Reversal Agents for Anticoagulants: Focus on N Andexanet

AMSRJ Spring 2014 Volume 1, Number 116

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ABSTRACT

INTRODUCTION

Due to projected increases in the incidence ofvenous thromboembolism in the United States(based on healthcare claims data), anticoagula-tion has become an extremely pertinent subjectof interest. An anticoagulant’s efficacy must befavored to, or balancedwith, its safety profile. Inoverdose or emergent situations, reversal agentsplay a crucial role. Examples of anticoagulantsthat have specific antidotes are warfarin (withvitaminK)andheparin (withprotamine).Neweranticoagulants, such as direct thrombin in-hibitors or factor Xa inhibitors (direct or indi-rect), do not have specific reversal agents asidefrom activated charcoal and blood products. Toalleviate bleeding associated with these antico-agulants, providers have utilized prothrombincomplex concentrates (activated, three-factor,four-factor), recombinant factor VIIa, and/orfresh frozen plasma. Andexanet alfa is an inves-tigational reversal agent for direct (e.g., apixa-ban, betrixaban, edoxaban, rivaroxaban) and in-direct (e.g., enoxaparin, fondaparinux) factorXa inhibitors. As there are no specific reversalagents for factor Xa inhibitors yet, this protein

potentially addresses an unmet need.Andexanetalfa is a modified factor Xa devoid of procoagu-lant and anticoagulant properties, which hasshown promising results via pre-clinical andclinical studies.More data on its safety and effi-cacy is expected in the upcoming years.

Virchow’s Triad explains that vascular injury,disruption in blood flow, and an imbalance inhemostasis are interconnected pathologicalmechanisms leading to thrombus formation.1Thrombi may form either in arteries or veins,and thromboembolism occurs when theseformed clots dislodge and travel to the distal cir-culation.1,2 In the venous circulation, a clot com-monly presents as deep vein thrombosis (DVT)and could lead to a pulmonary embolism (PE).2When formed in the arterial circulation, thrombicould ultimately lodge into arteries within or-gans and cause ischemia, such as a stroke in thebrain.2

The exact incidence and prevalence of venousthromboembolism (VTE) in theUnited States isunknown because of variances in studymethod-ologies (i.e., inclusion and exclusion criteria).3Based on a retrospective analysis of healthcareclaims data, there were 317 cases per 100,000patients (in 2002) and 422 cases per 100,000patients (in 2006), representing a 33.1% in-

Reversal Agents for Anticoagulants: Focus onAndexanet Alfa

1West Virginia University School of Medicine, Morgantown, WV2The Mount Sinai Hospital, New York, NY

Neal Shah, PharmD1; Mohammad A. Rattu, PharmD2

Corresponding Author: Neal Shah, PharmD, West VirginiaUniversity School of Medicine, P.O. Box 9100 Morgantown,West Virginia 26506.Email: [email protected] authors claim no conflicts of interest or disclosures.AMSRJ 2014; 1(1):16—28http://dx.doi.org/10.15422/amsrj.2014.05.010

AMSRJ Spring 2014 Volume 1, Number 1 17

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REVERSAL AGENTS FOR ANTICOAGULATION

crease.3 Inaddition, about2.7millionpeoplehadatrial fibrillation (AF) in 2010, and this numberis expected to increase to 12 million by 2050.4AF increases the risk of an ischemic stroke by 5-foldand leads to15-20%ofall ischemic strokes.4

Targeting clot formation is a crucial therapeuticobjective that has resulted in the development ofmany anticoagulant medications.5 However,preventing coagulation may increase bleedingrisk, with an average incidence of major bleed-ing estimated to be around0.5%per year in stud-ies and up to 3.4%per year based on surveys.5 Inemergency situations, rapid anticoagulation re-versal is crucial prior to invasive procedures orfor preventing hemorrhagic complications (e.g.,intracranial hemorrhage).6 Anticoagulants alsohave different therapeutic indices (e.g., druglevel, age, renal function) affecting the likeli-hood of a bleed.5

Patients who unfortunately present with bleed-ing complications may require hemodynamicsupport (e.g., volume expanders, oxygen, cor-rection of acidosis and hypothermia), reductionof drug exposure (e.g., antiplatelet, anticoagu-lant), and enhanced hemostasis (e.g., bleedingsite compression, topical epinephrine/thrombin/fibrin, desmopressin, correction of hypocal-cemia).5

