the pharmacokinetics of edoxaban for the prevention and...

1. Introduction

2. Chemistry

3. Preclinical pharmacology

4. Pharmacokinetics and

metabolism

5. Clinical studies

6. Additional therapeutic and

safety aspects

7. Expert opinion

Drug Evaluation

The pharmacokinetics ofedoxaban for the preventionand treatment of venousthromboembolismGines Escolar†, Maribel Diaz-Ricart, Eduardo Arellano-Rodrigo &Ana M Galan†Hospital Clınic, Servicio de Hemoterapia-Hemostasia, Barcelona, Spain

Introduction: Thromboembolic diseases will become the most important

contributors to mortality and morbidity for modern societies. Current antith-

rombotic strategies using heparins or vitamin K antagonists are inconvenient,

with limitations and inherent side effects. A series of new oral anticoagulants

with powerful and reliable antithrombotic actions have been developed

in the last decade.

Areas covered: Edoxaban is a direct and specific inhibitor of activated factor X,

delivered orally. This article reviews literature from PubMed and articles refer-

enced within. The text explores the pharmacological aspects of its antithrom-

botic action. Pharmacokinetics, metabolism and drug interactions are

examined. The review places the results of recent clinical trials that have evalu-

ated the antithrombotic potential of edoxaban versus standard antithrombotic

therapies in the prophylaxis and treatment of venous thromboembolism into

perspective. The possible relationship between the pharmacokinetic profile of

edoxaban and the favorable results in clinical trials is discussed.

Expert opinion: Edoxaban is perceived as a major advance, compared to

vitamin K antagonists, in the prevention and treatment of thromboembolic

disease given its favorable efficacy, safety, pharmacokinetic profile and renal

clearance. The results of ongoing large international trials exploring the

prevention of thrombotic complications in patients in different clinical

settings should ensure the approval of edoxaban to treat new indications.

Keywords: edoxaban, new oral anticoagulants, pulmonary embolism, venous thrombosis

Expert Opin. Drug Metab. Toxicol. (2014) 10(3):445-458

1. Introduction

Deep vein thrombosis (DVT) and pulmonary embolism (PE), usually referred asvenous thromboembolism (VTE), are becoming a major health concern due to theirelevated incidence, contribution to disability, mortality and their important burdenon health care systems. The global impact of VTE was estimated to cause a total of900,000 events for the USA population [1]. VTE represents a considerable impacton health care systems. Costs of an initial VTE episode have been estimated$3000 -- 9500 in the USA. The total costs related to VTE may rise up to $5000,$10,000 or $33,000 for treatments over 3, 6 or 12 months, respectively [2]. Studiesconducted in the European Union indicate lower additional inpatient costs afterVTE, though still having a profound economic impact on medical costs. Approxi-mately 10% of all hospital deaths can be attributed, at least in part, to PE. Anestimated 60% of cases of VTE are the result of a recent hospitalization suggestingthat universal safe and effective prophylaxis could significantly reduce VTE inci-dence and related mortality [3].

10.1517/17425255.2014.882897 © 2014 Informa UK, Ltd. ISSN 1742-5255, e-ISSN 1744-7607 445All rights reserved: reproduction in whole or in part not permitted

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http://informahealthcare.com/journal/EMT

Thrombotic complications are the result of a combinationof alterations in the venous vessel, modifications in bloodflow and a hypercoagulable condition developing in the circu-lating blood [4]. The hypercoagulable condition is often multi-factorial and may involve genetic or acquired deficiencies ofcoagulation inhibitors. An imbalance between activators andinhibitors of the coagulation mechanisms is definitely involvedin the precipitation of thrombotic events. In contrast with theclassic extrinsic and intrinsic pathways of the coagulation,recent models contemplate the coagulation mechanisms as aninteraction of cellular and enzymatic mechanisms organizedinto three differentiated steps: initiation, amplification andpropagation [5--6]. As shown in Figure 1, in this modern cell-based model of hemostasis, coagulation is initiated throughthe tissue factor (TF)/activated factor VII (FVIIa) complexon the surface of a TF-bearing cell [7].Pharmacological strategies available until recently for the

prophylaxis and treatment of VTE were based on parenteralagents working indirectly by potentiating plasma antithrom-bin (AT) activity (heparins) and vitamin K antagonists inhib-iting carboxylation of several coagulation factors. In the lastdecade, newer anticoagulant therapies have been developedto circumvent the inconveniences of classic therapies requiringparental administration with heparins or repeated controls asit is the case of classic oral vitamin K antagonists [8]. Thenew generation of oral anticoagulants has demonstrated topossess favorable pharmacokinetic profile, rapid onset, pre-dictable action, wider therapeutic range, better safety profileand fewer pharmacological interactions than precedent classicoral anticoagulants [9].New oral inhibitors of activated factor X (FXa) have shown

great promise as anticoagulant therapy without the limitations

inherent to traditional vitamin K antagonists 8,10,11. Inhibi-tion of the coagulation steps contributed by FXa has proveda very efficient mechanism to modulate excessive thrombingeneration (TG) [12]. Inhibition of FXa during the initiationstep reduces the initial generation of thrombin through theactivation of the FXa--FVa complex on the cell surface(Figure 1). Moreover, inhibition of FXa during the propaga-tion step prevents TG produced through the assembly of theprothrombinase complex (FVa--FXa and calcium).

Edoxaban tosilate (DU-176b (Daiichi-Sankyo, Inc.,Tokyo, Japan) is a new oral anticoagulant with a direct andspecific inhibitory action on FXa. The anticoagulant actionof edoxaban seems to interfere not only in the activity ofFXa generated in the initiation phase, but also in the finalpropagation phase preventing the action of the prothrombi-nase complex to generate thrombin on the platelet surface.Interestingly, recent studies have suggested that edoxabaninhibits both free FXa and FXa bound to prothrombinasereducing drastically TG mainly through the propagationphase in which large amounts of thrombin generated duringthe final step will convert fibrinogen into fibrin.

This review will provide an update on basic information onthe pharmacology and pharmacokinetics of edoxaban, andwill attempt to place in perspective the results of recent clini-cal trials that have comparatively evaluated the antithromboticpotential of edoxaban versus standard antithrombotictreatments in the prophylaxis and treatment of VTE.

2. Chemistry

Edoxaban (Figure 2) is the evolution of a prototype moleculeinitially coded as DX-9065a that was developed through the

Box 1. Drug summary.

Drug name Edoxaban tosilate (Eliquis�)Phase Phase III in Europe, Canada & USA, Phase IIIB in JapanIndication Prevention of VTE (Japan)Pharmacology description Direct inhibitor of FXaRoute of administration OralChemical structure Edoxaban tosilate

C31H40ClN7O8S2Molecular Weight 738.274

N NN

N

HNNH

NH

S

O

O

O

OCl

SO3H

H2O

Pivotal trial(s) NCT01203072 [42]

NCT01181102, NCT01181167 [46]

NCT000398216 [43]

NCT00986154 [48]

For additional information http://clinicaltrials.gov/ct2/results?term=Edoxaban

Pharmaprojects - copyright to Citeline Drug Intelligence (an Informa business). Readers are referred to Pipeline (http://informa-pipeline.citeline.com) and

Citeline (http://informa.citeline.com).

