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Perioperative Antiplatelet Therapy - American Family Physician

PerioperativeAntiplateletTherapy
PIERREGUYCHASSOT,MDCARLOMARCUCCI,MDandALAINDELABAYS,MD,UniversityHospitalofLausanne,Lausanne,Switzerland
DONATR.SPAHN,MD,UniversityHospitalofZrich,Zrich,Switzerland
AmFamPhysician.2010Dec1582(12):14841489.
Aspirinisrecommendedasalifelongtherapythatshouldneverbeinterruptedforpatientswithcardiovasculardisease.Clopidogreltherapyismandatory
forsixweeksafterplacementofbaremetalstents,threetosixmonthsaftermyocardialinfarction,andatleast12monthsafterplacementofdrugeluting
stents.Becauseofthehypercoagulablestateinducedbysurgery,earlywithdrawalofantiplatelettherapyforsecondarypreventionofcardiovascular
diseaseincreasestheriskofpostoperativemyocardialinfarctionanddeathfiveto10foldinstentedpatientswhoareoncontinuousdualantiplatelet
therapy.Theshorterthetimebetweenrevascularizationandsurgery,thehighertheriskofadversecardiacevents.Electivesurgeryshouldbepostponed
beyondtheseperiods,whereasvital,semiurgent,orurgentoperationsshouldbeperformedundercontinueddualantiplatelettherapy.Theriskofsurgical
hemorrhageisincreasedapproximately20percentbyaspirinorclopidogrelalone,and50percentbydualantiplatelettherapy.Thepresentclinicaldata
suggestthattheriskofacardiovasculareventwhenstoppingantiplateletagentspreoperativelyishigherthantheriskofsurgicalbleedingwhen
continuingthesedrugs,exceptduringsurgeryinaclosedspace(e.g.,intracranial,posterioreyechamber)orsurgeriesassociatedwithmassivebleeding
anddifficulthemostasis.
Longtermantiplatelettherapyisanimportantcomponentofsecondarypreventionafterastroke,myocardialinfarction(MI),myocardialrevascularization,ora
diagnosisofperipheralarterialdiseaseoracutecoronarysyndrome.Dualantiplatelettherapy(aspirinandclopidogrel[Plavix])preventsstentthrombosisfollowing
percutaneouscoronaryinterventionwithplacementofbaremetalordrugelutingstents.Intheperioperativeperiod,theindicationforantiplateletagentsisreinforced
bytheincreasedplateletactivityfollowingsurgeryhowever,theyalsoincreasetheriskofsurgicalbleeding.Whethertheriskofhemorrhagewithantiplatelettherapyis
lowerthantheriskofthrombosiswhenantiplateletagentsarewithdrawnisthekeyquestion.
View/PrintTable

SORT:KEYRECOMMENDATIONSFORPRACTICE
CLINICALRECOMMENDATION

EVIDENCE
RATING

REFERENCES

COMMENTS
Metaanalysesofhighqualitytrials20
andstentthrombosisstudies23

Aspirinmustbecontinuedpreoperativelywhenprescribedassecondarypreventionofcardiovascular
diseaseorstroke.

20,23

Earlyclopidogrel(Plavix)withdrawal(i.e.,lessthansixweeksafterbaremetalstents,lessthansix
monthsafteracutecoronarysyndrome,lessthan12monthsafterdrugelutingstents)shouldbe
avoidedbecauseitisthemainpredictorofcoronarythrombosis.

18,19,24

Largeprospectiveobservationalstudies

Antiplateletagentsshouldnotbeinterruptedpreoperativelybecausetheriskofcardiovascularevents
whenwithdrawingthemisgenerallyhigherthantheriskofsurgicalbleedingwhenupholdingthem.

3,4,14,
15,17,30

Bodyofobservationalandquasi
experimentalevidencefavorsthis
recommendation,butrandomized
controlledtrialsareneededtoascertain
it

Electiveoperationsshouldbedelayedbeyonddualantiplatelettherapyoperationsduringdual
antiplatelettherapymustbeperformedwithoutdruginterruption.