Although there are specific reversal agents forcertain drugs (e.g.,warfarin, heparin), “true” an-tidotes for direct thrombin inhibitors (DTI) andfactor Xa inhibitors (fXaI) are not yet availableon themarket.7This is concerningbecausenoveloral anticoagulants have rapidly entered outpa-tient settings,mostly due to comparative clinicalefficacies towarfarin and less routine blood lev-el monitoring.7

Figure 1. Coagulation cascade with selected drugs’ sites of action.10Red symbols (--|) point to sites of inhibition, while green symbols (++) point to sites of reversal.

Original artwork by: Mohammad A. Rattu, PharmD


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Recently, a protein called andexanet alfa(PRT064445 or PRT4445*, Portola) has shownefficacy in reversing the anticoagulant effects offXaI.8,9 Other potential reversal agents, includ-ing an antibody against dabigatran and a “uni-versal” small molecule antidote for DTI and fX-aI, are also under development.5

Vitamin K Antagonists (VKA)Warfarin (Coumadin, Bristol-Myers Squibb) isthe most commonly utilized oral anticoagulantin medical practice.11 Post-ribosomal synthesisof vitaminK dependent clotting factors requiresan important cofactor: vitamin K.11 By inhibit-ing the C1 subunit of vitamin K epoxide reduc-tase (VKORC1) and reducing vitaminK1 epox-ide regeneration, warfarin interferes with thesynthesisof factors II,VII, IX, andXin thecoag-ulation cascade (along with the anticoagulantproteins C and S).12

Warfarin is approved by the United States FoodandDrugAdministration (FDA) for the prophy-laxis and treatment of VTE (DVT and PE) andthromboembolic complications (e.g., stroke) ofAF and cardiac valve replacement.12 It is alsoindicated for reducing the risk of death, recur-rent myocardial infraction (MI), and throm-boembolic events (e.g., stroke, systemic em-bolization) after an MI.12

The safety and efficacy of warfarin depends onthe international normalized ratio (INR), a cal-culationbasedon theprothrombin time (PT) andameasure of the extrinsic pathway in the coagu-lation cascade.13 For the majority of patients re-quiring anticoagulation with warfarin, the 2012CHEST guidelines from the American CollegeofChest Physicians recommendgoal INR levelsbetween 2 and 3 (with an ideal target of 2.5).13,14

The goal INR is generally higher (i.e., 2.5 to 3.5)in patients who have received mechanical valvereplacements (e.g., aortic,mitral).13,14The riskofbleeding increases with higher INR values, andinterventions may be required to reverse the an-ticoagulant’s effects.13

Along with dietary vitamin K intake, there aremany factors affecting the INR, leading to eithersub- or supra-therapeutic levels.14 While age>70 years, the absence of chronic diseases, andmale gender have been found to be independentpredictors of stability, some factors associatedwith unstable INR are congestive heart failure,diabetes, and a target INR >3.14 In the inpatientsetting, the INR is typicallymonitored on a dailybasis for patients on warfarin, whereas, anecdo-tally, an outpatient monitoring schedule mayinitially be weekly, transition to every twoweeks, and eventually become monthly for sta-ble patients.14Outpatientmonitoringofwarfarintherapy realistically dependson individual insti-tution practices and patients’ respective abilitiesto arrive to clinics for blood work.14 These andother challenges are perceived as drawbacks,adding to the allure for utilizing neworal antico-agulants that could be administered at fixed dos-es without much laboratory monitoring.14

Fortunately, there are several reversal strategiesfor warfarin, based on the INR and need for re-versal.13-18 When patients are actively bleeding,first-line recommendations typically includediscontinuing warfarin and administering intra-venous (IV) phytonadione (vitamin K) with aninfusion of prothrombin complex concentrate(PCC).13,17 The combination is used becausePCC replaces clotting factors immediately,while vitamin K promotes future production ofclotting factors.13,17 Of note, IV vitamin K leadsto earlier reversal of warfarin-based anticoagu-lation compared to oral vitamin K, but bothroutes of administration seem to have similarclinical outcomes.17,19