G. Escolar et al.

446 Expert Opin. Drug Metab. Toxicol. (2014) 10(3)

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http://clinicaltrials.gov/ct2/results?term=Edoxaban

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research of Daiichi-Sankyo, Inc (Tokyo, Japan). DX-9065awas considered a promising direct, selective, synthetic inhibi-tor of FXa [13], with potent anticoagulant and antithromboticeffects [14]. Unfortunately, DX-9065a showed a reduced oralbioavailability [15]. Modifications of the original moleculeresulted in the final edoxaban compound with an improvedoral bioavailability [16]. Details on the synthesis of edoxabanhave been already published [17].

3. Preclinical pharmacology

3.1 Anticoagulant activity in vitro: mechanism of

action and specificityEdoxaban possess a high specific affinity to competitivelyinhibit human FXa with a Ki value of 0.561 nM [13], with avery weak direct inhibitory action on thrombin andFIXa, with Ki values of 6.00 and 41.7 µM, respectively;> 10,000-fold greater selectivity for FXa than for thrombin(FIIa) [18]. The antithrombotic effects of edoxaban are inde-pendent of plasma levels of AT as demonstrated in studiesin AT-deficient mice [19]. Edoxaban prolongs prothrombintime (PT) and activated partial thromboplastin time (aPTT)clotting times of human plasma in a concentration-dependentmanner, doubling PT and aPTT at concentrations equivalentto 0.256 and 0.508 µM, respectively. Higher concentrationsof edoxaban were required to double the coagulation timefor TT indicating that direct AT effect is not the prevalent

mechanism for its anticoagulant action. The anticoagulanteffects of edoxaban for PT prolongation were similar inhuman, monkey and rabbit plasma [18].

The inhibitory action of edoxaban on FXa results in thereduction of total thrombin generated during the activationof coagulation mechanisms. Edoxaban inhibits TG in humanplatelet rich or poor plasma. Comparative studies reveal thatthe inhibitory activity of edoxaban on TG is greater thanthat observed with fondaparinux. Table 1 [20] summarizes themost relevant information on the pharmacology of thisnew anticoagulant.

3.2. Antithrombotic action in animal models and

comparative studiesThe antithrombotic properties of edoxaban have beenconfirmed in several models of venous and arterialthrombosis [21--22]. Oral administration of edoxaban signifi-cantly inhibited thrombus formation in models of venousstasis in rats and rabbits. Similar results were observed in a plat-inum wire-induced venous thrombosis model in rats. In the lat-ter case, thrombus formation was significantly reduced by dosesof edoxaban-b equivalent to 2.5 mg/kg [18]. Antithromboticeffects elicited by edoxaban paralleled prolongations in PTand anti-FXa activities in the plasma of these animals. Edoxa-ban also exerted a significant anticoagulant effect in a rat modelof TF-induced disseminated intravascular coagulation [23].

The antithrombotic action of edoxaban has been comparedwith other anticoagulant agents under different experimentalconditions. In rats, edoxaban showed antithrombotic effectssimilar or even superior to fondaparinux (FXa inhibitor) ormegalatran (FIIa inhibitor) [24--26]. In other series of animalstudies, the antithrombotic effects of edoxaban were comparedwith those of unfractionated, LMWH, lepirudin andwarfarin [27--29]. The safety margins between antithromboticactions and bleeding-time prolongations of edoxaban in theprevious experimental studies were wider than those of unfrac-tionated heparin, dalteparin, lepirudin and warfarin suggestingthat antihemostatic actions of edoxaban may be less intensethan those of more conventional anticoagulants [29].

4. Pharmacokinetics and metabolism

Clinical safety, tolerability, pharmacokinetics and pharmaco-dynamics of the novel factor Xa inhibitor edoxaban wereexplored in healthy volunteers [30]. The pharmacokineticprofile of edoxaban is characterized by a rapid absorption,biphasic elimination and a terminal elimination half-life(t1/2) of 5.8 -- 10.7 h with an oral bioavailability of approxi-mately 62%. In pharmacokinetic studies, after single adminis-tration at doses ranging from 10 to 150 mg, edoxaban wasrapidly absorbed, with a tmax of 1 -- 2 h and Cmax from150 to 300 ng/ml for the 30 and 60 mg doses. NormalizedCmax per body weight and dose demonstrated an increaseuntil 60 mg/day [30]. The mean percentage of plasma proteinbinding ranged from 40 to 59%. Urine edoxaban amounts

Article highlights.

. Edoxaban (DU-176b) is an oral, direct and highly specificinhibitor of activated factor X, with antithromboticaction widely demonstrated in in vitro and in vivoexperimental models. A 10-fold dissociation betweenantithrombotic and bleeding effects could be predictedfrom different animal models.

. In humans, edoxaban has a favorable pharmacokineticprofile reaching a maximal concentration 1 -- 2 h afteroral administration with an elimination half-life of9 -- 11 h being predominantly secreted through kidneys.

. Evidence from different comparative trials with standardparenteral anticoagulants demonstrates that edoxaban issafe and effective in the prophylaxis of thromboticcomplications in patients subjected to total kneearthroplasty or hip replacement. Edoxaban is licensed inJapan for the prophylaxis of venous thromboembolism(VTE) after major orthopedic surgery.

. In a recent clinical trial, edoxaban has shown to be atleast as effective as warfarin in the treatment of patientswith acute VTE with a relative reduction inbleeding complications.

. Results of ongoing large international trials in theprevention of thrombotic complications in patients withatrial fibrillation ensure that the licensing company willseek an approval for new indications.

This box summarizes key points contained in the article.

Edoxaban tosilate

Expert Opin. Drug Metab. Toxicol. (2014) 10(3) 447

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from 0 to 48 h post-dose ranged from 34.7 to 39.0% for alldose levels, the majority of which was excreted within the first8 h post-administration.Pharmacokinetics of edoxaban after repeated administra-

tion showed a similar profile than that of the single-

administration study, the disposition of edoxaban in themultiple-administration study appeared predictable [30]. Thetmax for a 60-mg bid was 2 -- 3 h with Cmax of 266 ng/mlon the first day and reached 305 ng/ml after 10 days of con-tinuous treatment. Repeated administration of doses of90 or 120 mg/day indicated little systemic accumulation after10 days. Urinary excretion of unchanged edoxaban remainedconsistent along treatment with the 90 and 120 mg/daydoses, ranging from 36 to 45% of the dose administered.Absolute bioavailability of edoxaban in healthy volunteerswas 61.8% [31].

