, Volume 64, Issue 14, pp 1575-1596
Date: 18 Nov 2012

Fondaparinux Sodium

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Summary

Abstract

Fondaparinux sodium (Arixtra®; fondaparinux) is the first of a new class of synthetic pentasaccharide anticoagulants that bind to antithrombin and inhibit the action of factor Xa.

In three large, well designed trials, subcutaneous fondaparinux 2.5mg once daily was more effective than subcutaneous enoxaparin sodium (enoxaparin) 30mg twice daily or 40mg once daily at preventing venous thromboembolism (VTE) at day 11 in patients undergoing hip replacement, elective major knee or hip fracture surgery; a fourth trial demonstrated similar efficacy to enoxaparin 30mg twice daily in hip replacement. Fondaparinux recipients had a lower incidence of proximal deep vein thrombosis (DVT) in two studies. In a meta-analysis of the four trials, patients receiving fondaparinux had a >50% reduction in the relative risk of VTE at day 11. Fondaparinux compared favourably with enoxaparin in several pharmacoeconomic analyses.

In a large, controlled trial in hip fracture patients, extended prophylaxis with fondaparinux (duration 25–31 days) substantially reduced the incidence of VTE at day 25–32 compared with prophylaxis for 6–8 days, and was a cost-effective treatment strategy. Moreover, extended prophylaxis significantly decreased the rate of proximal, total and distal DVT and symptomatic VTE.

Fondaparinux was generally well tolerated in clinical trials in patients undergoing major orthopaedic surgery. However, following major knee surgery and in a meta-analysis of pooled data from four trials, fondaparinux recipients had a significantly higher incidence of overt bleeding with a bleeding index ≥2, but no increase in fatal bleeding, bleeding into a critical organ or bleeding leading to reoperation. The bleeding risk is related to the timing of the first dose and when fondaparinux was initiated between 6 and 8 hours after surgery, the bleeding risk was similar to enoxaparin. Extended prophylaxis with fondaparinux was not associated with a significantly increased risk of bleeding events.

In conclusion, fondaparinux is more effective than enoxaparin at preventing postoperative VTE in patients undergoing elective hip replacement, major knee or hip fracture surgery. Extended therapy with fondaparinux considerably increases its efficacy without a significant increase in the incidence of bleeding episodes. Fondaparinux was generally well tolerated in clinical trials. Fondaparinux is an effective and useful alternative to low molecular weight heparins for the prevention of VTE following major orthopaedic surgery.

Pharmacological Properties

Fondaparinux sodium (fondaparinux), a synthetic pentasaccharide anticoagulant, selectively binds to antithrombin (AT), catalysing the inhibition of factor Xa. The in vitro antifactor Xa activity of fondaparinux is ≈700 anti-XaIU/mg.

In vitro, fondaparinux does not bind to platelets or platelet factor 4 or inhibit platelet aggregation. It had no clinically significant effects on the activated partial thromboplastin time, prothrombin time, AT levels or the bleeding time in healthy volunteers.

After subcutaneous injection, fondaparinux is rapidly and completely absorbed, and shows linear pharmacokinetics over a 2–8mg dose range in healthy volunteers. The volume of distribution (8.2–10.2L) suggests that drug distribution is limited to the vascular compartment only. In plasma, fondaparinux binds almost exclusively to AT.

Fondaparinux is primarily excreted unchanged in the urine, with a correlation between clearance of fondaparinux and creatinine. In vitro studies suggest that fondaparinux does not undergo metabolism by liver enzymes and does not interfere with cytochrome P450-mediated metabolism of other drugs.

Therapeutic Efficacy

At 11 days’ follow-up, subcutaneous fondaparinux 2.5mg administered once daily for 5–9 days prevented venous thromboembolism (VTE) following major orthopaedic surgery in four large, well designed studies. Fondaparinux was more effective than standard prophylactic dosages of subcutaneous enoxaparin sodium (enoxaparin) at preventing postoperative VTE in patients undergoing elective hip replacement, major knee or hip fracture surgery. A meta-analysis showed that fondaparinux recipients had a >50% relative risk reduction of VTE by day 11 compared with those receiving enoxaparin undergoing major orthopaedic surgery. Furthermore, secondary endpoint analysis showed that by day 11, patients receiving fondaparinux had a significantly lower rate of total or distal deep vein thrombosis (DVT) in all studies and proximal DVT in two trials than enoxaparin recipients.