BRIEF REVIEW OF SELECTEDANTIGOAGULANTS


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Afour-factorPCC(PCC4)approach ispreferredbecause it would replace the clotting factors in-hibited by warfarin (II, VII, IX, and X).13,17 Thisincludes either using a PCC4 product (Kcentra,CSLBehring) or the combination of a three-fac-tor PCC (PCC3) product (Bebulin VH, Baxter;Profilnine SD, Grifols; and many others) withrfVIIa / recombinant coagulation factor VIIa(NovoSeven RT, Novo Nordisk).13,17,20-23 Acti-vatedPCC(aPCC) / factor eight inhibitor bypassactivity (FEIBA NF, Baxter) and fresh frozenplasma (FFP) are additional, but less preferable,options based on current evidence and guide-lines.18,24

Unfractionated Heparin (UFH) and Low-Molecular-Weight Heparins (LMWH)

By increasing the activity of antithrombin III(ATIII), UFH affects thrombin, plasmin, andfactors IX, X, XI, and XII.25 UFH also preventsthe conversionof fibrinogen to fibrin.25Thedrugis used in numerous settings, including acutecoronary syndrome (ACS), percutaneous coro-nary intervention (PCI), the prophylaxis andtreatment of VTE (i.e., DVT and PE), and linepatency maintenance.25 In hospitalized patientswho become eligible for outpatient treatment,UFHmaybebridgedwithwarfarinuntil the INRis therapeutic (or bridged with other oral antico-

agulants based on the respectivemanufacturers’recommendations).13,25 Of note, bridge therapy(i.e., using UFH simultaneously with warfarinand discontinuing UFH once the INR is thera-peutic) is important because the anticoagulanteffectsofUFHaremore immediate,while itmaytake warfarin several days to decrease the pro-duction of new vitamin K-dependent clottingfactors.12,13,25 In addition, the inhibition of fac-tors C and S by warfarin establishes an initialprocoagulant state andUFH couldminimize therisk of clotting in this period.12,13,25 UFH treat-ment is usually monitored with the activatedpartial thromboplastin time (aPTT).25

Enoxaparin (Lovenox, Sanofi-Aventis) has ahigher ratio of factor Xa to IIa (or thrombin)inhibition compared to UFH.26 It has been usedfor VTE prophylaxis and treatment, PCI, ST-elevation MI (STEMI), and unstable angina(UA) or non-ST-elevation MI (NSTEMI).26Al-though dalteparin (Fragmin, Eisai) and tinza-parin (Innohep, Celgene) have mechanisms ofaction similar to enoxaparin, they are prescribedless frequently.27 Dalteparin is used for the pro-phylaxis and treatment of VTE and UA or non-Q-wave MI.28 Tinzaparin is approved for VTEprophylaxis and treatment, aswell as anticoagu-lation in extracorporeal circuit duringhemodial-ysis.29 Similar to UFH, each LMWH may beused as bridge therapy with oral anticoagu-lants.13,26-29 LMWH therapy may be monitoredwith anti-Xa levels in select populations (e.g.,dialysis, obese, long-term anticoagulation).26-29Bleeding situations with LMWHs may be morecomplicated due to their longer half-lives com-pared to UFH.26-29

Recommendations for reversing UFH orLMWHincludediscontinuing the respectivean-ticoagulant and administering protamine sul-fate.17,30 Cationic hydrogenated protamine (pHof 6.8 to 7.1) reacts with anionic UFH (pH of 5to 7.5) or LMWH (e.g., enoxaparin with a pH of5.5 to 7.5) to form a stable, inactive salt com

Product Clotting Factor Composition

PCC4 II, VII, IX, X (inactivated)

PCC3 II, IX, X (inactivated)

rfVIIa VII (activated)

aPCC II, VII (activated), IX, X (inactivated)

1 Table 1. Composition of selected clotting factor products.18,20-24PCC4: four-factor prothrombin complex concentrate; PCC3: three-factorprothrombin complex concentrate; rfVIIa: recombinant coagulation factorVIIa; aPCC: activated prothrombin complex concentrate


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plex.25,26,30 Doses of protamine depend on theroute of, and time since, the previous adminis-tration of UFH or LMWH.17,30

Direct Thrombin Inhibitors (DTI)