Plasma edoxaban concentrations correlated with its phar-macodynamic effects in coagulation parameters (Table 1).Edoxaban exhibited dose-dependent effects on aPTT, PTand anti-factor Xa activities with a twofold increase in PT atthe single oral 60-mg dose, similar to that reported in previ-ous pharmacological studies [18]. Edoxaban increased theinternational normalized ratio (INR) up to a maximum of3.5, with values returning to normality within 24 -- 36 h after

Initiation

Edoxaban

Edoxaban

TF

TF

Vlla

Vlla

Vllla

X

X

TF-bearing cell

IX

IXa

IX

IXa

XIa

Xa Va

Xa Va

II

II

IIa

V VaXI XIa

VIlla

VIII/VWF

Amplification

V Platelet

Activated PlateletIIa IIa

IIa

IIaIIaIIa

Propagation

Figure 1. According to the modern cell-based model, the activation of the coagulation takes place through three different

steps. Initiation: During the initiation phase, tissue factor (TF) exposed on damaged vascular areas forms a complex with FVII/

FVIIa already present in reduced amounts in circulating blood. The TF:FVIIa complexes will activate FIX and FX. FXa generated

will activate small quantities of prothrombin (FII) into thrombin (FIIa). Amplification: During this phase, small amounts of

thrombin generated in this short loop will be able to promote further activation of the coagulation by further activating FV

and FVIII in the presence of platelet phospholipids and FIX [7]. Propagation: During the propagation step FIXa bound to FVIIa

on the surface of activated platelets form the tenase complex that will further activate FX into FXa. FXa binds to FVa on the

phospholipid surface provided by activated platelets and form the prothrombinase complex. During the final step of the cell-

based model, the prothrombinase complex will further magnify the generation of thrombin facilitating the conversion of

prothrombin into thrombin. Large amounts of thrombin generated during the final step will convert fibrinogen into fibrin.

Thrombin itself activates FXIII thus stabilizing the fibrin formed. Edoxaban will inhibit the procoagulant activity of FXa

generated in the initiation phase, but also in the final propagation phase preventing the action of the prothrombinase

complex to generate thrombin on the platelet surface. Edoxaban inhibits both free FXa and FXa bound to TF-bearing cells or

activated platelets reducing drastically thrombin generation.

N NN

N

HNNH

NH

S

O

O

O

OCl

SO3H

H2O

Figure 2. Chemical structure of edoxaban-b (Edoxaban

Tosilate; M.W. = 738.274). (A) The small molecule of

edoxaban-b, N1-(5-Chloropyridin-2-yl)-N2-[(1S,2R,4S)-4-(N,

N-dimethylcarbamoyl)-2-(5-methyl-4,5,6,7-tetrahydrothiazo-

lo[5,4-c]pyridin-2-ylcarboxamido)cyclohexyl]oxamide

p-toluenesulfonate monohydrate.

G. Escolar et al.


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single administration. Fewer than 8% of subjects had anincrease in bleeding time > 9.5 min, and none of the increasesappeared to be clinically significant. Bleeding time returned tonormal within 12 h in 9 of 10 participants who exhibited pro-longation and within 24 h for the remaining subject.

Edoxaban is eliminated through multiple pathways, with asignificant proportion of systemically absorbed drug elimi-nated via renal excretion [32--33]. Bathala and cols [32] investi-gated in detail the biotransformation, and mass balance ofradiolabeled edoxaban, after oral administration. The meanrecovery of radioactivity was > 97% of the administered radio-active dose, with 62.2% eliminated in feces and 35.4% inurine. Unchanged edoxaban accounted for the majority ofradioactivity, with 49.1 and 23.8% of the dose as parentobserved in feces and urine, respectively. Unchanged edoxa-ban was the most abundant species in plasma, with a meanarea under the curve (AUC) of 1596 ng h/ml. The nextmost abundant species was metabolite M4, with a meanAUC (0-infinity) 147 ng/h/ml. Edoxaban, as unchanged

parent, is the predominant species circulating in plasma andits minor metabolites are formed primarily throughhydrolysis.

Intake of high-fat food did not have an important effect onthe pharmacokinetics of edoxaban in Japanese and Caucasianhealthy volunteers [34]. aPTT were assessed as measures ofpharmacodynamic effect. The study demonstrated modestincreases ranging from 6 to 22% across pharmacokinetics(PK) parameters for both race cohorts. The disposition wassimilar in both Japanese and Caucasian matched volunteerswith slightly higher AUC values (ranging from 7 to 9%) inCaucasians. The modest effects observed were consideredclinically insignificant.

4.1 Interactions of edoxaban with other drugsAs with other new oral anticoagulants acting as direct inhibi-tors of factor Xa, edoxaban may have potential interactionswith other drugs (inhibitors of cytochrome P450 andP-glycoprotein, P-gp). Edoxaban is partially metabolized bycytochrome P450 3A4. Studies using human liver micro-somes indicated that edoxaban was metabolized to distinctmetabolites mainly by CYP3A4 [33].

Edoxaban is a P-gp substrate, and several cardiovasculardrugs have the potential to inhibit P-gp and increase drug expo-sure [35]. The potential pharmacokinetic interactions of edoxa-ban and six cardiovascular drugs used in the management ofatrial fibrillation (AF) and known P-gp substrates/inhibitorswere investigated in healthy subjects. Participants receivededoxaban 60 mg alone and coadministered with quinidine,verapamil, atorvastatin, dronedarone, amiodarone or digoxin.Edoxaban exposure measured as AUC increased for concomi-tant administration of edoxaban with quinidine, verapamiland dronedarone, and exposure measured as 24-h concentra-tions for these drugs did also increase. Administration of edox-aban with amiodarone decreased the 24-h concentration foredoxaban by 25.7%. Concomitant administration with digoxinor atorvastatin had minimal effects on edoxaban exposure.

In another study, Salazar and cols [36] investigated interactionsof edoxaban with concomitant administration of strong P-gpinhibitors (amiodarone, erythromycin, ketoconazole, quinidineand verapamil) in patients with AF and simulated possibleeffects of moderate renal insufficiency. Comparisons weremade to edoxaban exposure in a typical patient with non-valvular AF and normal renal function. Results demonstratedthat edoxaban exposure in patients with moderate renalimpairment receiving strong P-gp inhibitors could potentiallyincrease the exposure to edoxaban.

Interactions of edoxaban with digoxin have been also inves-tigated [37]. Edoxaban pharmacokinetic parameters showedmild increases in AUC and peak concentrations of 9.5 and15.6%, respectively, when coadministered with digoxin.Although digoxin PK parameters demonstrated increasedAUC and peak concentrations of 8.3 and 28%, respectively,plasma concentrations were within the established therapeuticrange. Edoxaban pharmacodynamics were consistent with

Table 1. Summary of pharmacological,

pharmacodynamic and pharmacokinetic characteristics

of edoxaban.

