Michael Rud Lassen | University of Copenhagen (original) (raw)

Papers by Michael Rud Lassen

British journal of clinical pharmacology, Jan 18, 2015

To analyze concomitant drug use and its association with outcome in patients (N=17 701) receiving... more To analyze concomitant drug use and its association with outcome in patients (N=17 701) receiving rivaroxaban or standard of care (SOC) for the prevention of venous thromboembolism after major orthopaedic surgery in the non-interventional, phase IV XAMOS study. Concomitant drug use was at the discretion of the treating physician. Prespecified co-medications of interest were cytochrome P450 (CYP) 3A4/P-glycoprotein inhibitors/inducers, platelet aggregation inhibitors (PAIs) and non-steroidal anti-inflammatory drugs (NSAIDs). Crude event incidences were compared between rivaroxaban and SOC groups. CYP3A4/P-glycoprotein inhibitor/inducer use was infrequent, in contrast to PAI (~7%) and NSAID (~52%) use. Rivaroxaban was associated with a lower incidence of overall symptomatic thromboembolic events compared with SOC regardless of co-medication use. In both treatment groups, PAI users, with higher age and prevalence of cardiovascular co-morbidities, had similar higher (>7-fold) inciden...

Clinical and applied thrombosis/hemostasis : official journal of the International Academy of Clinical and Applied Thrombosis/Hemostasis, 2014

This study was undertaken to provide evidence for the mechanism of venous thromboembolism (VTE) i... more This study was undertaken to provide evidence for the mechanism of venous thromboembolism (VTE) in healthy patients with minor lower limb injury (fracture; Achilles tendon rupture) that was medically managed with plaster cast/brace immobilization. The Plaster Cast clinical trial provided a unique opportunity to identify the natural history of VTE using placebo-controlled patients (n = 183) with validation of the mechanism using the low-molecular-weight heparin (LMWH; reviparin)-treated patients (n = 182). Confirmed VTE in this population was associated with a burst of tissue factor release (and a minor fibrinolytic deficit) leading to thrombin generation that was sustained at least 5 weeks, greater with fractures than with soft-tissue injuries and greater with surgery than with conservative treatment. The root cause likely involves platelet/leukocyte activation (inflammation) rather than endothelial cell injury. Thromboprophylaxis with a low dose of LMWH reduced thrombin generation,...

Vascular Health and Risk Management, 2012

Venous thromboembolism is a frequent and potentially life-threatening complication of orthopedic ... more Venous thromboembolism is a frequent and potentially life-threatening complication of orthopedic surgery. Rivaroxaban is an oral direct factor Xa inhibitor, which was shown to be effective for the prevention of venous thromboembolism after elective hip and knee arthroplasty in the RECORD study program. Rivaroxaban has the potential to overcome the limitations of the current standards of care in the prevention of venous thromboembolism. XAMOS (Xarelto ® in the prophylaxis of post-surgical venous thromboembolism after elective major orthopedic surgery of hip or knee) is an international, noninterventional, parallel-group study to gain insight into the safety (major bleeding, side effects) and effectiveness (prevention of symptomatic thromboembolic events) of rivaroxaban in daily clinical practice. XAMOS will follow 15,000 patients after major orthopedic surgery in approximately 200 centers worldwide, with about 7500 patients receiving rivaroxaban and about 7500 standard of care. XAMOS will supplement the clinical data obtained in the Phase III RECORD 1, 2, 3, and 4 trials in which rivaroxaban was shown to be superior for the primary efficacy endpoints, and with a safety profile similar to that of enoxaparin after hip or knee replacement surgery. XAMOS was started in 2009 and will complete recruitment and follow-up in 2011.

New England Journal of Medicine, 2001

Background Surgery for hip fracture carries a high risk of venous thromboembolism, despite the us... more Background Surgery for hip fracture carries a high risk of venous thromboembolism, despite the use of current thromboprophylactic treatments. Fondaparinux, a synthetic pentasaccharide, is a new antithrombotic agent that may reduce this risk. Methods In a double-blind study, we randomly assigned 1711 consecutive patients undergoing surgery for fracture of the upper third of the femur to receive subcutaneous doses of either 2.5 mg of fondaparinux once daily, initiated postoperatively, or 40 mg of enoxaparin once daily, initiated preoperatively, for at least five days. The primary efficacy outcome was venous thromboembolism up to postoperative day 11. Venous thromboembolism was defined as deep-vein thrombosis detected by mandatory bilateral venography, documented symptomatic deep-vein thrombosis, or documented symptomatic pulmonary embolism. The main safety outcomes were major bleeding and mortality from all causes. The duration of follow-up was six weeks. Results The incidence of venous thromboembolism by day 11 was 8.3 percent (52 of 626 patients) in the fondaparinux group and 19.1 percent (119 of 624 patients) in the enoxaparin group (P<0.001). The reduction in risk with fondaparinux was 56.4 percent (95 percent confidence interval, 39.0 to 70.3 percent). There were no significant differences between the two groups in the incidence of death or clinically relevant bleeding. Conclusions In patients undergoing surgery for hip fracture, fondaparinux was more effective than enoxaparin in preventing venous thromboembolism and was equally safe.

