edoxaban:afocused review of its clinical pharmacology · pharmacology gregory y. h. lip1* and...

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REVIEW New drugs Edoxaban: a focused review of its clinical pharmacology Gregory Y. H. Lip 1 * and Giancarlo Agnelli 2 1 University of Birmingham Centre for Cardiovascular Sciences, City Hospital, Dudley Road, Birmingham, UK; and 2 Internal and Cardiovascular Medicine – Stroke Unit, University of Perugia, Perugia, Italy Received 26 January 2014; revised 3 March 2014; accepted 7 April 2014; online publish-ahead-of-print 8 May 2014 Long-term anticoagulation treatment with warfarin has been associated with a number of limitations in clinical practice and there is a need for more convenient long-term anticoagulation treatment. One of the non-vitamin K oral anticoagulants in development is edoxaban, a factor Xa inhibitor that is administered once daily. The pharmacological properties of edoxaban have various advantages in anticoagulant therapy. Edoxaban quickly reaches peak plasma concentrations in 1.5 h, has a half-life of 10–14 h, has relatively high bioavailability of 62% and exhibits highly selective, competitive, concentration-dependent inhibition of human factor Xa. The plasma concentrations of edoxaban are also closely correlated with suppression of thrombin generation and a range of platelet activation parameters (fragment 1+2, thrombin–antithrombin complex, and b-thromboglobulin), which edoxaban has been shown to rapidly inhibit. The anticoagulant activity of edoxaban is not affected by food intake or ethnicity and a number of drug–drug interaction studies have been performed. Co-administration of edoxaban with strong P-glycoprotein inhibitors, such as dronedarone, quinidine, and verapamil requires edoxaban dose-reduction by 50% to avoid the risk of over-exposure. The ex- posure of edoxaban may also increase in patients with a body weight 60 kg and moderate renal impairment. This meant a dose-reduction strat- egy in patients at risk of over-exposure was utilized in Phase III clinical studies. In conclusion, the pharmacological properties of edoxaban provide rapid and specific inhibition of factor Xa, which is closely related to plasma concentrations. Given the limitations with long-term warfarin therapy, once-daily edoxaban may provide a convenient long-term alternative for patients. ----------------------------------------------------------------------------------------------------------------------------------------------------------- Keywords Edoxaban Oral anticoagulant Pharmacokinetics Pharmacodynamics Coagulation factors Introduction Dose-adjusted oral anticoagulant (OAC) therapy with warfarin is currently recommended for the prevention of stroke in patients with atrial fibrillation (AF). 1,2 Oral anticoagulant therapy overlapped with parenteral heparin is also recommended for the prevention of recurrent venous thromboembolism (VTE). 3,4 Warfarin therapy is low cost, its use is long established and well understood, and it can be administered once-daily. However, war- farin is subject to a range of limitations in clinical practice. These include: a slow onset of action; a narrow therapeutic margin; inad- equate anticoagulation; high discontinuation rates; frequent, complex dose adjustments; increased risk of bleeding, particularly in the elderly; variability in dose response; drug and food interactions; and lack of laboratory standardization in coagulation monitoring. 5 Non-vitamin K oral anticoagulants (NOACs, previously referred to as new or novel OACs) are now available in two broad classes, which act on the two key serine protease enzymes that drive clot formation and fibrin deposition, the oral factor Xa (FXa) inhibitors (rivaroxaban, apixaban, and edoxaban [DU-176b]), and the oral direct thrombin inhibitor dabigatran etexilate have recently been introduced, or are in clinical development, for stroke prevention in AF, and prevention of recurrence of VTE. 6,7 Potential advantages of the new OACs over once-daily warfarin include a rapid onset of action, no significant food interactions, lower potential for drug interactions, and a predictable anticoagulant effect that obviates the need for routine coagulation monitoring. However, there are pharmacodynamic and pharmacokinetic differ- ences between the new OACs, which may also have implications for their clinical use. 5 The objective of this review was to focus specifically on the pharmacology of the direct FXa inhibitor, edoxaban. PubMed was searched for original primary and secondary research publications with ‘edoxaban’ OR ‘DU-176b’ OR ‘DU 176b’ OR ‘DU176b’ in any field. Original primary and secondary congress research abstracts were also searched on BIOSIS from 2010 to January 2014 using the * Corresponding author. Tel: +44 01215075080, Fax: +44 01215544083, Email: [email protected] Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2014. For permissions please email: [email protected]. European Heart Journal (2014) 35, 1844–1855 doi:10.1093/eurheartj/ehu181

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Page 1: Edoxaban:afocused review of its clinical pharmacology · pharmacology Gregory Y. H. Lip1* and Giancarlo Agnelli2 ... One of the non-vitamin K oral anticoagulants in development is

REVIEW

New drugs

Edoxaban: a focused review of its clinicalpharmacologyGregory Y. H. Lip1* and Giancarlo Agnelli2

1University of Birmingham Centre for Cardiovascular Sciences, City Hospital, Dudley Road, Birmingham, UK; and2Internal and Cardiovascular Medicine–Stroke Unit, University of Perugia, Perugia, Italy

Received 26 January 2014; revised 3 March 2014; accepted 7 April 2014; online publish-ahead-of-print 8 May 2014

Long-term anticoagulation treatment with warfarin has been associated with a number of limitations in clinical practice and there is a need formore convenient long-term anticoagulation treatment. One of the non-vitamin K oral anticoagulants in development is edoxaban, a factor Xainhibitor that is administeredonce daily. The pharmacological propertiesof edoxabanhave various advantages in anticoagulant therapy. Edoxabanquickly reachespeak plasmaconcentrations in 1.5 h, has a half-life of 10–14 h, has relatively high bioavailability of 62% and exhibits highly selective,competitive, concentration-dependent inhibition of human factor Xa. The plasma concentrations of edoxaban are also closely correlated withsuppression of thrombin generation and a range of platelet activation parameters (fragment 1+2, thrombin–antithrombin complex, andb-thromboglobulin), which edoxaban has been shown to rapidly inhibit. The anticoagulant activity of edoxaban is not affected by food intakeor ethnicity and a number of drug–drug interaction studies have been performed. Co-administration of edoxaban with strong P-glycoproteininhibitors, such as dronedarone, quinidine, and verapamil requires edoxaban dose-reduction by 50% to avoid the risk of over-exposure. The ex-posure of edoxaban may also increase in patients with a body weight ≤60 kg and moderate renal impairment. This meant a dose-reduction strat-egy in patients at risk of over-exposure was utilized in Phase III clinical studies. In conclusion, the pharmacological properties of edoxaban providerapid and specific inhibition of factor Xa, which is closely related to plasma concentrations. Given the limitations with long-term warfarin therapy,once-daily edoxaban may provide a convenient long-term alternative for patients.- - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -Keywords Edoxaban † Oral anticoagulant † Pharmacokinetics † Pharmacodynamics † Coagulation factors