Reference, molecular weight DU-176bEdoxaban tosilateC31H40ClN7O8S2Molecular weight 738.274

Commercial name; licenser LIXIANA�, Daiichi SankyoMechanism of action;specificity

Anti-Xa; no prodrug, Ki0.561 nM [18]

Pharmacology Antithrombotic action in animalmodels [18,29]

Alteration in coagulationtests

PT, aPTT [18,30]

Measurement Anti-Xa test with appropriatecalibrators [30,52]

Therapeutic dose 15, 30 mg/day (prevention ofVTE) [45]60 mg/day (treatment of VTE)

Pharmacokinetics tmax

Half-life t1/2

1 -- 2 h9 -- 11 h [30]

Pharmacokinetics Cmax 152 ng/ml after a single dose of30 mg300 ng/ml after repeated dailydoses of 60 mg [30]

BioavailabilityElimination

62%35 -- 40 % kidney, 60%feces [30--32]

Patients who may requirespecial attention

Renal impairment [35--36]

Interference withcytochromes/P-gp

CYP3A4 (minimal) and P-gp [33]

Drug interactions Quinidine, verapamil, amiodaroneand dronedarone erythromycinand ketoconazole may alteredoxaban exposure [31,32,35--38].

aPTT: Activated partial thromboplastin time; PT: Prothrombin time;

VTE: Venous thromboembolism.

Edoxaban tosilate


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pharmacokinetic parameters. Both drugs were well toleratedalone or in combination. No clinically significant changesin renal elimination were observed with concomitantadministration of edoxaban and digoxin.Effects of the non-steroidal antiinflammatories, aspirin and

naproxen, on pharmacokinetics and pharmacodynamics ofthe anticoagulant edoxaban have been investigated [38]. Mod-ifications in pharmacodynamic and pharmacokinetic interac-tions of edoxaban 60 mg coadministered with low-doseASA, high-dose acetylsalicylic acid (ASA) or naproxen(500 mg) were investigated in 126 healthy subjects. Baselinebleeding times ranged from 4.72 to 6.13 min. Edoxabanadministered alone prolonged bleeding times by 21 -- 35%from baseline. Concomitant administration of edoxabanwith high-dose ASA, low-dose ASA or naproxen prolongedbleeding times approximately twofold. Edoxaban pharmaco-kinetics were not affected by concomitant low-dose ASA ornaproxen, but high-dose ASA increased systemic exposure ofedoxaban by approximately 30%. Inhibition of platelet aggre-gation by high-dose ASA, low-dose ASA or naproxen was notaffected by edoxaban.

5. Clinical studies

5.1 Dose findingA preliminary Phase I study explored the antithromboticaction of edoxaban by measuring modifications in size ofex vivo platelet-rich thrombus generated on a thrombogenicsurface using blood pre- and post-drug administration flow-ing through a well-characterized perfusion chamber. Bloodwas perfused at different shear rates. Twelve healthy subjectsreceived a single oral dose of 60 mg of edoxaban. Antithrom-botic effects were measured at 1.5, 5 and 12 h, along withother biomarkers of coagulation (Table 2). Studies revealedthat edoxaban significantly reduced ex vivo thrombus forma-tion at venous and arterial shear rates. The antithromboticeffects in perfusion studies were maximal at 1 h, remained sig-nificant at 5 h and disappeared at 12 h. Evolution of clottingparameters, effects on TG and levels of anti-factor Xa activityparalleled findings in perfusion studies [39].In a randomized, enoxaparin-controlled, multicenter,

double-blind parallel group study, A total of 264 patientswere randomized to edoxaban 15 or 30 mg once daily oropen-label, subcutaneous enoxaparin 20 mg (equivalent to2000 IU) bid administered for 11 -- 14 days [40]. The inci-dence of thromboembolic events (composite of asymptomaticDVT, symptomatic PE, or symptomatic DVT and safetywere evaluated. Oral administration of edoxaban 15 and30 mg showed potential efficacy similar to enoxaparin forthe prevention of thromboembolic events in patients under-going total hip arthroplasty. The incidence of major andclinically relevant non-major bleeding for edoxaban wascomparable to that of enoxaparin.Modifications in a panel of biomarkers of blood coagula-

tion and platelet responses induced by edoxaban and other

anticoagulants were evaluated in an open-label, randomized,non-treatment and active-controlled multiple dose study, inelderly patients. Patients were randomized to oral edoxaban(60 mg, twice daily, 7 doses), subcutaneous dalteparin(5000 IU, once-daily, 4 doses), oral ximelagatran (24 mg,twice daily, 7 doses) or not exposed to drugs. Blood sampleswere taken before, and at different intervals from 1.5 to144 h after the first dose. The primary outcomes were changesin thrombin--AT complex, prothrombin fragment 1+2 andD-dimer, and adverse events. Inhibition of TG lag time,peak and constant velocity index was significantly greaterand extended for a longer period of time, following edoxabanadministration compared with dalteparin. Changes in coagu-lation biomarkers following edoxaban administration (includ-ing prolongation of PT) reflected inhibition of factor Xa.There were no clinically significant changes in primary out-comes and no serious adverse events were reported. Theauthors concluded that oral administration of edoxabanresulted in effective FXa and TG inhibition, and waswell-tolerated [41].

5.2 Prevention of venous thromboembolism after

major orthopedic surgeryTable 2 summarizes information on clinical trials with edoxa-ban in the prophylaxis and treatment of VTE. The safety, effi-cacy and pharmacodynamics of edoxaban for the preventionof VTE were assessed in Japanese patients subjected to electivetotal knee arthroplasty in a randomized, double-blind,placebo-controlled, multicenter study [42]. The study (Study-ing Thrombosis After Replacement Surgery, STARS J-1,Phase IIb) included 523 patients that received edoxaban 5,15, 30 or 60 mg once daily or placebo for 11 -- 14 days.A placebo control was used as neither LMWH nor fondapar-inux had been approved for thromboprophylaxis at the timeof the study in Japan. The primary efficacy outcome was theincidence of VTE. The primary safety outcome was the inci-dence of major and clinically relevant non-major bleeding.The edoxaban therapy was associated with a significantdose-related reduction in VTE: the incidence of VTE from29.5 to 9.1% in for edoxaban treatment groups from 5 to60 mg treatment groups versus 48.3% in the placebo group.The incidence of major and clinically relevant non-majorbleeding was similar across all groups without any significantdifferences among edoxaban doses or between edoxaban andplacebo. The authors of the study concluded that edoxabandemonstrated significant dose-dependent reductions in VTEin patients undergoing total knee arthroplasty with a bleedingincidence similar to placebo.

