perioperative management of anticoagulant and antiplatelet … · 2019-11-28 · james d. douketis...
TRANSCRIPT
JamesD.DouketisMD,FRCP(C),FACP,FCCPDept.ofMedicine,St.Joseph’sHealthcareand
McMasterUniversity,Hamilton,Canada
PerioperativeManagementofAnticoagulantandAntiplateletTherapy:
Whatyouneedtoknowin2019
LifetimeDisclosuresfor: J.DouketisResearchSupport* CIHR,HSFC,Boehringer-Ingelheim
Employee Up-to-Date,MerckManual
ConsultantorAdvisoryBoardFees*
Actelion,AGEN,Astra-Zeneca,Bayer,Biotie,BMS,Daiichi-Sankyo,Portola,Boehringer-Ingelheim,Cytori,Janssen,LeoPharma,Pfizer,MedicinesCo.,Sanofi,Servier
Stockholder,Speaker’sBureau NoneUnlabeled/UnapprovedUse
Disclosure None
Speaker’sFees* Bayer,Boehringer-Ingelheim,Pfizer,LeoPharma, Sanofi
*Fundsdeposited intouniversity-based researchaccountsorSt.Joseph’s HealthcareFoundation. Last3years
4LearningObjectives1)VKApatients:isheparinbridgingneeded?
2)VKA/DOACpatients:isinterruptionneeded?
3)DOACpatients:howtomanage?
4)Dualantiplatelettherapy(coronarystent)patients:howtomanage?
• 70-yroldfemalewithAFonwarfarinwithhypertension,diabetes,TIA10yrs ago(CHADS2 =5)
• Scheduledforelectivecolonresectionforincidentallyfoundcoloncancer…
Onedoctortoldhersheneedstobeassessedforheparinbridging.Anotherdoctortoldhershedoesnotneedbridging.
CaseNo.1
Isheparinbridgingneeded?
BRIDGE:TrialDesign
Douketis J,etal.NEnglJMed2015
BRIDGETrial:PrimaryStudyOutcomesOutcomeNo.(%)
NoBridging(N=918)
Bridging(N=895)
P- value
ATE 4(0.4) 3(0.3) 0.01(non-infer.)0.73(super.)
- stroke 2(0.2) 3(0.3)
- TIA 2(0.2) 0(0)
- systemicembolism 0(0) 0(0)
Majorbleeding 12(1.3) 29(3.2) 0.005(super.)
Douketis J,etal.NEnglJMed2015
warfarin
*
Day-5stopwarfarin dalteparin
5,000IUQD
R
highbleedrisk
lowbleedrisk
placebo
Day-3startdalteparin,200IU/kgQD
(lastdose100IU/kgAMpre-op)
dalteparin200IU/kgQD
placebo
warfarin
Day+90majorTEmajorbleeddeath
Day+1startdalteparinORplacebo
Day+1resumewarfarin
surgeryprocedure
PERIOP-2:TrialDesign
PERIOP-2:Patients
Kovacs MJ, et al. 2018 Blood (abstract)
1,167 withatrialfibrillation304withmechanicalheartvalve(172 aortic,132 mitral)
Periop-2:ASH2019
Kovacs MJ, et al. 2018 Blood (abstract)
PERIOP-2:Results
strokepathophysiology
vasculardiseaserisk(CHADS2)↑procoagulantfactorsduringsurgery(D-dimer)
surgerytype(CABG,valve,peripheralbypass,carotidendarderectomy)
lipidandgeneticfactors
intra-opBP+volumecontrol?
perioperativestatins?
smokingcessation?
Whateffectofheparinbridging?
Whatcausesperioperativestrokeinanticoagulatedpatientsandhowcanwepreventit?
perioperativeASA?
ReboundhypercoagulabilityafterstoppingOAC
• 75-kgoldfemalewithAFonrivaroxaban,20mgQD– hypertension,diabetes,TIA10yrs ago(CHADS2=5)– CrCl =50mL/min
• ScheduledforcardiacpacemakerimplantationthisMonday9AM,fortach-brady syndrome…
Sheneedstobeoffrivaroxabanforatleast2days…
….shedoesNOTneedtostoprivaroxaban.
