related death. The primary safety outcome was the incidence of major bleeding. Results: The primary efficacy outcome was assessed in 464 patients. There was a significant dose-response across the five AVE5026 groups for VTE prevention ( P  <   0.0001), with the incidence of VTE ranging from 5.3% to 44.1% compared with 35.8% in the enoxaparin group and for proximal DVT ( P  =   0.0002). Also, a significant dose-response for AVE5026 was seen for major bleeding ( P  =   0.0231) and any bleeding ( P  =   0.0003). Six patients in the AVE5026 groups, four in the 60 mg group, experienced major bleeding; none did in the enoxaparin group. Conclusions: The safety and efficacy results of this study suggest that a AVE5026 dose of between 20 and 40 mg presents an adequate benefit-to-risk ratio.     

A cost analysis of fondaparinux versus enoxaparin in total knee arthroplasty

Several hundred thousand total knee replacement (TKR) surgeries are performed in the United States each year. The American College of Chest Physicians has classified TKR patients in the "highest-risk" category for developing venous thromboembolic events. Recommended prophylactic agents following TKR surgery include unfractionated heparin and low-molecular weight heparins. Fondaparinux is a selective inhibitor of factor Xa and has recently received approval for the prophylaxis of venous thromboembolism in TKR patients. In November 2001, an efficacy study comparing fondaparinux with enoxaparin as deep vein thrombosis prophylaxis in TKR surgery was published by Bauer et al. The purpose of the current study was to perform an incremental cost analysis for fondaparinux versus enoxaparin using the efficacy and safety data of the Bauer et al study. Specific comparisons evaluated included cost per venous thromboembolic event avoided, cost per death averted, and cost per life-year gained with fondaparinux and enoxaparin. All analyses were performed from an institutional perspective and projected to 1000 patients. The incremental cost analysis indicates an USD $1081.33 cost savings with fondaparinux over enoxaparin per venous thromboembolic event avoided. Cost per death averted in the enoxaparin group is USD $88,943.54; cost per death averted in the fondaparinux groups is USD $81,157.94. Cost per life-year gained of USD $5437 for enoxaparin and USD $4925 for fondaparinux.     

Semuloparin for prevention of venous thromboembolism after major orthopedic surgery: results from three randomized clinical trials,SAVE‐HIP1, SAVE‐HIP2 and SAVE‐KNEE

Background:  Semuloparin is a novel ultra‐low‐molecular‐weight heparin under development for venous thromboembolism (VTE) prevention in patients at increased risk, such as surgical and cancer patients. Objectives:  Three Phase III studies compared semuloparin and enoxaparin after major orthopedic surgery: elective knee replacement (SAVE‐KNEE), elective hip replacement (SAVE‐HIP1) and hip fracture surgery (SAVE‐HIP2). Patients/Methods:  All studies were multinational, randomized and double‐blind. Semuloparin and enoxaparin were administered for 7–10 days after surgery. Mandatory bilateral venography was to be performed between days 7 and 11. The primary efficacy endpoint was a composite of any deep vein thrombosis, non‐fatal pulmonary embolism or all‐cause death. Safety outcomes included major bleeding, clinically relevant non‐major (CRNM) bleeding, and any clinically relevant bleeding (major bleeding plus CRNM). Results:  In total, 1150, 2326 and 1003 patients were randomized in SAVE‐KNEE, SAVE‐HIP1 and SAVE‐HIP2, respectively. In all studies, the incidences of the primary efficacy endpoint were numerically lower in the semuloparin group vs. the enoxaparin group, but the difference was statistically significant only in SAVE‐HIP1. In SAVE‐HIP1, clinically relevant bleeding and major bleeding were significantly lower in the semuloparin vs. the enoxaparin group. In SAVE‐KNEE and SAVE‐HIP2, clinically relevant bleeding tended to be higher in the semuloparin group, but rates of major bleeding were similar in the two groups. Other safety parameters were generally similar between treatment groups. Conclusions:  Semuloparin was superior to enoxaparin for VTE prevention after hip replacement surgery, but failed to demonstrate superiority after knee replacement surgery and hip fracture surgery. Semuloparin and enoxaparin exhibited generally similar safety profiles.     