IntroductionDose-adjusted oral anticoagulant (OAC) therapy with warfarin iscurrently recommended for the prevention of stroke in patientswith atrial fibrillation (AF).1,2 Oral anticoagulant therapy overlappedwith parenteral heparin is also recommended for the prevention ofrecurrent venous thromboembolism (VTE).3,4

Warfarin therapy is low cost, its use is long established and wellunderstood, and it can be administered once-daily. However, war-farin is subject to a range of limitations in clinical practice. Theseinclude: a slow onset of action; a narrow therapeutic margin; inad-equateanticoagulation; high discontinuation rates; frequent, complexdose adjustments; increased risk of bleeding, particularly in theelderly; variability in dose response; drug and food interactions; andlack of laboratory standardization in coagulation monitoring.5

Non-vitamin K oral anticoagulants (NOACs, previously referredto as new or novel OACs) are now available in two broad classes,which act on the two key serine protease enzymes that drive clot

formation and fibrin deposition, the oral factor Xa (FXa) inhibitors(rivaroxaban, apixaban, and edoxaban [DU-176b]), and the oraldirect thrombin inhibitor dabigatran etexilate have recently beenintroduced, or are in clinical development, for stroke prevention inAF, and prevention of recurrence of VTE.6,7

Potential advantages of the new OACs over once-daily warfarininclude a rapid onset of action, no significant food interactions,lower potential for drug interactions, and a predictable anticoagulanteffect that obviates the need for routine coagulation monitoring.However, there are pharmacodynamic and pharmacokinetic differ-ences between the new OACs, which may also have implicationsfor their clinical use.5

The objective of this review was to focus specifically on thepharmacology of the direct FXa inhibitor, edoxaban. PubMed wassearched for original primary and secondary research publicationswith ‘edoxaban’ OR ‘DU-176b’ OR ‘DU 176b’ OR ‘DU176b’ in anyfield. Original primary and secondary congress research abstractswere also searched on BIOSIS from 2010 to January 2014 using the

* Corresponding author. Tel: +44 01215075080, Fax: +44 01215544083, Email: [email protected]

Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2014. For permissions please email: [email protected].

European Heart Journal (2014) 35, 1844–1855doi:10.1093/eurheartj/ehu181

Page 2: Edoxaban:afocused review of its clinical pharmacology · pharmacology Gregory Y. H. Lip1* and Giancarlo Agnelli2 ... One of the non-vitamin K oral anticoagulants in development is

same search terms. The results of all searches were reconciled toremove duplicate entries and all manuscripts and abstracts withoriginal research on the pharmacokinetics or pharmacodynamics ofedoxaban were assessed for inclusion in this review article (Figure 1).

Pre-clinical pharmacologicalanalyses with edoxaban

Effects on coagulation parametersStudies in vitroEarly investigationswithedoxabanassessed in vitropharmacologicalpro-files and in vivo effects of edoxaban in animal models of thrombosis andbleeding. Edoxaban inhibited FXa with Ki values of 0.561 nM for freeFXa, 2.98 nM for prothrombinase and exhibited .10 000-fold selectiv-ity for FXa. Inhibition of human FXabyedoxaban was concentration de-pendent and competitive (Figure 2).8 In human plasma, edoxabandoubled prothrombin time (PT) and activated partial thromboplastintime (aPTT) at concentrations of 0.256 and 0.508 mM, respectively.8

Edoxaban has also been analysed in an in vitro thrombin generation(TG)assay inhumanplasma. In this assay, edoxabansuppressedTGinaconcentration-dependent manner, suppressed TG peak height andprolonged lag time.9 The effects of edoxaban on TG have also beencompared with the indirect FXa inhibitor fondaparinux. In the studyby Samama et al.,10 edoxaban exhibited a three-fold greaterconcentration-dependent effect than fondaparinux across TG lagtime, peak thrombin, and time to peak, but this was not observedwith endogenous thrombin potential; also, edoxaban produced aconcentration-dependent prolongation of the PT ratio and aPTT.10

An analysis of the effects of edoxaban on human platelet aggregationinduced by tissue factor and clot-bound FXa in vitro found that edoxa-ban, a direct FXa inhibitor,was a more potent inhibitorof tissue factor-inducedplatelet aggregationandclot-boundFXathanfondaparinux,anindirect FXa inhibitor. These findings suggest that direct inhibition ofFXa may provide additional benefits over indirect FXa inhibition.11

Studies in animalsEdoxaban dose-dependently inhibited thrombus formation in rat andrabbit thrombosis models in vivo. Orally administered edoxaban inrats and rabbits significantly and dose-dependently reduced

Figure 1 Flowchart of edoxaban manuscript and abstract selection process.

Figure 2 Lineweaver–Burk kinetic analysis of the activity ofhuman FXa in the absence or presence of edoxaban (DU-176b).Data represent means+ SEM of triplicate assays. Reproducedfrom Furugohri et al. 8

Pharmacological analysis of edoxaban 1845

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thrombus formation and prolonged PT.8 Also, plasma samplesderived from edoxaban-treated rats inhibited exogenous FXa activityand, in rabbits, edoxaban exerted a dose-dependent antithromboticeffect on venous thrombus weight (Figure 3). Moreover, edoxaban 10and 30 mg/kg significantly prolonged rat tail bleeding time by 1.9-fold,compared with control.8

In addition, edoxaban has also been compared with fondaparinuxin venous and arterial thrombosis models and in an ex vivoperfusion-chamber thrombosis model under low- and high-shearrates, which simulated conditions in veins and stenosed arteries inrats. Effective doses of edoxaban that reduced thrombus formationby 50% (ED50) in venous and arterial thrombosis models were0.076 and 0.093 mg/kg/h, respectively.12 In contrast, the ED50 of fon-daparinux in the arterial thrombosis model (.10 mg/kg/h) wasmarkedly higher compared with the venous thrombosis model(0.021 mg/kg/h).12