Prophylaxis with fondaparinux for 25–31 days after hip fracture surgery substantially reduced the incidence of VTE by day 25–32 compared with fondaparinux treatment for 6–8 days. Moreover, prolonged prophylaxis was associated with a lower incidence of proximal, total or distal DVT and fewer symptomatic VTEs than treatment for the standard duration.

Tolerability

Fondaparinux is generally well tolerated when used for the prophylaxis of VTE in patients undergoing major orthopaedic surgery. A meta-analysis of pooled data from the four trials in major orthopaedic surgery showed a significantly higher incidence of overt bleeding with a bleeding index ≥2 with fondaparinux compared with enoxaparin, but no increase in fatal bleeding, bleeding into a critical organ or bleeding leading to reoperation.

A low incidence of thrombocytopenia was seen in patients receiving fondaparinux (2–4.9%) or enoxaparin (3–5.3%). Thrombocytopenia was not reported as a serious adverse event in any trial, and no cases of heparin-induced thrombocytopenia were reported.

Pharmacoeconomic Studies

No significant increase in the incidence of bleeding episodes was observed in patients receiving extended or standard-duration prophylaxis. Fondaparinux compared favourably with enoxaparin in pharmacoeconomic studies in patients undergoing major orthopaedic surgery or elective major knee or hip fracture surgery. In patients undergoing hip replacement, fondaparinux was cost effective with respect to the incremental cost-effectiveness ratio per VTE avoided compared with enoxaparin 40mg once daily, but not 30mg twice daily. Fondaparinux was generally cost saving relative to enoxaparin at timepoints ≥90 days after surgery. Extended prophylaxis with fondaparinux (duration of treatment 28 days) in patients undergoing surgery for hip fracture was also cost effective, and was cost saving relative to enoxaparin at timepoints ≥90 days after surgery.

Various sections of the manuscript reviewed by: R.L. Bick, Department of Medicine and Pathology, University of Texas Southwestern Medical Center, and Dallas Thrombosis, Hemostasis and Difficult Hematology Clinical Center, Dallas, Texas, USA; N.R. Bijsterveld, Department of Cardiology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; B. Boneu, Laboratoire d’Hématologie, Pavillon Charles Lefebvre, Hôpital Purpan, Toulouse, France; H. Bounameaux, Division of Angiology and Haemostasis, Department of Internal Medicine and Institute for Social and Preventive Medicine, University Hospitals of Geneva, Geneva, Switzerland; B.I. Eriksson, Department of Orthopedics, Sahlgrenska University Hospital — Östra, Göteborg, Sweden; A.S. Gallus, Department of Haematology, Flinders Medical Centre, Bedford Park, Adelaide, Australia; T.M. Hyers, Department of Internal Medicine, St Louis University School of Medicine, C.A.R.E. Clinical Research, St Louis, Missouri, USA; A.G.G. Turpie, Department of Medicine, Hamilton Health Sciences Corporation — General Division, Hamilton, Ontario, Canada; W.E. Wade, Department of Clinical and Administrative Pharmacy, College of Pharmacy, University of Georgia, Athens, Georgia, USA; J.I. Weitz, Hamilton Civic Hospitals Research Centre, Hamilton, Ontario, Canada.

Data Selection

Sources: Medical literature published in any language since 1980 on fondaparinux sodium, identified using Medline and EMBASE, supplemented by AdisBase (a proprietary database of Adis International). Additional references were identified from the reference lists of published articles. Bibliographical information, including contributory unpublished data, was also requested from the company developing the drug.
Search strategy: Medline search terms were ‘fondaparinux*’ or ‘fondaparin*’ or ‘SR-90107’. EMBASE search terms were ‘fondaparinux’ or ‘fondaparin’ or ‘SR-90107’. AdisBase search terms were ‘fondaparinux*’ or ‘fondaparin*’ or ‘SR 90107’ or ‘ORG 31540’. Searches were last updated 28 June 2004.
Selection: Studies in patients undergoing major orthopaedic surgery requiring prophylaxis for venous thromboembolism who received fondaparinux sodium. Inclusion of studies was based mainly on the methods section of the trials. When available, large, well controlled trials with appropriate statistical methodology were preferred. Relevant pharmacodynamic and pharmacokinetic data are also included.
Index terms: Fondaparinux sodium, deep vein thrombosis, pharmacodynamics, pharmacoeconomics, pharmacokinetics, pulmonary embolism, therapeutic use, venous thrombosis.