3,15,25,
28

AmericanCollegeofCardiologyand
AmericanHeartAssociation
recommendations,3,15comparative
clinicalstudies25,28

A=consistent,goodqualitypatientorientedevidenceB=inconsistentorlimitedqualitypatientorientedevidenceC=consensus,diseaseorientedevidence,usualpractice,expert
opinion,orcaseseries.ForinformationabouttheSORTevidenceratingsystem,gotohttp://www.aafp.org/afpsort.xml(http://www.aafp.org/afpsort.xml).

Preoperativecoronaryrevascularizationisrecommendedforpatientswithunstablecoronarysyndromeandrefractoryangina,butitoffersnobenefitcomparedwith
optimalmedicaltherapyandadequateheartratecontrolinpatientswithstable(evensevere)coronaryarterydisease.1,2Incasesofsemiurgentsurgery,theriskof
operatingundermaximalmedicalprotection(betablockers,antiplateletagents,statins)islessthanoperatingwithinsixweeksofcoronaryrevascularization.3,4This
reviewproposesrecommendationsfortheperioperativemanagementofantiplatelettherapybasedonthecurrentscientificevidence.However,therehavebeenno
largeprospectiverandomizedcontrolledtrials(RCTs)inperioperativepatientstoguidedecisionmakingmostofthecurrentdataarisefromnonrandomized
observationalorquasiexperimentalstudies.

AntiplateletTherapy

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Aspiriniseffectiveindosagesrangingbetween75and325mgperday.5Clopidogrel(75mgperday)isaprodrugoxidizedbyhepaticcytochromesintoanactive
metabolite.Somelipophilicstatinsandprotonpumpinhibitors(exceptperhapspantoprazole[Protonix]),andmidazolamcompetewithclopidogrelforthesame
cytochromesandmayreduceitslevelofactivemetabolitebyupto30percent.6,7Aftercessationofaspirinorclopidogrel,plateletaggregationreturnstobaselinein
fivedays.8Therearenomajordifferencesinbleedingriskbetweenaspirinandclopidogrelwhenadministeredalone.9
Comparedwithclopidogrel,thenewdrugprasugrel(Effient)ismoreeffectiveatpreventionofstentthrombosis,butitincreaseshemorrhagicriskby30percent.10
Threenewdrugsthatareinhibitorsoftheplateletadenosinediphosphatereceptorareunderclinicaltesting:cangrelor(anintravenousshortactingreversibleinhibitor)
andoraldirectreversibleinhibitorsticagrelorandelinogrel.11Comparedwithclopidogrel,thesedrugspresentlessvariability,fasteronset,andshorterdurationof
actionhowever,theireffectonclinicaloutcomesindirectcomparisonwithclopidogrelisunknown.
Dualantiplatelettherapy(i.e.,aspirinandclopidogrel)ismandatoryafteracutecoronarysyndromeorstentimplantationbecausecoronarylesionsandstentsbehave
likeunstableplaquesaslongastheyarenotfullycoveredbyacellularlayer.Themetalframeofabaremetalstentiscoveredbysmoothmusclecellswithinsixweeks
andbyanormalendotheliumwithinthreemonths.12Drugelutingstentshaveaslowerendothelializationrate:13percentatthreemonthsand56percentatthree
years.13Therefore,therecommendeddurationofclopidogreltreatmentissixweeksafterbaremetalstentsandatleast12monthsafterdrugelutingstents(Table
114).3,1517Theseminimaldurationscanbeprolongedbeyondoneyearinhighrisksituations(e.g.,drugelutingstentsimplantedindominant,proximal,ostial,or
bifurcatedpositions)andhighriskpatients(e.g.,advancedage,diabetesmellitus,lowejectionfraction,renalfailure).Latethrombosisfromdrugelutingstentsisarare
(incidenceof0.6percentperyear)butcatastrophicevent,withamortalityof19to45percent.18Itisanalogoustotheacuteinterruptionofflowinapreviouslynormal
throughoutvesseldevoidofcollateralsandwithouttissuepreconditioning.18,19
View/PrintTable

