08年ACCP指南

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The Perioperative Management of

Antithrombotic Therapy* : American Collegeof Chest Physicians Evidence-Based ClinicalPractice Guidelines (8th Edition)

James D. Douketis, Peter B. Berger, Andrew S. Dunn, Amir K. Jaffer,Alex C. Spyropoulos, Richard C. Becker and Jack Ansell

Chest 2008;133;299S-339SDOI 10.1378/chest.08-0675

The online version of this article, along with updated information andservices can be found online on the World Wide Web at:

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Chest is the official journal of the American College of ChestPhysicians. It has been published monthly since 1935.

Copyright2008by the American College of Chest Physicians, 3300Dundee Road, Northbrook, IL 60062. All rights reserved. No part of this article or PDF may be reproduced or distributed without the priorwritten permission of the copyright holder.

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SupplementANTITHROMBOTICANDTHROMBOLYTICTHERAPY8THED:ACCPGUIDELINESThePerioperativeManagementofAntithromboticTherapy*

AmericanCollegeofChestPhysicians

Evidence-BasedClinicalPracticeGuidelines(8thEdition)

JamesD.Douketis,MD,FRCP(C);PeterB.Berger,MD,FACP;AndrewS.Dunn,MD,FACP;AmirK.Jaffer,MD;

AlexC.Spyropoulos,MD,FACP,FCCP;RichardC.Becker,MD,FACP,FCCP;andJackAnsell,MD,FACP,FCCP

ThisarticlediscussestheperioperativemanagementofantithrombotictherapyandispartoftheAmericanCollegeofChestPhysiciansEvidence-BasedClinicalPracticeGuidelines(8thEdition).Theprimaryobjectivesofthisarticlearethefollowing:(1)toaddresstheperioperativemanagementofpatientswhoarereceivingvitaminKantagonists(VKAs)orantiplateletdrugs,suchasaspirinandclopidogrel,andrequireanelectivesurgicalorotherinvasiveprocedures;and(2)toaddresstheperioperativeuseofbridginganticoagulation,typicallywithlow-molecular-weightheparin(LMWH)orunfractionatedheparin(UFH).Asecondaryobjectiveistoaddresstheperioperativemanagementofsuchpatientswhorequireurgentsurgery.Therecommendationsinthisarticleincorporatethegradingsystemthatisdiscussedinthissupplement(GuyattGetal,CHEST2008;133:123S–131S).Briefly,Grade1recommendationsareconsideredstrongandindicatethatthebenefitsdo(ordonot)outweighrisks,burden,andcosts,whereasGrade2recommendationsarereferredtoassuggestionsandimplythatindividualpatientvaluesmayleadtodifferentmanagementchoices.

Thekeyrecommendationsinthisarticleincludethefollowing:inpatientswithamechanicalheartvalveoratrialfibrillationorvenousthromboembolism(VTE)athighriskforthromboembolism,werecommendbridginganticoagulationwiththerapeutic-dosesubcutaneous(SC)LMWHorIVUFHovernobridgingduringtemporaryinterruptionofVKAtherapy(Grade1C);inpatientswithamechanicalheartvalveoratrialfibrillationorVTEatmoderateriskforthromboembolism,wesuggestbridginganticoagulationwiththerapeutic-doseSCLMWH,therapeutic-doseIVUFH,orlow-doseSCLMWHovernobridgingduringtemporaryinterruptionofVKAtherapy(Grade2C);inpatientswithamechanicalheartvalveoratrialfibrillationorVTEatlowriskforthromboembolism,wesuggestlow-doseSCLMWHornobridgingoverbridgingwiththerapeutic-doseSCLMWHorIVUFH(Grade2C).

Inpatientswithabaremetalcoronarystentwhorequiresurgerywithin6weeksofstentplacement,werecommendcontinuingaspirinandclopidogrelintheperioperativeperiod(Grade1C);inpatientswithadrug-elutingcoronarystentwhorequiresurgerywithin12monthsofstentplacement,werecommendcontinuingaspirinandclopidogrelintheperioperativeperiod(Grade1C).

InpatientswhoareundergoingminordentalproceduresandarereceivingVKAs,werecommendcontinuingVKAsaroundthetimeoftheprocedureandcoadministeringanoralprohemostaticagent(Grade1B);inpatientswhoareundergoingminordermatologicproceduresandarereceivingVKAs,werecommendcontinuingVKAsaroundthetimeoftheprocedure(Grade1C);inpatientswhoareundergoingcataractremovalandarereceivingVKAs,werecommendcontinuingVKAsaroundthetimeoftheprocedure(Grade1C).

(CHEST2008;133:299–339S)

Keywords:arterialthromboembolism;aspirin;bleeding;bridginganticoagulation;clopidogrel;low-molecular-weightheparin;oralanticoagulant;perioperative;stroke;surgery;unfractionatedheparin;venousthromboembolism;vitaminKantagonist

Abbreviations:APTTϭactivatedpartialthromboplastintime;CABGϭcoronaryarterybypassgraft;CHADS2ϭCongestiveHeartFailure-Hypertension-Age-Diabetes-Stroke;CIϭconfidenceinterval;DDAVPϭ1-deamino-8-D-argininevasopressin;INRϭinternationalnormalizedratio;LMWHϭlow-molecular-weightheparin;NSAIDϭnonsteroidalantiinflammatorydrug;ORϭoddsratio;PCIϭpercutaneouscoronaryintervention;SCϭsubcutaneous;UFHϭunfractionatedheparin;VKAϭvitaminKantagonist;VTEϭvenousthromboembolism

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SummaryofRecommendations

2.0PerioperativeManagementofPatientsWhoAreReceivingVKAs

2.1.Inpatientswhorequiretemporaryinter-ruptionofaVKAbeforesurgeryoraprocedureandrequirenormalizationoftheINRforthesurgeryorprocedure,werecommendstoppingVKAsapproximately5daysbeforesurgeryoverstoppingVKAswithinashortertimeintervalbeforesurgerytoallowadequatetimefortheINRtonormalize(Grade1B).

2.2.Inpatientswhohavehadtemporaryinter-ruptionofaVKAbeforesurgeryoraproce-dure,werecommendresumingVKAsapproxi-mately12to24h(theeveningoforthenextmorning)aftersurgeryandwhenthereisade-quatehemostasisoverresumptionofVKAsclosertosurgery(Grade1C).

2.3.Inpatientswhorequiretemporaryinter-ruptionofaVKAbeforesurgeryoraprocedureandwhoseINRisstillelevated(ie,>1.5)1to2daysbeforesurgery,wesuggestadministeringlow-dose(ie,1to2mg)oralvitaminKtonormalizetheINRinsteadofnotadministeringvitaminK(Grade2C).

2.4.InpatientswithamechanicalheartvalveoratrialfibrillationorVTEathighriskforthrom-boembolism,werecommendbridginganticoag-ulationwiththerapeutic-doseSCLMWHorIVUFHovernobridgingduringtemporaryinter-ruptionofVKAtherapy(Grade1C);wesuggesttherapeutic-doseSCLMWHoverIVUFH(Grade2C).InpatientswithamechanicalheartvalveoratrialfibrillationorVTEatmoderateriskforthromboembolism,wesuggestbridginganticoagulationwiththerapeutic-doseSCLMWH,therapeutic-doseIVUFH,orlow-doseSCLMWHovernobridgingduringtemporaryinterruptionofVKAtherapy(Grade2C);wesuggesttherapeutic-doseSCLMWHoverother

*FromMcMasterUniversity(Dr.Douketis),Hamilton,ON,Canada;GeisingerClinic(Dr.Berger),Danville,PA;MountSinaiSchoolofMedicine(Dr.Dunn),NewYork,NY;UniversityofMiami(Dr.Jaffer),LeonardM.Miller,SchoolofMedicine,Miami,FL;ClinicalThrombosisCenter(Dr.Spyropoulos),LovelaceMedicalCenter,Albuquerque,NM;DukeUniversity(Dr.Becker),Durham,NC;andBostonUniversity(Dr.Ansell),Boston,MA.

ManuscriptacceptedDecember20,2007.

ReproductionofthisarticleisprohibitedwithoutwrittenpermissionfromtheAmericanCollegeofChestPhysicians(www.chestjournal.org/misc/reprints.shtml).

Correspondenceto:JackE.Ansell,MD,FACP,FCCP,Depart-mentofMedicine,BostonUniversityMedicalCenter,88EastNewtonSt,Boston,MA02118;e-mail:jack.ansell@bmc.orgDOI:10.1378/chest.08-0675300S

managementoptions(Grade2C).Inpatientswithamechanicalheartvalveoratrialfibrilla-tionorVTEatlowriskforthromboembolism,wesuggestlow-doseSCLMWHornobridgingoverbridgingwiththerapeutic-doseSCLMWHorIVUFH(Grade2C).

Valuesandpreferences:Inpatientsathighormoderateriskforthromboembolism,therecom-mendationsreflectarelativelyhighvalueonpre-ventingthromboembolismandarelativelylowvalueisonpreventingbleeding;inpatientsatlowriskforthromboembolism,therecommendationsreflectarelativelyhighvalueonpreventingbleed-ingandarelativelylowvalueonpreventingthrom-boembolism.

3.0PerioperativeManagementofPatientsWhoAreReceivingBridgingAnticoagulation

3.1.Inpatientswhorequiretemporaryinter-ruptionofVKAsandaretoreceivebridginganticoagulation,fromacost-containmentper-spectivewerecommendtheuseofSCLMWHadministeredinanoutpatientsettingwherefeasibleinsteadofinpatientadministrationofIVUFH(Grade1C).

Valuesandpreferences:Thisrecommendationre-flectsaconsiderationnotonlyofthetrade-offbe-tweentheadvantagesanddisadvantagesofSCLMWHandIVUFHasreflectedintheireffectsonclinicaloutcomes(LMWHatleastasgood,possiblybetter),butalsotheimplicationsintermsofresourceuse(costs)inarepresentativegroupofcountries(substantiallylessresourceusewithLMWH).

3.2.Inpatientswhoarereceivingbridginganticoagulationwiththerapeutic-doseSCLMWH,werecommendadministeringthelastdoseofLMWH24hbeforesurgeryoraproce-dureoveradministeringLMWHclosertosur-gery(Grade1C);forthelastpreoperativedoseofLMWH,werecommendadministeringap-proximatelyhalfthetotaldailydoseinsteadof100%ofthetotaldailydose(Grade1C).Inpatientswhoarereceivingbridginganticoagu-lationwiththerapeutic-doseIVUFH,werec-ommendstoppingUFHapproximately4hbe-foresurgeryoverstoppingUFHclosertosurgery(Grade1C).

3.3.Inpatientsundergoingaminorsurgicalorotherinvasiveprocedureandwhoarereceivingbridginganticoagulationwithther-apeutic-doseLMWH,werecommendresum-ingthisregimenapproximately24hafter(eg,thedayafter)theprocedurewhenthereisadequatehemostasisoverashorter(eg,<12h)timeinterval(Grade1C).Inpatientsunder-goingmajorsurgeryorahighbleedingrisk

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surgery/procedureandforwhompostopera-tivetherapeutic-doseLMWH/UFHisplanned,werecommendeitherdelayingtheinitiationoftherapeutic-doseLMWH/UFHfor48to72haftersurgerywhenhemostasisissecured,administer-inglow-doseLMWH/UFHaftersurgerywhenhemostasisissecured,orcompletelyavoidingLMWHorUFHaftersurgeryovertheadminis-trationoftherapeutic-doseLMWH/UFHincloseproximitytosurgery(Grade1C).Werecommendconsideringtheanticipatedbleedingriskandad-equacyofpostoperativehemostasisinindividualpatientstodeterminethetimingofLMWHorUFHresumptionaftersurgeryinsteadofresum-ingLMWHorUFHatafixedtimeaftersurgeryinallpatients(Grade1C).

3.4.Inpatientswhoarereceivingbridginganti-coagulationwithLMWH,wesuggestagainsttheroutineuseofanti-factorXalevelstomonitortheanticoagulanteffectofLMWHs(Grade2C).4.0PerioperativeManagementofPatientsWhoAreReceivingAntiplateletTherapy

4.2.Inpatientswhorequiretemporaryinter-ruptionofaspirin-orclopidogrel-containingdrugsbeforesurgeryoraprocedure,wesug-geststoppingthistreatment7to10daysbeforetheprocedureoverstoppingthistreatmentclosertosurgery(Grade2C).

4.3.Inpatientswhohavehadtemporaryinter-ruptionofaspirintherapybecauseofsurgeryoraprocedure,wesuggestresumingaspirinap-proximately24h(orthenextmorning)aftersurgerywhenthereisadequatehemostasisin-steadofresumingaspirinclosertosurgery(Grade2C).Inpatientswhohavehadtemporaryinterruptionofclopidogrelbecauseofsurgeryoraprocedure,wesuggestresumingclopi-dogrelapproximately24h(orthenextmorn-ing)aftersurgerywhenthereisadequatehe-mostasisinsteadofresumingclopidogrelclosertosurgery(Grade2C).

