Reversal of DOACs and Lab Measurement

With thanks to Dr Adam Cuker

Disclosures

MarkCrowther

Currentstateofaffairs

• Fiveoralanticoagulantsincommonuse– Warfarin– aboutwhichwewillnottalkmuch

• INRtestingisprettygood

– Rivaroxaban– oralXainhibitor– Apixaban– oralXainhibitor– Edoxaban – oralXainhibitor– Dabigatran– oralIIainhibitor

• Heparinandlowmolecularweightheparin

Firstlywhatshouldwecallthem?

DOACs:Commonalities

• AlloftheDOACssharecommoncharacteristics– Oral– RapidabsorptionwithprofilessimilartoLMWH

– Shorthalflives– Noofftargettoxicity– Lowerriskofmajorandfatalbleedingthanwarfarin

– Reversalagentfordabigatranhasbecomeavailable

Case (1)

• A 71-year old man presents to the emergency department at 8 PM on Saturday night with abdominal pain and hypotension. Imaging reveals a ruptured AAA.

• PMH: Non-valvular atrial fibrillation, Hypertension, Dyslipidemia, Stroke 1 year ago

• Meds: HCTZ 25 mg QD, Atorvastatin 20 mg QD, Apixaban 5 mg BID

• Last dose of apixaban was 12 hours ago

• The surgeon calls the lab and wants proof there is no anticoagulant effect present

Case (1.1)

10.2 292

11.8

35

140

3.8

23

1.42

99

105

24

PT 13.2sINR 1.1APTT 31.6sAnti-Xa Pending(willbeavailablein2hours)

Case (3)

Vascular surgery recommends emergent open repair. Two hours is too long to wait.

What do you recommend?a) PT and APTT are normal. Patient is cleared to go to the OR without anticoagulant

reversal.b) Treat patient empirically with PCC before releasing him to the OR.c) PT and APTT are normal. Patient may have drug present however OR cannot wait.

PCC likely ineffective – advise surgeons that there may be excess bleedingd) A rapid Xa heparin level is available - and the result is less than the lower limit of

detection

Pharmacology

Dabigatran etexilate

Rivaroxaban Apixaban Edoxaban

Target Thrombin FXa FXa FXaPeak activity 1-3 hr 1-3 hr 1-3 hr 0.5-2 hrHalf-life 14-17 hr 7-11 hr 12 hr 8-10 hrStandard dose 150 BID 20 QD 5 BID 60 QDFDA-approved indications

NVAF, VTE NVAF, VTE, TKA/THA

NVAF, VTE, TKA/THA

NVAF, VTE

Eikelboom JWetal.,Circulation2010;121:1523;Samama MMetal.,Clin LabMed2014;34:503

Laboratory MonitoringMeasurement

Exclude clinically relevant drug levels

Determine whether above on-therapy levels are present

Dabigatran TT Normal PT and APTT do notexclude clinically relevant levels

APTT • Prolonged APTT suggests that on-therapy or above on-therapy levels are present.

• Normal APTT likely excludes above on-therapy levels.

• Normal APTT may not exclude on-therapy levels.

Suggestionsfordabigatranmeasurementifspecializedassaysarenotavailable

Cuker,JThromb Thrombolysis2016

TodecideifidarucizumabistobeusedaTTwouldpotentiallybeaveryuseful,shortturn-aroundtest…

Exclude clinically relevant drug levels

Determine whether above on-therapy levels are present

RivaroxabanEdoxaban

None Normal PT and APTT do not exclude clinically relevant levels

PT • Prolonged PT suggests that on-therapyor above on-therapy levels are present.

• Normal PT likely excludes above on-therapy levels.

• Normal PT may not exclude on-therapy levels.

Apixaban None Normal PT and APTT do not exclude clinically relevant levels

PT • Prolonged PT suggests that on-therapyor above on-therapy levels are present.

• Normal PT may not exclude on-therapy or above on-therapy levels.