The Lancet, 2010

Background Low-molecular-weight heparins such as enoxaparin are preferred for prevention of venou... more Background Low-molecular-weight heparins such as enoxaparin are preferred for prevention of venous thromboembolism after major joint replacement. Apixaban, an orally active factor Xa inhibitor, might be as eff ective, have lower bleeding risk, and be easier to use than is enoxaparin. We assessed effi cacy and safety of these drugs after elective total knee replacement. Methods In ADVANCE-2, a multicentre, randomised, double-blind phase 3 study, patients undergoing elective unilateral or bilateral total knee replacement were randomly allocated through an interactive central telephone system to receive oral apixaban 2•5 mg twice daily (n=1528) or subcutaneous enoxaparin 40 mg once daily (1529). The randomisation schedule was generated by the Bristol-Myers Squibb randomisation centre and stratifi ed by study site and by unilateral or bilateral surgery with a block size of four. Investigators, patients, statisticians, adjudicators, and steering committee were masked to allocation. Apixaban was started 12-24 h after wound closure and enoxaparin 12 h before surgery; both drugs were continued for 10-14 days, when bilateral ascending venography was scheduled. Primary outcome was the composite of asymptomatic and symptomatic deep vein thrombosis, non-fatal pulmonary embolism, and all-cause death during treatment. The statistical plan required non-inferiority of apixaban before testing for superiority; analysis was by intention to treat for non-inferiority testing. The study is registered at ClinicalTrials.gov, number NCT00452530. Findings 1973 of 3057 patients allocated to treatment (1528 apixaban, 1529 enoxaparin) were eligible for primary effi cacy analysis. The primary outcome was reported in 147 (15%) of 976 apixaban patients and 243 (24%) of 997 enoxaparin patients (relative risk 0•62 [95% CI 0•51-0•74]; p<0•0001; absolute risk reduction 9•3% [5•8-12•7]). Major or clinically relevant non-major bleeding occurred in 53 (4%) of 1501 patients receiving apixaban and 72 (5%) of 1508 treated with enoxaparin (p=0•09). Interpretation Apixaban 2•5 mg twice daily, starting on the morning after total knee replacement, off ers a convenient and more eff ective orally administered alternative to 40 mg per day enoxaparin, without increased bleeding. Funding Bristol-Myers Squibb; Pfi zer.

Journal of Thrombosis and Haemostasis, 2012

Background: Semuloparin is a novel ultralow-molecular-weight heparin under development for venous... more Background: Semuloparin is a novel ultralow-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.

Journal of Thrombosis and Haemostasis, 2007

The efficacy and safety of apixaban, an oral, direct factor Xa inhibitor, as thromboprophylaxis i... more The efficacy and safety of apixaban, an oral, direct factor Xa inhibitor, as thromboprophylaxis in patients following total knee replacement.