In the 2012 CHEST guidelines, dabigatran(Pradaxa, Boehringer Ingelheim) is favoredover warfarin for the prevention of stroke andsystemic embolism in patients with non-valvu-lar AF.31,32 First-line recommendations for theemergent reversal of dabigatran include discon-tinuing the drug, using prolonged dialysis, andadministering aPCC.17 If dabigatranwas recent-ly ingested (within two hours) and the patientdoes not have a gastrointestinal bleed, activatedcharcoal should be given.18,32 Other options in-clude using a PCC4 product or a PCC3 productwith rfVIIa.18 Potential antidotes for dabigatranarediscussed later in the "OtherUpcomingAnti-dotes" Section.5,33

Factor Xa Inhibitors (fXaI)

Fondaparinux (Arixtra, GlaxoSmithKline) is asynthetic pentasaccharide that exhibits activityvia an ATIII-mediated selective inhibition offactor Xa (i.e., it is an indirect fXaI).34While thepentasaccharide structure is similar to the unitsin UFH, fondaparinux does not have affinity forplatelet factor 4 (PF-4) and it is less likely toinduce heparin-induced thrombocytopenia(HIT).34 Although it is FDA-approved for theVTE prophylaxis and treatment, fondaparinuxis usually reserved for patients who are allergicto UFH or LMWH and have normal renal func-tion (i.e., creatinine clearance >50 mL/min).17,34,35 Fondaparinux may also be used asbridge therapy with oral anticoagulants.13,34 An-ti-Xa levels could be monitored if the calibratordrug is fondaparinux; otherwise, results will beinaccurate.34 If patients require fondaparinux re-

versal, the drug should be discontinued andaPCC or rfVIIa could be administered.17

As of March 2014, apixaban (Eliquis, Bristol-Myers Squibb) and rivaroxaban (Xarelto,Janssen) are the only FDA-approved oral, directfXaI.36,37 Similar to dabigatran, apixaban is la-beled for reducing the risk of stroke and sys-temic embolism in patients with non-valvularAF.36 Apixaban has been used off-label forVTEprophylaxis postoperatively (knee or hip re-placement surgery) and VTE treatment.38,39 Ri-varoxaban (Xarelto, Janssen) has the broadestFDA-approved indications for an oral fXaI, as itis labeled for reducing the risk of stroke and sys-temic embolism innon-valvularAFpatients, theprophylaxis and treatment of VTE, and postop-erative (knee or hip replacement surgery) VTEprophylaxis.37 Betrixaban (PRT054021, Porto-la) is a fXaI currently in phase 3 trials; it has along half-life, minimal hepatic metabolism, andminimal renal clearance.40

Current recommendations for the emergent re-versal of apixaban or rivaroxaban are discontin-uing the respective fXaI and administering acti-vated charcoal if the last dose of the fXaI wastaken with the past two hours.18,36,37 Activatedcharcoal should be given again six hours after itsfirst administration.18,36,37 Preferred clotting fac-tor supplements in this setting include PCC4,aPCC, PCC3 with rfVIIa, and/or PCC3.17,18

History

Andexanet alfa is currently being studied for thereversal of anticoagulation due to direct (e.g.,apixaban, rivaroxaban, betrixaban) and indirect(e.g., enoxaparin, fondaparinux) fXaI.8,9,41-47Since there are no specific reversal agents forfXaI yet, this protein potentially addresses an

ARTICLE FOCUS: ANDEXANET ALFA


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unmet need.9 TheFDAdesignated andexanet al-fa as a breakthrough therapy in late 2013.48As ofMarch 2014, there are ongoing phase 3 trials andmanufacturers of apixaban, edoxaban, and ri-varoxaban have entered clinical collaborationsto study the promising antidote.49-53

Biochemical Composition

Andexanet alfa is a modified recombinant pro-tein derived from human coagulation factor X,with an approximate molecular weight of 39kDa (i.e., ~11 kDa light chain and ~28 kDaheavy chain).9 The protein lacks a membrane-binding γ-carboxyglutamic acid (GLA) domainand it is not catalytically active due to a serine→alanine residue mutation (S419A) in the pro-tease catalytic triad (which is typically com-posed of histidine, aspartic acid, and serine).9Andexanet alfa was expressed in its functional

