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!