Journal of the American College of Cardiology, 2008

This study assessed the dose response of SR123781A for the prevention of venous thromboembolism (... more This study assessed the dose response of SR123781A for the prevention of venous thromboembolism (VTE) in patients undergoing total hip replacement (THR) surgery. Background Despite VTE preventive measures, residual VTE complications still occur after THR. SR123781A, a synthetic oligosaccharide with a mixed profile of anti-factor Xa and IIa activities, could be an alternative to current treatments. Methods In this double-blind study, 1,023 patients undergoing THR were randomly assigned to 1 of 5 daily doses of SR123781A or to a calibrator arm of enoxaparin 40 mg. Treatment was continued for 10 days or until bilateral venography was performed after a minimum of 5 days. Results A significant dose-response effect for VTE was observed for SR123781A (p Ͻ 0.0001). The VTE rates were 21.2%, 17.7%, 13.5%, 7.0%, and 4.4% in the 0.25-, 0.5-, 1.0-, 2.0-, and 4.0-mg dose groups of SR123781A, respectively, and 8.7% in the enoxaparin group. Doses of 2.0 and 4.0 mg of SR123781A reduced the risk of VTE by 67% and 79%, respectively, compared with the 0.25-mg dose group. Major bleeding was observed in 1.2%, 0.6%, 0.6%, 0.6%, and 5.8% of the patients in the 0.25-, 0.5-, 1.0-, 2.0-, and 4.0-mg dose groups of SR123781A, respectively, and in 0.6% of patients in the enoxaparin group. The dose-response effect for major bleeding was significant (p ϭ 0.0037). Conclusions The model based on these dose-finding study results suggests that SR123781A doses ranging from 1.5 to 2.5 mg show a reasonable risk-to-benefit ratio for VTE prevention after major orthopedic surgery. (Dose Ranging Study in Elective Total Hip Replacement Surgery [DRIVE]; NCT00338897) (

The Journal of Bone and Joint Surgery. British volume, 2009

A once-daily dose of rivaroxaban 10 mg, an oral, direct Factor Xa inhibitor, was compared with en... more A once-daily dose of rivaroxaban 10 mg, an oral, direct Factor Xa inhibitor, was compared with enoxaparin 40 mg subcutaneously once daily for prevention of venous thromboembolism in three studies of patients undergoing elective hip and knee replacement (RECORD programme). A pooled analysis of data from these studies (n = 9581) showed that rivaroxaban was more effective than enoxaparin in reducing the incidence of the composite of symptomatic venous thromboembolism and all-cause mortality at two weeks (0.4% vs 0.8%, respectively, odds ratio 0.44; 95% confidence interval 0.23 to 0.79; p = 0.005), and at the end of the planned medication period (0.5% vs 1.3%, respectively; odds ratio 0.38; 95% confidence interval 0.22 to 0.62; p < 0.001). The rate of major bleeding was similar at two weeks (0.2% for both) and at the end of the planned medication period (0.3% vs 0.2%). Rivaroxaban started six to eight hours after surgery was more effective than enoxaparin started the previous evening...

The Journal of Bone and Joint Surgery. British volume, 2012

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

The New England journal of medicine, Jan 16, 2012

Patients receiving chemotherapy for cancer are at increased risk for venous thromboembolism. Limi... more Patients receiving chemotherapy for cancer are at increased risk for venous thromboembolism. Limited data support the clinical benefit of antithrombotic prophylaxis.

$Research paper thumbnail of Assessment of HIT Antibody Complex in Hip Fracture Patients Receiving Enoxaparin or Unfractionated Heparin$

Clinical and Applied Thrombosis/Hemostasis, 2011

Thromboembolic disease is a common complication of hip fracture in the elderly. Anticoagulants re... more Thromboembolic disease is a common complication of hip fracture in the elderly. Anticoagulants represent a standard of care in preventing postoperative thrombotic complications following surgical fixation. We asked whether levels of antibody to heparin–platelet factor 4 (PF4) complex were differentially present in unfractionated heparin (UFH) versus Enoxaparin, following hip fracture and whether one particular subtype of antibodies was more prevalent. Plasma samples from elderly patients sustaining a hip fracture treated with either enoxaparin or UFH were collected pre- and postoperatively and analyzed using enzyme-linked immunosorbent assay (ELISA) sandwich method for the prevalence of antiheparin-PF4 antibodies and later subtyped. The prevalence of antiheparin-PF4 antibodies was higher in the UFH group especially on postoperative day 7. Patients treated with UFH showed a greater prevalence of antiheparin-PF4 antibodies and a greater prevalence of immunoglobulin G (IgG) subtype. He...

