Introduction

Supplements and Featured Publications, Emerging Antithrombotic Therapies: New Developments in Acute Care Medicine, Volume 12, Issue 16 Suppl

Anticoagulant agents are mainstaytherapies in the prevention and treatmentof arterial and venous thrombosis.Available anticoagulants include thedirect and indirect thrombin inhibitors(Table).1 The direct thrombin inhibitors(DTIs; lepirudin, desirudin, bivalirudin,argatroban) exert their anticoagulant effectby sole inhibition of thrombin, whereas theindirect inhibitors (unfractionated heparin[UFH] and low molecular weight heparins[LMWH]) need a cofactor (antithrombin III)to exert their anticoagulant effect andblock both thrombin and activated factor X(FXa) (Figure).1,2 The heparins (UFH andLMWH) exert their anticoagulant effect onfluid phase thrombin and FXa, and areresistant to clot-bound thrombin and clotboundprothrombinase-associated FXa.3Although UFH and the DTIs suppress existingthrombin activity, thrombin generationis largely unaffected.4

The benefit of UFH is accepted and welldocumented in the treatment of arterial andvenous thrombosis; however, its use isfraught with many limitations. UFH is associatedwith variable anticoagulant effect,requires routine monitoring and dose adjustment,and carries the risk of heparininducedthrombocytopenia.1 The LMWHwere developed to overcome some of thelimitations of UFH. These agents have ahigher affinity for inhibiting FXa comparedwith that of thrombin, and are less complexto use in the clinical setting compared withUFH.5 The more favorable benefit-risk profile(ie, better side-effect profile) of LMWH,with a higher affinity for FXa inhibition comparedwith UFH, has triggered interest in thesearch and development of more selectiveanticoagulant agents, such as the FXainhibitors.6

As the penultimate enzyme in the coagulationcascade, FXa has a critical role byultimately regulating thrombin production(Figure).1 FXa converts prothrombin tothrombin via the prothrombinase complex,leading to platelet activation and formationof the fibrin clot. FXa is generated via theintrinsic or extrinsic pathways, and 1 moleculeof FXa can generate more than 1000thrombin molecules. In addition, a massiveburst of thrombin generation is caused byprothrombinase-bound FXa because itsreaction rate is 300 000-fold higher comparedwith free FXa.6,7 The inhibition ofthrombin generation by blocking FXa hasbeen validated as an effective antithromboticapproach with the use of the highlyselective, direct and indirect FXa inhibitors.The indirect FXa inhibitors (eg,fondaparinux) exert their effect via a cofactor(antithrombin III), whereas the directinhibitors (eg, DX-9065a, otamixaban) blockFXa directly.1,2,6,7

Ample clinical evidence now supports therole of the FXa inhibitors as anticoagulantsand as effective therapeutic agents for theprevention and treatment of venous andarterial thrombosis. Fondaparinux, an indirectFXa inhibitor, has equivalent or greaterefficacy than the LMWH enoxaparin in theprevention of venous thromboembolism(VTE) after orthopedic surgery,8 similar efficacyto dalteparin in prevention of VTE afterabdominal surgery,9 better efficacy thanplacebo in prevention of VTE in medicalpatients,10 similar efficacy to enoxaparinand UFH in treatment of deep vein thrombosisand pulmonary embolism,11,12 and similarefficacy to UFH and enoxaparin in treatmentof patients with acute coronary syndromes(ACS).13,14 In addition, in patients with ACS,there is a safety and mortality benefit in favorof fondaparinux compared with enoxaparin.14

Although these newer agents have higheracquisition costs than warfarin or UFH, theiruse has grown rapidly, making them amongthe highest ranked drug classes in terms ofhospital pharmaceutical expenditures.15With the expansion in the number of anticoagulantagents and the indications for whichthey can be used, clinicians can be challengedby selecting the most appropriateagents, optimal dosing regimens, and themost cost-effective options. This supplementwill review the medical and economicimpact, new treatment options, and cost-effectivenessof novel therapies for ACS.

Address correspondence to: Edith A. Nutescu, PharmD, Department ofPharmacy Practice, University of Illinois at Chicago, 833 S. Wood St., RM164, MC886, Chicago, IL 60612. E-mail: enutescu@uic.edu.

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11. Büller HR, Davidson BL, Decousus H, et al; to theMatisse Investigators. Fondaparinux or enoxaparin for theinitial treatment of symptomatic deep venous thrombosis:a randomized trial. 2004;140:867-873.

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12. The Matisse Investigators. Subcutaneous fondaparinuxversus intravenous unfractionated heparin in theinitial treatment of pulmonary embolism. 2003;349:1695-1702.

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13. The OASIS-6 Trial Group. Effects of fondaparinuxon mortality and reinfarction in patients with acute ST-segmentelevation myocardial infarction: the OASIS-6randomized trial. 2006;295:1519-1530.

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14. The Fifth Organization to Assess Strategies in AcuteIschemic Syndromes Investigators. Comparison of fondaparinuxand enoxaparin in acute coronary syndromes.2006;354:1464-1476.

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15. Schumock GT, Nutescu EA, Walton SM, ArondekarBV, Lewis RK. Survey of hospital policies regarding low-molecular-weight heparins. 2002;59:534-538.