ProthrombinComplex Concentrate for Major Bleeding on ...€¦ · Trauma related bleed 9 (26)...
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PB Prothrombin Complex Concentrate for Major Bleeding on Factor Xa Inhibitors: A Prospective Cohort Study Sam Schulman, 1 Peter L. Gross, 1 Bruce Ritchie, 2 Susan Nahirniak, 3 Yulia Lin, 4 Lani Lieberman, 5 Marc Carrier, 6 Mark A. Crowther, 7 Indy Ghosh, 8 Alejandro Lazo-Langner, 9 Michelle Zondag, 1 1 Department of Medicine, McMaster University and Thrombosis and Atherosclerosis Research Institute, Hamilton, ON; 2 Department of Medicine, and 3 Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, AB; 4 Department of Clinical Pathology, Sunnybrook Health Sciences Centre and Department of Laboratory Medicine and Pathobiology, University of Toronto, ON; 5 Department of Clinical Pathology, University Health Network, and University of Toronto, Toronto, ON; 6 Department of Medicine, The Ottawa Hospital Research Institute at the University of Ottawa, Ottawa, ON; 7 Department of Pathology and Molecular Medicine, Hamilton, ON; 8 Department of Emergency Medicine, Trillium Hospital, Mississauga, ON; 9 Department of Medicine, Western University, London, ON, all in Canada PB342 PB 341 Background Oral factor Xa inhibitors are increasingly used for anticoagulation but there is no approved reversal agent. Prothrombin complex concentrate (PCC) for management of Xa-inhibitor-associated bleeding has been described in a small case series [1]. The dose used was 2100-4800 units. The duration of bleeding after punch biopsy in volunteers treated with edoxaban was shortened by PCC in a dose-dependent manner [2] Methods Design Observational multicenter cohort study performed at hospitals in Canada where PCC was readily available and where a hospital protocol existed that suggested or recommended the use of PCC for reversal of dabigatran-associated bleeding. The study was originally planned for 35 patients but has now been expanded to 60 patients. Study patients Acute and active major bleeding (ISTH criteria). On treatment with rivaroxaban or apixaban. Treated with PCC, 2000 units, as per hospital protocol. Exclusion criteria Initial use of additional hemostatic agents. Do Not Resuscitate (DNR) order given. Drop of hemoglobin without source of bleeding. Acute coronary syndrome or ischemic stroke during the past 30 days . Refusal to provide informed consent for 30-day follow-up. Study procedures Treating physician requests PCC (Octaplex, Octapharma® or Beriplex® P/N, CSL Behring) from Transfusion medicine. Study staff is notified that PCC was given. Consent obtained for data collection and 30 day follow-up. Treating physician rates effectiveness using an Assessment Guide modified from Sarode et al [3]. Intracerebral hematoma volume was calculated using the 4/3 p abc formula [4]. Outcomes Effectiveness of treatment Safety: arterial or venous thromboembolism, assessed by an independent adjudication committee Results Time from onset of bleeding to PCC: Median 12.2 h (IQR, 5.7-30.2) Prolonged prothrombin time or INR >1.2 or ↗anti-Xa in 16 patients (46%) PCC: Mean 2077 units (SD ±539); 25.9 IU/kg (SD ±8.3). A second dose PCC was given to 1 patient. Effectiveness was assessed in 4 ways: Treatment set (n=35) by responsible physician using the modified Sarode Assessment Guide: Patients and antithrombotic treatment Percent Percent Conclusion • There is no approved reversal agent for factor Xa inhibitors. • The effectiveness of PCC in major bleeding was assessed as Good in 66%, and Moderate in 17%. • There was one (3%) thromboembolic event. References 1. Grandhi R et al. World Neurosurg. 2015; 84: 1956-61. 2. Zahir H et al. Circulation. 2015; 131: 82-90. 3. Sarode R, et al. Circulation 2013;128:1234-43. 4. Broderick JP et al. Stroke. 1993; 24: 987-93. 5. Connolly SJ et al. N Engl J Med. 2016; 375: 1131-41. 6. Khorsand N et al. J Thromb Haemost. 2016; 14: 211-4. Characteristic (n=35) Age, yr 77.6 (7.7) Male sex, no. (%) 22 (63) Weight, kg, median (IQR) 81 (66-90) Creatinine clearance, mL/min, median (IQR) 65.4 (35-90) <30 mL/min, no. (%) 2 (6) 30 to <60 mL/min, no. (%) 8 (23) Indication for anticoagulation, no. (%) Atrial fibrillation Venous thromboembolism Both indications Ischemic stroke 29 (83) 4 (11) 1 (3) 1 (3) Anticoagulant treatment Patients on rivaroxaban, no. (%) daily dose, mg, median (IQR) time from last dose to PCC, h 19 (54) 20 (17.5-20) 17.6 (10.4) Patients on apixaban, no. (%) daily dose, mg, median (IQR) time from last dose to PCC, h 16 (46) 10 (5-10) 18.4 (12.1) Results are mean (standard deviation) unless otherwise stated. Bleeding characteristic (n=35) Type of bleeding Intracranial Intraspinal Gastrointestinal Intramuscular Hemothorax Retroperitoneal Pelvic hematoma Hematuria 18 (36) 1 (3) 11 (31) 1 (3) 1 (3) 1 (3) 1 (3) 1 (3) Trauma related bleed 9 (26) Criteria for major bleeding* Critical organ Overt bleed, transfused ≥2 u Overt bleed, hemoglobin drop ≥20 g/L 21 (60) 8 (23) 18 (36) 0 20 40 60 80 Good Moderate Poor 0 20 40 60 80 Good Moderate Poor Post-hoc analysis using the ISTH recommendation from 2016 [6] Post-hoc analysis of only the 16 patients with prolonged PT/INR >1.2/ ↗anti-Xa Percent Post-hoc analysis of CNS bleeds using the original Sarode Assessment Guide [4] vs. ANNEXA-4 [5] 0 20 40 60 80 100 Exc/Good/Mod Poor/None This cohort Annexa 4 Percent 0 20 40 60 80 Effective Ineffective Safety: 1 stroke (3%) 5 deaths (14%), 4 from the index ICH
Transcript of ProthrombinComplex Concentrate for Major Bleeding on ...€¦ · Trauma related bleed 9 (26)...
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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
PB342
PB341
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
