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Clinical Pharmacology of Direct and Indirect Factor Xa Inhibitors

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Abstract

The limitations of conventional anticoagulants have stimulated the development of new anticoagulants. The central position of factor Xa (FXa) at the junction of the intrinsic and extrinsic pathways in the coagulation cascade means that direct and indirect FXa inhibitors have increasingly changed antithrombotic strategies. FXa inhibitors potently and selectively inhibit thrombin formation rather than thrombin activity. Direct FXa inhibitors may directly bind to FXa, whereas indirect inhibitors are dependent on antithrombin. Direct inhibitors may bind free FXa and, in contrast to indirect inhibitors, FXa within the prothrombinase complex or within clots as well.

Fondaparinux is the prototype indirect FXa inhibitor and has been extensively studied in the prevention and treatment of thromboembolic diseases, including acute coronary syndromes. Due to a favourable efficacy and safety profile and convenient once-daily dosing without the need for monitoring, fondaparinux is preferentially recommended in recent guidelines dealing with antithrombotic treatment.

A number of small-molecule direct FXa inhibitors are currently at different stages of clinical development. After an extensive clinical trial programme demonstrating superior efficacy without a significant increase in major bleeds compared with enoxaparin, rivaroxaban is now available for the prevention of thromboembolic events in patients undergoing orthopaedic surgery. Rivaroxaban also offers the convenience of oral once-daily dosing without the need for monitoring. Whereas most direct FXa inhibitors are orally active, otamixaban is administered intravenously, offering rapid on-off anticoagulant activity. Other compounds under development may offer additional options for tailored antithrombotic strategies according to differing indications, clinical situations and patient variables.

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Acknowledgements

No sources of funding were used in the preparation of this article. Professor Rupprecht has been involved in the conduct of a variety of antithrombotic trials, especially with fondaparinux. He has received honoraria for lectures and advisory boards from GlaxoSmithKline, Eli Lilly, BristolMyers Squibb and Sanofi. Dr Blank has received honoraria for lectures from Pfizer, Chiesi and Iroko, and for consultancy work from Boston Scientific and Terumo.

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  1. II. Medical Clinic, GPR Klinikum Ruesselsheim, August-Bebel-Str. 59, D-65428, Ruesselsheim, Germany

    Hans-Juergen Rupprecht (Director) & Ralf Blank

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  1. Hans-Juergen Rupprecht
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Correspondence to Hans-Juergen Rupprecht.

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Rupprecht, HJ., Blank, R. Clinical Pharmacology of Direct and Indirect Factor Xa Inhibitors. Drugs 70, 2153–2170 (2010). https://doi.org/10.2165/11538030-000000000-00000

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