The direct thrombin inhibitor melagatran followed by oral ximelagatran compared with enoxaparin for the prevention of venous thromboembolism after total hip or knee replacement: the EXPRESS study

Summary.  Background : Ximelagatran and its subcutaneous (s.c.) form melagatran are novel direct thrombin inhibitors for the prevention and treatment of thromboembolic disease. Methods : In a double-blind study, 2835 consecutive patients undergoing total hip or knee replacement were randomized to either melagatran/ximelagatran or enoxaparin. Melagatran 2 mg was started immediately before surgery; 3 mg was then administered postoperatively, followed by 24 mg of oral ximelagatran b.i.d. beginning the next day. Enoxaparin 40 mg, administered subcutaneously o.d., was started 12 h before surgery. Both treatments were continued for 8–11 days. The main efficacy outcome measures were major venous thromboembolism (VTE); [proximal deep vein thrombosis (DVT), non-fatal and/or fatal pulmonary embolism (PE), death where PE could not be ruled out], and total VTE (proximal and distal DVT; PE; death from all causes). DVT was detected by mandatory bilateral ascending venography at the end of the treatment period or earlier if clinically suspected. The main safety outcome was bleeding. Results : The rates of major and total VTE were significantly lower in the melagatran/ximelagatran group compared with the enoxaparin group (2.3% vs. 6.3%, P  = 0.0000018; and 20.3% vs. 26.6%, P  < 0.0004, respectively). Fatal bleeding, critical site bleeding and bleeding requiring reoperation did not differ between the two groups. 'Excessive bleeding as judged by the investigator' was more frequent with melagatran/ximelagatran than with enoxaparin. Conclusions : In patients undergoing total hip or knee replacement, preoperatively initiated s.c. melagatran followed by oral ximelagatran was significantly more effective in preventing VTE than preoperatively initiated s.c. enoxaparin.     

Prevention of venous thromboembolism with an oral factor Xa inhibitor,YM150, after total hip arthroplasty. A dose finding study (ONYX‐2)

Background: Anticoagulant prophylaxis substantially reduces the risk of venous thromboembolism (VTE) after major orthopedic surgery. The direct factor Xa inhibitor YM150 is currently under investigation for the prevention of VTE, stroke and ischemic vascular events in patients after orthopedic surgery, with atrial fibrillation and with acute coronary syndrome, respectively. Objectives: To investigate the efficacy and safety of YM150 for the prevention of VTE following elective total hip arthroplasty. Patients/methods: Patients were randomized to postoperative, once‐daily, oral YM150 (5, 10, 30, 60 or 120 mg) (double‐blind) or preoperative subcutaneous (open label) enoxaparin (40 mg) for 5 weeks. The primary efficacy endpoint comprised VTE diagnosed by mandatory bilateral venography or verified symptomatic deep vein thrombosis (DVT) plus all deaths up to 9 days after surgery. The primary safety outcome was major bleeding up to 9 days after surgery. Results: Primary efficacy endpoint: of 1017 patients randomized, 960 patients were evaluable for safety and 729 patients for efficacy. A dose‐related decrease in VTE incidence from YM150 5 to 60 mg (P = 0.0005) and from 5 to120 mg (P = 0.0002) was found. The VTE incidence was 27.4%, 31.7%, 19.3%, 13.3% and 14.5% for 5, 10, 30, 60 and 120 mg YM150, respectively, and 18.9% for enoxaparin. Primary safety endpoint: there was one major bleed with YM150 (60 mg) and one with enoxaparin. Conclusions: The oral direct FXa inhibitor YM150 demonstrated a significant dose response regarding efficacy. Doses from 30 to 120 mg had comparable efficacy to enoxaparin, without compromising safety regarding major bleeding events.     