Edoxabanalso inhibited the formation offibrin underboth high- andlow-shear rate conditions, whereby edoxaban 3 mg/kg/h reducedthrombus weight by 88% under the low-shear rate (venous model)and by 70% under the high-shear rate (arterial model), respectively.Incontrast, fondaparinux inhibitedfibrindepositionby84%under low-shear rate and only showed a slight reduction under the high-shearrate.12

The potential of edoxaban to influence tissue factor-induced coagu-lation and coagulation pathways in rats has been compared with thedirect thrombin inhibitor, melagatran.13 Edoxaban dose-dependentlyinhibited platelet consumption and thrombin–antithrombin (TAT)complex generation. Also, in a hypercoagulation model, edoxaban

did not exert any deleterious effects on platelet counts and inhibitedthe rapid pattern of platelet consumption observed with the directthrombin inhibitor melagatran. This observation of a lower possibilityof coagulation pathway activation points to a potential mechanisticbenefit with anticoagulation using a factor Xa inhibitor such as edoxa-ban, rather than a direct thrombin inhibitor.13

Effects on bleeding in animal modelsThe risks of bleeding with edoxaban have been compared with thoseassociated with warfarin and the low-molecular-weight heparin(LMWH), enoxaparin, in rat models of thrombosis and haemorrhage.The dose–response curves of the antithrombotic effects and bleedingtime prolongation of edoxaban, warfarin, and enoxaparin from Mor-ishima et al.14 are shown in Figure 4. In this study, the therapeuticindexofedoxabanwas .10.5,whereasthatofwarfarin andenoxaparinwere 1.3 and 3.4, respectively, indicating a wider therapeutic windowwith edoxaban compared with warfarin or enoxaparin treatment.14

Combination therapy in animal modelsThe combined effects of edoxaban with the antiplatelet agents,aspirin and clopidogrel have been investigated following oral admin-istration in fasted rats, 0.5, 1, and 2 h before thrombus induction.15

In the study by Morishima et al.,15 the combination of submaximaldoses of edoxaban 1 mg/kg and aspirin 50 mg/kg, or edoxaban1 mg/kg and clopidogrel 10 mg/kg showed additive antithromboticeffects. Edoxaban 1 mg/kg or aspirin 50 mg/kg alone had no effecton bleeding time, but combining both these agents induced lessthan two-fold bleeding prolongation. Clopidogrel 10 mg/kg also

Figure 3 Antithrombotic effect of edoxaban in venous stasis thrombosis models in rats (n ¼ 8, A–C) and rabbits (n ¼ 8, D). (A) thrombus weight,(B) PT, (C) exogenous FXa activity and (D) thrombus weight in rabbits. In the rat model, edoxaban was orally administered 30 min before thrombusinduction. Blood samples were drawn 29 min after dosing. In rabbits, edoxaban was orally administered 45 min before thrombus induction. Datarepresent themeans+ SEM. **P , 0.01, ***P , 0.0001 vs. control. Data represent means+ SEM of triplicate assays. PT, prothrombin time. Repro-duced from Furugohri et al.8

G.Y.H. Lip and G. Agnelli1846

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prolonged bleeding time 2.1-fold and the addition of edoxaban1 mg/kg had no effect on the prolongation of bleeding time by clopi-dogrel. Thus, perhaps unsurprisingly, edoxaban potentiates theeffects of antiplatelet therapy in pre-clinical models.15

Clinical pharmacokineticsof edoxaban

Absorption, distribution, metabolism,and excretion of edoxabanThe clinical pharmacokinetic studies with edoxaban are summarizedin Table 1. In healthy subjects, the pharmacokinetics of edoxaban arecharacterized by rapid absorption (1–3 h) and the elimination half-

life of edoxaban 60 mg once daily is 10–14 h.16,17 Peak plasma con-centrations of edoxaban are achieved at �1.5 h afteroral administra-tion (Figure 5A).16,18 The absolute oral bioavailability of edoxaban inhealthy subjects is 62% (Table 1).17

Edoxaban pharmacokinetics is also linearly correlated with coagu-lation parameters within its therapeutic dose range in healthy sub-jects. Accordingly, from 1 to 3 h post-dose, edoxaban 60 mg hasbeen observed to produce plasma concentrations approximatelydouble those achieved after administration of edoxaban 30 mg(Figure 5B).19 In a study by Fuji et al.,20 the profile of coagulation bio-markers with edoxaban 30 mg once daily compared with enoxaparin20 mg twice daily treatment, was assessed in VTE patients from theSTARS E-3 and STARS J-V trials. The investigators found that edox-aban reduced D-dimer, prothrombin fragment 1 + 2 (F1+2), andthe soluble fibrin monomer complex all to a significantly greaterextent than enoxaparin by 7 and 11–14 days of treatment (P , 0.001for edoxaban vs. enoxaparin in all comparisons).20

The elimination profile of radiolabelled [14C]edoxaban has beeninvestigated in healthy subjects and �60% of edoxaban is eliminatedin faeces, with �35% in urine. Edoxaban undergoes biotransforma-tion to various metabolites, the most abundant of which [M4] isformed through hydrolysis.21,22 In addition, over 70% of an edoxabandose is excreted unchanged.22 Gender has a minimal clinical effect onthe pharmacokinetics of edoxaban.23

In view of the role of the kidneys in the elimination of edoxaban, itspharmacokinetics has been assessed in patients with renal impair-ment. An initial 8-week study in 93 AF patients found that the useof edoxaban 15 mg once daily in patients with severe renal impair-ment resulted in similar safety outcomes and plasma levels 1–8 hpost-dose as edoxaban 30 or 60 mg once daily in patients with mildrenal impairment or normal renal function.24 A similar study hasbeen performed in 80 VTE patients undergoing lower-limb ortho-paedic surgery, with edoxaban15 mg in patients with severe renal im-pairment compared with edoxaban 30 mg in patients with mild renalimpairment and fondaparinux 1.5 mg in patients with severe renal im-pairment.25 By Day 7 of treatment, edoxaban plasma concentrationsoverlapped between patients with severe and mild renal impairmentand similar bleeding outcomes and adverse events were observed inthe edoxaban 15 and 30 mg groups. These two initial studies suggestthat edoxaban 15 mg once daily may be a suitable dosing regimen forboth AF and orthopaedic surgery VTE patients with severe renal im-pairment.25 In patients with end-stage renal disease (ESRD) with orwithout haemodialysis treatment, it has also been shown that haemo-dialysis had minimal effects on the clearance of edoxaban and thatadditional edoxaban dose adjustment may not be necessary whenESRD patients are undergoing haemodialysis.26