Table1.
RecommendedDurationofAntiplateletTherapyAfteraCoronaryEvent
THERAPYTYPEANDINDICATION

DURATION

Aspirin(75to325mgperday)

Lifelong,withoutinterruption

Clopidogrel(Plavix75mgperdaydualtherapy)
Simpleangioplastywithoutstenting

Twotofourweeks

PCIandbaremetalstents

Sixweeks

Myocardialinfarction

Threetosixmonths

Acutecoronarysyndrome(unstable)

Sixto12months

PCIanddrugelutingstents

Minimumof12months

PCI=percutaneouscoronaryintervention.
AdaptedwithpermissionfromEberliD,ChassotPG,SulserT,etal.Urologicalsurgeryandantiplateletdrugsaftercardiacandcerebrovascularaccidents.JUrol.2010183(6):2132.

WITHDRAWAL
Aspirincessationisassociatedwithanincreasedriskofcardiaccomplications(oddsratio[OR]=3.1),whichpeaksat10daysthisriskismuchhigheraftercoronary
stentplacement(OR=90).20Casesofacutethrombosisfromdrugelutingstentshavebeenreportedwithaspirinwithdrawalbeyondtwoyearsafterstent
implantation.21,22Themeandelaybetweenaspirinwithdrawalandlatethrombosisfromdrugelutingstentsissevendays.23Therefore,aspirinisalifelongtherapythat
shouldneverbeinterrupted.3,1517
Clopidogrelcessationisthemostsignificantindependentpredictorofstentthrombosis,withanORof14to57duringthefirst18monthsafterdrugelutingstent
implantation.19,24Althoughtheoptimaldurationofclopidogreltherapyafterimplantationremainsunsettled,thereisgoodclinicalevidencethatitscessationduringthe
firstyearisdangerous.18,19
Interruptionofantiplatelettherapyismorehazardousintheperioperativeperiod,whichischaracterizedbyincreasedplateletaggregability.Stoppingdualantiplatelet
therapytoallowmajorsurgeryduringthefirstsixweeksafterangioplastyandstenting(baremetalordrugeluting)leadstoacardiovascularmortalityofupto71
percent,whereasitisnomorethan5percentwhenthetreatmentismaintainedperioperatively2528(Table218,19,2429).Mortalityisinverselyrelatedtothedelay
betweenrevascularizationandsurgery.25,26,28
View/PrintTable

Table2.
ComplicationRatesFromPrematureDiscontinuationofAntiplateletAgentsDuringtheFirstSixWeeksAfterAngioplastyand
Stenting
SETTING

CARDIOVASCULAREVENTS*(PERCENT)

CARDIOVASCULARMORTALITY(PERCENT)

ALLCAUSEMORTALITY(PERCENT)

Nonsurgical18,19,24,29

25to60

19to65

20

Perioperative2529

42

71

30

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*Acutecoronarysyndrome,nonfatalmyocardialinfarction,cardiogenicshock.
Informationfromreferences18,19,and24through29.