Chest, 2004

Study objectives: To assess the relevance of various efficacy end points established for thrombop... more Study objectives: To assess the relevance of various efficacy end points established for thromboprophylaxis trials, we compared the results of the fondaparinux phase III program in major orthopedic surgery using the original primary efficacy end point with those obtained when the efficacy end points recently suggested by the American College of Chest Physicians (ACCP) Consensus Conference on Antithrombotic Therapy and the European Committee for Proprietary Medicinal Products (CPMP) were used. Setting and patients: Fondaparinux was compared with enoxaparin in four multicenter, randomized, double-blind trials of major orthopedic surgery. The original primary efficacy end point consisted of a composite of deep-vein thrombosis detected by mandatory bilateral venography, documented symptomatic deep-vein thrombosis, or pulmonary embolism up to day 11. The efficacy end point established by the ACCP Consensus Conference on Antithrombotic Therapy comprises any proximal deep-vein thrombosis, symptomatic proven deep-vein thrombosis or pulmonary embolism, or fatal pulmonary embolism, and that established by the European CPMP comprises any proximal deep-vein thrombosis, symptomatic proven pulmonary embolism, or death from any cause. Interventions: Patients were randomized to receive either subcutaneous fondaparinux (2.5 mg once daily) starting postoperatively or approved enoxaparin regimens. Results: Using the original end point of the fondaparinux studies, the incidence of venous thromboembolism was 13.7% (371 of 2,703 patients) in the enoxaparin group compared with 6.8% (182 of 2,682 patients) in the fondaparinux group, with a common odds reduction of 55.2% (p ‫؍‬ 10 ؊17 ; 95% confidence interval, 45.8% to 63.1%) in favor of fondaparinux. The respective incidences of efficacy end points with enoxaparin and fondaparinux were 3.3% and 1.7%, respectively, according to the ACCP definition, and 3.9% and 2.1%, respectively, according to the CPMP definition. The common odds reduction in favor of fondaparinux was 49.6% (p < 0.001) and 48.0% (p < 0.001), respectively. Conclusions: Fondaparinux was consistently more effective than enoxaparin in preventing venous thromboembolism in patients undergoing major orthopedic surgery, irrespective of the established composite outcomes used.

Chest, 2005

ABSTRACT This article discusses the prevention of venous thromboembolism (VTE) and is part of the... more ABSTRACT This article discusses the prevention of venous thromboembolism (VTE) and is part of the Seventh American College of Chest Physicians Conference on Antithrombotic and Thrombolytic Therapy: Evidence-Based Guidelines. Grade I recommendations are strong and indicate that the benefits do, or do not, outweigh risks, burden, and costs. Grade 2 suggests that individual patients' values may lead to different choices (for a full understanding of the grading see Guyatt et al, CHEST 2004; 126:179S-187S). Among the key recommendations in this chapter are the following. We recommend against the use of aspirin alone as thromboprophylaxis for any patient group (Grade 1A). For moderate-risk general surgery patients, we recommend prophylaxis with low-dose unfractionated heparin (LDUH) (5,000 U bid) or low-molecular-weight heparin (LMWH) [:5 3,400 U once daily] (both Grade 1A). For higher risk general surgery patients, we recommend thromboprophylaxis with LDUH (5,000 U tid) or LMWH (> 3,400 U daily) [both Grade 1A]. For high-risk general surgery patients with multiple risk factors, we recommend combining pharmacologic methods (LDUH three times daily or LMWH, > 3,400 U daily) with the use of graduated compression stockings, and/or intermittent pneumatic compression devices (Grade 1C+). We recommend that thromboprophylaxis be used in all patients undergoing major gynecologic surgery (Grade 1A) or major, open urologic procedures, and we recommend prophylaxis with LDUH two times or three times daily (Grade 1A). For patients undergoing elective total hip or knee arthroplasty, we recommend one of the following three anticoagulant agents: LMWH, fondaparinux, or adjusted-dose vitamin K antagonist (VKA) [international normalized ratio (INR) target, 2.5; range, 2.0 to 3.0] (all Grade 1A). For patients undergoing hip fracture surgery (HFS), we recommend the routine use of fondaparinux (Grade 1A), LMWH (Grade 1C+), VKA (target INR, 2.5; range, 2.0 to 3.0) [Grade 2B], or LDUH (Grade 1B). We recommend that patients undergoing hip or knee arthroplasty, or HFS receive thromboprophylaxis for at least 10 days (Grade 1A). We recommend that all trauma patients with at least one risk factor for VTE receive thromboprophylaxis (Grade 1A). in acutely ill medical patients who have been admitted to the hospital with congestive heart failure or severe respiratory disease, or who are confined to bed and have one or more additional risk factors, we recommend prophylaxis with LDUH (Grade 1A) or LMWH (Grade 1A). We recommend, on admission to the intensive care unit, all patients be assessed for their risk of VTE. Accordingly, most patients should receive thromboprophylaxis (Grade 1A).