The efficacy and safety of edoxaban in the prevention ofVTE was also assessed in a Phase IIb trial in patients undergo-ing elective total hip replacement (THR) [43]. A total of903 patients were randomly allocated to receive oral edoxaban15, 30, 60 or 90 mg once daily or subcutaneous dalteparinonce daily (initial dose 2500 IU, subsequent doses

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5000 IU). Both drugs were begun 6 -- 8 h postoperatively andcontinued for 7 -- 10 days, when bilateral venography was per-formed. The primary efficacy end point was the incidence oftotal VTE, which included proximal and/or distal DVT byvenography or symptomatic, objectively confirmed DVT orPE during the treatment period. The primary safety outcomewas the incidence of the composite of major and clinically rel-evant non-major bleeding. All venograms and bleeding eventswere reviewed by a central independent adjudication commit-tee blinded as to treatment allocation. Of the 903 patientsrandomized, 776 were evaluable for the primary efficacy anal-ysis. The incidences of VTE were 28.2, 21.2, 15.2 and 10.6%in patients receiving edoxaban 15, 30, 60 and 90 mg, respec-tively, compared with 43.8% in the dalteparin group(p < 0.005). There was a statistically significant (p < 0.001)dose--response for efficacy across the edoxaban dose groupsfor total VTE and for major VTE. The incidence of clinicallyrelevant bleeding was low and similar across the groups. Theauthors concluded that oral edoxaban once daily is effectivefor preventing VTE after THR [43].

Two Phase III clinical trials aimed to assess edoxaban forthe prevention of VTE after orthopedic surgery were con-ducted in Japanese population. The STARS E-3 trial assesseda 30-mg once-daily oral dose of edoxaban versus a twice-dailysubcutaneous dose of enoxaparin 20 mg in 716 Japanese

patients undergoing total knee arthroplasty [44]. The primaryefficacy outcome occurred in 22 of 299 (7.4%) patientsreceiving edoxaban and 41 of 295 (13.9%) patients receivingenoxaparin indicating non-inferiority (p < 0.001) as well assuperiority (p = 0.010) of edoxaban relative to enoxaparin.The incidence of major bleeding events was similar foredoxaban- and enoxaparin-treated groups.

The STARS J-5 trial included 610 patients undergoingTHR. Patients received edoxaban 6 -- 24 h or 20 mg bid enox-aparin 24 -- 36 h after surgery [45]. Both drugs were continuedfor 11 -- 14 days post-surgery. The primary end point was thecomposite of symptomatic and asymptomatic DVT and PE.The primary safety end point was major and clinically relevantnon-major bleeding. In the pooled analysis of both trials, theprimary end point occurred in 5.1 versus 10.7% of theedoxaban- versus enoxaparin-treated groups, respectively(p < 0.001). The primary safety end point occurred in 4.6versus 3.7% of the edoxaban- and enoxaparin-treatedpatients, respectively (p = 0.427).

The effects of edoxaban on key coagulation biomarkerssuch as D-dimer, prothrombin fragment F1+2 (F1+2) andsoluble fibrin monomer complex (SFMC) were also exploredin a pooled analysis of the 1326 patients included in bothSTARS E-3 and STARS J-V clinical studies [46]. For bothtreatment groups, D-dimer and SFMC levels were reduced

Table 2. Clinical trials with edoxaban in the prophylaxis and treatment of VTE.

Objective or clinical condition Phase # Patients Duration Results

Antithrombotic action ex vivo I 12 12 h Antithrombotic effects after a single dose(60 mg) were maximal at 1 h, remainedsignificant at 5 h and disappeared at 12 h

Modification in a panel of biomarkers inelderly patients subjected to differentanti-Xa therapies [62]

I 10 72 h PT and TG tests are suitable for theevaluation of FXa inhibitors

Dose finding for edoxaban versusenoxaparin (20 mg bid) [40] STARS J-2

IIb 264 11 -- 14 days Dose-dependent alteration of biomarkersof coagulation after edoxaban. Thrombingeneration significantly altered versusdalteparin

Prevention of VTE after total hipreplacement versus dalteparin (2500 IU,followed by 5000 IU daily) [43]

IIb 903 7 -- 10 days Dose-dependent efficacy observed withdoses from 15 to 60 mg/day. Similarincidence of bleeding versus dalteparin

Prevention of VTE after total hipreplacement versus enoxaparin (20 mgbid) STARS J-5 [45]

III 610 11 -- 14 days Edoxaban 30 mg/day has efficacy superiorto enoxaparin with similar incidence ofclinically relevant bleeding events

Prevention of VTE after hip fracturesurgery versus enoxaparin (20 mg bid) [47]STARS J-4

III 92 11 -- 14 days Edoxaban 30 mg/day similar efficacy andsafety than enoxaparin

Prevention of VTE after total kneearthroplasty versus enoxaparin (20 mgbid) [44] STARS E-3

III 716 11 -- 14 days Efficacy of edoxaban 30 mg/day superiorto enoxaparin without a significantincrease in bleeding events

Prevention of VTE after total kneearthroplasty versus placebo [42] STARS J-1,

IIb 523 11 -- 14 days Significant dose-dependent reductions inVTE, 15, 30 or 60 mg once daily versusplacebo

Treatment of acute DVT/PE andprevention of recurrences versuswarfarin [48]

III 8240 3 -- 12 months Edoxaban 60 mg/day as effective andsafer than standard warfarin

PT: Prothrombin time; TG: Thrombin generation; VTE: Venous thromboembolism.

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at day 7 compared to post-operation/pretreatment levels, thenincreased slightly by day 11 -- 14. Levels of F1+2 alsodecreased by day 7 in both treatment groups and furtherdecreased by day 11 -- 14. However, for each coagulationbiomarker, levels were significantly lower in the edoxabangroup compared to the enoxaparin group at both day 7 andday 11 -- 14.Edoxaban 30 mg/day has demonstrated similar efficacy and

safety than enoxaparin in Japanese patients undergoing hipfracture surgery (HFS) [47]. The study, a Phase III, random-ized, open-label trial, used subcutaneous enoxaparin 20 mgbid as comparator. The incidence of thromboembolic eventswas 6.5% (3/46, 95% CI 2.2 -- 17.5) in the edoxaban groupand 3.7% (1/27, 95% CI 0.7 -- 18.3) in the enoxaparin group.All the thromboembolic events were asymptomatic distalDVT. The incidence of adverse events was similar betweenthe treatment groups.Edoxaban was approved for the prevention of VTE after

major orthopedic surgery in Japan in 2011, based on its supe-riority as evidenced in the STARS trials. However, the 20-mgtwice-daily choice of enoxaparin is not commonly usedoutside Japan and, therefore, the results of the STARS trialsmay not be extrapolated to other populations [46].