HEMORRHAGICVERSUSTHROMBOTICRISKS
AlthoughthereisalackofRCTscomparingtheeffectsofwithdrawingversuscontinuingantiplateletagentsintheperioperativeperiod,itappearsthattheaverage
relativeincreaseinbleedingduringnoncardiacsurgeryis20percentwithaspirinorclopidogrelalone.9,30Someoperations,suchastonsillectomyortransurethral
prostatectomy,mightshowasignificantincreaseinpostoperativehemorrhage.3133Lifethreateninghemorrhagehasbeenreportedonlyinintracranialneurosurgery.34
Ametaanalysisincluding474studiescomparingsurgicalbleedingofpatientsoperatedonwithorwithoutaspirinreportednochangeinthemortalityandcomplication
rates.30Therelativeriskofhemorrhageincreasedupto50percentwithaspirinandclopidogreltogether,butdataarelimitedtovascular,visceral,andtransbronchial
surgeries.3537Althoughhemostasisislongerandmoredifficult,particularlybecauseoftheincreasedoozingfrombonesandrawtissues,thesurgicalmortalityand
longtermmorbidityarenotincreased.3537Thetransfusionratewasinconsistentlyaffectedinthreestudiescomparinggeneralsurgerywithandwithoutdual
antiplatelettherapy(nonsignificantrelativeincreaseof4,12,and16percentinantiplateletgroups).27,28,38Moreover,theshorttermcomplicationrate(0.4percent)39
andthelongtermrelativesurvivalreduction(16percent)40fromtransfusionarefarlessthanthe30percentaveragemortalitywhenantiplateletdrugsarewithdrawn
beforesurgery.19,2426,28Aspirinandclopidogreldonotappeartoincreasethelikelihoodofothersurgicalcomplications,exceptforwithsurgeryinaclosedspace
(e.g.,intracranialneurosurgery,surgeryofthespinalcanal,surgeryoftheposteriorocularchamber)orsurgeryassociatedwithmassivehemorrhageanddifficult
hemostasis.4,14
Inpatientswithstentswhoareoncontinuousdualantiplatelettherapy,thecombinedrateofperioperativeMIandmortalityisthesameasinstablecoronaryartery
disease(1to6percent,dependingonthetypeofsurgery),whereaswithdrawingantiplatelettherapyisassociatedwithafiveto10foldincreaseintheriskofMI(20to
40percent)andmortality(20to85percent),dependingonthedelaybetweenrevascularizationandsurgery.19,2428Therefore,theriskofcoronarythrombosisappears
higherthantheriskofsurgicalhemorrhage,andpreoperativecessationofaspirinand/orclopidogrelshouldbeavoidedwhenpossible.3,1517Thedecisionmustbe
madeonacasebycasebasisamongthecardiologist,anesthesiologist,andsurgeon,afterweighingalloftheriskfactors,includingcoronarystatus(e.g.,highriskor
lowriskstent,amountofmyocardiumthreatened),patientconditions(e.g.,age,coagulopathy,comorbidities),andtypeofsurgery.Table3outlinesperioperative
managementbasedonpatients'cardiovascularandsurgicalbleedingrisks.4
View/PrintTable

Table3.
PreoperativeManagementofPatientsonAntiplateletTherapyAccordingtoCardiacandBleedingRiskLevels
SURGICAL
BLEEDING
RISKLEVEL
Lowrisk

CARDIACRISKLEVEL
LOWRISK*
Maintainaspirinor
clopidogrel(Plavix)

INTERMEDIATERISK

HIGHRISK

Electivesurgery:okay

Electivesurgery:postponement

Maintainaspirin

Vitalorurgentsurgery:possibleunderaspirinandclopidogrel

Maintainclopidogrel,ifprescribed
Intermediate
risk

Maintainaspirinor
clopidogrel

Electivesurgery:accordingtorisk
balance

Electivesurgery:postponement
Vitalorurgentsurgery:possibleunderaspirinandclopidogrel

Vitalsurgery:okayMaintainaspirin
Maintainclopidogrel,ifprescribed
Highrisk

Stopaspirinorclopidogrelif
necessary(fivedaysbefore
surgery)

Restartwithin24hoursafter
surgery

Electivesurgery:postponement

Electivesurgery:postponement

Vitalsurgery:okay

Vitalorurgentsurgery:okay

Maintainaspirin

Maintainaspirin

Stopclopidogrelfivedaysbeforesurgery,
ifprescribedrestartwithin24hoursafter
surgery

Stopclopidogrelfivedaysbeforesurgerypossiblesubstitutionthreetofive
daysbeforesurgerywithintravenoustirofiban(Aggrastat)oreptifibatide
(Integrilin)**

