Introduction: The standard length of hospital stay after total hip arthroplasty (THA) can be as short as 4 days. However, the risk of venous thromboembolism (VTE) extends beyond this period of hospitalization. A pooled analysis of the RECORD1 and RECORD2 studies evaluated the efficacy, safety, and timing of events with rivaroxaban compared with enoxaparin for the prevention of VTE after THA.

Methods: Patients (N=7,050) were randomized to receive oral rivaroxaban 10 mg once daily starting postoperatively (for 31–39 days) or subcutaneous enoxaparin 40 mg once daily starting preoperatively (for 31–39 days in RECORD1, and 10–14 days followed by placebo in RECORD2). The primary efficacy endpoint was the composite of symptomatic VTE and all-cause mortality. The safety endpoints were treatment-emergent major bleeding, major bleeding including surgical-site bleeding, major bleeding plus clinically relevant non-major (CRNM) bleeding, and any bleeding. The primary efficacy endpoint was assessed during treatment. The incidence and timing of the safety endpoints were assessed after the first dose of study medication and up to 2 days after the last dose.

Results: Rivaroxaban significantly reduced the incidence of symptomatic VTE and all-cause mortality compared with enoxaparin regimens (0.44% vs 1.01%, respectively; p=0.006), with no significant differences in major bleeding (0.2% vs 0.09%; p=0.219) or the composite of major plus CRNM bleeding (3.23% vs 2.61%; p=0.141). Of the symptomatic VTE and all-cause mortality events, 73% and 86% occurred after day 4 with the rivaroxaban and enoxaparin regimens, respectively. For the composite of major plus CRNM bleeding, 48% and 33% of events occurred after day 4 with the rivaroxaban and enoxaparin regimens, respectively.

Conclusion: Rivaroxaban significantly reduced symptomatic VTE and all-cause mortality after THA compared with the enoxaparin regimens, with no significant difference in bleeding events. Major plus CRNM bleeding was more likely to occur earlier than day 4, whereas the majority of symptomatic venous thromboembolic events occurred after day 4. These results highlight the relevance of extended duration of thromboprophylaxis after THA as most VTE events occur post-discharge.

Introduction: The risk of venous thromboembolism (VTE) remains a major concern beyond the standard period of hospitalization of about 4 days after total knee arthroplasty (TKA). A pooled analysis of the RECORD3 and RECORD4 studies evaluated the efficacy, safety, and timing of events with rivaroxaban compared with enoxaparin for the prevention of VTE after TKA.

Methods: Patients (N=5,679) were randomized to receive oral rivaroxaban 10 mg once daily starting postoperatively or subcutaneous enoxaparin 40 mg once daily starting preoperatively (European Union regimen; RECORD3) or enoxaparin 30 mg every 12 hours starting postoperatively (North American regimen; RECORD4) for 10–14 days. The primary efficacy endpoint was the composite of symptomatic VTE and all-cause mortality, and this was analyzed over the treatment period. The safety endpoints were treatment-emergent major bleeding, major bleeding including surgical-site bleeding, major bleeding plus clinically relevant non-major (CRNM) bleeding, and any bleeding. The incidence and timing of the safety endpoints were assessed after the first dose of study medication and up to 2 days after the last dose.

Results: Rivaroxaban significantly reduced symptomatic VTE and all-cause mortality compared with enoxaparin regimens (0.73% vs 1.71%, respectively; p=0.001) with no significant differences in major bleeding (0.62% vs 0.36%, p=0.185) or composite of major plus CRNM bleeding (3.13% vs 2.48%, p=0.145). The majority of venous thromboembolic events occurred after day 4 for both regimens (rivaroxaban: 70%; enoxaparin: 68%). For the composite of major plus CRNM bleeding events, 44% occurred after day 4 with rivaroxaban regimens and 38% occurred after day 4 with enoxaparin regimens.

Conclusion: Rivaroxaban significantly reduced symptomatic VTE and all-cause mortality compared with enoxaparin regimens after TKA, with no significant difference in bleeding events between regimens. Major plus CRNM bleeding was more likely to occur before day 4, whereas the majority of symptomatic venous thromboembolic events occurred after day 4. These results highlight the importance of continuing thromboprophylaxis beyond the normal time of hospital discharge for TKA.