4.4.Inpatientswhoarereceivingantiplateletdrugs,wesuggestagainsttheroutineuseofplateletfunctionassaystomonitortheantithrom-boticeffectofaspirinorclopidogrel(Grade2C).4.5.Forpatientswhoarenotathighriskforcardiacevents,werecommendinterruptionofantiplateletdrugs(Grade1C).Forpatientsathighriskofcardiacevents(exclusiveofcoro-narystents)scheduledfornoncardiacsurgery,wesuggestcontinuingaspirinuptoandbeyondthetimeofsurgery(Grade2C);ifpatientsarereceivingclopidogrel,wesuggestinterruptingclopidogrelatleast5daysand,preferably,within10dayspriortosurgery(Grade2C).In

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patientsscheduledforCABG,werecommendcontinuingaspirinuptoandbeyondthetimeofCABG(Grade1C);ifaspirinisinterrupted,werecommenditbereinitiatedbetween6hand48hafterCABG(Grade1C).Inpatientssched-uledforCABG,werecommendinterruptingclopidogrelatleast5daysand,preferably,10dayspriortosurgery(Grade1C).InpatientsscheduledforPCI,wesuggestcontinuingaspi-rinuptoandbeyondthetimeoftheprocedure;ifclopidogrelisinterruptedpriortoPCI,wesuggestresumingclopidogrelafterPCIwithaloadingdoseof300to600mg(Grade2C).

4.6.Inpatientswithabaremetalcoronarystentwhorequiresurgerywithin6weeksofstentplacement,werecommendcontinuingaspirinandclopidogrelintheperioperativeperiod(Grade1C).Inpatientswithadrug-elutingcoro-narystentwhorequiresurgerywithin12monthsofstentplacement,werecommendcontinuingaspirinandclopidogrelintheperioperativepe-riod(Grade1C).Inpatientswithacoronarystentwhohaveinterruptionofantiplatelettherapybe-foresurgery,wesuggestagainsttheroutineuseofbridgingtherapywithUFH,LMWH,directthrombininhibitors,orglycoproteinIIb/IIIain-hibitors(Grade2C).

Valuesandpreferences:Theserecommendationsre-flectarelativelyhighvalueplacedonpreventingstent-relatedcoronarythrombosis,aconsiderationofcom-plexityandcostsofadministeringbridgingtherapyintheabsenceofefficacyandsafetydatainthisclinicalsetting,andarelativelylowvalueonavoidingtheunknownbutpotentiallylargeincreaseinbleedingriskassociatedwiththeconcomitantadministrationofaspi-rinandclopidogrelduringsurgery.

5.0PerioperativeManagementofAntithromboticTherapyinPatientsWhoRequireDental,Dermato-logic,orOphthalmologicProcedures

5.1.InpatientswhoareundergoingminordentalproceduresandarereceivingVKAs,werecommendcontinuingVKAsaroundthetimeoftheprocedureandcoadministeringanoralprohemostaticagent(Grade1B).Inpatientswhoareundergoingminordentalproceduresandarereceivingaspirin,werecommendcontinuingaspirinaroundthetimeoftheprocedure(Grade1C).Inpatientswhoareundergoingminordentalproceduresandarereceivingclopidogrel,pleaserefertotherecommendationsoutlinedinSection4.5andSection4.6.

5.2.Inpatientswhoareundergoingminorder-matologicproceduresandarereceivingVKAs,werecommendcontinuingVKAsaroundthetimeoftheprocedure(Grade1C).Inpatientswhoare

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undergoingminordermatologicproceduresandarereceivingaspirin,werecommendcontinuingaspirinaroundthetimeoftheprocedure(Grade1C).Inpatientswhoareundergoingminorder-matologicproceduresandarereceivingclopi-dogrel,pleaserefertotherecommendationsout-linedinSection4.5andSection4.6.

5.3.Inpatientswhoareundergoingcataractre-movalandarereceivingVKAs,werecommendcontinuingVKAsaroundthetimeoftheproce-dure(Grade1C).Inpatientswhoareundergoingcataractremovalandarereceivingaspirin,werecommendcontinuingaspirinaroundthetimeoftheprocedure(Grade1C).Inpatientswhoareundergoingcataractremovalandarereceivingclopidogrel,pleaserefertotherecommendationsoutlinedinSection4.5andSection4.6.

6.0PerioperativeManagementofAntithromboticTherapyPatientsWhoRequireUrgentSurgicalorOtherInvasiveProcedures

6.1.InpatientswhoarereceivingVKAsandrequirereversaloftheanticoagulanteffectforanurgentsurgicalorotherinvasiveprocedure,werecommendtreatmentwithlow-dose(2.5to5.0mg)IVororalvitaminK(Grade1C).Formoreimmediatereversaloftheanticoagulanteffect,wesuggesttreatmentwithfresh-frozenplasmaoranotherprothrombinconcentrateinadditiontolow-doseIVororalvitaminK(Grade2C).

6.2.Forpatientsreceivingaspirin,clopi-dogrel,orboth,areundergoingsurgery,andhaveexcessiveorlife-threateningperiopera-tivebleeding,wesuggesttransfusionofplate-letsoradministrationofotherprohemostaticagents(Grade2C).

heperioperativemanagementofpatientswhorequiretemporaryinterruptionofvitaminKantagonists(VKAs)orantiplateletdrugsbecauseofasurgicalorothernoninvasiveprocedureisacommonandchallengingclinicalproblem.1Approximately250,000suchpatientsarebeingassessedannuallyinNorthAmericaalone,whichisbasedonanestimateoftheprevalenceofpatientswhoarereceivinglong-termtreatmentwithaVKA,principallyduetoatrialfibrillationoramechanicalheartvalve(ϳ2.5million),2,3andanestimateoftheannualproportionofpatientswhoarereceivingaVKAandrequiresurgeryoraninvasiveprocedure(ϳ10%).4Themanagementofthesepatientsischallengingbecausetheriskofathromboembliceventduringinterrup-tionofVKAorantiplatelettherapyneedstobebalancedagainsttheriskforbleedingwhenanti-thrombotictherapyisadministeredincloseproxim-302S

Titytosurgeryoraninvasiveprocedure.Inassessingpatientswhoarereceivingantithrombotictherapyandareundergoingasurgicalorotherprocedure,twoprincipalissuesshouldbeaddressed:

Isinterruptionofantithrombotictherapyintheperioperativeperiodneeded?Inpatientswhoareundergoingamajorsurgicalorinvasiveprocedure,interruptionofantithrombotictherapyistypicallyrequiredtominimizetheriskforperioperativebleeding.ContinuationofVKAoraspirintherapyintheperioperativeperiodconfersanincreasedriskforbleeding.5–9Ontheotherhand,inpatientswhoareundergoingminorsurgicalorinvasiveprocedures,suchasdental,skin,oreyeprocedures,interruptionofantithrombotictherapymaynotberequired.Ifantithrombotictherapyisinterrupted,isbridg-inganticoagulationneeded?Inthecontextofperi-operativeanticoagulation,bridginganticoagulationmaybedefinedastheadministrationofashort-actinganticoagulant,suchassubcutaneous(SC)low-molecular-weightheparin(LMWH)orIVun-fractionatedheparin(UFH),administeredtypicallyasatherapeutic-doseregimenforapproximately8to10daysduringinterruptionofVKAtherapywhentheinternationalnormalizedratio(INR)isnotwithinatherapeuticrange.Inpatientswhoarere-ceivingantiplateletdrugsalone,bridginganticoagula-tionwithLMWHorUFHis,typically,notadminis-tered.Ingeneral,theneedforbridginganticoagulationisdeterminedbypatientriskforthromboembolismduringinterruptionofantithrombotictherapy.Thetherapeuticaimofbridginganticoagulationistominimizethetimepatientsarenotreceivingantico-agulanttherapy,therebyminimizingtheriskforthromboembolism,andtodothisinamannerthatminimizespatients’riskforperioperativebleeding.TheobjectiveofthisarticleistoprovidetreatmentrecommendationsforpatientswhoarereceivingaVKAorantiplateletdrugandmayrequiretemporaryinterruptionoftreatmentbecauseofasurgicalorotherinvasiveprocedure.Followingadiscussionofgeneralmanagementprinciples(Section1),thisreviewaddressesthefollowingpatientgroupsas-sessedinclinicalpractice:patientswhoarereceivingVKAs(Section2);patientswhoarereceivingbridg-inganticoagulationafterinterruptionofVKAs(Sec-tion3);patientswhoarereceivingantiplateletdrugs(Section4);patientswhoarereceivingVKAsorantiplateletdrugsandareundergoingminorsurgicalorinvasiveprocedures(Section5);andpatientswhorequireurgentinterruptionofantithromboticther-apy(Section6).ThesummaryrecommendationsfollowtheformatinTable1,whichframesthequestionsthisarticleaddresses.

Atthisjuncture,somequalifyingandexplanatoryremarksarewarranted.First,researchinperiopera-AntithromboticandThrombolyticTherapy8thEd:ACCPGuidelines

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Table1—PerioperativeAntithromboticTherapy:QuestionDefinitionandEligibilityCriteria

Section

Population

InterventionorExposure/Comparison*

Outcomes

AvailableMethodology

ExclusionCriteriaNoneNoneNone

2.0PerioperativemanagementofpatientswhoarereceivingVKAs2.1AnypatientreceivingVKAandTimingofinterruptionofVKAbeforeHemostasisattimeofObservational

havingelectivesurgerysurgerysurgery(INR)studies

2.2TimingofresumptionofVKAorHemostasisattimeofObservational

LMWHaftersurgerysurgery(bleedtime)studies

2.3INRtestingtomonitoranticoagulantHemostasisattimeofObservational

effectofVKAsbeforeandaftersurgery(APTT,studiessurgeryvsnotestinganti-factorXa)

2.4.1PatientswithamechanicalheartTemporaryinterruptionofVKAandStroke,othersystemicObservational

valvehavingelectivesurgerybridginganticoagulationwithembolism,majorstudies

LMWH/UFHvsnobridginghemorrhage

2.4.2PatientswithchronicatrialTemporaryinterruptionofVKAandStroke,othersystemicObservational

fibrillationhavingelectivebridginganticoagulationwithembolism,majorstudiessurgeryLMWH/UFHvsnobridginghemorrhage

2.4.3PatientswithVTEhavingTemporaryinterruptionofVKAandStroke,othersystemicObservational

electivesurgerybridginganticoagulationwithembolism,majorstudies

LMWH/UFHvsnobridginghemorrhage

3.0Perioperativemanagementofpatientswhoarereceivingbridginganticoagulation3.1CostsofbridginganticoagulationOutpatientSCLMWHvsinpatientHealth-caresystemObservational

IVUFHcostsstudies

3.2AnypatientreceivingUFHorTimingofinterruptionofLMWHorMajorpostoperativeObservational

LMWHasbridgingUFHbeforesurgerybleedingstudies

3.3anticoagulationandhavingTimingofresumptionofLMWHorMajorpostoperativeObservational

electivesurgeryUFHaftersurgerybleedingstudies

3.4APTT,andanti-factorXatestingtoMajorpostoperativeObservational

monitoranticoagulanteffectofbleedingstudiesLMWHandUFHbeforeandaftersurgery

4.0Perioperativemanagementofpatientswhoarereceivingantiplatelettherapy4.2AnypatientreceivinganTimingofinterruptionofantiplateletINRbeforeandafterObservational

antiplateletdrugandhavingdrugsbeforesurgerysurgerystudies

4.3electivesurgeryTimingofresumptionofantiplateletPlateletfunctionassayObservational

drugsaftersurgerytestingbeforeandstudies

aftersurgery

4.4PlateletfunctionassaytestingtoAPTTandanti-factorObservational

monitorantiplateleteffectofXabeforeandafterstudiesantiplateletdrugsbeforeandaftersurgerysurgeryvsnotesting

4.5AnypatientreceivingantiplateletTemporaryinterruptionvsMyocardialischemia,Randomized

drugandhavingnoncardiaccontinuationofantiplateletdrugsmajorhemorrhagecontrolledtrials,surgery,cardiacsurgery,orobservationalPCIstudies

4.6AnypatientwithacoronarystentTemporaryinterruptionvsMyocardialischemia,Randomized

receivingantiplateletdrugandcontinuationofantiplateletdrugsmajorhemorrhagecontrolledtrials,havingnoncardiacsurgery,observationalcardiacsurgery,orPCIstudies