Meta-analysis of venous thromboembolism prophylaxis in medically Ill patients

BACKGROUND: Venous thromboembolism (VTE) prophylaxis in medically ill patients has received a level 1A recommendation in previously published clinical guidelines. Pharmacologic prophylaxis for VTE includes unfractionated heparin (UFH), low-molecular-weight heparin (LMWH), and fondaparinux. Few direct comparisons between anticoagulants exist in medically ill patients. OBJECTIVE: This meta-analysis was conducted to assess UFH and LMWH (including the selective factor Xa inhibitor fondaparinux) in the reduction of in-hospital VTE in unselected medically ill patients. METHODS: We searched MEDLINE, EMBASE, and the Cochrane Controlled Trials Registry databases from January 1981 through September 2007 (English language) for randomized controlled trials using the following terms: dalteparin, enoxaparin, fondaparinux, nadroparin, and heparin. References of included articles and key review papers for additional studies were also searched. Data from studies were included in the analysis if the studies included medically ill patients with risk factors for VTE who had been followed up for 7 to 21 days. RESULTS: A total of 12,391 patients (of whom 8357 were in placebo-controlled trials) from 9 studies were included. Mean age for the entire cohort was 72.8 years; mean (SD) body mass index, 25.6 kg/m2; and mean (SD) actual body weight, 68.2 kg. Deep vein thrombosis (DVT) was significantly reduced with the addition of an LMWH compared with placebo (odds ratio [OR], 0.60; 95% CI, 0.47-0.75; P < or = 0.001), but rates of DVT were similar when comparing LMWH with UFH (OR, 0.92; 95% CI, 0.56-1.52). No significant differences in pulmonary embolism (PE) or death were found among the UFH, LMWH, and placebo groups. LMWH was associated with a significant increased risk for minor bleeding compared with placebo (OR, 1.64; 95% CI, 1.18-2.29; P = 0.003). However, no significant difference was found between LMWH and UFH (OR, 0.68; 95% CI, 0.27-1.70). Major bleeding events were similar among all groups: LMWH/fondaparinux versus placebo, OR, 1.65 (95% CI, 0.8-3.4); LMWH/fondaparinux versus UFH, OR, 0.69 (95% CI, 0.29-1.68); LMWH/fondaparinux versus UFH or placebo, OR, 1.16 (95% CI, 0.66-2.04). CONCLUSIONS: This analysis suggests that VTE prophylaxis with an LMWH (including fondaparinux) or UFH is effective in reducing the rate of DVT, but this benefit did not extend to enhanced protection against PE. Additionally, LMWH and UFH had similar bleeding outcomes.     

Fondaparinux (Arixtra): a new anticoagulant

Fondaparinux is a promising new antithrombotic agent. This pentasaccharide selectively and specifically inhibits coagulation factor Xa, and requires antithrombin as co-factor It is entirely synthetic, in contrast to conventional heparin and low molecular heparins which are derived from animal tissues. Fondaparinux exhibits a high bioavailability and is convenient to use as it only needs to be given once daily by subcutaneous injection. Peak plasma levels are achieved within two hours of dosing and the plasma half-life of fondaparinux is approximately 17 hours. There is no specific antidote for fondaparinux: it is not neutralised by protamine sulphate. Fondaparinux shows no cross-reactivity with antibodies associated with heparin-induced thrombocytopenia. Several randomised, double-blind studies have demonstrated superiority with respect to a low molecular weight heparin (enoxaparin) in preventing venous thromboembolism in the setting of orthopaedic surgery. The results of clinical trials of fondaparinux in the treatment of deep vein thrombosis and acute coronary syndrome are also presented.     

利伐沙班与依诺肝素预防髋关节置换术后下肢深静脉血栓形成的对照研究

目的比较利伐沙班与依诺肝素预防股骨颈骨折人工全髋关节置换术后下肢深静脉血栓形成（DVT）的有效性及安全性。方法选取本院2012年7月至2013年7月收治的105例股骨颈骨折行人工全髋关节置换术的老年患者为研究对象,经患者及家属知情同意用药方案,将以上患者分为利伐沙班组和依诺肝素组。通过观察两组患者术后静脉血栓栓塞症（VTE）的相关临床症状及体征,行血管彩超及 CTA检查诊断统计 DVT和肺栓塞（PE）例数,评价其有效性。统计两组患者出血事件、额外输血率评价其安全性。结果两组患者均没有出现PE,均无出现大出血事件。而DVT的发生率,一般出血事件发生率,额外输血率,两组比较差异均无统计学意义（P ＞0.05）。结论利伐沙班对比依诺肝素,对老年股骨颈骨折患者行人工全髋关节置换术后预防 VTE 发生具有同样良好的效果,并且未增加出血风险。     

Impact of stage 3B chronic kidney disease on thrombosis and bleeding outcomes after orthopedic surgery in patients treated with desirudin or enoxaparin: insights from a randomized trial