Relationship between edoxabanpharmacokinetics and bleedingThe pharmacokinetics of various doses of edoxaban were alsoassessed in a Phase II dose-finding study in patients with AF, whichshowed that edoxaban exposure parameters (minimum steady-stateconcentration [Cminss], area under the plasma concentration-timecurve from 0 to 24 h at steady-state [AUCss] and maximumsteady-state plasma concentration [Cmaxss]) increased with highertotal daily doses of edoxaban.27 With the same total daily dose of

Figure 4 Dose relationship of antithrombotic effects andbleeding-time prolongation of edoxaban, warfarin, and enoxaparinin rats. (A) Edoxaban, (B) warfarin, (C ) enoxaparin. Antithromboticeffect (% control of thrombus formation) and bleeding-time pro-longation (ratio to control) were plotted against doses. Datarepresent the means+ SEM (n ¼ 8). Reproduced from Morishimaet al.14

Pharmacological analysis of edoxaban 1847

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Table 1 Clinical pharmacokinetic studies with edoxaban

Study Patients Treatment groups Design Principal findings Comment

Ogata et al.16 Healthy adult males(n ¼ 121)

SD group: edoxaban 10, 30, 60 90, 120,and 150 mg q.d.

MD group: edoxaban 90 mg q.d., 90 mgb.i.d., 120 mg q.d.

Phase I, single-blind, randomized,placebo-controlled, ascendingsingle and multiple oral dosestudy

Edoxaban plasma levels were proportional todose, consistently peaked1.5 h post-dose andcorrelated with coagulation parameters.

Edoxaban 10 mg q.d. to 150 mg q.d. weresafe and well tolerated, withpredictable pharmacology

Matsushimaet al.17

Healthy adults(n ¼ 35)

Edoxaban 60 mg or 30 mg IV over30 min

Randomized, two-arm studyassessing bioavailability of oraland IV edoxaban

The ratios of geometric LSM of thedose-adjusted AUC0-inf between oral and IVedoxaban indicated bioavailability of 61.80%(95% CI: 57.70, 66.19). Edoxaban 60 mg half-life was 11.5+5.63 h

Edoxaban has a relatively highbioavailability of 62%

Mendellet al.35

Healthy Japaneseand Caucasianadults (n ¼ 32)

Edoxaban 60 mg with or without food,then an alternative diet

Open-label, randomized, foodeffect study

Edoxaban plasma concentration, elimination,changes in PT and aPTT were not affected byrace or food intake

Edoxaban can be administered withoutregard to food

Bathalaet al.22

Healthy males(n ¼ 6)

[14C]Edoxaban 60 mg Open-label study Over 97% of the administered radioactive[14C]Edoxaban dose was recovered, with62.2% eliminated in faeces and 35.4% in urine

A substantial proportion of edoxaban isexcreted by the renal system in urine

Raskobet al.29

VTE patientsfollowingorthopaedicsurgery(n ¼ 903)

Edoxaban 15, 30, 60, or 90 mg q.d. ordalteparin q.d., 6–8 hpost-operatively for 7–10 days

Incidences of VTE were 28.2, 21.2,15.2, and10.6% in the edoxaban 15, 30, 60, or 90 mggroups, respectively, vs. 43.8% in thedalteparin group

Edoxaban 15, 30, 60, or 90 mg is moreeffective than dalteparin in preventingVTE, with a dose–responserelationship observed

Fuji et al.25 Japanese VTE,orthopaedicsurgery patients(n ¼ 80)

Edoxaban 15 mg (CrCl ≥15 to,20 mL/min), edoxaban 15 mg orfondaparinux 1.5 mg mg (CrCl ≥20to ,30 mL/min), edoxaban 30 mg(CrCl ≥50 to ,80 mL/min)

Open-label study Bleeding events occurred in 6 (20.7%), 8 (40.0%),and 10 (33.3%) and CRNM bleeding in 1(3.4%), 1 (5.0%), and 2 (6.7%) patients in theedoxaban 15 mg, fondaparinux 1.5 mg, andedoxaban 30 mg groups

Edoxaban 15 mg may be a suitable dosein VTE, orthopaedic surgery patientswith severe renal impairment

Weitz et al.27 AF patients withCHADS2 ≥2(n ¼ 1,146)

Edoxaban 30 mg q.d., 30 mg b.i.d., 60 mgq.d., or 60 mg b.i.d. or open-label,dose-adjusted warfarin

Parallel-group, multinational,active-controlled, 12-weekstudy

Major and CRNM bleeding in 3.1% of warfarin,10.6% of edoxaban 60 mg b.i.d. (P ¼ 0.002 vs.warfarin), 7.8% of 30 mg b.i.d. (P ¼ 0.029 vs.warfarin), 3.8% of 60 mg q.d., 3.0% of 30 mgq.d. treatment groups. Bleeding frequencyandCminss were higher in the 30 mg b.i.d. groupthan in the 60 mg q.d. group

Edoxaban 30 or 60 mg q.d. resulted insimilar bleeding outcomes as warfarinin AF patients, both q.d. doses werewell tolerated and bleeding withedoxaban is related to Cminss

Fuji et al.20 VTE patients inSTARS E-3and J-V

Edoxaban 30 mg q.d., enoxaparin 20 mgb.i.d.