RECORD3 was a multicentre, phase III study designed to investigate the efficacy and safety of rivaroxaban – a novel, oral, once-daily, direct Factor Xa inhibitor – compared with subcutaneous enoxaparin for thromboprophylaxis in patients undergoing total knee arthroplasty (TKA).

Patients scheduled to undergo TKA (N=2,531) were randomized to receive either rivaroxaban 10 mg once daily (initiated 6–8 hours after surgery) or enoxaparin 40 mg once daily (initiated the evening before surgery, then given 6–8 hours after surgery), and daily thereafter for 10–14 days.

The primary efficacy outcome was the composite of any deep vein thrombosis (DVT; symptomatic or asymptomatic detected by mandatory, bilateral venography), non-fatal pulmonary embolism (PE) and all-cause mortality within 13–17 days after surgery.

Rivaroxaban significantly reduced the incidence of the primary efficacy outcome compared with enoxaparin (9.6% vs 18.9%, respectively; p< 0.001; relative risk reduction [RRR] 49%). Rivaroxaban significantly reduced the incidence of major VTE (the composite of proximal DVT, non-fatal PE and VTE-related death) compared with enoxaparin (1.0% vs 2.6%, p=0.01; RRR 62%), and the incidence of symptomatic VTE (0.7% vs 2.0%, p=0.005; RRR 66%). The incidence of bleeding events was similar in both groups (major bleeding: 0.6% and 0.5% in the rivaroxaban and enoxaparin groups, respectively; any on-treatment bleeding: 4.9% and 4.8%, respectively; haemorrhagic wound complications [the composite of excessive wound haematoma and surgical-site bleeding]: 2.0% and 1.9%, respectively). There were no deaths or PEs in the rivaroxaban group during the treatment period, and two deaths and four PEs in the enoxaparin group.

Rivaroxaban was significantly more effective than enoxaparin for the prevention of VTE after TKA, with a similar rate of bleeding. The oral, direct Factor Xa inhibitor rivaroxaban, given once daily as a fixed, unmonitored dose of 10 mg, has the potential to change clinical practice for thromboprophylaxis after TKA.

Introduction: Four randomized, double-blind, phase III studies (RECORD1–4) investigated the oral, direct Factor Xa inhibitor rivaroxaban for the prevention of venous thromboembolism (VTE) after major orthopaedic surgery. Patients (N=12,729) were randomized to receive oral rivaroxaban 10 mg once daily or subcutaneous enoxaparin 40 mg once daily (RECORD1–3), or 30 mg twice daily (RECORD4). In RECORD1 and 2, patients undergoing total hip arthroplasty received rivaroxaban for 31–39 days. Enoxaparin was given for 31–39 days in RECORD1, 10–14 days followed by placebo in RECORD2. In RECORD3 and 4, patients undergoing total knee arthroplasty received prophylaxis for 10–14 days. After prophylaxis, all patients were followed up for a further 30–35 days. Rivaroxaban significantly reduced the incidence of the primary efficacy outcome for the individual studies (total VTE; composite of any deep vein thrombosis, non-fatal pulmonary embolism [PE] and all-cause mortality) compared with the enoxaparin regimens, with similar rates of major bleeding.

Methods: A pre-specified pooled analysis of all four trials was performed on all randomized patients who received at least one dose of double-blind study medication to evaluate the effect of rivaroxaban on the composite of symptomatic VTE and all-cause mortality (primary outcome for pooled analysis), and bleeding. This outcome was analysed at day 12±2 in the active treatment pool (enoxaparin-controlled in all studies) and in the total study duration pool (including follow-up after treatment).