CaseNo.2
BRUISECONTROL-1Trial• PatientswithAFonVKAhavingpacemaker/ICD
continueVKA(INR<3.0)
interruptVKA+LWMHbridging®
BirnieDH,etal.NEngl JMed2013;368:2084
681patients
Outcomes Continue Interrupt P-value
stroke/TIA(%) 0.3 0 1.0
hematoma*(%) 3.5 16.0 <0.001
*requiring treatment interruption
PerioperativeHemostasis:(1)continueOACvs.(2)interrupt+
bridgecontinueOAC
Anticoa
gulant
Effect
day-3 day-2 day-1 day0 day1 day2 day3
Interrupt+bridge
Safetyofon-anticoagulationprocedures?…redundancyinclottingpathway
BRUISECONTROL-2Trial• PatientsonDOAChavingpacemaker/ICD
continueDOAC(includingdayofprocedure)
interruptDOACfor1daypre-procedure(2daysifondabigatranandCrCl <50mL/min)
®
Outcomes Continue Interrupt P-value
stroke/TIA(%) 0.3 0.3 1.0
hematoma(%) 2.1 2.1 0.97
BirnieDH,etal.Eur Heart J2017*requiring treatment interruption
662patients
• 75-yroldfemalewithAFonapixaban,5mgBID–hypertension,diabetes,TIA10yearsago(CHADS2=5)–CrCl =50mL/min,forhipreplacementMon9AM
• Sheneedstobeoffapixabanfor2days
• …sheneedstobeoffapixabanfor3daysand receivepre-opheparinbridgingfor1-2daysand havecoagulationtestingpriortoneuraxial anesthesia
CaseNo.3
2015ASRA/ESRAGuidelinesonPeriprocedure DOACManagementNarouze S,etal.RegAnesthPainMed 2015
Pre-opInterruption Post-opResumptiondabigatran 4-6days 24hrs
apixaban 3-5days 24hrs
rivaroxaban 3days 24hrs/edoxaban
CrCl 30-50…120hrCrCl 50-80…96hrCrCl>80……72hr
………………..72hr
………………..72hrASRA2018updateHorlockerTT,etal.RegAnesthPainMed2018
Douketis J,etal.JAMAIntMed2019ePub Aug5
PerioperativeAnticoagulantUseforSurgeryEvaluation(PAUSE)Study(NCT2228798)
• Design:Multi-centre prospectivecohortstudy• Patients:2,961patientswithatrialfibrillation(987perDOAC– dabigatran,rivaroxaban,apixaban)
• Intervention:• DOAC-specificpre-procedureinterruptioninterval• flexiblepost-procedureresumption• noheparinbridging• pre-procedurebloodsample
Douketis J,etal.ThrombHaemost 2017
Methods:PatientEligibilityandInterventionConsecutiveadults (≥18years)withatrial fibrillation:
- receivingDOAC(apixaban, dabigatran, rivaroxaban)- requireDOACinterruption forelective surgery/procedure- canadheretoplannedDOACinterruption
Excludedif:- CrCl<30mL/min(dabigatran, rivaroxaban)- CrCl<25mL/min(apixaban)- cognitiveimpairment/psychiatric Illness- non-consenting- previousparticipation instudy
Bloodsample:dayof(justbefore)surgery/procedureFollow-up:weeklyfor4weekspost-procedureNoheparinbridging (low-doseheparinasVTEprophylaxisOK)
Surg./proced.classifiedasHIGHorLOWbleeding
risk
Methods:HypothesisTestingandSampleSize• Samplesize=2,961(987perDOAC)toshowthatperioperativemanagementforeachDOAC associatedwith:• riskforMB=1%(95%confidencetoexclude2%)• riskforATE=0.5%(95%confidencetoexclude1.5%)
Methods:PerioperativeManagement
Methods:PerioperativeManagement
SurgeryProced
ure
anticoa
gulantlevel(ng
/mL)
Day 5 234 1 54321
lowbleedriskhighbleedrisk
dabigatrancohortCrCl<50
DOAChalf-life=10-14 hrsPeakaction=1-3 hrs
50100150200
250
PracticalPointsonPerioperativeManagement
1)CHADS2 scoredidNOTfactorintomanagement2)HeparinorLMWHbridgingwasnotindicated.3)VTEprophylaxispost-operativelywasacceptableforhigh-riskpatients.4)Pre-operativebloodsamplestaken…butNOTusedforclinicaldecision-making.