Pooled post hoc analysis Edoxaban 30 mg reduced D-dimer, F1+2 andSFMC significantly more than enoxaparin

Edoxaban is more effective at reducingblood coagulation markers thanenoxaparin

Yamashitaet al.28

Japanese AF patientswith CHADS2

≥1 (n ¼ 536)

Edoxaban 30, 45, or 60 mg q.d. oropen-label, dose-adjusted warfarin

Multicentre, randomized,dose-ranging, 12-week study

All bleeding events increased with increasingedoxaban doses, but a significant doseresponse was not found with edoxaban for all,major, or major and CRNM bleeding.Edoxaban Cmin in the ≤60 kg subgroup washigher than the Cmin in the .60 kg subgroupwith all doses

Edoxaban 30, 45, or 60 mg are safe andwell tolerated in AF patients, andpatients ,60 kg are at risk ofedoxaban under-exposure

G.Y

.H.Lip

andG

.Agnelli

1848

Page 6: Edoxaban:afocused review of its clinical pharmacology · pharmacology Gregory Y. H. Lip1* and Giancarlo Agnelli2 ... One of the non-vitamin K oral anticoagulants in development is

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Chung et al.19 Asian AF patientswith CHADS2

score ≥1(n ¼ 235)

Edoxaban 30 mg q.d., 60 mg q.d. orwarfarin

Multicentre, active-controlled,double-blind edoxaban andopen-label warfarin,parallel-group, safety study

The incidence of all bleeding events (95% CI) was20.3% for edoxaban 30 mg, 23.8% foredoxaban 60 mg, and 29.3% for warfarin.Adverse events were similar between theedoxaban 60 mg and warfarin groups andwere lower with the edoxaban 30 mg group

Edoxaban 30 and 60 mg were safe andwell tolerated and this studysuggesteda trend towards less bleeding thanwarfarin

Koretsuneet al.24

Japanese AF patients(n ¼ 93)

Edoxaban 15 mg (severe renalimpairment), 30 mg or 60 mg(moderate renal impairment ornormal renal function)

Open-label, randomized study Edoxaban 15 mg resulted in similar bleedingoutcomes and plasma concentrations asedoxaban 30 mg or 60 mg

Edoxaban 15 mg may be a suitable dosein AF patients with severe renalimpairment

Matsushimaet al.26

ESRD,haemodialysispatients (n ¼ 9)

Edoxaban 15 mg 2 h prior tohaemodialysis, then on a day withouthaemodialysis at least 7 days after

Open-label, two-way crossoverstudy

Haemodialysis had minimal effects on theclearance and exposure of active metabolitesand protein binding of edoxaban andtreatment was well tolerated

Additional dose adjustment of edoxaban15 mg may not be necessary in ESRDpatients undergoing haemodialysis

AF, atrial fibrillation; AUC, area under the plasma concentration-time curve; aPTT, activated partial thromboplastin time; b.i.d., twice daily; CHADS2, congestive heart failure, hypertension, aged ≥75 years, diabetes mellitus, stroke or transientischaemic attack or thromboembolism (doubled); Cminss, minimum steady-state concentration; CI, confidence interval; CrCl, creatinine clearance; CRNM, clinically relevant non-major bleeding; F1+2, fragment 1+2; LSM, least-squares mean; MD,multiple dose; PT, prothrombin time; q.d., once daily; SD, single dose; SFMC, soluble fibrin monomer complex; TG, thrombin generation; IV, intravenous; VTE, venous thromboembolism.

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doses for subsequent Phase III studies.30 Dose reduction by 50% inpatients with moderate renal impairment (creatinine clearance30–50 mL/min) or who required strong P-glycoprotein (P-gp) inhibi-tors was also suggested by the modelling observations. These find-ings, together with those regarding body weight by Yamashitaet al.,28 meant that in Phase III studies with edoxaban, body weight≤60 kg, moderate renal impairment or concomitant treatmentwith strong P-gp inhibitors were criteria for dose reduction.30 –32

A large proportion of patients (17.5%) met the criteria for dose ad-justment in Hokusai-VTE and analogous results to the overall popu-lation were reported in this group.32 The rate of recurrent VTE was3.0% in the dose-adjusted edoxaban group vs. 4.3% in the warfaringroup (hazard ratio 0.73 [95% confidence interval] 0.42–1.26).32

Clinical pharmacodynamicsof edoxabanTheclinicalpharmacodynamic studieswithedoxabanaresummarized inTable 2. In healthy subjects, edoxaban 60 mg once daily has been shownto inhibit TG for over 24 h (Figure 7),33 providing further support thatonce-daily dosing provides suitable anticoagulation efficacy with once-daily dosing (Table 2). The antithrombotic effects of edoxaban havebeen investigated under arterial and venous flow conditions.34 Undervenous flow conditions 1.5 and 5 h post-edoxaban, thrombus size wasreduced by 28 and 21%, respectively (P , 0.05 vs. baseline). Under

arterial conditions, the reduction was 26 and 17% at 1.5 and 5 h post-edoxaban, respectively (P , 0.05 vs. baseline), which was also statistic-ally significant. Changes in INR, PT and anti-FXa activity also correlatedclosely with edoxaban plasma concentrations,34 and the strongestcorrelation among these clotting parameters was observed with PTchanges (R2¼ 0.79), followed closely by INR changes (R2¼ 0.78).The correlation with aPTT, whilst statistically significant, was less close(R2¼ 0.40).34 In addition, a study of the effects of edoxaban on PTand aPTT in Japanese and Caucasian patients has shown that ethnicitydoes not influence the anticoagulant activity of edoxaban (Figure 8).35

Compared with fondaparinux 2.5 mg, edoxaban 30 mg, 60 and120 mg once-daily causes significantly larger reductions in the TGand platelet activation parameters, F1+2, the thrombin-antithrombin(TAT) complex and platelet activation marker b-thromboglobulin(b-TG).18 This analysis also found a direct linear correlationbetween the observed range of plasma concentrations of edoxabanduring the dosing interval and the blood coagulation parametersaPTT and PT, with correlation coefficients of 0.738 and 0.957,respectively.18 When compared with the LMWH dalteparin anddirect thrombin inhibitor ximelagatran, edoxaban 60 mg twice-dailyalso caused a larger reduction in PT activity compared with ximelaga-tran, but did not for TAT, F1+2 or D-dimer.36

The clinical pharmacodynamics of edoxaban have also been inves-tigated 24-h post-warfarin therapy, with edoxaban causing a signifi-cant increase in PT within 2 h (from 27.0 to 43.9 s; P , 0.001 vs.placebo).37 PT values returned to near post-warfarin baseline