5.0Perioperativemanagementofantithrombotictherapyinpatientswhorequireminorprocedures5.1AnypatientreceivingVKAorTemporaryinterruptionvsArterialorVTE,majorRandomized

antiplateletdrugandhavingacontinuationofVKAorantiplatelethemorrhagecontrolledtrials,minordentalproceduretherapyobservational

studies

5.2AnypatientreceivingVKAorTemporaryinterruptionvsArterialorVTE,majorRandomized

antiplateletdrugandhavingacontinuationofVKAorantiplatelethemorrhagecontrolledtrials,minorskinproceduretherapyobservational

studies

5.3AnypatientreceivingVKAorTemporaryinterruptionvsArterialorVTE,majorRandomized

antiplateletdrugandhavingacontinuationofVKAorantiplatelethemorrhagecontrolledtrials,minoreyeproceduretherapyobservational

studies

NotreceivingVKANotreceivingVKANotreceivingVKA

NoneNoneNoneNone

NoneNone

None

ReceivingVKA

None

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Table1—Continued

Section

Population

InterventionorExposure/Comparison

Outcomes

AvailableMethodology

ExclusionCriteria

6.0Perioperativemanagementofantithrombotictherapypatientswhorequireurgentsurgicalorotherinvasiveprocedures6.1AnypatientreceivingVKAandVitaminKviadifferentroutes(IVvs(1)HemostasisattimeRandomizedNone

havingurgentsurgeryoral/SC)toreverseanticoagulantofsurgery(INR)controlledtrials,

(2)MajorbleedingeffectofVKAs;bloodproductsobservationalandsurrogate(FFP,PC)toreverseanticoagulantstudies

effectofVKAsvsnobloodproducts

6.2AnypatientreceivinganDDAVP/prohemostaticdrugsandMyocardialischemia,ObservationalNone

antiplateletdrugandhavingplatelettransfusiontoreversemajorhemorrhagestudiesurgentsurgeryantiplateleteffectofantiplatelet

drugsvsnoDDAVP/prohemostaticdrugsandplatelettransfusions*FFPϭfreshfrozenplasma;PCϭprothrombinconcentrate.

tiveantithrombotictherapyisanemergingfield,witharelativepaucityofrandomizedtrialsandapreponderanceofobservationalstudiesassessingperioperativemanagementstrategies.Consequently,comparisonsofcertainmanagementstrategies(eg,bridgingvsnobridging)arelackingwhereascom-parisonsofotherstrategies(eg,continuationvsinterruptionofVKAsforminorprocedures)arebetterdeveloped.Second,asmanyofthepertinentobservationalstudiesarebasedonsmallpatientsamples,theymaybeunderpoweredtodetermineifamanagementapproachisefficacious(ie,associatedwithalowriskforthromboembolism)orsafe(ie,associatedwithalowriskforbleeding).Suchstudiesshould,therefore,beinterpretedwithcautionbothbecauseoftheobservationalstudydesignandthesmallsamplesize.Third,itshouldbeacknowledgedthatthereisnostandardizeddefinitionof“bridginganticoagulation.”Althoughitmaybedefinedastheadministrationofatherapeutic-doseregimenofSCLMWHorIVUFHduringinterruptionofaVKA,bridginganticoagulationmayalsoincludearegimenoflow-doseSCLMWH.Ultimately,theperioperativeanticoagulantregimenusedwilldepend,toalargeextent,onpatientclinicalcharacteristicsandthetypeofsurgeryorproceduretheyareundergoing.

1.0PerioperativeManagementofAntithromboticTherapy:General

Principles1.1AssessmentofThromboembolicRiskAfterInterruptionofAntithromboticTherapy

Interruptionofantithrombotictherapyexposespatientstoanincreasedriskforthromboembolicevents,suchasstrokeormechanicalvalvethrombo-sis,withtheriskvaryingdependingontheindicationforantithrombotictherapyandthepresenceof

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comorbidconditions.10Theseeventscanhavedev-astatingclinicalconsequences:embolicstroke,whichcanresultinmajordisabilityordeathin70%ofpatients11,12;thrombosisofamechanicalheartvalve,whichisfatalin15%ofpatients13;andperioperativemyocardialischemia,whichisassociatedwithatwo-fold-tofourfold-increasedriskfordeath.14,15Similarly,interruptionofantiplateletdrugsinpatientswithasirolimusorpaclitaxeldrug-elutingcoronarystent,es-peciallywithin6monthsofstentplacement,signifi-cantlyincreasestheriskforintracoronarystentthrom-bosisandmyocardialinfarction.16,17Stratifyingpatientsaccordingtotheirriskforperioperativethromboembolismisbasedonpatients’clinicalindicationforantithrombotictherapyandthepresenceofcomorbidities.Althoughthereisnovalidatedriskstratificationofsuchpatients,theapproachwehaveusedintheseguidelinesistoseparatepatientsintoahigh-risk,moderate-risk,orlow-riskgroupaccordingtotheirindicationforanti-thrombotictherapy(Table2).

1.2AssessmentofBleedingRiskAssociatedWithSurgeryorOtherInvasiveProcedures

Theadministrationofantithrombotictherapyintheperioperativeperiodshouldbedoneinawaythatconsiderstheriskforbleedingassociatedwiththesurgeryorprocedure.Althoughbleedingisatreat-ableperioperativecomplication,thereisemergingevidencethattheclinicalimpactofbleedingisconsiderableand,perhaps,greaterthanpreviouslyappreciated.18–20Furthermore,postoperativebleed-ingdelaystheresumptionofantithrombotictherapy,withthepotentialtofurtherexposepatientstoanincreasedriskforthromboembolism.21,22Stratifyingpatientsaccordingtotheirriskforperioperativebleedingcanbebasedontheriskforbleedingassociatedwiththesurgeryorprocedure

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Table2—SuggestedPatientRiskStratificationforPerioperativeArterialorVenousThromboembolism

IndicationforVKATherapy

RiskStratumHigh

MechanicalHeartValveAnymitralvalveprosthesis

Older(caged-ballortiltingdisc)aorticvalveprosthesis

Recent(within6mo)strokeortransientischemicattack

AtrialFibrillationCHADS2scoreof5or6

Recent(within3mo)strokeortransientischemicattack,Rheumaticvalvularheartdisease

VTE

Recent(within3mo)VTE

Severethrombophilia(eg,deficiencyofproteinC,proteinSor

antithrombin,antiphospholipidantibodies,ormultipleabnormalities)VTEwithinthepast3to12moNonseverethrombophilicconditions(eg,heterozygousfactorVLeidenmutation,heterozygousfactorIImutation)RecurrentVTE

Activecancer(treatedwithin6moorpalliative)SingleVTEoccurredϾ12moagoandnootherriskfactors

Moderate

Bileafletaorticvalveprosthesisandoneofthefollowing:atrialfibrillation,priorstrokeortransientischemicattack,hypertension,diabetes,

congestiveheartfailure,ageϾ75yr

CHADS2scoreof3or4

Low

BileafletaorticvalveprosthesiswithoutatrialfibrillationandnootherriskfactorsforstrokeCHADS2scoreof0to2(andnopriorstrokeortransientischemicattack)

*CHADS2ϭCongestiveheartfailure-Hypertension-Age-Diabetes-Stroke.

andshouldbecoupledwithanassessmentofpost-operativehemostasis.21–24Althoughthereisnovali-datedmethodthatquantifiesperioperativebleedingrisk,specialattentioniswarrantedforcertainsurgi-calorotherinvasiveproceduresassociatedwithahighriskforbleeding.Insuchpatients,postoperativeantithrombotictherapyshouldbeadministeredwithcaution,especiallytherapeutic-doseLMWHorUFHwhenusedasbridginganticoagulation.Surgicalandotherinvasiveproceduresassociatedwithahighbleed-ingriskinclude:coronaryarterybypassorheartvalvereplacementsurgery25,26;intracranialorspinalsur-gery27;aorticaneurysmrepair,peripheralarterybypass,andothermajorvascularsurgery;majororthopedicsurgery,suchashiporkneereplacement28;reconstruc-tiveplasticsurgery29;majorcancersurgery;andpros-tateandbladdersurgery.30,31Inaddition,cliniciansshouldnoteproceduresthat,onthesurface,mayappeartobeassociatedwithalowriskforbleedingbutinwhichperioperativeanticoagulationshouldbeundertakenwithcaution.Suchproceduresinclude:resectionofcolonicpolyps,especiallysessilepolypsϾ2cmindiameter,inwhichbleedingmayoccuratthetransectedstalk32;biopsyoftheprostateorkidney,inwhichthepresenceofhighlyvasculartissueandendogenousurokinasemaypromotepost-biopsybleeding33;andcardiacpacemakerordefibrillatorimplantation,inwhichseparationoftheinfraclavicularfasciallayersandlackofcauteryorsuturingofunopposedtissueswithinthepacemakerordefibrillatorpocketmaypredisposetopockethematomadevelopment.34www.chestjournal.org

1.3BalancingThromboembolicRiskandBleedingRisk

Inherentinperioperativeantithromboticmanage-mentistheneedforindividualizedpatientmanage-mentthatbalancesindividualriskforthromboem-bolismandbleeding.Inpatientsclassifiedas“highriskforstrokeorthromboembolism,”theneedtopreventathromboemboliceventsuchasembolicstrokeorintracoronarystentthrombosiswilldomi-nateperioperativeantithromboticmanagement,ir-respectiveofbleedingrisk.Insuchpatients,thepotentialclinicalconsequencesofsuchevents,whichmaybefatalormaycausepermanentdisability,will,inmostpatients,outweighthepotentialclinicalconsequencesofbleedingandwilljustifytheneedforbridginganticoagulationorperioperativecontin-uationofantithrombotictherapy.Thisapproach,ifadopted,shouldnonethelessconsiderjudicioususeofpostoperativebridginganticoagulation(ie,asout-linedinSection3.0)andoptimizingintraoperativehemostasis(ie,cauteryandotherlocalmeasures),withtheintentofsimultaneouslyminimizingthepotentialformajorsurgicalbleedingthatwouldhavetheundesiredeffectofdelayingtheresump-tionofornecessitatinginterruptionofantithrom-botictherapy.

Inpatientsclassifiedas“moderateriskforthrom-boembolism,”asingleperioperativeantithromboticstrategywillnotbedominantandmanagementwilldependmoreonanindividualpatientriskassess-ment.Thus,inpatientsatmoderateriskforthrombo-CHEST/133/6/JUNE,2008SUPPLEMENT

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embolism,theneedtopreventthromboembolismwillhavelessdominancethanin“high-risk”patientsandbridginganticoagulationmayincorporateamodified,lessaggressive,approachpostoperativelyinpatientsundergoingsurgeryoraprocedureassociatedwithahighbleedingrisk.Inpatientsclassifiedas“lowriskforthromboembolism,”theneedtopreventthromboem-bolismwillhaveevenlessdominanceandcliniciansmayavoidbridginganticoagulationaltogether;ifgiven,bridgingshouldbecurtailedpostoperativelyinsuchpatientswithahighbleedingrisk.

1.4PerioperativeAntithromboticManagement:PracticalConsiderations

Inmanagingantithrombotictherapybeforeandaftersurgeryoraprocedure,cliniciansshouldnotethefollowingpracticalmanagementconsiderations:•Forpatientsundergoingamajorsurgicalorinva-siveprocedure,iftheintentistoeliminateanyeffectofantithrombotictherapy,itshouldbestoppedatatimebeforetheprocedure(eg,approx-imately5daysinpatientsreceivingaVKAand7to10daysinpatientsreceivinganantiplateletdrug)thatleavesminimalornoresidualantithromboticeffectattimeoftheprocedure;doingsowillmini-mizetheriskforintraproceduralbleeding.

•Theadministrationofarapidlyactinganticoagu-lant,suchasLMWHorUFH,aftersurgeryoranotherinvasiveprocedureincreasestheriskforbleeding.Thisriskisdependentonthedoseofanticoagulant(eg,therapeutic-dosemorethanlow-dose)andtheproximitytosurgerythatitisadministered(higherbleedingriskwhenadminis-teredclosertosurgery).Delayingresumptionofatherapeutic-doseLMWHorUFHregimen(for48to72haftersurgery),decreasingthedoseofLMWHorUFH(toalow-doseregimen),oravoidingitsusealtogetherinthepostoperativeperiodcanmitigatetheriskforbleeding.

•Forperioperativeanticoagulantdosing,althoughthereisevidencethatlow-dose(prophylactic-dose)LMWHorUFH(eg,dalteparin5,000IUqdorUFH5,000IUbid)iseffectiveinpreventingvenousthromboembolism(VTE),evidenceislack-ingthatsuchlow-dosetreatmentiseffectiveinpreventingarterialthromboembolism.