Results: Rivaroxaban significantly reduced the incidence vs enoxaparin of the composite of symptomatic VTE and death (day 12±2: 0.47% vs 0.97%, respectively, p=0.001; total study duration: 0.81% vs 1.6%, respectively, p< 0.001) and the composite of PE and death (day 12±2: 0.19% vs 0.39%, respectively, p=0.049; total study duration: 0.47% vs 0.76%, respectively, p=0.039). The rates of major bleeding with the rivaroxaban and enoxaparin regimens were 0.34% and 0.21%, respectively, p=0.175 at day 12±2 and at total study duration were 0.44% and 0.27%, respectively, p=0.135. Rivaroxaban also reduced the composite of death, infarction, stroke, symptomatic VTE and major bleeding vs enoxaparin (total study duration: 1.6% vs 2.2%, respectively, p=0.006).

Conclusion: Rivaroxaban reduced the composites of major clinical outcomes compared with enoxaparin regimens, with similar rates of major bleeding, in patients undergoing major orthopaedic surgery.

Background and Aim: SF-36 has been used frequently as a measurement tool to evaluate the effect of total hip arthroplasty (THA) operation on the patient’s quality of life (QoL). There is though a lack of data describing how QoL is affected if the patients have medical co-morbidities before the operation or if they suffer postoperative complications after THA. With this study we wanted to describe the effect on QoL of pre-operative co-morbidity and post-operative surgical and thromboembolic complications after THA.

Material and methods: This study was part of the ESMOS study where 500 consecutive THA patients (both primary and revision THA) were followed prospectively for one year, with the purpose to collect all surgical and thromboembolic events that these patients experienced. The patients were asked to fill in a SF-36 form the day before the operation and one year after the operation. 397 (79.4%) of the patients had two forms sufficient for further data analysis in this study. Co-morbidity data was measured before the operation. Complications were measured with structured interviews by two study persons the fifth postoperative day and at telephone interviews after 3 and 12 month. All reported events were verified according to predefined criteria in the patient’s medical journal.

Results: The majority of the THA patients experienced a gain in their quality of life one year after THA. One year after THA the co-morbid patients had a significantly lower QoL score in all scales, but they still gained from the operation. Patients that experienced either a surgical or a thromboembolic complication had lower SF-36 score one year post-operatively compared to patients without complications. Subgroup analysis revealed that the small group of patients with deep infection, aseptic loosening or re-operation because of malfunction of the prosthesis had a fall in QoL compared to the pre-operative value and scored significantly worse than all other patient groups.

Conclusion: THA is a successful operation when QoL is measured one year postoperatively. Pre-operative co-morbidity and postoperative surgical or thrombo-embolic complications does give a smaller gain in QoL compared to patients without co-morbidity and patients without complications. The small but important group of patients with deep infection, aseptic loosening and malfunction re-operation, were the only to loose QoL one year after THA in this study.

Introduction: Four randomized, double-blind phase III studies (RECORD1–4) investigated the oral, direct Factor Xa inhibitor rivaroxaban for the prevention of venous thromboembolism (VTE) after elective total hip and total knee arthroplasty (THA and TKA). Patients (N=12,729) were randomized to receive oral rivaroxaban 10 mg once daily, or subcutaneous enoxaparin 40 mg once daily (RECORD1–3), or 30 mg twice daily (RECORD4). Those undergoing THA received rivaroxaban or enoxaparin for 31–39 days in RECORD1, and rivaroxaban for 31–39 days or enoxaparin for 10–14 days followed by placebo in RECORD2. In RECORD3 and 4 (TKA), prophylaxis was for 10–14 days.

Methods: A prespecified pooled analysis of all four studies evaluated the effect of rivaroxaban on the composite of symptomatic VTE and all-cause mortality, and bleeding, relative to enoxaparin. The present subgroup analysis investigated potential drug–drug interactions with concomitant non-steroidal anti-inflammatory drugs (NSAIDs) or acetylsalicylic acid (ASA) – commonly used pain medications known to affect bleeding risk. The risk of on-treatment bleeding in the total study duration pool of all four RECORD studies was investigated. These prespecified analyses focused on on-treatment, adjudicated bleeding events, any bleeding, and the composite of major bleeding and clinically relevant non-major bleeding – after the first tablet intake (rivaroxaban or matching placebo). Co-medication use was evaluated over time. Relative bleeding rates with and without co-medication were calculated separately for the rivaroxaban and enoxaparin/placebo groups. Time after surgery (day of surgery was day 1) was stratified into three periods (days 1–3, days 4–7 and day 7 up to 2 days after the last dose), based on the decreasing risk with time of a first bleeding event after surgery and because prevalence of co-medication use can vary over time. Bleeding rates were recorded for each time period over the at-risk period (the day of surgery until the last day of double-blind study medication intake +2 days or until initial event onset). The ratio of the bleeding rate for co-medication exposed vs unexposed patient-days in the rivaroxaban group was compared with the corresponding rate ratio for the enoxaparin/placebo group for bleeding events (Mantel–Haenszel methods).

