Clinical Trial Outcomes BAUERSACHS Edoxaban: a new oral direct factor Xa inhibitor 4 Clinical Trial Outcomes Edoxaban: a new oral direct factor Xa inhibitor for the prevention and treatment of thromboembolic disorders Clin. Invest. Anticoagulants have a key role in the treatment of arterial and venous thromboembolic Rupert Bauersachs disorders. The recently introduced novel oral anticoagulants target a single Department of Vascular Medicine, coagulation factor (factor Xa or thrombin) and address several of the limitations Vascular Center Darmstadt, Klinikum Darmstadt GmbH, Grafenstraße 9, associated with traditional agents. Edoxaban is an oral direct factor Xa inhibitor D–64283 Darmstadt, Germany that inhibits free and clot bound factor Xa and has been investigated in an extensive Tel.: +49 6151 107 4401 clinical development program. This article provides an overview of the mechanism Fax: +49 6151 107 4499 of action, pharmacokinetics and pharmacodynamics of edoxaban. Phase III studies [email protected] have evaluated edoxaban versus conventional therapy to prevent stroke in patients with atrial fibrillation (ENGAGE AF-TIMI 48) and in the treatment and prevention of recurrent venous thromboembolism in patients with deep vein thrombosis and/or pulmonary embolism (Hokusai-VTE). Keywords: atrial fibrillation • direct factor Xa inhibitor • edoxaban • novel oral anticoagulant • pharmacodynamics • pharmacokinetics • stroke prevention • thromboembolic disorders • venous thromboembolism Activation of the plasma coagulation cas­ optimal conditions difficult and which cade is central to thrombus formation in consequently impact on patient care. Both 10.4155/CLI.14.49 the pathogenesis of thromboembolic disor­ VKAs and heparin require frequent labora­ ders in several cardiovascular diseases. Anti­ tory monitoring. Although LMWH enabled coagulants have long been the mainstay for once­daily administration without the need the long­term treatment and prophylaxis for coagulation monitoring, it is inconvenient of thromboembolic diseases such as venous due to daily subcutaneous administration thromboembolism (VTE), as well as stroke and may cause heparin­induced thrombo­ 7 prevention in patients with atrial fibrilla­ cytopenia [3,4]. In addition, the VKAs are tion (AF). For several decades, conventional associated with a slow onset of action, multi­ antithrombotic therapy comprised unfrac­ ple food and drug interactions, variable anti­ tionated heparin, the low­molecular­weight coagulant effect and a narrow therapeutic 2014 heparins (LMWHs), the synthetic penta­ window; this necessitates close monitoring saccharide fondaparinux and the oral vita­ to achieve a target international normalized min K antagonists (VKAs), such as warfarin. ratio (INR) of 2.5 (range: 2.0–3.0). This con­ Indeed, warfarin remains one of the most stitutes the background for a 40­fold range in widely used anticoagulants as it is low cost, dosing (0.5–20 mg/day) to achieve the same can be administered once­daily (QD) and therapeutic effect, but increases the risk for its use is well established, with meta­analyses bleeding or recurrent thrombotic event (from having shown warfarin to be highly effective excessive or insufficient anti coagulation, in prevention of stroke and recurrent VTE respectively) [3,5,6]. In view of these limita­ under optimal conditions [1,2]. tions, VKAs are significantly underutilized, However, these agents are associated with with an analysis of over 183,000 patients with a number of limitations that make achieving AF showing no antithrombotic protection by part of 10.4155/CLI.14.49 © 2014 Future Medicine Ltd Clin. Invest. (2014) 4(7), 619–639 ISSN 2041-6792 619 Clinical Trial Outcomes Bauersachs anticoagulant of nearly 50% of the observed patient­ nonfunctional enzymes following coagulation factor days [7]. In addition, a systematic review found nearly activation [5,6,9]. 90% of studies reported under­treatment with oral In contrast, the NOACs have been designed to act anticoagulant [8]. via direct (antithrombin­independent) inhibition of These limitations highlight the need for new anti­ a specific coagulation factor (Figure 1). Direct oral coagulants that are at least as effective but safer and thrombin inhibitors (dabigatran) bind directly to the more convenient to use. Knowledge of the various thrombin active site thereby suppressing its activity factors in the coagulation cascade and targeted drug and preventing formation of fibrin and activation of design has led to the development of novel/non­VKA platelets. FXa is an attractive target for anticoagulation oral anticoagulants (NOACs). A key step in the for­ as it is the primary and rate­limiting source of amplifi­ mation of a thrombus is the conversion of fibrinogen