•Inresumingantithrombotictherapyafterasurgi-calorinvasiveprocedure,ittakes2to3daysforananticoagulanteffecttobeginafterthestartofwarfarin,35ittakes3to5hforapeakanticoagulanteffecttobereachedafterthestartofLMWH,36whereasittakesminutesforanantiplateleteffecttobeginafterthestartofaspirin37and3to7days

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forpeakinhibitionofplateletaggregationtobereachedafterthestartofa(75mg)maintenancedoseofclopidogrel.38•Themajorityofsurgicalorotherinvasivepro-ceduresarebeingdonewithouthospitalizationorwithashorthospitalstay;consequently,potentialthromboembolic-orbleeding-relatedcomplicationsarelikelytooccurwhilethepa-tientisathome,especiallyduringtheinitial2weeksafteraprocedure.21,22,39,40Closefollow-upofpatientsduringtheearlyperiodafteraprocedureis,therefore,warrantedtoallowearlydetectionandexpeditedtreatmentofpotentialcomplications.2.0PerioperativeManagementofPatients

WhoAreReceivingVKAsLong-termVKAtherapyiswidelyusedfortheprimaryandsecondarypreventionofarterialthrombo-embolismandVTEforawidespectrumofclinicalindicationsthatincludeatrialfibrillation,mechanicalheartvalveplacement,VTE,coronaryandperipheralarterydisease,dilatedcardiomyopathy,andprimarypulmonaryhypertension.InSection2.0,wewillfocusontheperioperativeanticoagulantmanagementofpatientswiththemostcommonclinicalindicationsforlong-termVKAtherapy:mechanicalheartvalve,chronicatrialfibrillation,andVTE.2.1InterruptionofVKAsBeforeSurgery

Inpatientsundergoingmajorsurgery,interruptionofVKAsisgenerallyrequiredtominimizetheriskforperioperativebleeding,5–7whereasinpatientsundergoingcertainminorsurgicalorotherproce-dures,someofwhicharediscussedinSection5.0,interruptionofVKAsmaynotberequired.Toourknowledge,therearenorandomizedtrialscompar-inginterruptionofVKAsvsnointerruptionorpartialinterruptionofVKAsbeforemajorsurgery.Threeobservationalstudieshaveassessedcontinuation8,41orpartialinterruption42ofVKAsinpatientsunder-goingsurgery,withsuggestivebutnotdefinitivefindingsthatcontinuationofVKAsincreasestheriskforperioperativebleeding.Inoneretrospectiveco-hortstudyinvolving603VKA-treatedpatientswhounderwentsurgery,themajorityofwhomdidnothaveinterruptionofVKAtherapypriortosurgery,theincidenceofperioperativemajorbleedingwas9.5%(95%confidenceinterval[CI]:7.1–12.1),whichishigh;moreover,comparedtopatientswithanINRϽ2.0,patientswithanINRϾ3.0appearedtobeathigherriskforbleedingcomplications(oddsratio[OR],1.6;95%CI:0.4–4.0).8Anotherretro-spectivestudyassessed100patientswhounderwentsurgery(58hadmajorsurgery)andwhohadpartial

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interruptionofVKA,withameanINRof1.8(range:1.2to4.9)onthedayofsurgery;inthisstudy,onlytwo(2%)patientshadmajorbleedingalthough34(34%)patientsrequiredabloodtransfusion.42ForpatientswhoarereceivingVKAtherapywithwarfarin,whichhasahalf-lifeof36to42h,treat-mentshouldbeinterruptedapproximately5daysbeforesurgery(correspondingapproximatelyto5half-livesofwarfarin)toensurethereisno(orminimal)residualanticoagulanteffectremainingbythetimeofsurgery.43,44Previousprospectivecohortstudiesassessingstandardizedperioperativeantico-agulationregimensinterruptedwarfarin5to6daysbeforesurgery.21,22,39Inoneofthesestudies,22inwhichwarfarinwasstopped5daysbeforesurgeryandtheINRwasroutinelymeasuredonthedaybeforesurgery,only15of224(7%)patientshadanelevatedINR(Ͼ1.5)onthedaybeforesurgery,whichwascorrectedwithlow-dose(1mg)oralvitaminK.Alonger(eg,Ͼ5days)durationofVKAinterruptiontoattainanormalizedINRbythetimeofsurgerymayberequiredinpatientswithamechanicalheartvalve,whohaveahighertargetedINRrange,whichistypically2.5to3.5.45Inaddi-tion,advancedagemaybeassociatedwithaprolon-gationinthedecayoftheanticoagulanteffectofwarfarinafteritsinterruption.Thus,inaretrospec-tivecohortstudyof633patientswhohadexcessiveanticoagulation(INRϾ6.0),increasingage,in10-yearincrements,conferredanincreasedlikelihoodfordelayednormalizationoftheINRafterwarfarinwasstopped(hazardratio,1.18;CI:1.01–1.38).46ForaminorityofpatientswhoarereceivingVKAtherapywithphenprocoumon,inwhomtheVKA-relatedrecommendationsinthisarticlewouldnotapply,treatmentshouldbeinterruptedapproxi-mately10daysbeforesurgerybasedonthehalf-lifeofphenprocoumonof96to140h.47Someinvesti-gatorshavesuggestedthat,inselectedpatients,warfarincanbeinterrupted2to3daysbeforesurgerytoaimforanINRof1.5to1.9atthetimeofsurgery;however,thefeasibilityandsafetyofthisapproachremainuncertain.8,42,48Recommendation

2.1.Inpatientswhorequiretemporaryinter-ruptionofaVKAbeforesurgeryoraproce-dureandrequirenormalizationoftheINRforthesurgeryorprocedure,werecommendstoppingVKAsapproximately5daysbeforesurgeryoverashortertimeintervaltoallowadequatetimefortheINRtonormalize(Grade1B).

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2.2ResumptionofVKAsAfterSurgery

WhenresumingVKAsaftersurgery,approxi-mately48hisrequiredtoattainapartialanticoag-ulanteffect,withanINRϾ1.5.43Consequently,thepotentialeffectofVKAstopromotepostoperativebleedingislikelytobemitigatedbythedelayedonsetoftheiranticoagulantactivity.Itisreasonable,therefore,toresumeVKAtherapyontheeveningofthedayofsurgeryorthenextday,withanantici-patedpartialanticoagulanteffecttooccur48hlater.Inonestudyof650patientswhoresumedVKAafterbridginganticoagulation,withadosecorrespondingtopatients’usualdose,themeandurationtoachieveatherapeuticINRwas5.1days(SD:1.1).21Inanotherstudyof224patientswhoresumedVKAafterbridginganticoagulation,withdoublingofpa-tients’usualdosefortheinitial2daysafterVKAresumption,themeandurationtoachieveathera-peuticINRwas4.6days(range:0to10).22Oneretrospectivecohortstudyinvolving100patientswhoreceivedbridgingwithLMWHfoundalongerthanexpectedtimetoattainatherapeuticINRaftersurgery,whichwasamedianof7.5days(inter-quartilerange:4.3to13.0)afterwarfarinwasresumedpostoperatively.49ThedelayinattainingtherapeuticlevelsofanticoagulationinthisstudywaspossiblyrelatedtosuboptimalINRmonitoringaftersurgery.Recommendation

2.3LaboratoryMonitoringofVKATherapyPerioperativemonitoringoftheINRinpatientswhoarereceivingVKAtherapyispredicatedonseveralfactors,whichincludethefeasibilityofINRmonitoringpriortosurgeryandthetimeperiodbetweeninterruptionofVKAsandsurgery.Inthepreoperativeperiod,itisreasonabletohaveINRtestingdoneatleastoncebeforesurgery(preferably1to2daysbeforesurgery)toconfirmanormalornear-normalINRand,inpatientswithanelevatedINR(eg,INRϾ1.5),toadministerlow-dosevitaminK.AdministrationofvitaminKatthistimewillavoidtheneedtoadministerplasmaorotherbloodprod-uctsbyensuringtheINRhasnormalizedbythedayofsurgery.Inoneretrospectivecohortstudyinvolv-ing43patientswhorequiredtemporaryinterruption

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ofVKAandhadanINRbetween1.5and1.9(mean:1.6)onthedaybeforesurgery,administering1mgoralvitaminKresultedin91%ofpatientshavinganormalornearnormalINR(ie,Յ1.4)onthedayofsurgery.50Thisstudyalsosuggestedthatpreopera-tiveadministrationoflow-dosevitaminKdoesnotappeartoconferresistancetore-anticoagulationwhenaVKAisresumedaftersurgery.Inthepost-operativeperiod,INRtestingcanbedonetoapprox-imatewhentherapeuticanticoagulationis(orwillbe)attainedand,therefore,whenLMWHorUFHcanbestoppedforpatientswhohavebeenreceivingbridginganticoagulation.Recommendation

2.4PatientRiskStratificationandAssessingNeedforBridgingAnticoagulation

InassessingpatientswhoarereceivingVKAsforthethreeprincipalindications,amechanicalheartvalve,chronicatrialfibrillation,orVTE,periopera-tiveanticoagulantmanagement(andneedforbridg-ing)willbedriventoalargeextentbypatients’riskfordevelopingthromboembolism,eitherarterialorvenous,intheperioperativeperiod.Inthissection,wehaveattemptedtoprovideareasonable,thoughlargelyempiric,stratificationofpatientsaccordingtotheirriskforthromboembolism(high,moderate,low)whileacknowledgingthatcomparativedataonrisksforperioperativethromboembolismfortheproposedriskstrataarelimited.Thisriskstratifica-tionschememaybecombinedwithindividualpa-tientfactors,whichmayincludepriorthromboem-bolismduringVKAinterruptionorapriorembolicstroke,todeterminetheoverallriskforthromboem-bolism(andneedforbridging).

2.4.1PatientsWithaMechanicalProstheticHeartValve

RiskStratification:Patientswithmechanicalheartvalvesareatincreasedriskforarterialthromboem-bolism,whichincludesstroke,systemicembolism,andvalvularorintracardiacthrombosis.Riskstrati-ficationforpatientswithamechanicalheartvalveisbasedonstudiesthathaveassessedtheriskforarterialthromboembolismduringanticoagulantther-apyandonolderstudiesthatassessedthromboem-308S

bolicriskwhilepatientswerereceivingeithernoantithrombotictherapyortreatmentthatiscurrentlyconsideredsuboptimal.51–53Whatislacking,how-ever,areestimatesoftheriskforthromboembolisminpatientswhohavemodern(bileaflet)prosthesesandhavenotreceivedantithrombotictherapyoveranextendedtimeperiod.Astrialsthatincludesuchpatientsarelackingandareunlikelytobeper-formed,clinicianscanusetheriskclassificationproposedhereasageneralguideforpatientman-agement.

Patientsathighriskforarterialthromboembolism(Ͼ10%/yr)mayincludethosewithoneormoreofthefollowing:(1)amitralvalveprosthesis;(2)anolder-generation(caged-ballortiltingdisk)aorticvalveprosthesis;and(3)arecent(within6months)strokeortransientischemicattack.Patientsatmod-erateriskforthromboembolism(4to10%/yr)mayincludethosewithabileafletaorticvalveprosthesisandoneofthefollowing:(1)atrialfibrillation;(2)priorstrokeortransientischemicattack;and(3)otherstrokeriskfactors(hypertension,diabetes,congestiveheartfailure,ageϾ75years).Patientsatlowriskforthromboembolism(Ͻ4%/yr)mayin-cludethosewithabileafletaorticvalveprosthesiswithoutatrialfibrillationandwhodonothaveotherriskfactorsforstroke.

AssessingNeedforBridgingAnticoagulation:In14prospectivecohortstudies,bridginganticoagula-tionwasassessedinapproximately1,300patientswithamechanicalheartvalve.7,21,22,40,54–AsshowninTable3,investigatorsstudiedpredominantlyther-apeutic-doseLMWHregimens,althoughtwostudiesinvolvingatotalof118patientsalsoassessedlow-doseLMWHregimens.54,Theissueofwhetheralow-doseanticoagulantregimenisefficaciousforthepreventionofarterialthromboembolisminpatientswithamechanicalheartvalve,asitisforpreventingVTE,65cannotbedefinitivelyaddressedbasedonthelimitedavailableevidence.Itisprobablethatamoreintense,therapeutic-dose,anticoagulantregimenwouldberequiredtopreventvalvethrombosisandvalve-relatedsystemicembolismduringVKAinter-ruptionand,untilfurtherevidencetothecontrarybecomesavailable,isthepreferredregimen.Theoverallcruderiskforperioperativearterialthrombo-embolismwas0.83%(95%CI:0.43–1.5).Therewerenoreportedepisodesofmechanicalvalvethrombosis.Theinterpretationofthisfindingislimitedbecausetherearenostudies,toourknowledge,assessingtheriskforarterialthromboembolismin(acomparatorgroupof)patientswithamechanicalheartvalvewhohaveVKAinterruptionforsurgerybutdonotreceivebridginganticoagulation.