Results: Concomitant use of ASA in the rivaroxaban groups showed rate ratios similar to those in the enoxaparin/placebo group (1.32 and 1.40, respectively, for any bleeding). Rate ratios were also similar with concomitant use of NSAIDs (1.22 in both groups, for any bleeding).

Conclusion: In the RECORD1–4 subanalysis, there was no indication of increased bleeding associated with the use of these co-medications in patients taking rivaroxaban, compared with enoxaparin.

Background: Results after Total Hip Replacement (THR) including prosthetic design, surgical complications and prosthetic survival are frequently reported – however, information on the rate of complications in general is sparse.

Aim and Methods: The aim was to collect information on all complications after THR within the first year after surgery. This study consisted of 500 consecutive patients (386 with primary THR operated due to degenerative osteoarthritis (OA) and 112 with primary THR due to secondary OA or revision THR). These patients were followed by structured interviews at surgery and 3 and 12 months after discharge. Surgical and cardiovascular complications were registered. No interventions related to this study were done. The patients followed the standard care of departments.

Results: 500 patients were included; two withdrew their consent, leaving 498 for the follow up one year after surgery or until death. Of the 498 patients 103 (20.6%) experienced at least one complication related to the operation within the one year observation period. Among the 386 primary THR with degenerative OA the complicationrate was 17.9%.

Of the 498 patients 6.6% experienced one or more symptomatic cardiovascular complications (deep vein thrombosis, pulmonary embolism (PE), myocardial infarction, and stroke, transient ischemic attack or retinal vein thrombosis). In the degenerative OA group 4.7% (95% Cl: 2.6–6.8%) had a cardiovascular event and in the secondary OA + revision group the rate was 13.4% (95% Cl: 10.2–16.6). The rate of complications directly related to the surgery (dislocation, perioperative fracture, bleeding, aseptic loosening, deep infection, peroneal palsy or superficial wound infection) was 15.4% (95% Cl: 12.3–18.6). In the degenerative OA and secondary OA/revision group the rates were: 14.2% and 19.6% respectively. Nine (1.8%) patients died, five of cardiovascular reasons (disseminated intravascular coagulation, PE followed by renal failure, PE followed by cerebral ischemia and stroke), the first three in close relation to the operation.

Discussion: A complication-rate of 20.6% as found in the present study seems to be very high. There is no reason to think that these numbers are not correct. To our knowledge, only one other study has been published with data about complications in general (Williams O., J Arthroplasty17:165–171, 2002). Their results are based on a mix of hospital file data, patient and general practitioner questionnaires with varying response rates – and their findings, although a bit lower in number, support the data from this study. The present study indicates, that there is a need for continuous registration of these common complications– even in the group of primary THR due to degenerative osteoarthritis, usually thought of as being the least complicated. The complication rate must be included in the information given to patients offered THR.

Introduction: Venous thromboembolism (VTE) after major orthopaedic surgery remains an important clinical problem. Convenient, oral antithrombotic agents that are both safe and effective could improve adherence to guidelines for VTE prevention. Recently, the focus has been on the development of oral agents that target a single step in the coagulation cascade. Factor Xa is the pivotal point in the coagulation cascade, making it a particularly attractive target for anticoagulant drugs. Rivaroxaban is an oral, direct Factor Xa inhibitor. Four international phase III trials (the RECORD programme) are being undertaken to investigate the safety and efficacy of once-daily rivaroxaban for thromboprophylaxis after major orthopaedic surgery. The results of RECORD3 showed that rivaroxaban was more effective than enoxaparin 40 mg once daily after total knee replacement (TKR), with a 48% risk reduction in VTE and all cause mortality. RECORD4 is designed to compare rivaroxaban 10mg once daily with enoxaparin 30 mg every 12 hours for thromboprophylaxis following TKR.