Figure 6 (A) Edoxaban plasma exposure by dosing regimen; (B) incidence of all bleeding events by edoxaban group. AUC, area under plasmaconcentration-time curve; BID, twice daily; Cmaxss, maximum steady-state concentration; Cminss, minimum steady-state concentration; QD, oncedaily. Reproduced from Weitz et al.27

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levels (26.3 s) at 12 h post-edoxaban dose and remained higherthan with placebo at all measured time points between 1 and 12 h.Warfarin treatment increased aPTT values from 35.6 to 50.8 s, andedoxaban also increased aPTT further to 67.4 s at 1 h post-dose,demonstrating that edoxaban has a bigger effect on aPTT thanwarfarin. Also, anti-FXa activity was mostly undetectable duringwarfarin treatment (,0.10 IU/mL), but increased following edoxa-ban administration, reaching peak levels of 2.68 IU/mL at 1 to 2 hpost dose, and then declining to approximately baseline levels by24 h post dose (Figure 9).37 The transient increases in various coagu-lation parameters returned to baseline levels 24-h after edoxabandosing.

Edoxaban metabolism, drug,and food interactionsA study in healthy, fasted or fed Japanese and Caucasian volunteersshowed that the absorption, mean plasma concentration and awide range of other PK characteristics of edoxaban are not affectedby food.35 Also, food does not affect edoxaban absorption, elimin-ation, peak concentrations, half-life or the influence of edoxabanon aPTT and PT (Figure 8).35

The drug–drug interaction studies with edoxabanare summarizedin Table 3. No effect on edoxaban absorption has been observed inco-administration with digoxin, atorvastatin or esomeprazole.38,39

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Table 2 Clinical pharmacodynamic studies with edoxaban

Study Patients Treatment groups Design Principal findings Comment

Woltzet al.18

Healthy adultmales(n ¼ 100)

Edoxaban 30, 60, or120 mg,fondaparinux2.5 mg or placebo

Open-label, randomized, study ofblood coagulation markersF1+2, TAT and b-TG in venousand shed blood

All edoxaban doses inhibitedF1+2, TAT and b-TG in shedblood samples significantlymore than fondaparinux

Single oral doses ofedoxaban 30, 60, or120 mg cause rapid andsustained inhibition ofcoagulation for up to 24 h

Mendellet al.37

Healthy adults(n ¼ 72)

Edoxaban 60 mg q.d.or placebo,followed bywarfarin

Randomized, placebo-controlled,safety study of edoxabanpost-warfarin therapy

Edoxaban 60 mg administered24 h post-warfarin appearedto be safe and well tolerated.Adverse events were similaracross treatments

Edoxaban causes transientincreases in coagulationparameters, whenadministered 24 hpost-warfarin therapy

Samamaet al.36

Healthyelderlymales(n ¼ 40)

Edoxaban 60 mgb.i.d., dalteparin5000 IU orximelagatran24 mg

Open-label, randomized, study ofblood coagulation markersF1+2, TAT, D-dimer andadverse events

There were no differences inTAT, F1+2 and D-dimer levelspost-edoxaban andpost-ximelagatran dosing.Edoxaban caused a greaterchange in TAT and F1+2 levelsthan dalteparin. Edoxabanreduced PT more rapidly andfor longer than ximelagatranand dalteparin. Edoxaban didnot affect platelet activation,tissue factor pathwayinhibition or endothelialbreakdown

This was the first study tocompared a FXainhibitor, DTI andLMWH, and showededoxaban inhibits TGand FXa

Zahiret al.33

Healthy adultsaged 18–45years(n ¼ 32)

Edoxaban,enoxaparin,edoxaban plusenoxaparin,enoxaparin plusedoxaban 12 hlater

Phase I, open-label, randomized,four-period, four-treatment,cross-over safety study ofenoxaparin 1 mg/kg followedby edoxaban 60 mg 12 h later

Edoxaban alone and combinedwith enoxaparin inhibited TGfor over 24 h. No adverseevents were reported in anygroup and changes in drugpharmacology were notobserved

Edoxaban 60 mg can besafely administered 12 hafter enoxaparin 1 mg/kg

Zafaret al.34

Healthy adults(n ¼ 12)

Edoxaban 60 mg Phase I, open-label, single-armpharmacology study

Peak plasma edoxabanconcentrations observed 1.5 hafter dosing. TG wassignificantly reduced undervenous and arterial conditions1.5 and 5 h post-dosingCorrelation of plasmaedoxaban with: FXa activityR2 ¼ 0.85, INR R2 ¼ 0.78, PTR2 ¼ 0.79, aPTT R2 ¼ 0.40

Plasma edoxaban levelsclosely correlated withreductions in TG andchanges in clottingparameters

b-TG, b-thromboglobulin; b.i.d., twice daily; DTI, direct thrombin inhibitor; FXa, factor Xa; F1+2, fragment 1+2; INR, international normalized ratio; LMWH, low-molecular-weightheparin; PT, prothrombin time; q.d., once daily; TAT, thrombin-antithrombin; TG, thrombin generation.

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The pharmacokinetics of edoxaban are not affected by enoxaparin,whether they are administered concomitantly or 12 h apart.33

When co-administered with the P-gp inhibitor digoxin, the extentof exposure to edoxaban (AUC0-tau) was similar vs. edoxaban admi-nistered alone and edoxaban Cmax increased by �16% in combin-ation with digoxin. Overall, there was a minimal effect on the PKprofile of either edoxaban or digoxin during co-administration.40

With regard to concomitant administration of amiodarone withedoxaban, an increase of 39.8% in edoxaban exposure and reductionof 25.7% in the 24-h concentration for edoxaban was observed.39

In combination with a strong P-gp inhibitor quinidine, edoxaban

Cmax and AUC0 –24 increased substantially by 85.4 and 76.7%,respectively. Moreover, peak increases from baseline in PT, INR,and aPTT with edoxaban were augmented by 73, 70, and 46%,respectively, by quinidine.39,41 The pharmacokinetics of edoxabanis influenced by co-administration with dronedarone, which increasesAUC0-inf and Cmax by 84.5 and 45.8%, respectively. Co-administrationof dronedarone also increased 24-h edoxaban concentration by157.6%.39 A similar strong P-gp inhibitor, verapamil, caused reductionsof 41, 44 and 29%, in PT, INR, and aPTT, respectively, consistentwith increased edoxaban exposure.41 Verapamil also substantiallyincreasededoxabanCmax andAUC0–24 by53.3 and52.7%, respective-ly. These findings meant that in Phase III studies with edoxaban,co-administration with a strong P-gp inhibitor such as dronedarone,quinidine, or verapamil was a criteria for edoxaban dose reduction(Table 3).31,42