Mathematicalmodelingcanbeusedtoestimate

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Table3—NonrandomizedProspectiveCohortStudiesAssessingBridgingAnticoagulationAfterInterruptionofVKATherapy:ClinicalDescriptionandResults(Section2.4)ClinicalOutcomes,%www.chestjournal.org

PatientsStudy/yrNotspecified1mo00000No.IndicationforVKATherapyNo.andTypeofProcedureBridgingAnticoagulationRegimenFollow-upAfterProcedureNotapplicableNotapplicableArterialThromboembolisminPatientsWithRecurrentVTEMechanicalHeartValve/inPatientsArterialThromboembolismWithVTEDeath00MajorBleed21Katholietal7/197825surgical21nonsurgical10surgicalUFH:intermittentorcontinuousinfusionEnoxaparin:1mg/kgbid235Spandorferetal60/199920GallaandFuhs54/2000Enoxaparin:30mgbid1mo3mo1mo010000103mo088Notapplicable0323Notapplicable001000000Nutescuetal237/2001*Tinmouthetal61/200118surgical7nonsurgical9surgical17nonsurgicalDalteparin:100IU/kgbidDalteparin:200IU/kgqd24Wilsonetal62/200115surgical32nonsurgicalDalteparin:200IU/kgqdor120IU/kgbid(5,000IUqdin9patients)47Notspecified0Ferreiraetal56/200353surgical29nonsurgical82Mechanicalheartvalve(typenotspecified)12mechanicalheartvalve(10aortic,2mitral)4atrialfibrillation4VTE88mechanicalheartvalve(27aortic,50mitral,9aorticϩmitral,2tricuspid)21ischemicstrokeϩhypercoagulablestate12mechanicalheartvalve(7aortic,5mitral);6atrialfibrillation;6VTE7mechanicalheartvalve(typenotspecified)11atrialfibrillation26VTE3other(cardiomyopathy)82mechanicalheartvalve(43aortic,39mitral)NotapplicableNotavailable1Downloaded from chestjournal.chestpubs.org at Charlesworth on April 22, 2011

Notspecified2(1/1)000.5mo131mo00Baudoetal72/2007411107Douketisetal21/2004†650Notapplicable46CHEST/133/6/JUNE,2008SUPPLEMENT

Hammerstingletal58/2007116Enoxaparin:1mg/kgbid(doseadjustedforrenalimpairment)344mechanicalheartvalveoratrial77surgicalVarioustherapeutic-fibrillation334nonsurgicaldose(22%)or67VTEprophylactic-dose(78%)regimens134mechanicalheartvalve(52251surgicalDalteparin:100IU/kgaortic,52mitral,30aorticϩ399nonsurgicalbidmitral)416atrialfibrillationMechanicalheartvalve(76aortic46surgicalEnoxaparin:1mg/kgvalve,31mitralvalve,9aortic70nonsurgicalqdorbidandmitralvalves)01309S

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Table3—ContinuedClinicalOutcomes,%PatientsStudy/yr3mo11No.IndicationforVKATherapyNo.andTypeofProcedureBridgingAnticoagulationRegimenFollow-upAfterProcedureArterialThromboembolisminPatientsWithMechanicalRecurrentVTEHeartValve/ArterialinPatientsThromboembolismWithVTENotapplicableDeath0MajorBleed15Kovacsetal22/2004‡224112mechanicalheartvalve(typenotspecified)112atrialfibrillationConstansetal/20073mo98000000TurpieandDouketis40/2004§1mo2203mo0Notapplicable38Jafferetal57/20066900002Spyropoulosetal55/20069011mo8࿣2࿣631Dunnetal39/20062601mo4030112086Downloaded from chestjournal.chestpubs.org at Charlesworth on April 22, 2011

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Malatoetal63/200622867surgicalDalteparin:200IU/kg157nonsurgicalqd(5,000IUpostoperativein35patientsathighriskforbleeding)30mechanicalheartvalve(14aortic,98nonsurgicalBemiparin:3,500IU16mitral)qd56atrialfibrillationorarterialdisease12VTE220mechanicalheartvalve(165NotspecifiedEnoxaparin:1mg/kgaortic,51mitral,5aorticϩbidmitral)20mechanicalheartvalve18surgicalEnoxaparin:1mg/kg27atrialfibrillation47nonsurgicalbid(30mgbid18VTEpostoperativeafter4otherarterialindicationssurgicalprocedures)246mechanicalheartvalve394surgicalTherapeutic-dose349atrialfibrillation507nonsurgical(75%)and230VTEprophylactic-dose76otherarterialindications(25%)UFHorLMWHregimens176atrialfibrillation105surgicalEnoxaparin:1.5mg/kg81VTE145nonsurgicalqd53mechanicalheartvalve101surgicalTherapeutic-dose139atrialfibrillation127nonsurgical(40%)or26VTEprophylactic-dose10otherarterialindications(60%)LMWHregimens*Bridgingepisodesin21patients.†110patientsconsideredhighriskforpostoperativebleedingdidnotreceivepostoperativeLMWH.‡FivepatientshadintraoperativeorpostoperativemyocardialinfarctionbutwerenotincludedinTable3tofacilitateacross-studycomparisons,asotherstudiesdidnotdocumentperioperativemyocardialischemicoutcomes.§FortypatientsconsideredhighriskforpostoperativebleedingdidnotreceivepostoperativeLMWH.ʈPatientgroup(accordingtoindicationforVKA)thatoutcomeeventsoccurredinnotspecified.¶311bridgingepisodesin268patients.Table3—Continued55mechanicalheartvalve(29aortic,65surgicalTherapeutic-dose246nonsurgicalLMWHorUFHin26mitral)62%ofmechanical124atrialfibrillationheartvalve,47%of50LVdysfunctionatrialfibrillation,59VTEand55%ofleft23other(notspecified)ventriculardysfunctionBridgingAnticoagulationRegimentheperioperativeriskofarterialthromboembolismifbridginganticoagulationisnotgivenbasedontheproratedfractionoftheannualriskofthisout-come.66Thus,theriskofthromboembolisminapatientwithmechanical(mitraloraortic)heartvalvewhoisnottreatedwithaVKAisestimatedat0.046%/d(ie,17%annualrisk67Ϭ365)orϳ0.4%for8dayswhenpatientsarenottherapeuticallyanticoagulatedduringVKAinterruption.Thefindingofahigherrateofperioperativethromboembolisminstudiesofbridginganticoagulationcomparedtothatderivedfrommathe-maticalmodelingsuggeststhattheriskforthrombo-embolismishigherthanexpected.Whatremainsuncleariswhethertheadministrationofbridginganticoagulationdecreasesthisratefurtherthanthatwhichwouldbeobservedifbridginghadnotbeenadministeredorwhetherbridgingtherapyhasnoeffectontheperioperativeriskforarterialthromboembolism.Thisissuecanonlybead-dressedthroughrandomizedtrialscomparingabridgingvsnobridgingstrategyinpatientswithamechanicalheartvalve,whichposeschallengesintermsoffeasibility.Inthemeantime,cliniciansshouldconsiderbridginganticoagulationinpa-tientswithamechanicalprostheticheartvalvewhoareathighormoderateriskforarterialthromboembolism(ie,strokeorvalvethrombosis).2.4.2PatientsWithChronicAtrialFibrillationRiskStratification:Riskstratificationinpatientswithchronicatrialfibrillationisbasedonplacebo-controlledrandomizedtrialsthatassesseddifferentantithromboticstrategiesinpatientswithnonvalvu-laratrialfibrillation.68Patientswithrheumaticval-vularheartdiseasewerenotincludedinthesetrialsbutareconsideredtobeathighriskforstroke.Bridginganticoagulationshouldbeconsideredinselectedpatientswithchronicatrialfibrillationwhoareathighormoderateriskforarterialthromboem-bolism(ie,strokeorsystemicembolism).3,69–71Clinicalpredictionrules,suchastheCongestiveHeartFailure-Hypertension-Age-Diabetes-Stroke(CHADS2)score,mayhelptostratifypatientswithnonvalvularatrialfibrillationaccordingtotheirriskforstroke.70Anadministrativelinkeddatabasestudy4suggestedthattheCHADS2scorecouldbeappliedtotheperioperativesettingtoestimatestrokeriskinpa-tientswithchronicatrialfibrillationwhowereun-dergoingsurgery.Thescorerangesfrom0to6andisbasedonthewhetheranyoffiveriskfactorsarepresent:congestiveheartfailure,hypertension,dia-betes,ageϾ75years(1pointeach);andpriorstrokeortransientischemicattack(2points).Patientsathighriskforarterialthromboembolism(ie,Ͼ10%riskperyear)mayincludethosewithoneormoreof

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MajorBleedDeathArterialThromboembolisminPatientsWithRecurrentVTEMechanicalHeartValve/inPatientsArterialThromboembolismWithVTENo.Study/yrIndicationforVKATherapyNo.andTypeofProcedurePatientsFollow-upAfterProcedureClinicalOutcomes,%Halbritteretal81/2007¶3111347www.chestjournal.org311S

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thefollowing:(1)CHADS2scoreof5or6;(2)arecent(within3months)strokeortransientischemicattack;or(3)rheumaticvalvularheartdisease.Pa-tientsatmoderateriskforthromboembolism(ie,5to10%riskperyear)includethosewithaCHADS2scoreof3or4,whereaspatientsatlowriskforthromboembolism(ie,Ͻ5%riskperyear)includethosewithaCHADS2scoreof0to2whohavenothadapriorstrokeortransientischemicattack.AssessingNeedforBridgingAnticoagulation:In10prospectivecohortstudies,bridginganti-coagulationhasbeenassessedinapproximately1,400patientswithchronicatrialfibrilla-tion.21,22,39,55,57,58,60–AsoutlinedinTable3,inves-tigatorsstudiedpredominantlytherapeutic-doseLMWHregimens,althoughlow-doseLMWHregi-menswerealsoassessedin4studiesinvolvingap-proximately300patients(exactnumbernotdiscern-ablefrompublisheddata).56,63,,72Asinpatientswithamechanicalheartvalve,theissueofwhetherlow-doseanticoagulantregimensareefficacioustopreventarterialthromboembolismisalsopertinenttopatientswithatrialfibrillation.Similartopatientswithamechanicalheartvalve,thereisinadequatedatatoformulatedefinitiveconclusions.Itisproba-blethatamoreintense,therapeutic-dose,anticoag-ulationregimenismoreefficacioustopreventem-bolicstrokeandsystemicembolismthanalow-doseregimenand,untilevidencetothecontraryisavail-able,itisthepreferredmanagement.Theoverallcruderiskforperioperativearterialthromboembo-lisminpatientswhoreceivedbridginganticoagula-tionwas0.57%(95%CI:0.26–1.1).Instudiesthatdescribedtheclinicalcharacteristicsofsuchpatients,mostpatientshadatleastoneadditionalriskfactorforstroke(ie,priorstroke,ventriculardysfunction,hypertension,diabetes,ageϾ75years).

Thereareemergingdataassessingtheriskforarterialthromboembolisminpatientswithatrialfibrillationwhodonotreceivebridginganticoag-ulation.Inacommunity-basedprospectivecohortstudy(AnticoagulationConsortiumtoImproveOutcomesNationally[ACTION])involvingpa-tientswhowerereceivingaVKA,726patientswithatrialfibrillationhadtemporaryinterruptionofaVKAanddidnotreceivebridging.73Four(0.6%)patientsdevelopedarterialthromboembolism(2strokes,1transientischemicattack,1systemicembolism)duringa1-monthfollow-upperiodaftersurgery.Inaretrospectivecohortstudyassessing690patients(ϳ90%withatrialfibrilla-tion)whorequiredtemporaryinterruptionofVKAtherapypriortoGIendoscopy,therewere11(1.6%)patientswhodevelopedastrokewithin1monthoftheprocedure(A.Jaffer,submittedfor

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publication).Anotherstudyexaminedalinkedadministrativedatabaseofpatientsdischargedfromhospitalaftersurgeryoraninvasiveproce-durebetween1996and2001,duringatimeperiodwhenbridgingwasnotroutinelygiven.4Inthisstudy,the30-dayincidenceofpostoperativestrokeinpatientswithatrialfibrillationwas1.3%,whichwasmorethanfourfoldhigherthaninpatientswithoutatrialfibrillation(OR,4.6;95%CI:4.2–5.0).Takentogether,thesestudiessuggestthatinpatientswithatrialfibrillationwhoundergosur-geryanddonotreceivebridginganticoagulation,theriskforperioperativearterialthromboembo-lism,consistingofstrokeandtransientischemicattack,isapproximately1%.Furthermore,basedonanaverageannualriskofstrokeof5%(0.013%/dorϳ0.1%during8daysofVKAinter-ruption),thesestudiessuggestthattheriskforarterialthromboembolismintheperioperativeperiodwithoutbridgingishigherthanthatpre-dictedbasedonmathematicalmodeling.742.4.3PatientsWithPriorVTE

RiskStratification:Comparedtopatientswithatrialfibrillationoramechanicalheartvalve,thereareseveraldistinctionsintheassessmentofVKAinterruptionandneedforbridginganticoagulationinpatientswithpriorVTE(ie,deepveinthrom-bosis,pulmonaryembolism).Whereasthefirsttwogroupsareatriskforstrokeandotherarterialthromboembolism,patientswithVTEareatriskforrecurrentdeepveinthrombosisorpulmonaryembolism.Theconsequencesoftheseoutcomesdiffermarkedly.Embolicstrokeisfatalorassoci-atedwithsignificantneurologicdeficitin70%ofpatients.11,12Ontheotherhand,recurrentVTEisfatalinapproximately4to9%ofpatientsandisassociatedwithlessmorbidity.75,76Inaddition,thoughlow-doseanticoagulationhasnotbeenproventodecreasetheriskofarterialthrombo-embolicevents,ithasbeenshowninnonbridgingtrialstodecreasetheriskofpostoperativeVTE.65Thus,althoughthereisalesserroleforlow-doseLMWHorUFHforpatientswithatrialfibrillationormechanicalheartvalves,thereisastrongerrationaleforusingthesemedicationsasbridgingtherapyforpatientswithpriorVTE.