Methods: RECORD4 is a prospective, double-blind trial in which approximately 3000 TKR patients worldwide are being studied. Patients are randomized to receive either oral rivaroxaban 10 mg (starting 6–8 hours after surgery and continued once daily), or subcutaneous enoxaparin 30 mg (given every 12 hours and starting 12–24 hours after surgery). Study medication is given for 10–14 days, and mandatory bilateral venography is undertaken the following day. The primary efficacy outcome is a composite of deep vein thrombosis (DVT; symptomatic, or detected by mandatory venography), non-fatal pulmonary embolism (PE), and all-cause mortality. The major secondary efficacy outcome is major VTE (the composite of proximal DVT, PE and VTE-related death). The primary safety outcome is major bleeding. Other safety endpoints include all bleeding events, cardiovascular events and abnormal laboratory parameters.

Results: The final results of this trial will be presented.

Conclusions: The results of this trial will provide valuable data concerning the use of rivaroxaban for thromboprophylaxis after TKR in the North American setting.

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.

Background: Data on thromboembolic complications (TEC) following major orthopaedic surgery are generally obtained retrospectively from registries or prospectively from large industry-sponsored international multicentre trials. However, the results may differ from those observed in unselected patients in routine operations performed by orthopaedic surgeons. The purpose of the ESMOS study was to describe the number and time of onset of serious symptomatic arterial and venous TEC within 90 days after surgery in an unselected population of patients undergoing total hip replacement (THR).

Patients and methods: A total of 500 (430 primary THR and 70 revision THR) consecutive patients were included in the study performed between January 2004 and May 2005 in Frederiksborg County (Denmark). They were to be followed for 90 days after surgery. Patients were interviewed before surgery for medical history and on days 5 (while in hospital) and 90 (by telephone call) for signs and symptoms of acute myocardial infarction (AMI), pulmonary embolism (PE), deep-vein thrombosis (DVT), transitory cerebral ischemia (TCI)/stroke and retinal vein thrombosis (RVT). The validity of the events was confirmed using files from hospital, general practitioner and international criteria.

Results: Overall, 498 patients were followed-up for 90 days, 2 patients having withdrawn consent. In-hospital pharmacological thromboprophylaxis was performed in 499 patients. Twenty-four patients (4.8%) experienced at least one serious TEC up to day 90: 2 (0.4%) patients died from surgical-related complications (no autopsy was performed); 1 (0.2%) patient experienced AMI, 5 (1.0%) had PE, 10 (2.0%) DVT, 4 (0.8%) TCI, and 2 (0.4%) RVT. Moreover, 2 patients experienced two TEC: AMI followed by TCI in a first patient, PE and TCI in a second patient. The first event occurred up to day 5 in 9 patients (38%) and after day 5 in 15 patients (62%). Five patients (1%) had clinically relevant bleeding complications: 3 patients had a single, minor, upper gastrointestinal bleeding episode while in hospital, one patient developed a huge expanding haematoma at the operation site treated with hip spica and another patient a peritoneal haematoma leading to re-operation.

Conclusion: This study performed in an unselected population clearly shows that THR still results in serious TEC in spite of a wide use of modern anaesthesia techniques, thrombosis prophylaxis and early mobilisation. In the future, we need to better identify at-risk patients in order to optimise their management, in particular post-discharge care, and reduce the risk of serious TEC.

To target postoperative patients in need for prolonged pharmacologic thromboprophylaxis due to persistent coagulation activation, we developed and evaluated a qualitative test method, which detects the urinary excretion of prothrombin fragment 1+2 (uF1+2). The test was developed as a dip-stick device consisting of a one step rapid lateral flow immunoassay with visual readout on one test line and one control line. The assay time was between 5 and 10 minutes.