(or activated) form in mammalian cell (ChineseHamster Ovary [CHO]) culture.9 Unlike in thecoagulation cascadewith factorX (to obtain fac-tor Xa), andexanet alfa did not require any acti-vation steps by factors VIIa (from the extrinsicpathway) or IXa (from the intrinsic path-way).9,54-57

Clinical Pharmacology

In contrast to human coagulation factor Xa, an-dexanet alfa is unable to assemble into a pro-thrombinase complex to cleave prothrombin(factor II) to thrombin (factor IIa) and prothrom-bin fragments F1 and F2.8,9 The investigationalantidote does not exhibit detectable procoagu-lant or anticoagulant activity, as found in a clot-ting assay examining the effects of rivaroxaban(1 micromole) and andexanet alfa (up to 1.9 mi-cromoles) on human plasma PT prolongation.9

Figure 2. Schematic structure and mechanism of action of andexanet alfa.9,43,56,58GLA: gamma(γ)-carboxyglutamic acid; EGF1,2: epidermal growth factor-like domains 1 and 2; ATIII: antithrombin III; LMWH: low-molecular-weight heparins.

Original artwork by: Mohammad A. Rattu, PharmD


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Asa result of aforementionedmodifications, an-dexanet alfa has high affinity for direct fXaI(e.g., apixaban, betrixaban, rivaroxaban).9 Theprotein acts as a decoy for direct fXaI, binding tothese drugs in dose-dependent manner and pre-venting the antidote-direct-fXaI complex fromacting on the coagulation cascade.9 As depictedin Fig. 2, andexanet alfa could also bind to, andmodulate the activity of, the complex formed byATIII and indirect fXaI (e.g., LMWH, fonda-parinux).9

Pre-Clinical Studies

A study of rivaroxaban 0.23 micromoles in hu-man and rat plasma found that at least 0.5micro-moles of andexanet alfa reversed most of theanticoagulant’s anti-Xa activity.8,9,42 Studies inrats infused with fXaI and andexanet alfa aredescribed in Table 2.8,9,42 In general, while theplasmaconcentrations (Cp) of the fXaI increasedafter bolus and infusion administrations of an-dexanet alfa (secondary to redistribution fromextravascular compartments), the overall per-centage of unbound or free drug dramatically

decreasedwithin90minutes.8,9,42 Thesedecreas-es in the plasma free fractions (Fp) of fXaI corre-lated with respective INR normalizations.8,9,42

To confirm if the normalization of aforemen-tioned surrogate markers (e.g., anti-Xa, PT/INR,aPTT)correlatedwith thecessationof clin-ical bleeding, investigators utilized a rabbitmodel of liver laceration.8,9,45 Anesthetized rab-bits were injected with a bolus of rivaroxaban 1mg/kg, and after 30 minutes, the rabbits eitherreceived a bolus of the vehicle or andexanet alfa75mg.8,9,45 The experiment found that andexanetalfa reduced blood loss by more 85%, as well asdecreased peak anti-Xa activity by 98%, PT by74%, aPTT by 66%, and the Fp of rivaroxabanfrom26%+/- 0.9% to 0.5%+/- 0.3% (i.e., a 98%reduction).8,9,45

In addition to direct fXaI, researchers also testedthe effects of andexanet alfa on LMWH (e.g.,enoxaparin) and pentasaccharide (e.g., fonda-parinux) anticoagulants, both of which increasethe activity of ATIII.9,44 Results from a rat tailresection model of blood loss with bolus dosesof enoxaparin and andexanet alfa are summa-

Post-fXaI Post-fXaI + Andexanet Alfa

fXaIa Drug Cpb

Drug Fp, % Andexanet

Alfaa

Drug Cpb

Drug Fp, %

Apixaban

0.5 mg/kg/hr

1.4 +/- 0.3 1.5 +/- 0.3 6 mg +

6 mg/hr

4.2 +/- 0.7 0.05 +/- 0.02

Betrixaban

1 mg/kg/hr

0.2 +/- 0.01 40 +/- 7.2 6 mg +

9 mg/hr

2 +/- 0.4 0.3 +/- 0.1

Rivaroxaban

0.25 mg/kg/hr

1.4 +/- 0.4 2.2 +/- 0.8 4 mg +

4 mg/hr

1.9 +/- 0.09 0

1 Table 2. Studies in rats infused with direct factor Xa inhibitors and andexanet alfa.8,9,42a Direct fXaI were infused for 30 minutes, followed by andexanet alfa bolus over 5 minutes and infusion for 90 minutes.b Measured in micromoles, with the mean +/- standard deviation.fXaI: factor Xa inhibitors; Cp: plasma concentration; Fp: plasma free fraction; hr: hour.