In addition, there are restrictions on the co-administration ofedoxaban with certain macrolide antibiotics (erythromycin, azithro-mycin, and clarithromycin) and azole antifungals (ketoconazole anditraconazole) were also prohibited in the Phase III trials.42

However, edoxaban metabolism by cytochrome P450 isozymes is,4% of parent exposure and they play an insignificant role in the me-tabolism of edoxaban.22

Regarding co-administration of edoxaban with acetylsalicylic acid(ASA) 100 or 325 mg once daily, combining treatments increasedbleeding time to a larger extent than observed with either monother-apy.43 Also, co-administration with ASA 325 mg affected edoxabanpharmacokinetics, and geometric mean ratios (90% CI) for AUCand Cmax were129.9 (122.6, 137.7) and 134.6 (123.8, 146.3), respect-ively. However, the coagulation markers PT, aPTT and change in

Figure 7 Changes in thrombin generation following dosing ofedoxaban 60 mg in healthy subjects. Adapted from Zahir et al.33

Figure8 Profile of arithmetic mean (A) PTand (B) aPTT followingedoxaban 60 mg administration in Japanese and Caucasian patients, in fasted andfed states. aPTT, activated partial thromboplastin time; PT, prothrombin time. Reproduced from Mendell et al.35

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anti-FXa activity were similar in combination therapy with both ASAdoses compared with monotherapy.43 With these results in mind,ASA ≤100 mg once daily was permitted with edoxaban in subse-quent Phase III clinical studies.31,42 The effects of co-administrationof the platelet aggregation inhibitor naproxen on the pharmaco-dynamics of edoxaban have also been evaluated. Combining bothtreatments increased PT and did not substantially change the areaunder the curve or maximum plasma concentrations comparedwith either monotherapy.44

Theeffectsofwarfarin andedoxabanon theserumconcentrationoftotal, gamma-carboxylated (Gla-osteocalcin), andunder-carboxylatedosteocalcin (uc-osteocalcin) in ratshave been assessed because osteo-calcin plays a role in bone homoeostasis. This study found that warfarinimpaired thecarboxylationofosteocalcin in rats. In contrast, edoxabanat doses needed for an antithrombotic effect or higher sustained circu-lating Gla-osteocalcin levels. Thus, edoxaban had no significant effecton the production of Gla-osteocalcin; therefore, it may potentiallyhave a lower risk of adverse effects on bone health in humans.45

Reversal of edoxaban anticoagulanteffectsIncreased risk of haemorrhage is the principal side-effect of anticoa-gulation and the ability to reverse excessive anticoagulation is an im-portant option in certain clinical situations. Potential reversal agentsfor edoxaban have been investigated in pre-clinical studies.

Recombinant human factor VIIa (rhFVIIa), anti-inhibitor coagu-lant complex (FEIBA), and prothrombin complex concentrate(PPSB-HT) are all able to significantly reduce the changes in PTcaused by edoxaban in a concentration-dependent manner.46 Com-pared with edoxaban alone, rhFVIIa (1 and 3 mg/kg), and FEIBA(100 U/kg) reversed edoxaban-induced prolongation of bleedingtime in rats to a significant extent. Also, rhFVIIa significantly increasedthrombus formation when combined with edoxaban.46 An ex vivostudy has also been performed with human plasma samples, to deter-mine the effective doses and time course required for either rhFVIIaor FEIBA to reverse anticoagulation by supratherapeutic doses ofedoxaban.47 A TG assay indicated both rhFVIIa and FEIBA reversed45 and20% of the effect of edoxabanat500and 1000 ng/mL, respect-ively, 4 h after adding the reversal agents. With the exception of onebaseline sample, levels of D-dimer did not show significant changeswith the addition of edoxaban or with its subsequent reversal byeither rhFVIIa or FEIBA. Therefore, low therapeutic concentrationsof rhFVIIa and FEIBA induced significant and rapid reversal ofsupratherapeutic concentrations of edoxaban.47 These were prom-ising initial pre-clinical results and they did not include comparisonswith the reversal of anticoagulation after dabigatran administration.Further studies may help clarify the clinical efficacy of rFVIIa, FEIBA,and PPSB-HT.

The recombinant factor Xa protein andexanet alpha (PRT4445) iscatalytically inactive, does not inhibit factorXa, and may bea potentialreversal agent for factor Xa inhibition.48 A Phase II proof-of-conceptstudy in healthy volunteers to evaluate the safety, tolerability,pharmacokinetics, and pharmacodynamics of andexanet alfa after

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Table 3 Clinical drug–drug interaction studies with edoxaban

Study Drug tested Potential interaction Comment

Mendell et al.38 Esomeprazole No influence on edoxaban AUC0-t or Cmax

Mendell et al.39 Atorvastatin No influence on edoxaban absorption

Mendell et al.39,40 Digoxin No influence on edoxaban absorption

Mendell et al.39 Amiodarone Increased edoxaban exposure by 39.8%

Mendell et al.39 Quinidine Increased edoxaban exposure by 76.7%; reduced peakincreases in PT, INR, and aPTT

Dose-adjustment recommended

Mendell et al.39 Verapamil Increased edoxaban exposure by 52.9%; reduced peakincreases in PT, INR, and aPTT

Dose-adjustment recommended

Mendell et al.39 Dronedarone Increased edoxaban exposure by 84.5% Dose-adjustment recommended

Zahir et al.33 Enoxaparin No significant changes in edoxaban pharmacokinetics

Mendell-Harary et al.44 Naproxen No significant changes in edoxaban pharmacokinetics

Mendell-Harary et al.43 ASA No significant changes in edoxaban pharmacokineticswith ASA 100 mg

Concomitant ASA limited to≤100 mg/day

AUC, area under the plasma concentration-time curve; aPTT, activated partial thromboplastin time; ASA, acetylsalicylic acid; Cmax, maximum concentration; INR, internationalnormalized ratio; PT, prothrombin time.