Spot urine samples were collected in 113 patients undergoing elective hip arthroplasty preoperatively and on day 5 after operation. Specimens were frozen immediately and stored until batch analysis. Pharmacologic thromboprophylaxis was administered according to national guidelines until day 7±2 after the operation. The results of the new dip-stick device were compared with the results of a laboratory based enzyme-linked-immunosorbent-assay (ELISA) method and a predetermined cut-off value. Patients were followed for development of vascular thrombotic complications/unexpected death until day 90 after the operation.

10 (8.8%) patients experienced an event during the study: 2 (1.8%) died unexpectedly and 8 (7.1%) had a vascular thrombotic event. All patients with clinical events had significantly raised postoperative levels of uF1+2. The clinical accuracy of the dip-stick test was acceptable with a sensitivity of 100% and a negative predictive value of 100%. Compared to the standard ELISA method the dip-stick test had a sensitivity of 93% and a specificity of 48%.

Laboratory ELISA analysis of urinary excretion of uF1+2 is neither feasible nor applicable in postoperative patients. Bed-side testing of persistent coagulation activation, however, could help to determine the need for prolonged thromboprophylaxis. The new dip-stick urine test was very easy to use, had a high negative predictive value and sensitivity and thus appears to be safe. However, the number of false positive test results prompts a fine-tuning of the test device. In terms of clinical applicability the test was acceptable. The study showed that about one third of the patients could be excluded from further extension of thromboprophylaxis beyond the first week.

Aims: The fondaparinux thromboprophylaxis phase III studies database including 7344 patients in orthopaedic surgery provides information regarding patient management according to country specificities. Methods: 4 randomized double-blind trials were conducted in 376 centers in 23 countries comparing fondaparinux to enoxaparin – 1 in major knee surgery (MKS) in North America (NA); 2 in total hip replacement (THR) in NA and in Europe, respectively; and 1 in hip-fracture (HF) surgery worldwide except in NA. The use of regional anesthesia or cement during surgery, use of stockings during hospitalization, or prolonged prophylaxis (PP) after discharge were left to the investigators. Results: In all studies the majority of patients were women, particularly in HF. The median age was 67 years for THR, 69 years for MKS, and 79 years for HF. In THR studies, regional anesthesia was used more frequently in Europe (59%) than in NA (24.4%). The table summarizes investigators’ practice. Conclusions: There are important differences in the management of orthopedic surgery patients according to country specificities and type of surgery. However, fondaparinux is more effective than enoxaparin for thromboprophylaxis irrespective of patient or surgery characteristics.

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

Aims: To assess whether there was a relationship between the timing of the first administration of fondaparinux and its efficacy and safety in preventing venous thromboembolism (VTE) in orthopaedic surgery. Methods: Overall, 3616 patients received fondaparinux in 4 randomized, double-blind studies in this setting. We performed a post-hoc analysis of the effect of this timing on VTE up to day 11 (primary efficacy) and bleeding with a bleeding index (BI) ≥2, using logistic regression. These 2 parameters were also analyzed according to whether fondaparinux started before 6 hours or at 6 hours or later postoperation. Results: Logistic regression showed that the efficacy of fondaparinux was not affected by the timing of its first administration (p=0.67). However, there was a statistically significant relationship between this timing and bleeding with a BI ≥2 (p=0.008). The table gives the incidence of VTE and bleeding with a BI ≥2 according to the interval between skin closure and the first fondaparinux injection. Conclusions: The efficacy of fondaparinux in preventing VTE in orthopaedic surgery was not related to the timing of its first administration. In addition, a significant reduction in the incidence of bleeding with a BI ≥2 was observed when the first fondaparinux injection took place between 6 and 9 hours after skin closure.

Aims: In major orthopedic surgery, fondaparinux provided a major benefit over enoxaparin, with an overall venous thromboembolsim (VTE) risk reduction of > 50% and similar safety profile regarding clinically relevant bleeding (leading to death or reoperation, or occurring in critical organ). The aim of the present study was to analyze this superior efficacy according to patients and surgery characteristics. Methods: In four phase III trials, the primary efficacy outcome was the VTE incidence up to day 11, defined as deep-vein thrombosis (DVT) detected by mandatory bilateral venography or documented symptomatic DVT or pulmonary embolism. Primary efficacy was further analyzed according to predefined categorical covariates using a logistic regression model. Results: Fondaparinux was more effective than enoxaparin irrespective of age, gender, obesity, the use of cement or surgery duration (odds reduction from −46.9% to −59.7% in favor of fondaparinux. Clinically relevant bleeding did not differ between the two groups according to predefine covariates. Conclusions: For VTE prevention in major orthopaedic surgery, the superiority of fondaparinux over enoxaparin was consistent irrespective of patient or surgery characteristics.