Results:PatientRecruitment3,640patientsscreened
663(17.4%)excluded- 503 non-consenting- 68 cancelledsurgery/procedure
34 withdrewconsent- 21 becameineligible- 7losttofollow-up
n=1,257apixabancohort
n=668dabigatrancohort
n=1,082rivaroxaban
cohort
23centresinCanada,US,Europe(July2014-July2018)
Results:PatientCharacteristicsCharacteristic Cohort
Apixabann=1,257
Dabigatrann=668
Rivaroxabann=1,082
Age– mean 73.1 72.4 72.0Malesex,% 64.0 68.6 67.0CHADS2 score– mean 2.1 2.2 2.0ModifiedHASBLEDscore– mean 2.0 1.9 1.8
CrCl– mean,inmL/min 77.9 85.9 82.2Lower-doseDOAC,% 20.0 37.1 16.7ASAuse,% 12.4 14.7 9.1Highbleedrisksurgery/procedure,%
32.3 34.1 34.5
Results:AdherencetoPre- andPost-operativeManagementProtocols
• 3,007patientsinprimaryITTanalysis– 159(5.3%)deviatedpre-procedureprotocol– 202(6.7%)deviatedfrompost-procedureprotocol– 22(0.7%)losttofollow-up
• 2,624(87.3%)patientsinperprotocolanalysis– adheredtopre- andpost-procedureprotocolandnotlosttofollow-up
Results:PrimaryOutcomes(ITTAnalysis)Outcome(%,95%CI)(expected)
CohortApixabann=1257
Dabigatrann=668
Rivaroxabann=1082
*Arterialthromboembo- lism(0.5%)
0.16(0-0.48)n=2
0.60(0-1.33)n=4
0.37(0-0.82)n=4
**Majorbleeding (1.0%)
1.35(0-2.00)n=17
0.90(0-1.73)n=6
1.85(0-2.65)n=20
*Ischemicstroke,TIA,systemicembolism**ISTHdefinition
1.2(0-1.89)n=13
1.7(0-2.53)n=16
0.5(0-1.25)n=3
perprotocolanalysis(87.3%)
Results:BleedingAccordingtoSurgery/Procedure-relatedBleedRisk
ClinicalPredictorsofMajorBleeding:Multivariateanalysis*
PredictorVariable OR(95%CI) P-value
DOACgroup
dabigatranvs.apixaban 0.67(0.26-1.71) 0.401
rivaroxabanvs.apixaban 1.24(0.64-2.40) 0.514
Hypertension 3.93(1.40-11.07) 0.010
Femalegender 0.62(0.31-1.24) 0.174
Activecancer 2.30(1.10-4.81) 0.026
Surgerybleed risk:lowvs.high 0.59(0.30-1.16) 0.126
modelAUC=0.69 *unpublisheddata
Ispre-operativecoagulationfunctiontestingneeded?
…don’ttellmeIneedanotherbloodtest!
PAUSE:Pre-operativeBloodSample(2,541patients)
Surgery
Proced
ureanticoa
gulantlevel(ng
/mL)
Day 5 234 1 54321
lowbleedriskhighbleedrisk
50100150200
250
30-36 hourinterruptioninterval
60-66 hourinterruptioninterval
Low/Mod-Bleed-Risk: 1d(30-36hr)offpre-op
0100200300400500600700800
apixaban dabigatran rivaroxaban
<30ng/mL 30-49.9ng/mL ≥50ng/mL
050
100150200250300350400
apixaban dabigatran rivaroxaban
<30ng/mL 30-49.9ng/mL ≥50ng/mL
93.1%<30ng/mL
98.9%<30ng/mL
85.3%<30ng/mL
98.9%(823/832) withDOAClevel<50ng/mLHigh-Bleed-Risk: 2d(60-68hr)offpre-op
LabPredictorsofBleeding:EffectofResidualDOACLevelonMajororAnyBleeding*
MajorBleeding Major+CRNMBleedingn,%(95%CI) OR(95%CI) n,%(95%CI) OR(95%CI)
DOACLevel(ng/mL):
<30n
=2020n=27
1.3(0-1.8)reference
n=693.4(0-4.2)
reference
30-49.9 n=363n=6
1.7(0-3.2)n=14
3.9(0-5.9)
≥50 n=158n=3
1.9(0-4.7)n=4
2.5(0-5.5)
1.24(0.5-2.8)1.43
(0.3-4.1)
1.1(0.6-2.0)
0.7(0.3-2.0)
*unpublisheddata
• 75-yearoldwomanwithCAD/CABGanddrug-elutingstent(DES)5monthsagoafterNSTEMI.