5.3 Treatment of acute venous thromboembolism

and prevention of recurrencesEdoxaban 60 mg once daily (or 30 mg once daily in the caseof patients with creatinine clearance of 30 -- 50 ml/min or abody weight below 60 kg) compared to dose-adjusted warfa-rin has been assessed in the HOKUSAI-VTE randomized,double-blind, double-dummy Phase III clinical trial [48].This study evaluated the prevention and treatment of VTEin patients with acute DVT and/or PE after an initial 5-dayheparin treatment period (either unfractionated heparin orLMWH). The HOKUSAI-VTE is the largest single clinicaltrial for the treatment and secondary prevention of acuteDVT and/or PE with an enrolment of 8240 patients(4921 with DVT and 3319 with PE). The primary end pointwas defined as the composite of DVT, non-fatal and fatal PEover a 12-month time frame from randomization. Treatmentduration was pre-specified by the patient’s individual risk foreither 3, 6 or 12 months. The secondary end point wasdefined as the composite of symptomatic recurrent DVT,non-fatal symptomatic recurrent PE, all-cause mortality, andmajor or clinically relevant non-major bleeding during treat-ment. Among patients receiving warfarin, the time in thetherapeutic range was 63.5%. Edoxaban was non-inferior towarfarin with respect to the primary efficacy outcome, whichoccurred in 130 patients in the edoxaban group (3.2%) and146 patients in the warfarin group (3.5%) (hazard ratio,0.89; 95% confidence interval [CI] 0.70 -- 1.13;p < 0.001 for non-inferiority). The safety outcome occurredin 349 patients (8.5%) in the edoxaban group and423 patients (10.3%) in the warfarin group (hazard ratio,

0.81; 95% CI 0.71 -- 0.94; p = 0.004 for superiority). Therates of other adverse events were similar in the twogroups. Table 3 summarizes main efficacy and safety outcomesin the HOKUSAI study. A total of 938 patients with PE hadright ventricular dysfunction, as assessed by measurement ofN-terminal pro-brain natriuretic peptide levels; the rate ofrecurrent VTE in this subgroup was 3.3% in the edoxabangroup and 6.2% in the warfarin group (hazard ratio, 0.52;95% CI 0.28 -- 0.98). Results were similar in the subgroupof patients who met the criteria for the 30-mg/day edoxabandose: 0.73 (95% CI 0.42 -- 1.26) for recurrent VTE,0.62 (95% CI 0.44 -- 0.86) for clinically relevant bleedingand 0.50 (95% CI 0.24 -- 1.03) for major bleeding.

A remarkable aspect of the HOKUSAI-VTE study was thatpatients were treated for at least 3 months but were evaluatedat 12 months whether or not they remained on randomizedtherapy. Results demonstrated that the relative efficacy ofedoxaban was not limited to patients receiving medication,but it was evident even among those who stopped treatmentbefore 12 months. Patients in the HOKUSAI study wererandomized after at least 5 days of open-label enoxaparin orunfractionated heparin indicating that the trial was designedto enroll patients at very high risk. Members of the writingcommittee concluded that edoxaban administered once dailyafter initial treatment with heparin was non-inferior tohigh-quality standard therapy and caused significantly lessbleeding in a broad spectrum of patients with VTE, includingthose with severe PE.

6. Additional therapeutic and safety aspects

6.1 Transitions and bridging with other

anticoagulantsManagement of patients with thrombotic complications willrequire a transition from anti-vitamin K anticoagulants orheparin to the newly developed oral drugs. Mendell andcols [49--50] have explored the safety, tolerability and pharma-cokinetics of edoxaban in healthy subjects bridging from war-farin therapy. Participants in the study received open-labelwarfarin titrated to INR 2.0 -- 3.0 for 3 days. Twenty-fourhours after discontinuation, subjects were randomized toreceive edoxaban-b 60 mg/day or placebo for 5 days. Admin-istration of edoxaban was associated with a rapid effect on theINR increasing to a peak of 3.8 over 2 h and returning tobaseline within 12 h (24 h after warfarin). The study inhealthy patients concluded that edoxaban could be safelyadministered 24 h after the last dose of warfarin.

Pharmacodynamics and safety of enoxaparin 1 mg/kgfollowed 12 h post-dose by edoxaban 60 mg were exploredin a Phase I, open-label, randomized, four-period, four-treatment cross-over study [51]. Treatments were edoxabanalone, enoxaparin alone, edoxaban plus enoxaparin and enox-aparin followed by edoxaban 12 h later. Serial blood sampleswere collected for pharmacodynamic (TG, anti-FXa) andpharmacokinetic variables (edoxaban and its principal

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metabolite M4, and anti-FIIa as a surrogate of enoxaparin).The highest effect on thrombin AUC endogenous thrombinpotential (ETP), thrombin (peak), TG lag time and velocityindex was observed for the association edoxaban plus enoxa-parin, followed by enoxaparin alone, enoxaparin followed byedoxaban 12 h later and edoxaban alone. The greatest effecton anti-FXa activity was observed for edoxaban plus enoxa-parin, followed by enoxaparin followed by edoxaban 12 hlater. Neither edoxaban nor enoxaparin significantly alteredthe pharmacodynamics of the other drug. There were no seri-ous adverse events during the study. It was concluded that a60-mg dose of edoxaban can be safely administered 12 hfollowing enoxaparin 1 mg/kg [51].

6.2 Laboratory evaluation of the anticoagulant

action of edoxabanAccording to pharmacokinetic and pharmacodynamic prolife,repeated laboratory monitoring is not necessary duringedoxaban treatment. However, occasional evaluation of itsanticoagulant effect may be necessary under some circumstan-ces (excessive bleeding or surgical emergencies). As other oralfactor Xa inhibitors edoxaban causes a dose-dependentincrease in aPTT, PT and one-step prothrombinase-inducedclotting time, especially at supratherapeutic doses [30,52]. Edox-aban inhibits TG measured with the calibrated automatedthrombogram [20,53]. The magnitude of concentration-dependent increase of PT seems dependent on the thrombo-plastin reagent. Linear correlations were observed betweenplasma concentration of edoxaban and anti-FXa activity andresults of clotting time assays. In any case, PT and aPTT donot have enough sensitivity to measure plasma levels of edox-aban and TG test are not specific to detect its anticoagulant

effect. Measurement of anti-Xa activity with a specific calibra-tor appears as the more appropriate test to assess plasmaconcentration of oral factor Xa inhibitors [30,52].

6.3 Reversal of the anticoagulant action of edoxaban

in bleeding emergenciesWhile the hemorrhagic action of excessive treatment withclassic vitamin K antagonists can be rapidly reversed withprothrombin complex concentrates (PCCs) in case of emer-gencies [54], there is reasonable concern on the reversion ofthe antihemostatic action of new oral anticoagulants in life-threatening hemorrhages [55]. Experimental studies indicatedthat the prolongation of PT induced by edoxaban could bereversed by addition of rFVIIa. Further studies on the reversalof edoxaban using human plasma and rat experimental mod-els of bleeding demonstrated that rFVIIa, PCCs and activatedPCCs (Feiba�) have potential to reverse the antihemostaticaction of edoxaban [56].

A Phase I study is currently evaluating a specific antidote(PER977) aimed at antagonizing the inhibitory action ofedoxaban on FXa [57]. The study explores whether a singledose of PER977 administered alone, and following a singledose of edoxaban PER977 monotherapy and coadministra-tion following 60 mg edoxaban will have an acceptable safetyand tolerability profile with no impact on pro-coagulant bio-markers. Other specific antidotes are being developed for arapid reversal of new oral anticoagulants with an anti-Xaaction [58].