RiskstratificationinpatientswithVTEisbasedonanassessmentoftheriskforrecurrentVTEafterthestartoftreatment,77andriskfactorsforrecurrentdiseaseafteranticoagulanttherapyhasbeenstopped.78,79Patientsathighriskforrecur-rentdiseasemayincludethosewith:(1)recent(within3months)VTE;or(2)severethrombo-philicconditions(deficiencyofproteinC,protein

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Sorantithrombin,antiphospholipidantibodies,ormultiplethromobophilicabnormalities).PatientswhohavehadpriorVTEaftersurgerymightbeconsideredhighriskdependingonthetypeofsurgerytheyareundergoing(andtheassociatedthromboembolicrisk)andperioperativeanti-thromboticmanagementshouldbeindividualized.Riskstratificationislesspreciseinotherpatientsandwouldbepredicatedonindividualizedfactors.PatientsatmoderateriskforrecurrentdiseasemayincludethosewithpriorVTEwithinthepast3to12months,nonseverethrombophilicconditions(heterozygouscarrieroffactorVLeidenmutationorfactorIImutation),recurrentVTE,oractivecancer(treatedwithin6monthsorpalliative).PatientsatlowriskmayincludethoseinwhomVTEoccurredϾ12monthsagoanddonothaveanyoftheabove-mentionedriskfactors.

AssessingNeedforBridgingAnticoagulation:Pro-spectivecohortstudieshaveevaluatedbridgingan-ticoagulationusingtherapeuticandlow-doseregi-mensofvariousLMWHsinapproximately500patientswithpriorVTE39,55,57,59–(Table3).TheoverallcruderiskforrecurrentsymptomaticVTEwas0.60%(95%CI:0.13–1.7).However,theefficacyoflow-doseLMWHorUFHasperioperativeantico-agulationisunknownasdataarelackinginregardtotheriskofrecurrentVTEwithoutbridgingantico-agulation.Recommendation

2.4.InpatientswithamechanicalheartvalveoratrialfibrillationorVTEathighrisk(Table2)forthromboembolism,werecommendbridg-inganticoagulationwiththerapeutic-doseSCLMWHorIVUFHovernobridgingduringtem-poraryinterruptionofVKAtherapy(Grade1C);wesuggesttherapeutic-doseSCLMWHoverIVUFH(Grade2C).InpatientswithamechanicalheartvalveoratrialfibrillationorVTEatmoder-aterisk(Table2)forthromboembolism,wesug-gestbridginganticoagulationwiththerapeutic-doseSCLMWH,therapeutic-doseIVUFH,orlow-doseSCLMWHovernobridgingduringtemporaryinterruptionofVKAtherapy(Grade2C);wesuggesttherapeutic-doseSCLMWHoverothermanagementoptions(Grade2C).InpatientswithamechanicalheartvalveoratrialfibrillationorVTEatlowrisk(Table2)forthromboembo-lism,wesuggestlow-doseSCLMWHornobridg-ingoverbridgingwiththerapeutic-doseSCLMWHorIVUFH(Grade2C).

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Valuesandpreferences:Inpatientsathighormoderateriskforthromboembolism,therecommendationsre-flectarelativelyhighvalueonpreventingthromboem-bolismandarelativelylowvalueisonpreventingbleeding;inpatientsatlowriskforthromboembolism,therecommendationsreflectarelativelyhighvalueonpreventingbleedingandarelativelylowvalueonpreventingthromboembolism.

3.0PerioperativeManagementofPatients

WhoAreReceivingBridging

AnticoagulationInpatientswhorequiretemporaryinterruptionofVKAsandaretoreceivebridginganticoagula-tion,severaltreatmentregimenshavebeenas-sessed21,22,39,40,56,57,80,81andaresummarizedinTable3.Intotal,Ͼ4,000patientswhohadtemporaryinter-ruptionofaVKAandreceivedbridginganticoagulationhavebeenstudiedtodate,ofwhomapproximately72%receivedtherapeutic-doseLMWH,approximately20%receivedlow-doseLMWH,andapproximately8%receivedtherapeutic-doseUFH.

3.1PerioperativeAnticoagulationTreatmentRegimens

3.1.1Therapeutic-DoseUFH

Therapeutic-doseIVUFHhadbeenthemostcom-monlyusedbridgingregimen7,82,83butitsusehasdeclinedinrecentyears,84,85likelybecauseoftheincreasedinconvenienceofIVdrugadministrationandtheincreaseinthenumberofsurgicalproceduresthatarebeingdonewithouthospitalization.86Instudiesthatassessedbridginganticoagulationwiththerapeutic-doseUFH,adose-adjustedIVinfusionwasused,administeredtoachieveatargetactivatedpartialthromboplastintime(APTT)of1.5to2.0timesthecontrolAPTTvalue,withtheinfusionstoppedapprox-imately4hbeforesurgeryandresumedduringtheinitial24haftersurgery.7,83AnemergingalternativetoIVUFHisSCUFH,whichisadministeredasafixed,weight-baseddoseregimen(250IU/kgbid)withoutAPTTmonitoringandhasshowntobeefficaciousandsafeforthetreatmentofacuteVTE.87Theuseoffixed-doseSCUFHmayprovideapracticalalternativetoIVUFHforbridginganticoagulation,thoughithasonlybeenassessedinasmallnumberofpatientswhorequiredtemporaryinterruptionofwarfarinforsurgery.553.1.2Therapeutic-DoseLMWH

Clinicianshave,inrecentyears,increasinglyturnedtotherapeutic-doseSCLMWHinlieuofUFHasbridginganticoagulation,84,85likelybecause

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itcanbeeasilyadministeredoutsideofhospitalandwithoutlaboratorymonitoring.36Thereisnostan-dardizedbridgingregimenwithLMWH,andseveraltherapeutic-doseregimenshavebeenstudied:dalte-parin200IU/kgqd;enoxaparin1.5mg/kgqd;tinza-parin175IU/kgqd;dalteparin100IU/kgbid;andenoxaparin1mg/kgbid.21,22,39,80Inthepostoperativeperiod,theuseoftherapeutic-doseLMWHadministeredcanvary.The3principalmanagementapproachesthathavebeenstudiedare:(1)toadministertherapeutic-doseLMWHwithinafixedtimeperiodafteraprocedure(withininitial24h);(2)toadministertherapeutic-doseLMWHwithinavariedtimeperiodafteraprocedure(24to72h),withtheinitiationdependingontheprocedure-relatedbleedingriskandtheadequacyofpostopera-tivehemostasis;and(3)toreplacetherapeutic-doseLMWHwithlow-doseLMWHinselectpatientswhoareundergoingaprocedureassociatedwithahighbleedingrisk.

3.1.3Low-DoseLMWHorUFH

Low-doseUFH(eg,UFH,5,000IUbid)orlow-doseLMWH(eg,enoxaparin,30mgbid,dalte-parin,5,000IUqd),whichistypicallyusedforthepreventionofdeepveinthrombosisinat-risksurgicalandmedicalpatients,providesanotherbridgingan-ticoagulationtreatmentoption.65Thisapproachforperioperativeanticoagulationhasnotbeenaswidelystudiedastherapeutic-doseregimensandhasbeenassessedmainlyinlower-riskpatientswithatrialfibrillationorthosewithpriorVTE.Thoughthisanticoagulantregimenhasbeenusedwiththepre-sumedintentofprovidingsomeantithromboticeffi-cacybutatalowerriskforperioperativebleeding,dataareverylimitedinregardtotheefficacyoflow-doseUFHorLMWHtopreventarterialthrom-boembolisminpatientswithamechanicalheartvalveorchronicatrialfibrillation.54,63,,72IndirectevidencefromnonsurgicalclinicalsettingsinvolvingpatientswithatrialfibrillationwhoreceivedVKAsindicatesthat,comparedtopatientswhowerether-apeuticallyanticoagulated,patientswhohadsub-therapeuticanticoagulation(INRϽ2.0)weremorelikelytodevelopastrokeandsuchstrokesweremoresevereandassociatedwithgreatermortality.88–90Although,toourknowledge,therehavebeennostudiesthathaveassessedtheefficacyoflow-doseLWMHorUFHtopreventarterialthromboembo-lism,arecenttrialinvolvingpatientswithchronicatrialfibrillationfoundthattreatmentwithidrapa-rinux,asyntheticanti-Xainhibitor,whenadminis-teredinatherapeutic-doseregimenwasaseffica-ciousasVKAtherapy(INRrange2.0to3.0)forthepreventionofstrokeandsystemicembolism.91This

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findingsupportsthepremisethatadministrationofatherapeutic-doseregimenofanon-VKAanticoagu-lantwithpropertiessimilartoLMWHsisefficaciousforthepreventionofarterialthromboembolism.Low-doseLMWHorUFHmaybeincorporatedintoaperioperativeanticoagulationregimenintwopossibleclinicalscenarios.Thefirstisasa“stand-alone”regimeninpatientswithpriorVTEwhoarereceivingVKAtherapyandareatmoderateorlowriskforrecurrentdiseaseinwhomatherapeutic-doseanticoagulationregimenmaynotbeconsid-ered.Insuchpatients,alow-doseLMWHorUFHregimencouldbeusedduringinterruptionofaVKAwiththeintentofpreventingrecurrentvenous(butnotarterial)thromboembolism.Therationaleforthisapproachisbasedontheestablishedefficacyoflow-doseLMWHorUFHtopreventpostoperativeVTE.65ThesecondscenarioisinpatientswithanyclinicalindicationforVKAtherapywhoareunder-goingsurgerythatisassociatedwithahighriskforbleeding(eg,cardiac,neurosurgical,urologic,majororthopedic).Insuchpatients,administrationoftherapeutic-doseLMWHorUFHduringtheinitial48to72haftersurgery(orfortheentirepostoper-ativeperiod)mayconferanunacceptablyhighriskforbleedingcomplicationsandalessintenseantico-agulantregimenconsistingoflow-doseSCLMWHorUFHislikelytoconferalowerriskforpostoper-ativebleeding.Thus,inaregistryinvolving1,077patientswhoreceivedbridginganticoagulation,post-operativelow-doseLMWHorUFHwasassociatedwithalowerriskforminorbleedingcomparedtobridginganticoagulationwiththerapeutic-doseLMWHorUFH(ORϭ0.46;CI:0.20–1.01).80However,thisregistrywasunderpoweredtodetectpotentialdifferencesinmajorbleedingwithlow-doseortherapeutic-doseanticoagulation.

Toourknowledge,noprospectivetrialshavecomparedlow-doseandtherapeutic-doseLMWHorUFHasbridginganticoagulationtoassessbothefficacy,intermsofpreventingarterialthromboem-bolism,andsafety,intermsofassociatedbleedingrisk.Althoughitisplausiblethatlow-doseLMWHorUFHwillconferalowerriskforbleedingcomplica-tions,onecannotexcludethepossibilitythatsuchtreatmentwillbelesseffectiveinpreventingarterialthromboembolismthanatherapeutic-doseregimen.Thisissuecanonlyberesolvedthroughwell-designedrandomizedtrialsassessingdifferentbridg-inganticoagulationstrategies.

3.1.4CostsofBridgingAnticoagulationTreatmentRegimens

Recentstudieshavecomparedthecostsofbridg-inganticoagulationbeforeandaftersurgerywith

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in-hospitaladministeredIVUFHandout-of-hospitalbridginganticoagulationSCLMWH.92–95Inapro-spectivecohortstudyassessingperioperativeantico-agulationwithpatient-administeredSCLMWH,nurse-administeredSCLWMH,andin-hospitalad-ministeredIVUFH,theanticoagulant-relatedcostsforpatientsundergoinganovernightsurgicalproce-durewereestimatedat$672,$933,and$3,916(allUSD),respectively.93Anothercohortstudycompar-ingcostsin26patientswhoreceivedin-hospitalIVUFHand40patientswhoreceivedout-of-hospitalSCLMWHandunderwentelectivesurgeryfoundasignificantlylowermeantotalhealth-carecost(by$13,114USD)inpatientswhoreceivedperiopera-tiveLMWH.94InadecisionanalysisstudyinvolvingpatientswhorequiredVKAinterruptionforGIendoscopy,similarfindingswerefoundintermsoflowercostsassociatedwithout-of-hospitaluseofLMWHasbridginganticoagulation.96Takento-gether,thesefindingsindicatethat,comparedtoin-patientadministrationofIVUFH,thereiscon-siderablecostsavingswiththeuseofSCLMWHs,whichcanbeadministeredinanoutpatientsetting,typicallybythepatientorbyanotherhealth-careprovider.92–95AdditionalstudiesareneededtoassessthefeasibilityandcostsofunmonitoredSCUFHasbridginganticoagulationforpatientsinwhomLMWHmaybecontraindicated,suchasthosewithsevererenalinsufficiencyorinwhomLMWHsmaybeunavailableortoocostly.87Recommendation

3.1.Inpatientswhorequiretemporaryinter-ruptionofVKAsandaretoreceivebridginganticoagulation,fromacostcontainmentper-spectivewerecommendtheuseofSCLMWHadministeredinanoutpatientsettingwherefeasibleinsteadofinpatientadministrationofIVUFH(Grade1C).