cation in the coagulation cascade. It is a serine protease to fibrin, which is mediated by thrombin (factor IIa that binds to FVa, with the resulting prothrombinase [FIIa]) and plays a central role in the coagulation (FXa/FVa) complex assembled on the membrane sur­ cascade (Figure 1). Heparins and fondaparinux act face efficiently converting prothrombin to thrombin; indirectly by binding to the natural anticoagulant one molecule of FXa (in the prothrombinase complex) antithrombin, thereby accelerating inactivation of can activate approximately 1000 prothrombin mol­ thrombin and several other activated coagulation fac­ ecules. Direct FXa inhibitors (apixaban, rivaroxaban tors. VKAs act indirectly by blocking a step in the and edoxaban) bind directly to the active site of free biosynthesis of several coagulation factors. Specifi­ and clot­bound FXa, blocking the interaction with its cally, VKAs prevent the γ­carboxylation of FII (pro­ substrate [5,6]. thrombin), FVII, FIX and FX, as well as anticoagulant The NOACs have a number of potential advantages protein C (γ­carboxylation is required for the activity over warfarin, including a rapid onset of action, no of coagulation factors) leading to the production of significant food interactions, lower potential for drug Surface activation (aPTT) XII XIIa Tissue factor activation Warfarin (PT) XI XIa IX IXa VIIa VII Direct factor Xa inhibitor Warfarin Edoxaban Apixaban VIII VIIIa Rivaroxaban X Xa Va V Direct thrombin inhibitor Dabigatran Warfarin Prothrombin Thrombin (II) (IIa) Fibrinogen (I) Fibrin (Ia) XIIIa Cross-linked fibrin clot Figure 1. The coagulation cascade and anticoagulant sites of action. Warfarin acts indirectly by blocking a step in the biosynthesis of FII (prothrombin), FVII, FIX and FX (dashed lines and rectangles). The nonvitamin K antagonist oral anticoagulants are direct inhibitors of thrombin (FIIa; dabigatran) or FXa (edoxaban, apixaban, rivaroxaban) (solid lines and ovals). aPTT: Activated partial thromboplastin time; PT: Prothrombin time. Reproduced with permission from [5]. 620 Clin. Invest. (2014) 4(7) future science group Edoxaban: a new oral direct factor Xa inhibitor Clinical Trial Outcomes interactions and a predictable anticoagulant effect, Given the importance of renal excretion in the obviating the need for routine monitoring of anti­ elimination of edoxaban, studies have evaluated coagulation parameters [6]. Based on the results of the drug in patients with normal renal function or Phase III clinical studies, dabigatran, apixaban, riva­ mild renal impairment (creatinine clearance [ClCr] roxaban and edoxaban have gained approval for the ≥50 ml/min) compared with severe renal impairment prevention and treatment of several thromboembolic (ClCr ≤30 ml/min), suggesting that edoxaban expo­ disorders in adult patients [10–14], while several agents sure increases in patients with renal impairment, and are in various stages of development. that a lower dose (15 mg QD) seems appropriate [22,23]. Results from Phase III studies of edoxaban in VTE However, in patients with end­stage renal disease, and stroke prevention in AF have also recently become hemodialysis had minimal effects on the clearance available. In addition, the manufacturers of edoxaban of edoxaban and further dose adjustment may not be have recently submitted applications to the US FDA necessary [24]. This is likely due to the plasma protein and the EMA for the approval of edoxaban for use in binding of 40–59% for edoxaban [15] and therefore these conditions. The objective of this review is to pro­ hemo dialysis is not an effective means for removing vide an overview of the pharmacokinetics and phar­ edoxaban from the blood. macodynamics of edoxaban, and discuss the findings With edoxaban being a substrate for P­gp, practi­ from the recent clinical studies in VTE and patients tioners need to be aware of potential interactions with with AF. inhibitors or inducers of this transporter, particularly as some drugs used in patients with AF are also P­gp sub­ Pharmacokinetic & pharmacodynamic strates. Strong P­gp inhibitors may increase systemic properties of edoxaban absorption and decrease drug elimination (increasing Pharmacokinetics, metabolism & excretion, bleeding risk due to increased exposure), while P­gp & drug–drug interactions inducers may increase drug elimination and reduce Studies in healthy subjects using single and multiple systemic exposure (increasing risk of thromboembolic doses have shown that edoxaban demonstrates predict­ events due to insufficient anticoagulation). As such, able and consistent pharmacokinetics, with dose lin­ the FDA now recommends that all investigational earity and low intrasubject variability (summarized in drugs be evaluated for potential