6.4 Modeling of edoxaban exposure: predictive

value on efficacy and safety clinical outcomesPharmacometric analyses are important for understandingthe relationship of plasma concentrations of edoxaban tobleeding and to efficacy. A pharmacometric analysis wasapplied to characterize the population pharmacokinetics ofedoxaban and the relationships between edoxaban exposureand clinical outcomes in different studies on surgical patientsfollowing THR [59]. A total of 1795 subjects were included.The exposure--response analysis included data from surgicalpatients assigned to edoxaban in the Phase IIb study. Edoxa-ban disposition in healthy and post-surgical patients was welldescribed with a linear, two-compartment model. Creatinineclearance correlated significantly with edoxaban clearanceand the rate of oral absorption was affected by surgery. Theprobability of a post-operative VTE was significantly corre-lated with steady-state metrics of edoxaban exposure esti-mated for each subject by Bayesian post-hoc methods withage and gender being the significant and expected covariates.Plasma concentration of edoxaban, as either AUC, Cmin orCmax, was a significant predictor of VTE in these patients.These three measures of plasma exposure were all similarlypredictive with same order of magnitude of statistical signif-icance (p < 0.005). There were no significant relationshipsbetween metrics of edoxaban exposure at steady state and

Table 3. Summary of main efficacy and safety

outcomes for the HOKUSAI-VTE study [48]: hazard ratio

(HR) (95% CI) for primary and secondary outcomes,

edoxaban (n = 4118) versus warfarin (n = 4122).

End points HR (95% CI) p

Primary efficacy outcome* Non-inferiority12-months study period 0.89 (0.70 -- 1.13) < 0.001While on treatmentz 0.82 (0.60 -- 1.14) < 0.001

Safety outcomes(on treatment)

Superiority

Primary§ 0.81 (0.71 -- 0.94) 0.004Major bleeding 0.84 (0.59 -- 1.21) 0.35Clinically relevant

non-major bleeding0.80 (0.68 -- 0.93) 0.004

Any bleeding 0.82 (0.75 -- 0.90) < 0.001

*First symptomatic recurrent VTE (DVT or fatal or non-fatal PE) or VTE-related

death.zWhile taking or within 3 days of stopping or interrupting drug.§First major or clinically relevant non-major bleeding.

DVT: Deep vein thrombosis; PE: Pulmonary embolism;

VTE: Venous thromboembolism.

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incidences of major bleeding or major plus clinically relevantnon-major bleeding events detected by logistic regressionanalysis.A similar simulation model was applied to determine possi-

ble relationships between edoxaban pharmacokinetics or bio-markers and risk of bleeding in 1281 edoxaban-treatedpatients with non-valvular AF [36]. Patients analyzed had addi-tional intrinsic factors such as renal impairment or extrinsicfactors such as concomitant medications. The study revealedsignificant effects of renal impairment and concomitant strongP-gp inhibitors on the pharmacokinetics of edoxaban. Expo-sure--response analysis found that the incidence of bleedingevents increased significantly with increasing edoxaban expo-sure, with steady-state minimum concentration showing thestrongest association. Clinical trial simulations of bleeding inci-dence were used to select 30 and 60 mg once-daily edoxabanwith 50% dose reductions for patients with moderate renalimpairment or receiving concomitant strong P-gp inhibitorsas the treatment regimens.

6.5 Post-marketing safety experienceEdoxaban was approved in Japan for the prevention of VTEfollowing major orthopedic surgery. Data from early post-marketing phase vigilance in Japan after the first 6 monthsof commercial use of edoxaban for thromboprophylaxisfollowing major orthopedic surgery did not identify anyunforeseen safety signals [60]. Adverse drug reactions werespontaneously reported during early post-marketing phasevigilance in Japan. The study was conducted during the initial6 months after edoxaban commercial launch in July 2011. Alladverse drug events that were spontaneously reported werecollected and analyzed. The estimated exposure during theinitial 6 months was approximately 20,000 patients. Themajority of adverse events were bleeding (51 in 42 patients),and serious adverse drug events included cerebral hemorrhage(n = 1), gastric hemorrhage (n = 2) and surgical site hemor-rhage (n = 12). Most of these adverse events occurred withinthe first week of treatment and there were no fatalities. Resultsof this early post-marketing phase vigilance confirm the safetyof edoxaban observed in previous clinical trial and furthersubstantiate the safety profile of edoxaban predicted in modelsof exposure and clinical outcomes for the prevention of VTEafter orthopedic surgery.

7. Expert opinion

Introduction of new oral anticoagulants represents a consider-able therapeutic advance over classic parenteral heparins ororal vitamin K antagonists. Edoxaban is a highly specificinhibitor of FXa, a coagulation factor with a key role in theinitiation and propagation phases during the cell-based modelof the activation of coagulation. The antithrombotic action ofedoxaban was confirmed in experimental models of venousand arterial thrombosis. Studies in different animal models

predicted a 10-fold dissociation between antithrombotic andbleeding effects.

Edoxaban is well tolerated at doses up to 150 mg in phar-macokinetic studies in humans, with no dose-dependentincrease in adverse events. Exposure is proportional to dose.Pharmacokinetic profiles are consistent across dose with rapidabsorption, biphasic elimination, with elimination half-life of8.75 -- 10.4 h and mean accumulation of 1.10 -- 1.13 afterdaily dosing and intrasubject variability ranging from 12 to17% for AUC.

Phase II and III clinical trials have demonstrated that edox-aban is at least as effective as dalteparin or enoxaparin and hasa risk of major bleeding similar to that of heparins in theprevention of DVT in patients undergoing major orthopedicsurgery. Edoxaban is approved for the prevention of DVTin patients undergoing major orthopedic surgery by agovernment agency only in Japan.

Some specific limitations of past clinical studies of edoxa-ban for the prophylaxis of DVT after major orthopedic sur-gery should be recognized: i) the ethnic distribution of thesetrials is biased with the majority of patients recruited fromJapan or Taiwan; ii) the scale of all studies was small; andiii) treatment with enoxaparin 20 mg twice daily was startedaccording to the standard of care in Japan but is not com-monly used in other countries. Consequently, multinationaltrials are needed to confirm the efficacy and safety as well asthe optimal dose of edoxaban for the prevention of VTE afterorthopedic surgery in Caucasian populations.

Edoxaban is the fourth agent in a sequence of other neworal anticoagulants (dabigatran, rivaroxaban and apixaban)being approved or seeking approval from regulatory authori-ties as antithrombotic agents on three main indications:i) prevention of DVT after major orthopedic surgery;ii) treatment of DVT and PE; and iii) prevention of TE inpatients with non-valvular AF. Licensing companies have con-ducted or are developing clinical trials to support these indica-tions. One of the limitations of these clinical trials is that noneof them has directly compared one of the new anticoagulantagents with another.

The HOKUSAI-VTE Phase III trial represents the largestsingle clinical study in VTE therapy so far. In this event-driven trial, after initial therapy with open-label enoxaparinor unfractionated heparin, edoxaban or warfarin was adminis-tered in a double-blind, double-dummy fashion [48]. As shownin Table 4, HOKUSAI-VTE trial included a considerablenumber of patients with a broad spectrum of venous throm-boembolic manifestations as is frequent in clinical diary prac-tice. In addition, the use of once-daily regimen of edoxabanfor VTE treatment in comparison with other new oral antico-agulants (dabigatran, rivaroxaban or apixaban) had additionalbenefits as such more practical and feasible therapy inthis setting.