BridginganticoagulationwithIVUFH,whichhasahalf-lifeofapproximately45min,canbeinter-rupted4hbeforeplannedsurgery,atimeintervalthatapproximates5eliminationhalf-livesofUFH,36www.chestjournal.org

andisinaccordancewiththepracticeusedinbridginganticoagulationstudies.7,55InpatientswhoarereceivingbridginganticoagulationwithSCLMWHs,whichhaveeliminationhalf-livesof4to5h,36thelastdoseshouldbeadministered20to25hbeforesurgery(oronthemorningofthedaybeforesurgery),atimeintervalthatapproximates5elimi-nationhalf-livesofLMWHs.36Thereisevidencesuggestingthattherewillbearesidualanticoagulanteffectiftherapeutic-doseLMWHisgiventooclosetothetimeoftheprocedure.Thus,inaprospectivecohortstudyinvolving73patientswhoreceivedtherapeutic-doseorlow-doseLMWHasbridginganticoagulation,30%(11of37)ofpatientswhoreceivedtherapeutic-doseLMWH(qdorbiddoseregimens)hadaresidualanticoagulanteffect(de-finedasananti-factorXaՆ0.10IU/mL)atthetimeofsurgerywhereasϽ1%(1of36)ofpatientswhoreceivedlow-doseLMWHhadaresidualanticoag-ulanteffectatsurgery.97Inanotherprospectivecohortstudyof98patientswhoreceivedbridginganticoagulationwithenoxaparin1mg/kgbid,withthelastdosegivenontheeveningbeforesurgery,adetectableresidualanticoagulanteffect(anti-factorXaՆ0.10IU/mL)wasfoundin100%(98of98)ofpatients.98Furthermore,34%ofpatientshadananticoagulanteffectatthetimeofsurgerythatisconsideredwithinthetherapeuticrange(anti-factorXaՆ0.50IU/mL).Althoughtherewerenomajorbleedsinthepatientsfrombothofthesestudies,mostpatientsunderwentlowbleedingriskproce-duresandthepotentialforbleedinginpatientshavingmajorsurgicalorotherhigher-riskinvasiveprocedurescannotbeexcluded.Takentogether,thesefindingssuggestthatthelastpreoperativedoseoftherapeutic-doseLMWHbeforesurgeryshouldbereducedtominimizetheriskforaresidualanticoagulanteffectatthetimeofsur-gery.Untilprospectivetrialsaddressthisissuefurther,onemanagementoption,especiallyinpatientswhoareundergoingmajorsurgeryorarereceivingspinal/epiduralanesthesia,istoadminis-teronlythemorningdoseofLMWHinpatientsreceivingatwice-dailytherapeutic-doseregimenandtoreduceby50%thetotaldoseofLMWHgiveninpatientswhoarereceivingaonce-dailytherapeutic-doseregimen.Recommendation

3.2.Inpatientswhoarereceivingbridginganticoagulationwiththerapeutic-doseSCLMWH,werecommendadministeringthelastdoseofLMWH24hbeforesurgeryoraprocedureoveradministeringLMWHclosertosurgery(Grade1C);forthelastpreoperativedoseof

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LMWH,werecommendadministeringap-proximatelyhalfthetotaldailydoseinsteadof100%ofthetotaldailydose(Grade1C).Inpatientswhoarereceivingbridginganticoag-ulationwiththerapeutic-doseIVUFH,werecommendstoppingUFHapproximately4hbeforesurgeryoverstoppingUFHclosertosurgery(Grade1C).

3.3ResumptionofBridgingAnticoagulationAfterSurgery

Followingparenteraladministration,LMWHsin-ducearapidanticoagulanteffect,withthepotentialforadetectableanticoagulanteffecttooccurwithin1handapeakanticoagulanteffecttooccurwithin3to5hafteradministration.36WithUFH,thoughthetimetoapeakanticoagulanteffectvaries,thereisthepotentialforthistoalsooccurwithin3to5hfollowinganIVbolusandinfusion.36Consequently,cliniciansshouldexercisecautionwhenadminister-ingthesedrugsinpatientswhohaverecentlyhadsurgeryorotherinvasiveproceduresbecauseofthepotentialforbleedingatthesurgicalsite,especiallywhenhemostasisisnotsecured.Threefactorsap-peartoaffecttheriskforsurgery-relatedbleeding:(1)theproximitytosurgerythattheanticoagulantisadministered;(2)thedoseofanticoagulantadminis-tered;and(3)thetypeofsurgeryanditsassociatedbleedingrisk.Asuperimposedconsiderationisthatbleedingcanoccurafteranysurgeryorprocedure,irrespectiveoftheanticipatedsurgery-relatedriskforbleedingandpostoperativeanticoagulantman-agement.Consequently,postoperativeadministra-tionofUFHandLMWHsshouldconsiderboththeanticipatedriskforbleeding,whichisdeterminedpreoperatively,andtheadequacyofsurgicalhemo-stasis,whichisdeterminedpostoperatively.3.3.1ProximitytoSurgeryThatAnticoagulantsAreAdministered

Inapooledanalysisofstudiesinvolvingpatientswhohadmajororthopedicsurgeryandreceivedlow-dosefondaparinux(2.5mg/d)4to8hpostoper-ativelyorlow-doseenoxaparin(40to60mg/d)12to24hpostoperatively,theriskformajorbleedingwassignificantlyhigherinfondaparinux-treatedpatients(2.7%vs1.7%;pϽ0.01).99Inanotherpooledanal-ysisthatcomparedbleedinginpatientswhoreceivedlow-doseLMWHeitherwithin6hor12to24haftermajororthopedicsurgery,theriskforbleedingwashigherinpatientswhoreceivedLMWHclosertosurgery(6.3%[95%CI:5–7]vs2.5%[95%CI:1–3]).100Inpatientswhoreceivedbridginganticoagulation,threeprospectivecohortstudiessuggestthatdelay-ingthepostoperativeinitiationoftherapeutic-dose

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LMWHuntilhemostasisissecuredanddeferring(oravoidingaltogether)postoperativetherapeutic-doseLMWHareassociatedwithalowriskforbleeding.Inonestudyassessing650patientswhounderwentabroadspectrumofsurgicalandnonsurgicalproce-duresandreceivedtherapeutic-dosebridginganti-coagulation,postoperativemanagement,whichin-cludedresumptionoftherapeutic-dosebridgingwithLMWH,dependedontheanticipatedbleedingriskandadequacyofpostoperativehemostasis.21Thus,patientswhohadproceduresassociatedwithalowriskforbleeding(eg,GIendoscopy,cardiaccathe-terization)resumedLMWHapproximately24haftertheprocedure(ie,dayafterprocedure);pa-tientswhohadmajorsurgery(eg,openabdominalsurgery)orinwhomtherewasinadequatepostoper-ativehemostasisresumedLMWH48to72haftersurgery;andpatientswhohadmajorsurgeryassoci-atedwithahighriskforbleeding(eg,cardiac,neurosurgical,urologic,majororthopedic)didnotreceiveanypostoperativeLMWH.Withthisap-proach,theincidenceofmajorbleedingwas1.0%duringthefirstweekaftersurgery,withnofatalbleeds.Inanotherstudyinvolving220patientswithamechanicalheartvalvethatusedthesamepostop-erativeanticoagulantmanagementapproach,thein-cidenceofmajorbleedingwas2.3%duringthefirstweekaftersurgery,withnofatalbleeds.40Anotherprospectivecohortstudyinvolved224patients,inwhomonce-dailytherapeutic-doseLMWHorlow-doseLMWH(inpatientshavingsurgeryassociatedwithahighbleedingrisk)startedonthedayaftersurgeryandadministeredonlyifpostoperativehe-mostasiswassecured.22Theriskforbleedingduringthefirstweekaftersurgeryinpatientswhoreceivedtherapeutic-doseLMWHwas2.9%,withnofatalbleeds.Theriskforarterialthromboembolismwiththeperioperativemanagementapproachusedinthesestudiesislow(Ͻ1%)andisdiscussedfurtherinSection2.4.

3.3.2DoseofAnticoagulantAdministered

Aprospectivemulticenterregistryevaluated493patientswhorequiredinterruptionofaVKAandreceivedbridgingwithLMWHorUFHornobridg-ing(JafferA,submittedforpublication).Afterad-justmentforsurgicalandpatient-specificbleedingriskfactors,theadministrationoftherapeutic-doseLMWHorUFHafterthesurgeryorprocedureconferredagreaterthanfourfoldgreaterriskformajorbleeding(OR,4.4;95%CI:1.5–14.7)com-paredtothepostoperativeadministrationofeitheralow-doseLMWHorUFHregimenornobridging.

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3.3.3TypeofSurgeryandAssociatedBleedingRiskAprospectivebridgingstudy39of260patientsinwhichallpatientsreceivedtherapeutic-doseonce-dailyLMWHperioperatively,withthefirstpostop-erativedoseadministered12to24haftersurgery,categorizedsurgeriesorproceduresasmajor(ex-pecteddurationϾ1h)orminor(expecteddurationՅ1h).Thisstudy39foundthatmajorbleedingoccurredin0.7%(1of148)ofpatientswhohadaninvasiveprocedure,in0%(0of72)ofpatientswhohadminorsurgery,andin20.0%(8of40)ofpatientswhohadmajorsurgery.

Takentogether,thesefindingssuggestthatinpatientswhoreceivebridginganticoagulationwiththerapeutic-doseLMWH,thisregimenshouldbeadministeredcarefullyinthepostoperativeperiod.Itappearsthattherapeutic-doseLMWHcanbesafelyresumedonthedayaftersurgeryinpatientswhohavehadaminorsurgicalorotherinvasiveproce-dureandinwhomthereisadequatehemostasis.Ontheotherhand,administeringtherapeutic-doseLMWHwithin24haftermajorsurgeryappearstoconferanunacceptablyhighriskforbleedingcom-plications.

Inpatientsundergoingmajorsurgeryoraproce-dure(surgicalornonsurgical)associatedwithahighbleedingrisk,managementoptionsthatareprefera-bleoveradministeringtherapeutic-doseSCLMWHorIVUFHincloseproximitytosurgery(ie,within24h)include:(1)delayingtheresumptionoftherapeutic-doseLMWHorUFHfor48to72hafterthesurgery/procedure;(2)administeringonlylow-doseLMWHafterthesurgery/procedure;and(3)avoidingtheuseofLMWHaltogetherinthepostoperativeperiod.Themanagementoptioncho-senisindividualizedandwilldependonboththebleedingriskassociatedwiththesurgicalorotherinvasiveprocedureandtheadequacyofpostopera-tivehemostasis.Forexample,inpatientsundergoingmajorsurgery(eg,bowelresection),itmayberea-sonabletodelaytheresumptionoftherapeutic-doseLMWHorUFH.Inpatientsundergoingasurgery(eg,radicalprostatectomy)orprocedure(eg,kidneybiopsy)associatedwithahighriskforbleeding,itmaybereasonabletonotadministeranyLMWHorUFHaftersurgeryandtosimplyresumeVKAs.Recommendation

3.3.Inpatientsundergoingaminorsurgicalorotherinvasiveprocedureandwhoarereceivingbridginganticoagulationwiththerapeutic-doseLMWH,werecommendresumingthisregi-menapproximately24hafter(eg,thedayafter)theprocedurewhenthereisadequate

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hemostasisoverashorter(eg,<12h)timeinterval(Grade1C).Inpatientsundergoingmajorsurgeryorahighbleedingrisksurgery/procedureandforwhompostoperativetherapeutic-doseLMWH/UFHisplanned,werecommendeitherdelayingtheinitiationoftherapeutic-doseLMWH/UFHfor48to72haftersurgerywhenhemostasisissecured,administer-inglow-doseLMWH/UFHaftersurgerywhenhemostasisissecured,orcompletelyavoidingLMWHorUFHaftersurgeryovertheadminis-trationoftherapeutic-doseLMWH/UFHincloseproximitytosurgery(Grade1C).Werecommendconsideringtheanticipatedbleedingriskandad-equacyofpostoperativehemostasisinindividualpatientstodeterminethetimingofLMWHorUFHresumptionaftersurgeryinsteadofresum-ingLMWHorUFHatafixedtimeaftersurgeryinallpatients(Grade1C).

3.4LaboratoryMonitoringofBridgingAnticoagulation

InpatientswhoarereceivingIVUFHasbridginganticoagulation,clinicianscanusetheAPTTtoguidepreoperativeandpostoperativeanticoagulation.How-ever,useofanUFHdosingnomogram,whichwasnotdesignedforuseintheperioperativesetting,maybemisleading.39,101Forexample,adosingnomo-gramforIVUFHmayresultinexcessiveanticoag-ulation(ie,APTTϾ150s)foruptoa24-hperiodwhiledoseadjustmentsarebeingmade.AlthoughshortperiodsofexcessiveanticoagulationwithUFHmaynotincreasetheriskforbleedinginnonopera-tiveclinicalsettings,102,103suchshortperiodsofover-anticoagulationmightincreasetheriskforbleed-inginapostoperativesetting.

Inpatientswhoarereceivingbridginganticoagu-lationwiththerapeutic-doseLMWH,thereisnoestablishedroleforroutineperioperativemonitoringofanti-factorXalevels,asincertainnonoperativeclinicalsettings.36Inselectedpatientgroups,suchasthosewithsevererenalinsufficiency(ie,calculatedcreatinineclearanceϽ30mL/minorserumcreati-nineϾ178mmol/LorϾ2g/dL)oratextremesofbodyweight,anti-factorXamonitoringmaybecon-sideredtoguidetreatmentasinnonoperativeclinicalsettings.36Recommendation

3.4.InpatientswhoarereceivingbridginganticoagulationwithLMWH,wesuggestagainsttheroutineuseofanti-factorXalevelstomonitortheanticoagulanteffectofLMWHs(Grade2C).