CHEST Journal, 2008

PURPOSE:This meta-analysis evaluated the efficacy of rivaroxaban for the prevention of symptomati... more PURPOSE:This meta-analysis evaluated the efficacy of rivaroxaban for the prevention of symptomatic venous thromboembolism in the three completed pivotal RECORD studies, which compared rivaroxaban with enoxaparin 40 mg once daily (od). METHODS:Patients (n=9581) were randomized to receive oral rivaroxaban 10 mg od starting at least 6-8 hours after surgery, or subcutaneous enoxaparin (40 mg od starting the evening before surgery). In RECORD1, all patients undergoing total hip replacement (THR) received extended thromboprophylaxis for 35 days. In RECORD2, patients undergoing THR received rivaroxaban for 35 days or enoxaparin for 10-14 days. In RECORD3, patients undergoing total knee replacement received prophylaxis for 10-14 days. All outcomes, including objectively confirmed symptomatic outcomes, were blindly adjudicated by an independent committee. In all three studies, the rivaroxaban regimens significantly reduced the incidence of the primary outcome (the composite of any deep vein thrombosis [DVT], non-fatal pulmonary embolism [PE], and death) and major VTE (proximal DVT, non-fatal PE, and VTE-related death), compared with the enoxaparin regimens, without increasing the risk of bleeding.This meta-analysis evaluated the effect of rivaroxaban on the composite of symptomatic VTE (DVT and PE) and death, and major bleeding at 2 weeks (predefined), and at the end of the planned medication period, in the safety population. RESULTS:Rivaroxaban significantly reduced the incidence of symptomatic VTE and death compared with enoxaparin (2 weeks: 0.4% vs 0.8%, respectively, odds ratio [OR] 0.44, 95% confidence intervals [CIs] 0.23, 0.79, p=0.005), and the rivaroxaban regimens were more effective at the end of planned study medication (0.5 vs 1.3, respectively, OR 0.38, 95% CIs 0.22, 0.62, p<0.001). Both groups had similar rates of major bleeding (2 weeks: 0.2% vs 0.2%, respectively, p=0.662; end of planned study medication: 0.3% vs 0.2%, respectively, p=0.305). CONCLUSION:The rivaroxaban regimens significantly reduced symptomatic VTE and death, compared with the enoxaparin regimens, without an increased risk of bleeding in patients undergoing major orthopaedic surgery. CLINICAL IMPLICATIONS:Rivaroxaban significantly reduces clinically important VTE outcomes, without compromising safety. DISCLOSURE:Alexander Turpie, Consultant fee, speaker bureau, advisory committee, etc. Consultant fees received from Bayer HealthCare AG and Scios Inc.; Product/procedure/technique that is considered research and is NOT yet approved for any purpose. Rivaroxaban is an oral anticoagulant in advanced clinical development (phase III) for thromboprophylaxis after major orthopaedic surgery, treatment of venous thromboembolism, and stroke prevention in atrial fibrillation. Three phase III trials were previously reported at ASH 2007. The study reported in the abstract submitted here describes a meta-analysis of these three trials.

British Journal of Surgery, 1992

This review discusses the problem of deep vein thrombosis (DVT) after operation and identifies th... more This review discusses the problem of deep vein thrombosis (DVT) after operation and identifies three levels of risk of DVT: low (< 10 per cent), moderate (10–40 per cent) and high (40–80 per cent). Special emphasis is placed on the most recent prophylactic treatment, low molecular weight heparins (LMWHs), particularly enoxaparin. Several LMWHs are now available, but they difer slightly and each must be evaluated on its own merits. In general, however, LMWHs are both efective and safe in those patients at moderate or high risk of DVT. Thromboprophylaxis is cost effective when analysed using healtheconomic methodology.

BMJ, 2006

Objective To determine the efficacy and safety of the anticoagulant fondaparinux in older acute m... more Objective To determine the efficacy and safety of the anticoagulant fondaparinux in older acute medical inpatients at moderate to high risk of venous thromboembolism. Design Double blind randomised placebo controlled trial. Setting 35 centres in eight countries. Participants 849 medical patients aged 60 or more admitted to hospital for congestive heart failure, acute respiratory illness in the presence of chronic lung disease, or acute infectious or inflammatory disease and expected to remain in bed for at least four days. Interventions 2.5 mg fondaparinux or placebo subcutaneously once daily for six to 14 days. Outcome measure The primary efficacy outcome was venous thromboembolism detected by routine bilateral venography along with symptomatic venous thromboembolism up to day 15. Secondary outcomes were bleeding and death. Patients were followed up at one month. Results 425 patients in the fondaparinux group and 414 patients in the placebo group were evaluable for safety analysis (10 were not treated). 644 patients (75.9%) were available for the primary efficacy analysis. Venous thrombembolism was detected in 5.6% (18/321) of patients treated with fondaparinux and 10.5% (34/323) of patients given placebo, a relative risk reduction of 46.7% (95% confidence interval 7.7% to 69.3%). Symptomatic venous thromboembolism occurred in five patients in the placebo group and none in the fondaparinux group (P = 0.029). Major bleeding occurred in one patient (0.2%) in each group. At the end of follow-up, 14 patients in the fondaparinux group (3.3%) and 25 in the placebo group (6.0%) had died. Conclusion Fondaparinux is effective in the prevention of asymptomatic and symptomatic venous thromboembolic events in older acute medical patients. The frequency of major bleeding was similar for both fondaparinux and placebo treated patients.

