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Prothrombin ComplexConcentrateforMajorBleedingonFactorXaInhibitors:AProspectiveCohortStudySamSchulman,1 PeterL.Gross,1 BruceRitchie,2 SusanNahirniak,3 Yulia Lin,4 Lani Lieberman,5 MarcCarrier,6 MarkA.Crowther,7 IndyGhosh,8AlejandroLazo-Langner,9 MichelleZondag,11DepartmentofMedicine,McMasterUniversityandThrombosisandAtherosclerosisResearchInstitute,Hamilton,ON;2DepartmentofMedicine,and3DepartmentofLaboratoryMedicineandPathology,UniversityofAlberta,Edmonton,AB;4DepartmentofClinicalPathology,SunnybrookHealthSciencesCentreandDepartmentofLaboratoryMedicineandPathobiology,UniversityofToronto,ON;5DepartmentofClinicalPathology,UniversityHealthNetwork,andUniversityofToronto,Toronto,ON; 6DepartmentofMedicine,TheOttawaHospitalResearchInstituteattheUniversityofOttawa,Ottawa,ON;7DepartmentofPathologyandMolecularMedicine,Hamilton,ON;8DepartmentofEmergencyMedicine,TrilliumHospital,Mississauga,ON;9DepartmentofMedicine,WesternUniversity,London,ON,allinCanada

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BackgroundOralfactorXa inhibitorsareincreasinglyusedforanticoagulationbutthereisnoapprovedreversalagent.Prothrombin complexconcentrate(PCC)formanagementofXa-inhibitor-associatedbleedinghasbeendescribedinasmallcaseseries[1].Thedoseusedwas2100-4800units.ThedurationofbleedingafterpunchbiopsyinvolunteerstreatedwithedoxabanwasshortenedbyPCCinadose-dependentmanner[2]

MethodsDesignObservationalmulticentercohortstudyperformedathospitalsinCanadawherePCCwasreadilyavailableandwhereahospitalprotocolexistedthatsuggestedorrecommendedtheuseofPCCforreversalofdabigatran-associatedbleeding.Thestudywasoriginallyplannedfor35patientsbuthasnowbeenexpandedto60patients.StudypatientsAcuteandactivemajorbleeding(ISTHcriteria).Ontreatmentwithrivaroxabanorapixaban.TreatedwithPCC,2000units,asperhospitalprotocol.ExclusioncriteriaInitial useofadditionalhemostaticagents.DoNotResuscitate(DNR)ordergiven.Dropofhemoglobinwithoutsourceofbleeding.Acutecoronarysyndromeorischemicstrokeduringthepast30days.Refusaltoprovideinformedconsentfor30-dayfollow-up.StudyproceduresTreatingphysicianrequestsPCC(Octaplex,Octapharma® orBeriplex® P/N,CSLBehring)fromTransfusionmedicine.StudystaffisnotifiedthatPCCwasgiven.Consentobtainedfordatacollectionand30dayfollow-up.TreatingphysicianrateseffectivenessusinganAssessmentGuidemodifiedfromSarode etal[3].Intracerebralhematomavolumewascalculatedusing the4/3p abc formula[4].OutcomesEffectivenessoftreatmentSafety: arterialorvenousthromboembolism,assessedbyanindependentadjudicationcommittee

ResultsTimefromonsetofbleedingtoPCC:Median12.2h(IQR,5.7-30.2)ProlongedprothrombintimeorINR>1.2or↗anti-Xa in16patients(46%)PCC:Mean2077units(SD±539);25.9IU/kg(SD±8.3).AseconddosePCCwasgivento1patient.Effectivenesswasassessedin4 ways:Treatmentset(n=35)byresponsiblephysicianusingthemodifiedSarode AssessmentGuide:

Patients andantithrombotictreatment

Percent

Percent

Conclusion• ThereisnoapprovedreversalagentforfactorXa

inhibitors.• TheeffectivenessofPCCinmajorbleedingwas

assessedasGoodin66%,andModeratein17%.• Therewasone(3%)thromboembolicevent.

References1. Grandhi Retal.WorldNeurosurg.2015;84:1956-61.2. Zahir Hetal.Circulation.2015;131:82-90.3. Sarode R,etal.Circulation 2013;128:1234-43.4. BroderickJPetal.Stroke.1993;24:987-93.5. ConnollySJetal.NEngl JMed.2016;375:1131-41.6. Khorsand Netal.JThromb Haemost.2016;14:211-4.

Characteristic (n=35)

Age,yr 77.6(7.7)

Malesex,no.(%) 22(63)

Weight,kg,median(IQR) 81(66-90)

Creatinineclearance,mL/min,median(IQR) 65.4(35-90)

<30mL/min,no.(%) 2(6)

30to<60mL/min,no.(%) 8(23)

Indicationforanticoagulation,no.(%)

Atrialfibrillation

Venousthromboembolism

Bothindications

Ischemicstroke

29(83)

4(11)

1(3)

1(3)

Anticoagulanttreatment

Patientsonrivaroxaban,no.(%)

dailydose,mg,median(IQR)

timefromlastdosetoPCC,h

19(54)

20(17.5-20)

17.6(10.4)

Patientsonapixaban,no.(%)

dailydose,mg,median(IQR)

timefromlastdosetoPCC,h

16(46)

10(5-10)

18.4(12.1)

Resultsaremean(standarddeviation)unlessotherwisestated.

Bleedingcharacteristic (n=35)

Typeofbleeding

Intracranial

Intraspinal

Gastrointestinal

Intramuscular

Hemothorax

Retroperitoneal

Pelvichematoma

Hematuria

18(36)

1(3)

11(31)

1(3)

1(3)

1(3)

1(3)

1(3)

Traumarelatedbleed 9(26)

Criteriaformajorbleeding*

Criticalorgan

Overtbleed,transfused≥2u

Overtbleed,hemoglobindrop≥20g/L

21(60)

8(23)

18(36)

0

20

40

60

80

Good Moderate Poor

0

20

40

60

80

Good Moderate Poor

Post-hocanalysisusingtheISTHrecommendationfrom2016[6]

Post-hocanalysisofonlythe16patientswithprolongedPT/INR>1.2/↗anti-Xa

Percent

Post-hocanalysisofCNSbleedsusingtheoriginalSarode AssessmentGuide[4]vs.ANNEXA-4[5]

0

20

40

60

80

100

Exc/Good/Mod Poor/None

Thiscohort

Annexa4

Percent

0

20

40

60

80

Effective Ineffective

Safety: 1stroke (3%)5deaths (14%),4fromtheindexICH