SuggestionsformeasurementofFXa inhibitorsifspecializedassaysarenotavailable

Cukeretal.,JThromb Thrombolysis2016

• 79yearoldmalereceivingdabigatranforstrokepreventioninthesettingofatrialfibrillation

• Presentswithnewhemiparesisandaphasia

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Back to the case

What do you recommend?a) PT and APTT are normal. Patient is cleared to go to the OR

without anticoagulant reversal.b) Treat patient empirically with PCC before releasing him to the

OR.c) PT and APTT are normal. Patient may have drug present

however OR cannot wait. PCC likely ineffective – advise surgeons that there may be excess bleeding

d) A rapid Xa heparin level is available - and the result is less than the lower limit of detection

ReversingtheDOACs

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Reversalagents

• Atpresent,XaDOACsdonothavereversalagents– IdarucizumabnowavailableintheUnitedStatesfordabigatran

• Availablereversalstrategiesrelyonnon-specificstrategiesthathaveunknowneffectiveness

• PCC/aPCC widelyusedbutwithNOevidenceofefficacy

• Whyisthisrelevanttothelaboratoryprofessional?– Youarelikelytobeaskedtogetinvolvedindecisionsaboutaccessduetocost

Per 977/Ciraparantag/Aripazine

• Smallmolecularweightmoietythatbindstoawidevarietyofanticoagulantsneutralizingtheiranticoagulantactivity

• Doesnotappeartoreversewarfarinorargatroban• Per977reportedlyinterfereswithassayssystemsforcoagulation

assays– Efficacyreportedusingchangesin“wholebloodclottingtime”

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Per977(Ciraprantag)

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http://www.perosphere.com/content/presentations/documents/PER977ReversesUnfractionatedandLowMolecularWeightHeparinsFondaparinuxandNOACs.pdf

Andexanet(aFXa decoy)

Andexanet:DesignedtoReverseActivityofFactorXa Inhibitors

Factor Xa

Andexanet

Catalytic DomainGla

Recombinant engineered version of human factor Xa produced in CHO cells

S S

S419

S S

A419Factor Xa inhibitor Factor Xa inhibitor

• No known interaction with other coagulation factors except Tissue Factor Pathway Inhibitor (TFPI)

• No significant antibody signal found in development program to date

• Acts as a fXa decoy and retains high affinity for all fXa inhibitors• Change of Serine to Alanine to eliminate catalytic activity and

prevent prothrombin cleavage

• GLA domain removed to prevent anticoagulant effect

Gla

Summaryresultsfromhealthyoldervolunteers

• Apixaban: 400 mg +/- 4 mg/min infusion for 2 hours

• Rivaroxaban: 800 mg +/- 8 mg/min for 2 hours

Idarucizumab: a specific reversal agent for dabigatran

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Healthyvolunteerstudy:immediate,dose-dependentreversalofdabigatran

anticoagulation

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‘Normal upper reference limit’: mean+2SD of 86 predose measurements from a total of 51 subjects, Data shown as mean ± SDGlund S et al. AHA 2013; abstract 17765

Dabigatran plus:Placebo (n=9)1 g idarucizumab (day 4) (n=9)2 g idarucizumab (day 4) (n=9)4 g idarucizumab (day 4) (n=8)Normal upper reference limit (n=86)Mean baseline (n=86)

End of idarucizumab injection (5 min infusion)

Dabigatran + placebo

–2

Time after end of infusion (hours)

dTT

(s)

DabigatranAntidote

70

65

60

55

50

45

40

35

30

0 2 4 6 8 10 12 24 36 48 7260

Reversal

• Majororlifethreateningbleedingshouldleadtotheinitiationofaanticoagulantreversalstrategythatisgeneric

• Thekeycomponentofthisstrategyisinvestigatingandtreatingthecauseofthebleed

• Theavailabilityofhighlyeffective“antidotes”forwarfarinhasnotmitigatedthehighriskofdeathwithwarfarinassociatedbleeding– ImpactofPCCsawaitedwithinterest

• Yourlabislikelytogetcalledandaskedifapatienthasdrugonboardbeforeaveryexpensiveagentisadministered– Inthedabigatranstudyalargefractionofpatientshadnodrugonboard

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