Summary. Background: Venous thromboembolism (VTE) remains a significant complication of major orthopedic surgery, and chronic kidney disease (CKD) is common among elderly patients undergoing total hip replacement (THR). Objectives: The purpose of this study was to evaluate thrombosis and bleeding outcomes in patients with stage 3B CKD treated with either desirudin or enoxaparin after elective THR. Patients/Methods: This was a post hoc subgroup analysis of a randomized, multicenter, double‐blind study of desirudin vs. enoxaparin in patients undergoing elective THR. Results: Patients received either subcutaneous desirudin 15 mg twice daily or subcutaneous enoxaparin 40 mg once daily. Of the 2078 randomized patients who received study medication, 577 had stage 3B CKD or worse (27.8%), and the proportion of these patients who experienced a major VTE in the enoxaparin treatment group was found to be much higher than in the desirudin treatment group (11.1% vs. 3.4%, model‐adjusted odds ratio 3.52, 95% confidence interval 1.48–8.40, P = 0.004). There was no statistically significant difference between treatment groups in terms of rates of major bleeding, regardless of stage of renal function. Conclusions: CKD has been reported previously to increase the risk of bleeding with anticoagulants, and these findings suggest that CKD may also increase the risk of major VTE for patients treated with enoxaparin, but not for patients treated with desirudin. Clinicians should consider the impact of CKD on the risk of VTE when choosing a prophylaxis agent.     

Current perspectives on the treatment of venous thromboembolism: need for effective, safe and convenient new antithrombotic drugs

Treatment of venous thromboembolism (VTE) has evolved significantly over the last decade. Low-molecular-weight heparins have largely replaced unfractionated heparin in the treatment of deep-vein thrombosis (DVT) but the majority of patients with pulmonary embolism (PE) continue to be treated with unfractionated heparin. Fondaparinux is the first synthetic selective inhibitor of factor Xa. It has recently been proved to be more effective than, and as safe as, a low-molecular-weight heparin for the prevention of VTE after major orthopaedic surgery. The two large randomised MATISSE trials demonstrated that fondaparinux was at least as effective and as safe as previous reference heparin therapies in the treatment of VTE. Fondaparinux should further simplify the treatment of this frequent disease since a single once-daily fixed dosage regimen may effectively and safely treat both DVT and PE, an important point especially considering the frequent though clinically silent concomitance of these two thrombotic events.     

Challenges in the prevention of venous thromboembolism in the elderly

Aging itself is a risk factor for venous thromboembolism, and the prevalence in the elderly of additional risk factors (e.g. cancer, orthopedic surgery, immobility) increase its intrinsic risk. Many in the medical community are reluctant to prescribe anticoagulation (for primary and secondary prevention of venous thromboembolism) to their geriatric patients for the fear that bleeding complications may outweigh the benefits. A thorough analysis of the data support the concept that the under-use of heparin in primary prevention in the elderly is more related to medical beliefs than to facts. The risk of bleeding due to oral anticoagulants (secondary prevention) is greatly reduced by keeping the International Normalized Ratio (INR) values within therapeutic ranges and carefully avoiding conditions/drugs that may interfere with such treatment. The oral direct thrombin inhibitor ximelagatran has been studied for primary (hip and knee replacement surgery) and for secondary prophylaxis of venous thromboembolism, and for acute venous thromboembolism treatment. The selective factor Xa inhibitor fondaparinux has been approved for primary prophylaxis of venous thromboembolism in hip and knee replacement surgery and in hip fracture surgery. Studies on the latter drugs, where most of the patients were > 65 years of age, further show that the fear of bleeding complications due to anticoagulation in the elderly is largely unjustified.     

Apixaban: an Oral Direct Factor-Xa Inhibitor

Apixaban is a highly selective, reversible, direct factor Xa inhibitor that inhibits both free factor Xa and prothrombinase activity, and clot-bound factor Xa activity. A predictable pharmacokinetic profile, multiple pathways of elimination, an improved bleeding profile relative to warfarin with a lack of other significant adverse events, and no need for routine anticoagulation monitoring make apixaban appealing. Apixaban is currently approved for venous thromboembolism (VTE) prophylaxis in total hip replacement and total knee replacement in Europe, Brazil, Australia, and New Zealand, and has been pre-approved in Indonesia and the Philippines. Completed phase 3 trials suggest that apixaban has promise as an alternative to aspirin and warfarin for prevention of stroke and systemic embolism in patients with atrial fibrillation. Results of a large phase 3 trial were the first to show a survival benefit for this new class of oral anticoagulants in patients with atrial fibrillation. In patients with acute coronary syndrome, apixaban added to dual antiplatelet therapy with aspirin and clopidogrel resulted in unacceptably high rates of major bleeding. In medically ill patients, an extended course of thromboprophylaxis with apixaban was not superior to a shorter course with enoxaparin, and was associated with significantly more major bleeding events than enoxaparin. Ongoing phase 3 trials will provide data regarding the efficacy and safety of apixaban for treatment of acute deep vein thrombosis and pulmonary embolism.