Aims: In orthopedic surgery, the optimal duration of thromboprophylaxis is debated, and very few data are available in hip fracture. We addressed these issues in 5 randomized double-blind clinical trials of fondaparinux. Methods: In four studies in 7344 orthopedic surgery patients, fondaparinux was administered up to 11 days and compared to approved enoxaparin regimens. In the PENTHIFRA-Plus study in 656 hip fracture surgery patients, after an initial treatment with fondaparinux for 7±1 days, patients were randomized to fondaparinux or placebo for additional 21±2 days. In all trials, primary efficacy was venous thromboembolism (VTE), at the end of the treatment period. Results: In the four 11-day prophylaxis studies, fondaparinux reduced the incidence of VTE from 13.7% with enoxaparin to 6.8% (risk reduction [RR]: 55.2%; P< 0.001). Fondaparinux efficacy was significantly influenced by treatment duration (P< 0.001): for instance, the incidence of VTE was lower in patients treated for 9 to11 days (5.2%) than in patients treated for ≤5 days (8.7%, P= 0.038). In the PENTHIFRA-Plus study, the incidence of VTE up to 4 weeks was reduced to 1.4% compared with 35.0% with placebo (relative RR: 95.9%, P< 0.001). The incidence of symptomatic VTE was also significantly lower with fondaparinux (0.3%) than with placebo (2.7%, relative RR: 88.8%, P=0.021). Conclusions: Fondaparinux efficacy in preventing VTE in orthopedic surgery increased significantly with a longer duration of treatment. Hip fracture surgery patients are at high risk of VTE up to 4 weeks after surgery and treatment with fondaparinux for 4 weeks postoperatively provides greater benefit than active treatment for only 1 week.

Aims: To evaluate the inßuence of the type of anesthesia on the superior efþcacy of fondaparinux over enoxaparin in preventing venous thromboembolism (VTE) in orthopedic surgery (RRR > 50%; P< 0.0001). Methods: 4 randomized, double-blind trials were performed: 2 in hip replacement (THR), 1 in North America (NA) and 1 in Europe; 1 in knee surgery (MKS); and 1 in hip-fracture surgery (HF). The choice of anesthesia was left to the investigators. A predeþned covariate analysis according to the type of anesthesia was performed on primary efþcacy.

Conclusions: Fondaparinux once-daily started postoperatively provided superior efþcacy versus enoxaparin in preventing VTE whatever the type of anesthesia and may improve convenience in current practice.

Aims: Whether the use of elastic stockings (ES) on top of pharmacological thromboprophylaxis is beneficial remains debated. In a worldwide phase III program including 7344 patients in major orthopaedic surgery, fondaparinux, the first synthetic selective factor Xa inhibitor, demonstrated a substantial benefit over enoxaparin in preventing venous thromboembolism (VTE); risk reduction > 50% without increasing clinically relevant bleeding. The aim of this study was to evaluate the influence of ES on this superior efficacy of fondaparinux. Methods: In all four randomized, double-blind trials, comparing a once daily 2.5 mg s.c. injection of fondaparinux to enoxaparin, the primary efficacy outcome was VTE up to day 11, defined as deep-vein thrombosis (DVT) detected by mandatory bilateral venography, or documented symptomatic DVT or pulmonary embolism. A post-hoc analysis on primary efficacy was performed according to the use of ES. Results: The table shows VTE incidences by day 11 without and with ES. Conclusions: In major orthopaedic surgery, fondaparinux showed a similar superior efficacy over enoxaparin in patients with and without ES, indicating that ES did not influenced the major benefit of this new agent. An additive effect of ES in enoxaparin-treated patients cannot be excluded but the effect is insufficient compared with fondaparinux alone.