Factor Xa inhibition in the prevention of venous thromboembolism and treatment of patients with venous thromboembolism.
ABSTRACT Venous thromboembolism (VTE) is a life-threatening complication following orthopedic surgery. Selective factor Xa inhibition is a new antithrombotic approach designed to avoid difficulties associated with heparins and other current anticoagulants. Several antifactor Xa compounds are in early investigation, but fondaparinux (Arixtra; NV Organon, Oss, The Netherlands; Sanofi-Synthelabo, Paris, France) is the first and most advanced compound in the development of a new class of synthetic antithrombotic agents--the selective factor Xa inhibitors. Fondaparinux has a highly favorable pharmacokinetic profile; four large phase 3 trials comparing subcutaneous fondaparinux 2.5 mg once daily with the low molecular weight heparin (LMWH) enoxaparin in doses approved by regulatory bodies showed that fondaparinux reduced the overall risk of VTE in major orthopedic surgery by > 50% without increasing clinically relevant bleeding. Fondaparinux also appears to be a very promising candidate for the treatment of patients with existing VTE.
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ABSTRACT: Venous thromboembolic disease is a major cause of morbidity and mortality, necessitating antithrombotic therapy. A human monoclonal anti-factor (F)VIII antibody, LCL-mAb-LE2E9, produced by a lymphoblastoid cell line derived from a hemophilia A patient with inhibitor to wild-type but not mutant self FVIII, was previously reported to achieve efficient inhibition of thrombosis in an experimental vena cava thrombosis model in mice. Here, the antithrombotic efficacy of a recombinant DNA-derived version of this anti-FVIII antibody (rec-mAb-LE2E9) was tested in mice which carry a type II heparin binding site antithrombin deficiency mutation and display spontaneous chronic thrombosis in several sites including the penile vein of sexually active males. The recombinant anti-FVIII antibody (100 microg, repeated after 3 days) prevented thrombotic priapism in all treated males, whereas all control animals treated with saline (group of four animals) developed priapism within 6 days after mating (P < 0.05 for treated vs. saline). The rec-mAb-LE2E9 and the original LCL-mAb-LE2E9 were equally effective (five and seven males/group, respectively). These results confirm that FVIII inhibition represents a potent antithrombotic strategy, and show that both LCL-mAb-LE2E9 and rec-mAb-LE2E9 efficiently prevent thrombosis in a physiological model representative of thrombosis in patients with a severe prothrombotic risk.Journal of Thrombosis and Haemostasis 02/2004; 2(1):77-84. DOI:10.1111/j.1538-7836.2004.00524.x · 5.55 Impact Factor
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ABSTRACT: Fondaparinux is a novel synthetic antithrombotic that has been evaluated for the prevention of venous thromboembolism (VTE). In four large trials in patients who underwent major hip or knee surgery, fondaparinux was found to have a good safety profile and be more effective than enoxaparin. To generate Canadian pharmacoeconomic data for fondaparinux, an internationally developed cohort deterministic model was used to estimate the costs and consequences of prophylaxis with fondaparinux compared with enoxaparin in the Canadian orthopedic surgical setting. A health economic advisory group was assembled to guide the pharmacoeconomic evaluation. Efficacy and safety data for fondaparinux relative to enoxaparin were abstracted from a meta-analysis of four randomized trials. Canadian cost data to populate the model were obtained from a resource-use survey of four large Canadian hospitals, from the Canadian Institute for Health Information (CIHI), and from the Canadian economic literature. Case-mix information obtained from CIHI was incorporated into the cohort deterministic model, which predicted the number of VTEs and bleeds following prophylaxis with fondaparinux or enoxaparin within 90 days of surgery, and the associated overall cost difference. The stability of the base-case findings was evaluated with sensitivity analyses. Canadian healthcare system perspective. Assuming a case mix of 50,693 major hip or knee surgeries performed in Canada in 1999/2000 (as reported by CIHI), the model predicted that prophylaxis with fondaparinux would avoid an additional 16 symptomatic VTEs per 1000 patients over the first 90 days, with an average cost savings of Can 55 dollars per patient. These findings were stable when key economic and clinical parameters were varied, including bleeding events. Our results suggest that in Canada, prophylactic fondaparinux compared with enoxaparin avoids VTEs and is associated with lower costs in patients who undergo major hip or knee surgery.American Journal of Cardiovascular Drugs 02/2004; 4(5):325-33. DOI:10.2165/00129784-200404050-00005 · 2.20 Impact Factor