Factor Xa inhibition in the prevention of venous thromboembolism and treatment of patients with venous thromboembolism

VA Boston Healthcare System and Beth Israel Deaconess Medical Center, Boston, MA 02215, USA.
Current opinion in pulmonary medicine (Impact Factor: 2.76). 09/2002; 8(5):398-404. DOI: 10.1097/00063198-200209000-00010
Source: PubMed


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: 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, SR90107AIOORG31540, 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 Unpublished data were provided by the manufacturer of fondaparinux, and additional information was obtained from abstracts presented at the 2001 congress of the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 111, 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).
    No preview · Article · Dec 2002 · Clinical Therapeutics
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    ABSTRACT: This chapter presents adverse effects and interactions of drugs affecting blood coagulation, fibrinolysis, and hemostasis. Heparin-induced thrombocytopenia is a well-characterized immunoglobulin-mediated disorder that is often complicated by life- and limb-threatening thrombotic complications. Argatroban is metabolized by CYP3A4/5, and its pharmacokinetics might be altered by inhibitors of CYP3A. Thrombocytopenia, often severe, occurs in 1-2% of patients treated with the fibrinogen receptor antagonist, abciximab. Moreover, in a 46-year-old woman anaphylactic shock occurred after abciximab readministration.
    No preview · Article · Dec 2002 · Side Effects of Drugs Annual
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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.
    No preview · Article · Feb 2004 · American Journal of Cardiovascular Drugs
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