Melagatran

01061 INTRAOPERATIVE CEREBRAL MICROEMBOLI ASSAY DURING HIP AND KNEE ARTHROPLASTY

R.V. Patel, J. Stygall. J. Harrington, S. Newman, F.S. Haddad.

University College London Hospitals Trust, England

Aims: To compare the intraoperative cerebral microemboli load between primary total hip (THA) and knee arthroplsty (TKA) using transcranial Doppler ultrasound and to investigate whether a patent foramen ovale influences cerebral embolie load in general. The timing of the microemboli will be related to certain surgical activities to determine if a specific relationship exists. Methods: Patients undergoing primary TKA or THA. with no history of stroke. TIA. ongoing CNS dis ease or alcoholism included. All operations carried out under a standardised general anaesthetic and performed by two consultant orthopaedic surgeons. Microemboli load recorded, using transcranial Doppler ultrasound (TCD). onto VHS tape for subsequent playback and analysis. Patent foramen ovale detection performed using bolus intravenous injection of agitated saline followed by valsalva manoeuvre technique and TCD. Timing of specific surgical steps recorded for each operation and emboli load calculated for that period. Results: 20 THA and 20 TKA patients were studied. Cerebral microembolisation occurred in 50% of THA and 40% of TKA patients. Total microembolic load for THA patients was 137 (range=0-83) and 50 (range=0- 21) for TKA patients. Prevalence of PFO in the THA group was 35%. and 20% in the TKA group. 57.1% of PFO positive THA patients and 75% of PFO positive TKA patients displayed microemboli. Insertion of the femoral component in THA and release of the tourniquet in TKA were associated with higher cerebral microemboli load. Conclusion: Intraoperative cerebral microembolisation occurs in almost half of patients during hip and knee arthroplasty. Patients who have a PFO appear more likely to be associated with cerebral embolisation. Specific surgical activities are associated with larger embolie loads.

01062 ELASTIC STOCKINGS DO NOT INFLUENCE SUPERIOR EFFICACY OF FONDAPARINUX OVER ENOXAPARIN FOR THROMBOPROPHYLAXIS IN ORTHOPAEDIC SURGERY

M.R. Lassen, K.A. Bauer, B.I. Eriksson, A.G.G.Turpie.

University Hospital of Copenhagen Hillerød, Hillerød, Denmark

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.

01063 EFFECT ON EFFICACY AND SAFETY OF THE TIMING OF THE FIRST FONDAPARINUX ADMINISTRATION FOR THE THROMBOPROPHYLAXIS IN ORTHOPAEDICSURGERY

M.R. Lassen, K. A. Bauer, B.I. Eriksson, A.G.G.Turpie.

University Hospital of Copenhagen Hillerød, Hillerød, Denmark

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.

01064 MANAGEMENT OF ORTHOPEDIC SURGERY PATIENTS IN NORTH AMERICA, EUROPE AND OTHER COUNTRIES: LESSONS FROM THE FONDAPARINUX DATABASE

B.I. Eriksson, K.A. Bauer. M.R. Lassen, A.G.G. Turpie.

Suhlgrenska University Hospital/Östra, Göteborg, Sweden

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.

01065 XIMELAGATRAN, AND ITS SUBCUTANEOUS FORM MELAGATRAN, VS. ENOXAPARIN AS THROMBOPROPHYLAXIS IN TOTAL HIP OR TOTAL KNEE REPLACEMENT

Bengt I. Eriksson, G. Agnelli.A.T. Cohen, O.E. Dahl, M.R. Lassen, P. Mouret, N. Rosencher.

for the EXPRESS investigators. Department of Orthopaedics, Sahlgrenska University Hospital/ Östra, Göteborg, Sweden

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 nig 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

01066 FONDAPARINUX IS SUPERIOR TO ENOXAPARIN FOR THROMBOPROPHYLAXIS IN ORTHOPEDIC SURGERY IRRESPECTIVE OF PATIENTS OR SURGERY CHARACTERISTICS

B.I. Eriksson. K.A. Bauer, M.R. Lassen, A.G.G. Turpie.