ACS=acutecoronarysyndromeCABG=coronaryarterybypassgraftingENT=ear,nose,andthroatMI=myocardialinfarctionPCI=percutaneouscoronaryintervention.
*MorethanthreemonthsafterPCI,baremetalstenting,orCABGmorethansixmonthsafterACSorMImorethan12monthsafterregulardrugelutingstenting.
Sixto12weeksafterPCI,baremetalstenting,orCABGsixto24weeksafterACSorMImorethan12monthsafterhighriskdrugelutingstenting.
LessthansixweeksafterPCI,baremetalstenting,CABG,ACS,orMI(lessthanthreemonthsifcomplications)lessthan12monthsafterdrugelutingstentingmaybelongerin
casesofhighriskdrugelutingstenting.Thesedelayscanbemodifiedaccordingtotheamountofmyocardiumatrisk,theinstabilityofthecoronarysituation,ortheriskofspontaneous
hemorrhage.Thesamerecommendationsapplytonewersecondgenerationdrugelutingstenting.

CurrentGuidelineRecommendations
Intheabsenceofclinicaltrials,thecurrentrecommendationsfromspecialtysocietyguidelinesarebasedonobservationaldataandattempttoprovidethesafest
possiblemanagementgiventhehighriskofprematurediscontinuationofantiplateletagents.3,1517Aspirinisalifelongtherapythatshouldnotbeinterruptedfor
surgerywhenprescribedforsecondarypreventionafterstroke,acutecoronarysyndrome,MI,orcoronaryrevascularization,regardlessofthetimesincetheeventthat
ledtotherecommendationofaspirin.20,23Interruptionofaspirininprimarypreventiondoesnotincreasetheperioperativerisk,exceptinpatientswithdiabetes.41

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Dualantiplatelettherapyisrecommendedduringthetwoweeksaftersimpledilatation,sixweeksafterbaremetalstents,andatleast12monthsafterdrugeluting
stents.3,1517Allelectiveoperationsshouldbepostponedbeyondthesedelays.Onlyvitalsurgeryshouldbeperformedwhenthepatientsarestilltakingaspirinand
clopidogrelunlessthehemorrhagicriskisexcessive,dualantiplatelettherapyshouldnotbeinterruptedbeforesurgery.Duringthefirstsixweeksafterbaremetal
stentsorsurgicalrevascularization,theoperativeriskishigherthanwithoutrevascularization.Thefullbenefitofrevascularizationismanifestedonlyafterthree
months,whenmortalitybecomesidenticaltothepostoperativemortalityofpatientswithoutcoronaryarterydisease.25Therefore,therecommendeddelayforelective
surgeryislongerthanthedelayforvitaloperations.
Evenifclopidogreltreatmentmustbeinterruptedinhighrisksurgicalsituations,aspirinmustbecontinuedwithoutinterruption.3,15,17,23Heparinhasnoantiplatelet
activityandthereforeisnotanadequatesubstitutionforaspirinorclopidogreltreatmentbecausestentthrombosisisaplateletmediatedphenomenon.15Althoughnot
provenbyanyRCTs,bridgingtherapywithashortactingplateletglycoproteinIIb/IIIainhibitor(i.e.,eptifibatide[Integrilin],tirofiban[Aggrastat])isapossiblesubstitution
forclopidogrelwhileaspirinisbeingmaintained.42,43Aftertheoperation,antiplatelettherapyisresumedwithinthefirst12to24hoursclopidogreltherapyisreinitiated
witha300mgloadingdose,whichreducesthetimetoachievemaximalplateletinhibitiontofourtosixhoursanddecreasestheriskofhyporesponsivenessfrom
competitionofotherdrugswithhepaticcytochromes.

TheAuthors showallauthorinfo
PIERREGUYCHASSOT,MD,isaconsultantinanesthesiologyandwastheformerchiefofcardiovascularanesthesiaattheUniversityHospitalofLausannein
Switzerland....

REFERENCES showallreferences
1.McFallsEO,WardHB,MoritzTE,etal.Coronaryarteryrevascularizationbeforeelectivemajorvascularsurgery.NEnglJMed.2004351(27):27952804....

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