Figure 9 Relationship between edoxaban concentration andanti-factor Xa (FXa) activity. Reproduced from Mendell et al.37

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dosing of a direct or indirect factor Xa inhibitor is currently ongoing(NCT01758432). Recent results from this ongoing clinical trialshowed that andexanet alpha is able to dose-dependently, partiallyreverse the anticoagulant effects of rivaroxaban and apixaban, asassessed by pharmacodynamic markers.49

In addition, a novel, synthetic small molecule (PER977) has beendesigned and synthesized for the reversal of anticoagulation withNOACs. Preliminary studies with PER977 in vitro and assessment ofrat tail bleeding models have shown that it directly and specificallybinds the NOACs to reverse anticoagulant activity. PER977 exhibitsno binding to any human plasma coagulation factors or albumin andhas shown no pro-coagulant properties. It reverses the anticoagulanteffects of edoxaban within 20 min after administration.50,51 A first-in-human clinical trial to assess the safety and efficacy of PER977 3 hafter administration of edoxaban 60 mg in healthy human volunteersis ongoing (NCT01826266).

There mayalso be other potential options for the reversal of antic-oagulation, such as tranexamic acid or desmopressin, which utilizedifferent approaches to induce a pro-coagulant response comparedwith the antidotes in development.52–54 However, studies with theseagents following administration of edoxaban have not beenperformed.

DiscussionAnticoagulation treatment with warfarin is associated with a numberof limitations in clinical practice. Therefore, new OACs have beendeveloped for a number of indications, such as acute VTE treatmentand stroke prevention in AF patients. Extensive pharmacologicalstudies have been performed with edoxaban, with important insightsinto the drug, and these havealso influenced the designof subsequentclinical studies. Importantly, in healthy subjects edoxaban has beenshown to maintain adequate anticoagulant activity and appearedwell tolerated when administered 24 h after the last dose ofwarfarin.37

Edoxaban has various properties that may be advantageous in anti-coagulant therapy. It is rapidly absorbed, has relatively high bioavail-ability, quickly reaches peak plasma concentrations, and exhibitshighly selective, competitive, concentration-dependent inhibitionof FXa. Edoxaban quickly induces anticoagulation activity and has awider therapeutic window than warfarin. The plasma concentrationsof edoxaban are also closely correlated with its anticoagulantactivity.16– 18,27

Two large Phase III clinical studies with edoxaban have re-cently been completed. The Hokusai-VTE study in patients withacute symptomatic VTE (n ¼ 8292) demonstrated that LMWH/edoxaban 60 mg once daily was non-inferior to the standardtherapy with LMWH/warfarin in the treatment and prevention ofrecurrent VTE. In terms of safety, patients in the edoxaban 60 mgonce daily group had a significantly lower rate of major or clinicallyrelevant non-major bleeding events than the conventional therapygroup.32

In addition, the ENGAGEAF-TIMI 48 study showed that in patientswith AF (n ¼ 21 105), the high-dose edoxaban strategy (60 mg once-daily, reduced to 30 mg based on patient characteristics) andlow-dose edoxaban strategy (30 mg once-daily, reduced to 15 mgod based on patient characteristics) were both non-inferior to

warfarin for the prevention of stroke or systemic embolism, andwere also associated with significantly lower rates of bleeding andcardiovascular death than warfarin.55 On the basis of these Phase IIIstudy results, marketing authorization for edoxaban 60 mg oncedaily (with adjustment to 30 mg if required) for both stroke preven-tion in AF and the treatment and prevention of recurrence of VTE inthe USA and EU was requested in January 2014.

The clinical pharmacology studies with edoxaban provided im-portant insights that influenced the design of the Phase III edoxabanstudies. Drug interaction studies with edoxaban showed thatco-administration with strong P-gp inhibitors and body weight,60 kg may lead to increased exposure, and a reduced dose of edox-aban should be utilized in such situations.40,41 They also showed thatthe optimum balance between stroke prevention and bleeding risk isachieved with edoxaban once daily dosing, rather than twice daily.27

Anedoxabanonce daily regimen was thereforeutilized in the Phase IIIHokusai-VTE and ENGAGE AF-TIMI 48 trials.31,42 Edoxaban wasalso safe when co-administered with ASA ≤100 mg and this wasthe limit permitted in Phase III studies.43

The food and drug interaction profile of warfarin poses numerousrestrictions on physicians and patients. As edoxaban can be adminis-tered without regard to food, this drug (as well as other new OACs)may provide a more convenient long-term anticoagulant treatmentfor patients.35 The other potential advantages with edoxaban treat-ment are a lack of routine laboratory monitoring, reliable pharmacol-ogy, reliable dose response and a simplified once-daily dosingschedule that may help promote patient adherence.

It has also been observed that inhibition of FXa with edoxabandoes not stimulate coagulation pathways, as is observed with direct-thrombin inhibition.13 This may prove to be a significant theoreticaladvantage with anticoagulation by FXa inhibition rather than throm-bin inhibition. Edoxaban is also a more effective anticoagulant thanfondaparinux, the direct-thrombin inhibitor ximelagatran andLMWH dalteparin.10,11,36

The pharmacological properties of edoxaban allow it to providerapid and specific inhibition of FXa, which has been shown toclosely relate to edoxaban plasma concentration. Preliminarypharmacology studies with edoxaban identified the optimumdosing regimens to provide adequate anticoagulant efficacy withminimal bleeding risk in VTE and AF patients.

AcknowledgementsWe thank Faysal Riaz, PhD and Simon Lancaster, BSc of inScienceCommunications, Springer Healthcare, Chester, UK, who providedassistance with literature research, outlining and editing of themanuscript.

FundingEditorial assistance during the preparation of this manuscript was fundedby Daiichi Sankyo Europe GmbH.

Conflict of interest: G.Y.H.L. has served as a consultant for BayerHealthcare, Astellas, Merck, Sanofi Aventis, BMS/Pfizer, Daiichi Sankyo,Biotronik, Medtronic, Portola and Boehringer Ingelheim and has beenon the speakers bureau for Bayer Healthcare, BMS/Pfizer, BoehringerIngelheim, Daiichi Sankyo, Medtronic and Sanofi Aventis. G.A. reportspersonal fees that were outside the submitted work from Bayer

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Healthcare, Boehringer Ingelheim, BMS, Daiichi Sankyo, Sanofi Aventisand Pfizer.

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