Sahlgrenska University Hospital/Östra, Göteborg, Sweden

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.

01067 INFLUENCE OFTHE DURATION OF FONDAPARINUX PROPHYLAXIS IN PREVENTING VENOUS THROMBOEMBOLISM FOLLOWING HIP FRACTURE SURGERY

B.I. Eriksson, K.A. Bauer, M.R. Lassen, A.G. G. Turpie.

Sahlgrenska University Hospital/Östra, Göteborg, Sweden

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

O1068 PROLONGED ENOXAPARIN THERAPY TO PREVENT VENOUS THROMBOEMBOLlSM AFTER PRIMARY HIP OR KNEE REPLACEMENT: A COST-UTILITY ANALYSIS

P. Haentjens, K. De Groote. L. Annemans.

Vrije Universileil Brussel and Universileil Gem, Belgium

Aims: Wc conducted an cost-utility analysis to compare standard (in-hospital) with prolonged (out-of-hospital) enoxaparin prophylaxis after elective total hip and knee replacement. Methods: The perspective was that of a societal healthcare payer, taking Belgium as a case country. The main outcome measure was the incremental cost-utility ratio, reported as the incremental cost per quality-adjusted life year gained (Euro/OALY). Costs for diagnosis and treatment of proximal and distal deep vein thrombosis,pulmonary embolism, postphlebitic syndrome, and major bleeding were obtained from a Delphi panel (orthopaedic surgeons) and the official reimbursement rates (Federal Ministery of Health). QALYs for these health states were based on utility scores as reported in the literature. Results: In the base-case analysis, incremental costs of prolonged prophylaxis amounted 58 Euro and 114 Euro per patient, with an additional gain in QALY of 0.0083 and 0.0018 after total hip and

knee replacement, respectively. Thus, a strategy of prolonged enoxaparin prophylaxis was associated with a cost-utility ratio of 6.964 Euro/QALY and 64,907 Euro/ QALY after total hip and knee replacement, respectively. Applying a societal willingness-to-pay threshold value of 20,000 Euro/QALY, prolonged enoxaparin prophylaxis is cost-effective after elective total hip replacement. Sensitivity analyses confirmed the general robustness of these findings. Conclusions: After elective total hip or knee replacement, prolonged enoxaparin prophylaxis leads to increased effectiveness at increased cost. Nevertheless, given the additional costs healthcare decision makers in Europe are usually prepared to pay for a gain in effectiveness, prolonged prophylaxis with enoxaparin is cost-effective after total hip replacement

01069 THE INCIDENCE AND MANAGEMENT OF HIP FRACTURE PATIENTS ADMITTED ON WARFARIN, A PROSPECTIVE STUDY

A.J. Brooksbank. S. Sckhtivel, RK. Rickhuss.

Ninewells Hospital, Dundee, Scotland

Aims: Following hip fracture, a delay to surgery of greater than 24 hours is associated with a higher morbidity and mortality. In our unit, one of the common perceived delays is patients admitted on warfarin. The elective perioperative management of patients on warfarin is well documented. We aimed to define the incidence and delay of patients admitted with hip fractures on warfarin, and how its reversal was managed. Methods: Data was collected prospectively from 14 hospitals who contribute to the Scottish Hip Fracture Database. In addition to the data recorded on the Standardised Audit of Hip fractures in Europe form (SAHFE). specific questions relating to warfarin and its reversal were asked. Results: During 1.8.01-31.12.01. 1641 patients were admitted with a hip fracture. 42 patients (2.6%) were taking warfarin with the commonest indication being atrial fibrillation (40.5%). Mean INR on admission was 2.83 (range 1.2-8.2), and at surgery was 1.43 (range 1.0-2.0). Active reversal occurred in 19 patients. A delay to theatre of >48 hours occurred in 72.7% of the warfarin group versus 19.0% in the non-warfarin group. There were wound complications in 5 patients taking warfarin. Conclusions: The number of patients admitted on warfarin was lower than we had anticipated. Delay to theatre was significantly higher in the warfarin group. The approach to the perioperative management of patients taking warfarin was varied.

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