Archives of Internal Medicine, 2002

Background: Orthopedic surgery remains a condition at high risk of venous thromboembolism (VTE). ... more Background: Orthopedic surgery remains a condition at high risk of venous thromboembolism (VTE). Fondaparinux, the first of a new class of synthetic selective factor Xa inhibitors, may further reduce this risk compared with currently available thromboprophylactic treatments. Methods: A meta-analysis of 4 multicenter, randomized, double-blind trials in patients undergoing elective hip replacement, elective major knee surgery, and surgery for hip fracture (N = 7344) was performed to determine whether a subcutaneous 2.5-mg, once-daily regimen of fondaparinux sodium starting 6 hours after surgery was more effective and as safe as approved enoxaparin regimens in preventing VTE. The primary efficacy outcome was VTE up to day 11, defined as deep vein thrombosis detected by mandatory bilateral venography or documented symptomatic deep vein thrombosis or pulmonary embolism. The primary safety outcome was major bleeding. Results: Fondaparinux significantly reduced the incidence of VTE by day 11 (182 [6.8%] of 2682 patients) compared with enoxaparin (371 [13.7%] of 2703 patients), with a common odds reduction of 55.2% (95% confidence interval, 45.8% to 63.1%; PϽ.001); this beneficial effect was consistent across all types of surgery and all subgroups. Although major bleeding occurred more frequently in the fondaparinux-treated group (P = .008), the incidence of clinically relevant bleeding (leading to death or reoperation or occurring in a critical organ) did not differ between groups. Conclusion: In patients undergoing orthopedic surgery, 2.5 mg of fondaparinux sodium once daily, starting 6 hours postoperatively, showed a major benefit over enoxaparin, achieving an overall risk reduction of VTE greater than 50% without increasing the risk of clinically relevant bleeding.

Clinical Orthopaedics & Related Research, 2008

Anticoagulation for thromboprophylaxis after THA and TKA has not been confirmed to diminish allca... more Anticoagulation for thromboprophylaxis after THA and TKA has not been confirmed to diminish allcause mortality. We determined whether the incidence of all-cause mortality and pulmonary embolism in patients undergoing total joint arthroplasty differs with currently used thromboprophylaxis protocols. We reviewed articles published from 1998 to 2007 that included 6-week or 3-month incidence of all-cause mortality and symptomatic, nonfatal pulmonary embolism. Twenty studies included reported 15,839 patients receiving low-molecular-weight heparin, ximelagatran, fondaparinux, or rivaroxaban (Group A); 7193 receiving regional anesthesia, pneumatic compression, and aspirin (Group B); and 5006 receiving warfarin (Group C). All-cause mortality was higher in Group A than in Group B (0.41% versus 0.19%) and the incidence of clinical nonfatal pulmonary embolus was higher in Group A than in Group B (0.60% versus 0.35%). The incidences of all-cause mortality and nonfatal pulmonary embolism in Group C were similar to those in Group A (0.4 and 0.52, respectively). Clinical pulmonary embolus occurs despite the use of anticoagulants. Group A anticoagulants were associated with the highest all-cause mortality of the three modalities studied. Level of Evidence: Level III, therapeutic study. See the Guidelines for Authors for a complete description of levels of evidence. Each author certifies that he or she has no commercial associations (eg, consultancies, stock ownership, equity interest, patent/licensing arrangements, etc) that might pose a conflict of interest in connection with the submitted article.

*The Regulation of Coagulation in Orthopedic Surgery to Prevent Deep Venous Thrombosis and Pulmon... more *The Regulation of Coagulation in Orthopedic Surgery to Prevent Deep Venous Thrombosis and Pulmonary Embolism (RECORD3) study group and investigators are listed in the Appendix.