• Othermedicalproblems:hypertension,obesity,type2diabetes
• TakingASA,81mgdaily,andticagrelor,90mgBID• Needssurgeryforbreastcancerresection
CaseNo.4
Albaladejo P,etal.Heart2011
Antiplateletinterruption
Surgeryurgency
RiskfactorsforMACCEin1,134patientswithstentsduringnoncardiacsurgery(observationalstudy)
RiskfactorsforMACCEin432patientswithstentsduringnon-cardiac-surgery (observationalstudy)
Rodriguezetal.BJA2018
Majorbleeding
Antiplateletinterruption
PerioperativeriskforMIpost-cardiacstent
• U.S.VAretrospectivecohortstudyofpatientswithcoronarystents
• 20,590 caseshavingsurgeryvs.41,180 matchedcontrolsnothavingsurgery
PerioperativeRiskforMIpost-DES
surgery<1monthpostDES
surgery1-2monthspostDES controls
Egholm G,etal.JACC2016
Danishcohortofpatientshavingsurgery:4,303caseswithDESvs.20,323matchedcontrolswithoutDES
ASAbeforenon-cardiacsurgery:stoporcontinue?
• POISE-2– double-blind2×2factorialRCT– ASA(continue/start)vs.placebo
• Inclusioncriteria:– patients(≥45yrs)withoratriskforCVdiseasehavingnon-cardiacsurgery±takingASA
• Exclusioncriteria:– tookASA<72hrsbeforesurgery– BMSwithin6weeks,DESwithin12months
DevereauxPJ,etal.NEnglJMed 2014;370:1494
POISE-2SubgroupwithCoronaryStents(n=470)
• ASAdecreasedriskforCVevents:death+non-fatalMI…ARR=5.5%(CI:0.4-10.5;p=0.04)myocardialinfarction...ARR=5.9%(CI:1.0-10.8;p=0.02)
• ASAconferrednon-significant increasedriskforbleeding:majorbleeding…………ARI=1.3%(CI:−2.6-5.2)
GrahamMM,etal.AnnInternMed2018
WhentointerruptP2Y12 inhibitor?
Neumannetal.EurHeart J2019
1-3months
StableCAD NSTEMI STEMI
6months
6months
Rossinietal.JACC:CI 2018
When(maybe)toNOTinterruptP2Y12inhibitor?
BridgingDAPTwithGPIIb/IIIaInhibitorsorCangrelor?
Rossinietal.JACC:CI 2018
IVheparin IVheparin
Cor
onar
yO
cclu
sion
B
leed
ing
-24h + 6h + 12h - 48 h
RIS
K
-2h
STOPaspirin 100mg
clopidogrel 75mg
2 plateletconcentrates
surgery
aspirin 100mg
ThieleT,etal.JThrombHaemost 2012ContinuingDAPTandTransfusionofPlatelets
aspirin 100mg
clopidogrel 75mg
…backtotheLearningObjectives1)VKApatients:isheparinbridgingneeded?– fewpatientswithatrialfibrillation– mostpatientswithmechanicalheartvalve(pre-op)
2)VKA/DOACpatients:isinterruptionneeded?– notforcardiacdeviceprocedures– otherminorprocedures(eye,skin,dental)
…backtotheLearningObjectives3)DOACpatients:howtomanage?– omit1daybefore/afterlow-bleed-risk and2daysbefore/afterhigh-bleed-risk surgeryorprocedure
– nobridgingorcoagulationfunctiontesting
4)Dualantiplatelettherapy(coronarystent)patients:howtomanage?– inmostpatients,continueASAandstopP2Y12 inhibitor5-7dayspre-surgery
– inafewpatients,continueASA+P2Y12±platelettransfusionOR bridgewithanticoagulant
Mercipourvotreattention!