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rized in Table 3.44 Although bolus doses of an-dexanet alfa significantly reduced anti-Xa activ-ity in a dose-dependent manner, there was onlya partial reduction in blood loss.44

A similarmodel inwhichenoxaparin (4.5mg/kgbolus over 5 minutes) was combined with an-dexanet alfa (2mgbolus and 2mg/hour infusionor4mgbolus and4mg/hour infusion) found thatanti-Xa activity decreased dose-dependentlyand higher doses of andexanet alfa reducedblood loss to baseline.9 The 2 mg bolus with 2mg/hour infusion resulted in only a partial cor-rection (i.e., 42% reduction) in blood loss.9 Inaddition, fondaparinux (25 mg/kg bolus over 5minutes) combined with andexanet alfa (6 mgbolus and 6 mg/hour infusion) significantly de-creased anti-Xa activity within 15 minutes andled to a cessation of bleeding.9

Clinical Studies

There is very limited, but promising, clinical da-ta on andexanet alfa. An ongoing phase 2, dou-

ble blind, placebo controlled, dose responsestudy is examining the safety, tolerability, phar-macokinetics, and pharmacodynamics (i.e., re-versal effects) of andexanet alfa on fXaI (e.g.,apixaban, betrixaban, enoxaparin, rivaroxaban)in 144 healthy volunteers.46,47,59 Subjects willreach a steady state (days 1 to 6) with a fXaI; onday6, three hours after the last dose of fXaI, theywill receive an IV bolus dose of andexanet alfaor placebo.46,47 Pharmacokinetic datawill be col-lected through day 10, while safety and pharma-codynamic data will be collected through day48.46,47 Preliminary results are summarized inTable 4.46,47

Overall, an IV bolus of andexanet alfa immedi-ately decreased theCp of apixaban and rivaroxa-ban compared to placebo.46,47 Similar to whatwas observed in pre-clinical studies, there werealso initially significant, dose-dependent de-creases in anti-Xa activity, but anti-Xa activityslowly increased to high levels again within 2hours.9,46,47 This phenomenonwillmost likely bealleviated in future studieswith an IV bolus plusextended-infusion regimenof andexanet alfa (asperformed in a pre-clinical experiment).9,60

Adverse Drug Reactions

Researchers have presented some data, but thetrue incidence and complete description of ad-verse reactions from andexanet alfa will requirelarger study populations.46,47

In a phase 2 cohort of patients who receivedapixaban and andexanet alfa, there were tran-sient reductions in tissue factor pathway in-hibitor (TFPI) activity.46 Of note, TFPI is an en-dogenous, reversible fXaI.61Therewere increas-es in prothrombin fragments F1 and F2, but nochanges in D-dimer.46 Andexanet alfa was well-tolerated; no thrombotic, allergic-type, or seri-ous adverse events were observed, and therewere no deaths.46 Although 5 of 9 (56%) of pa

Post-fXaI + Andexanet Alfa

Andexanet

Alfaa

Reduction in

Anti-Xa Activityb

Reduction in

Blood Loss

0.5 mg 13% N/A

1 mg 35% 60%

2 mg 52% 56%

4 mg 81% 62%

1 Table 3. Study of rats infused with boluses of enoxaparin and andexanetalfa.44a

Indirect fXaI (i.e., enoxaparin 4.5 mg/kg) were given as anintravenous bolus over 5 minutes; the rat’s tail was then resected; 10minutes after the injury, andexanet alfa was given as a bolus over 5minutes. Blood loss was measured for an additional 45 minutes afterandexanet alfa was administered.b Within the first 5 minutes after andexanet alfa was administered.