Edoxaban offers the common benefits and limitations ofthe new oral anticoagulants. Among the benefits: i) rapidonset and offset of action; ii) relative ease of oral

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Table

4.Efficacy

andsafety

outcomesofpublish

edtrials

onvenousthromboembolism

therapywithnoveloralantico

agulants.

Trials

Patients

Drugs

Dosingschedule

Design

Duration

Recu

rrent

thrombosis

Major

bleeding

Comments

RE-COVERI,

2009[63]

Acute

venous

thromboembolism,

n=2539

Dabigatran

versus

warfarin

Dabigatran150mg

twiceaday

Double

blind,

double-dummy,

randomized,

non-inferiority

6months

2.4

versus2.1%

,p<0.001

(non-inferiority)

1.6

versus1.9%

,p=0.38

Initialparenteralheparin

anticoagulation.Deep-

vein

thrombosisonlyin

68.8%

.INRin

therapeutic

range:59.9%

RE-M

EDY,

2013[64]

Acute

venous

thromboembolism,

n=2866

Dabigatran

versus

warfarin

Dabigatran150mg

twiceaday

Double-blind,

randomized,

extended,

non-inferiority

6--36months

1.8

versus.

1.3%

,p=0.01

(non-inferiority)

0.9

versus1.8%

,p=0.06

Enrolledpatients

completedatleast

3monthsoftreatm

ent.

Deep-vein

thrombosis

onlyin

65.1%

.INRin

therapeuticrange:65.3%

RE-SONATE,

2013[64]

Acute

venous

thromboembolism,

n=1353

Dabigatran

versus

placebo

Dabigatran150mg

twiceaday

Double-blind,

randomized,

extended,

superiority

6--12months

0.4

versus5.6%

,p<0.001(superiority)

0.3

versus0%

,p=1.0

Deep-vein

thrombosis

onlyin

64.9%

EINSTEIN-DVT,

2010[65]

Acute

deep-vein

thrombosis,n=3449

Rivaroxaban

versus

vitamin

Kantagonist

Rivaroxaban15mg

twicedaily

for

3weeks,followed

by20mgonce

daily

Open-label,

randomized,

event-driven,

non-inferiority

3,6and

12months

2.1

versus3.0%

,p<0.001

(non-inferiority)

0.8

versus1.2%

,p=0.21

Initialanticoagulation

withheparin.INRin


EINSTEIN-Extended,

2010[65]

Acute

venous

thromboembolism,

n=1197

Rivaroxaban

versus

placebo

Rivaroxaban20mg

once

daily

Double-blind,

randomized,event-

driven,extended,

superiority

6--12months

1.3

versus7.1%

,p<0.001(superiority)

0.7

versus0%

,p=0.11

Enrolledpatients

completedatleast

6monthsoftreatm

ent.

Deep-vein

thrombosis

onlyin

62.0%

EINSTEIN--PE

2012[66]

Acute

pulm

onary

embolism,n=4832

Rivaroxaban

versusvita-

min

Kantagonist

Rivaroxaban15mg

twicedaily

for

3weeks,followed

by20mgonce

daily

Open-label,

event-driven,

non-inferiority

3--12months

2.1

versus44%

,p=0.003

(non-inferiority)

1.1

versus2.2%

,p=0.003


withheparin.INRin


AMPLIFY

-EXT,

2013[67]

Acute

venous

thromboembolism,

n=2482

Twodoses

ofapixaban

versus

placebo

Apixaban2.5

or

5mg,tw

icedaily

Double-blind

randomized,

extended,

superiority

12months

1.7

versus1.7

versus8.8%

,p<0.001forboth

comparisons

(superiority)

0.2

versus0.1

versus0.5%

,p=0.11

Enrolledpatients

completedatleast

6-12monthsof

treatm

ent.Deep-vein

thrombosisonlyin

65.3%

HOKUSAI-VTE,

2013[48]

Acute

venous

thromboembolism,

n=8292

Edoxaban

versus

warfarin

Edoxaban60mg

orally

once

daily

Double-blind,

double-dummy,

randomized,

non-inferiority

3--12months

3.2

versus3.5%

,p<0.001(non-

inferiority)

1.4

versus1.6%

,p=0.35


withheparin.Deep-vein

thrombosisonlyin

59.7

%.INRin

therapeutic

range:63.5%

DVT:Deepvein

thrombosis;

INR:Internationalnorm

alizedratio;PE:Pulm

onary

embolism;VTE:Venousthromboembolism.

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administration; iii) no need for routine monitoring of antico-agulant effect; and iv) lack of significant drug interactions.Potential limitations for all these new agents are: i) the possi-ble lack of compliance considering their relative short life;ii) technical difficulties for occasional monitoring; andiii) lack of specific antidotes for the reversal of their anticoag-ulant action in case of emergencies.Potential advantages of edoxaban are: its favorable phar-

macokinetic profile, the reduced rate of accumulation afterdaily intake, the predictability of the anticoagulant actionand the simplicity of the dosing. Efficacy and safety of edox-aban observed in clinical trials have been confirmed in phar-macometric modeling analyses in exposed populations anddata seem to be reaffirmed in post-marketing vigilancestudies.

Despite the need for some additional studies on dosing ofedoxaban for wider ethnic groups, edoxaban can be perceivedas a major advance in the prevention and treatment of throm-boembolic disease given its favorable efficacy, safety, pharma-cokinetic profile and renal clearance. Results of ongoing largeinternational trials in the prevention of thrombotic complica-tions in patients with AF [61] ensure that the licensing com-pany will seek for a wider approval of new indications fromregulatory authorities.

Declaration of interest

G Escolar has received honoraria/consultant fees from Bayer,BMS, Boehringer Ingelheim, CSL Behring and NovoNordisk.The other authors declare no relevant conflicts of interest.

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2. Ruppert A, Steinle T, Lees M. Economic

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a systematic review. J Med Econ

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3. Geerts WH, Bergqvist D, Pineo GF,

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AffiliationGines Escolar†1 MD PhD,

Maribel Diaz-Ricart2 PhD,

Eduardo Arellano-Rodrigo3 MD PhD &

Ana M Galan4 PhD†Author for correspondence1Senior Consultant,

Universitat de Barcelona, Hematologist, Hospital

Clinic, Servicio de Hemoterapia y Hemostasia,

Villarroel 170, 08036 Barcelona, Spain

Tel: 34 93 227 54 00 Ext: 2571;

Fax: 34 93 227 93 69;

E-mail: [email protected], Pharmacist,

Universitat de Barcelona, Hospital Clinic,

Servicio de Hemoterapia y Hemostasia,

Barcelona, Spain3Specialist, Hematologist,



Barcelona, Spain4Associated Scientist, Biochemist,



Barcelona, Spain

G. Escolar et al.


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