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tients experienced some type of adverse event,Crowther M, et al. described all of the reactionsas mild in nature.46

Patients who received rivaroxaban and andex-anet alfa in a phase 2 cohort had no increases inprothrombin fragmentsF1andF2, thrombin-an-tithrombin, orD-dimer (highlighting the inabili-ty of andexanet alfa to form a prothrombinasecomplex with factor Va or exhibit other pro-thrombotic properties).47 As observed previous-ly, TFPI activity expectedly decreased due tobinding with andexanet alfa.47 The investiga-tional antidote was well tolerated; no thrombot-ic, serious, or severe adverse events were ob-served.47 Reported adverse events in the nine-patient cohort includedmild infusion-related re-

actions (n=3; 33%), post-procedural hematoma(n=2; 22%), headache (n=2; 22%), posturaldizziness (n=2; 22%).47

Idarucizumab

Idarucizumab (aDabi-Fab / BI 655075,Boehringer Ingelheim) is a fully humanized an-tibody fragment (Fab) against dabigatran.33Based onX-ray crystallization techniques, thereare many structural similarities between thedabigatran-thrombin and dabigatran-idaru-cizumab complexes; in the latter complex, there

fXaI

(days 1 to 6)

Andexanet

alfa dose

(IV bolus)

Total

Subjects

Andexanet

alfa to fXaI

Cp molar ratio

Anti-Xa

activity after

andexanet alfa

Anti-Xa

activity after

placebo

Apixaban

5 mg BID

(11 doses)

90 mg 9 0.66

(474:314)

(n=4)

2 min: -65%

10 min: -47%

30 min: -29%

60 min: -17%

(n=2)

2 min: +6%

10 min: +7%

30 min: +11%

60 min: +3%

Rivaroxaban

20 mg QD

(6 doses)

210 mg 9 0.8

(1.2:1.6)

(n=6)

2 min: -20%

(n=3)

2 min: +0%

Rivaroxaban

20 mg QD

(6 doses)

420 mg 9 1.2

(2.6/2.1)

(n=6)

2 min: -53%

Same as

above

1 Table 4. Preliminary results from ongoing phase 2 trials of andexanet alfa and factor Xa inhibitors.46,47fXaI: factor Xa inhibitors; Cp: plasma concentration; BID: twice daily; IV: intravenous

OTHER UPCOMING ANTIDOTES


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REFERENCES

is a 350-fold stronger affinity for the oral DTI.33Idarucizumab does not seem to bind knownthrombin substrates nor does it demonstrate pro-thrombotic properties.33

Promising results from pre-clinical (rat and pigmodels) and phase 1 trials have been presented,and more data is expected as the potential anti-dote enters larger studies.62-74

Aripazine

Aripazine (PER977, Perosphere) is a rationally-designed, synthetic, small molecule with broadreversal activity.75-79 Based on dynamic lightscattering (DLS) techniques, it is a potential an-tidote for oral (e.g., direct fXaI [apixaban, edox-aban, rivaroxaban], DTI [dabigatran]) and par-enteral (e.g.,UFH, LMWH, fondaparinux) anti-coagulants.75-79 As with andexanet alfa andidarucizumab, the agent is devoid of procoagu-lant properties.75-79

Pre-clinical (rat and dogmodels) data is promis-ing, but more studies need to be conducted toelucidate its safety and efficacy.75-79

In addition to vitamin K and protamine, andex-anet alfa has the potential to become an ap-proved, specific antidote for currently irre-versible and increasingly prescribed anticoagu-lants (i.e., direct and indirect fXaI). Pre-clinicalandclinical studies haveonlyprovidedglimpsesof the novel protein’s pharmacokinetics andpharmacodynamics. Andexanet alfa is expectedto benefit both patients and providers, as it suc-cessfully reversed the anticoagulant effects ofrivaroxabanandapixabanwithout establishingapro-coagulant state in pre-clinical and initial hu-

man trials. As the protein enters larger-scale tri-als to reverse anticoagulation, more data will bepublished related to its safety and efficacy. Ad-ditional antidotes for fXaI and DTI are also un-der investigation, and their respective clinicaloutcomes data is highly anticipated.

1.Wolberg AS, AlemanMM, LeidermanK, et al. Procoagulant activityin hemostasis and thrombosis: Virchow's triad revisited. AnesthAnalg. 2012 Feb;114(2):275-85.

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Reversal Agents for Anticoagulants: Focus on N Andexanet