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4.0PerioperativeManagementofPatientsWhoAreReceivingAntiplateletTherapyAnincreasingnumberofpatientsarereceivinganti-plateletdrugsfortheprimaryandsecondarypreven-tionofmyocardialinfarctionorstrokeandforthepreventionofcoronarystentthrombosisafterplace-mentofabaremetalordrugelutingstent.104,105Theperioperativemanagementofthesepatientsisincreas-ingincomplexitybecausethespectrumofriskforacardiovasculareventvarieswidely.Inaddition,thesepatientsmaybereceivingtreatmentwithoneofseveralantiplateletdrugregimens,whichinclude:(1)aspirinalone;(2)clopidogrelalone;(3)aspirincombinedwithclopidogrel;(4)aspirincombinedwithdipyridamole;or(5)cilostozol,eitheraloneorcombinedwitheitheraspirinorclopidogrel.Thissectionwillfocusonpatientswhoarereceivingaspirinand/orclopidogrel.4.1RiskStratification

Patientswhoarereceivingantiplatelettherapyencompassaspectrumofriskforcardiovasculareventsthatdepends,toalargeextent,ontheclinicalindicationforantiplatelettherapyandwhetherpa-tientsarereceivingsuchtreatmentfortheprimaryorsecondarypreventionofcardiovasculardisease.Cli-niciansshouldincorporateriskstratificationindeci-sionsconcerningtemporaryinterruptionorcontinu-ationofantiplatelettherapyintheperioperativeperiod.Therearenoriskclassificationschemes,toourknowledge,thatencompassthespectrumofbenefitfromantiplateletagents.Nonetheless,pa-tientsatlowriskforperioperativecardiovasculareventsinwhomtemporaryinterruptionofantiplate-letdrugswouldnotbeexpectedtoconferasubstan-tialincreasedriskforcardiovasculareventsincludethosewhoarereceivingantiplatelettherapy(typi-callyaspirin)fortheprimarypreventionofmyocar-dialinfarctionorstroke.106Ontheotherhand,patientsathighriskforcardiovasculareventsinwhomitmaybepreferabletocontinueantitplatelettherapyperioperativelyincludethosewhohavehadrecent(within3to6months)placementofabaremetalordrug-elutingcoronarystent,andtoalesserextent,whohavesufferedamyocardialinfarctionwithinthepast3months.107Theriskforcardiovas-culareventsinthesehigh-riskgroupsshouldbeweighedagainsttheriskandclinicalimpactofbleedingwiththeoperationplannedwhenantiplate-letdrugsarecontinuedintheperioperativeperiod.4.2InterruptionofAntiplateletTherapyBeforeSurgery

Forpatientswhoarereceivingaspirin,whichirreversiblyinhibitsplateletfunctionthroughcyclo-318S

oxygenase-1inhibition,cliniciansintendingnoanti-plateleteffectatthetimeofsurgeryshouldinterrupttherapy7to10daysbeforesurgery.108Althoughaspirinhasahalf-lifeof15to20min,itirreversiblyinhibitsplateletcyclooxygenase-1and,therefore,itseffectpersistsfor7to10days,whichapproximatestheplateletlifespan.109,110Consequently,4to5daysafterstoppingaspirinwillresultinapproximately50%ofplateletshavingnormalfunction,whereas7to10daysafterstoppingaspirinwillresultinϾ90%ofplateletshavingnormalfunction.Inpatientswhoarereceivingclopidogrel,athienopyridinederivativethatirreversiblyinhibitsadenosinediphosphatere-ceptor-mediatedplateletactivationandaggregationandhasahalf-lifeof8h,treatmentshouldbeinterrupted7to10daysbeforesurgerysinceittakesaboutthatmanydaystoreplacetheplateletpool.111Thisapproachalsoappliestoticlopidine,anotherthienopyridinederivativewhichisusedlessfre-quentlycomparedtoclopidogrel,inpartbecauseofanincreasedriskfordrug-inducedadverseeffectssuchasneutropenia.112,113Anotherantiplateletagentthatisusedincombi-nationwithaspirinisdipyridamole,apyrimidopyri-midinederivativewithantiplateletandvasodilatorpropertiesthatisindicatedforsecondarystrokepreventioninpatientswithcerebrovasculardis-ease.114Dipyridamolehasreversibleeffectsonplate-letfunctionandhasaneliminationhalf-lifeofap-proximately10h.115However,sincedipyridamoleiscombinedwithaspirin(200mgdipyridamoleϩ25mgaspirin),thisdrugwouldneedtobeinterrupted7to10daysbeforeelectivesurgerytoallowelimi-nationoftheantiplateleteffectsofbothdrugs.

Cilostazolisaphosphodiesteraseinhibitorwithantiplateletandvasodilatorypropertiesthatrevers-iblyaffectsplateletfunctionthroughcyclicadeno-sinemonophosphate(cAMP)mediatedinhibitionofplateletactivationandaggregation.Cilostazolmaybeusedinpatientswithcoronaryarterydisease,typi-callyiftheyhaveacoronarystent116orperipheralarterialdisease.117Thepharmacokineticsofcilosta-zolaredose-dependent,withaneliminationhalf-lifeofapproximately10h.118Consequently,thisdrugwouldneedtobeinterrupted2to3days(corre-spondingto5eliminationhalf-livesofcilostazol)beforesurgerytoensureeliminationofitsantiplate-leteffectatthetimeofsurgery.

Forpatientswhoarereceivinganonselectivenonsteroidalantiinflammatorydrug(NSAID)oracyclyooxygenase-2selectiveNSAID(ie,celecoxib),thereisreversibleinhibitionofplatelet-mediatedcyclooxygenaseactivity.Toensurethereisnoresid-ualantiplateleteffectatthetimeofsurgery,theNSAIDshouldbestoppedatatimethatcorrespondsto5eliminationhalf-livesforthatdrug.119,120For

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NSAIDswithashort,2to6h,half-life(eg,ibupro-fen,diclofenac,ketoprofen,indomethacin),thesedrugsshouldbestoppedonthedaybeforesurgery.ForNSAIDswithanintermediate,7to15h,half-life(eg,naproxen,sulindac,diflunisal,celecoxib),suchtreatmentshouldbestopped2to3daysbeforesurgery.Finally,forNSAIDswithalong,Ͼ20hhalf-life(eg,meloxicam,nabumetone,piroxicam),thesedrugsshouldbestopped10daysbeforesurgery.Recommendation

4.3ResumptionofAntiplateletTherapyAfterSurgery

Inpatientswhohavetemporaryinterruptionofantiplateletdrugsbeforesurgery,theseagentsshould,ingeneral,beresumedassoonasthereisadequatepostoperativehemostasisaftersurgery.Fourstudiesassessedbridginganticoagulationinpatientswithamechanicalheartvalve,someofwhomwerereceivingbothVKAsandaspirin.21,22,40,55Inthesestudies,aspirinwasresumedonthesamedayasVKAs,startingwiththeusualmaintenancedoseof81mgdaily.Dataarelackinginregardtotheresumptionofclopidogrelorotherantiplateletdrugsaftersurgery.Oneissuethatwarrantsconsiderationiswhetherresumptionoftreatmentshouldbewithamainte-nancedoseofclopidogrel(75mg/d),whichachievesmaximalplateletfunctioninhibition5to10daysafteritsadministration,121–123orwithaloadingdose(300to600mg/d),whichachievesmaximalplateletfunctioninhibitionwithin2to15hafteradministra-tion.124–126Thedoseofclopidogrelresumptionwilldependlargelyonwhetherapatienthasacoronarystent,thetypeofstentimplanted,andhowrecentlythestentwasimplanted.Recommendation

4.3.Inpatientswhohavehadtemporaryinterrup-tionofaspirintherapybecauseofsurgeryoraprocedure,wesuggestresumingaspirinapproxi-mately24h(orthenextmorning)aftersurgerywhenthereisadequatehemostasisinsteadofresumingaspirinclosertosurgery(Grade2C).Inpatientswhohavehadtemporaryinterruptionofclopidogrelbecauseofsurgeryoraprocedure,

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wesuggestresumingclopidogrelapproximately24h(orthenextmorning)aftersurgerywhenthereisadequatehemostasisinsteadofresumingclopidogrelclosertosurgery(Grade2C).4.4LaboratoryMonitoringofAntiplateletTherapyPlateletfunctionassaysareavailabletomeasuretheantiplateletactivityofaspirin,clopidogreland,potentially,otherantiplateletdrugs,priortosur-gery.127However,thesemethodsarenotwellstud-iedoutsideofacardiacsurgeryorpercutaneouscoronaryintervention(PCI)setting.128Furthermore,theclinicalsignificanceoftheassayresultsisuncertainastheyhavenotbeenshowntoidentifypatientsatincreasedriskforperioperativebleeding.127Additionalresearchisneededtoidentifythepotentialclinicalutilityofplateletfunctionassays.Recommendation

4.4.Inpatientswhoarereceivingantiplateletdrugs,wesuggestagainsttheroutineuseofplateletfunctionassaystomonitortheanti-thromboticeffectofaspirinorclopidogrel(Grade2C).

4.5SurgeryinPatientsReceivingAntiplateletTherapy

4.5.1NoncardiacSurgery

Inpatientswhoarereceivingantiplateletdrugtherapyandareundergoingnoncardiacsurgery,therearenorandomizedtrialsorprospectivecohortstudiesthatcomparetheclinicalbenefitsandrisksofcontinuingantiplateletdrugswiththeirtemporaryinterruption.Arandomizedplacebo-controlledtrialinvolvingpatientsundergoinghipfracturerepairorjointreplacementsurgeryassesseddenovouseofaspirincomparedtonoaspirinuseintheperioper-ativeperiodandreportedhigherratesofmajorbleedinginaspirintreatedpatients(2.9%vs2.4%,pϭ0.04).9Studiesinpatientsundergoingabdominalorpelvicsurgeryarelimited.Aretrospectivecohortstudyin52patientsfoundthatperioperativecontinuationofaspirinincreasestheriskforbleedingafterprosta-tectomy.31Aretrospectivecohortstudyinvolving200patientswhounderwentintraabdominalsurgeryfoundthat12of55(22%)patientswithaspirin-associatedabnormalplateletfunctionhadexcessiveperioperativebleeding,whereas7of97(7%)withnormalplateletfunctionhadexcessivebleeding.129However,anotherstudyinvolving52patientswhohadsurgeryfoundthatperioperativeaspirinusedidnotconferanincreasedriskforbleeding.130CHEST/133/6/JUNE,2008SUPPLEMENT

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Retrospectivecohortstudieshavesuggestedin-creasedratesofbleedingwithperioperativecontin-uationofclopidogrel.131,132Inaddition,oneprospec-tivecohortstudyinpatientswhounderwentbronchoscopyfoundsignificantlyhigherincidencesofmoderateorseverebleedingafterbiopsyinpatientswhoreceivedclopidogrel(61%)orclopi-dogrelandaspirin(100%)comparedtonoantiplate-letdrug(2%).1334.5.2CABG

Electivecoronaryarterybypassgraft(CABG)surgeryisfrequentlydoneinpatientswhoarere-ceivingantiplatelettherapywithaspirinand/orclo-pidogrel.134Inaddition,10to15%ofpatientshos-pitalizedwithanacutecoronarysyndromewillrequireurgentCABGsurgeryduringtheirhospital-izationandsuchpatientsaretypicallyreceivingantiplatelettherapy(aspirinaloneoraspirinandclopidogrel)andanticoagulanttherapy,thelaterwithLMWHorUFH.135Minimizingtheriskforperiop-erativebleedinginpatientsundergoingCABGsur-geryisimportantbecauseofanincreasedriskfordeathandotheradverseoutcomesinpatientswhorequireabloodtransfusionintheperioperativeperiod.136Inonestudyinvolving11,963patientswhounderwentCABG,ofwhom49%receivedtransfu-sionofRBCs,transfusionwasassociatedwithsignif-icantincreasesinmortality(OR,1.77;CI:1.67–1.87),renalfailure(OR,2.06;CI:1.87–2.27),andneurologicevents(OR,1.37;CI:1.30–1.44).137Theperioperativemanagementofanticoagulanttherapyiscomparabletothatofnoncardiacsurgery,withinterruptionofLMWHorUFHatatimepriortoCABGsurgerythatwilleliminatetheanticoagulanteffectbythetimeofsurgery.Ontheotherhand,theperioperativemanagementofantiplatelettherapyismoreproblematicsince7to10daysafterstoppingtreatmentisrequiredtoeliminateanantiplateleteffectandurgentCABGisoftenrequiredwithoutadvancenoticeof7to10days.

InpatientswhoarereceivingaspirinandrequireCABGsurgery,observationalstudiesshowthatcon-tinuingaspirinintheperioperativeperiodappearstoconferanincreasedriskformediastinalbleeding,bloodtransfusion,andreoperation,138,139althoughthisfindingwasnotfoundinallstudies.140Againsttheserisks,aspirinusewithin5dayspriortoCABGwasshowninalargecohortstudytoconferalowerriskofpostoperativemortalityandwithoutacon-comitantincreaseinreoperationforbleedingorneedforbloodtransfusion.26Basedonthisbenefitofcontinuedperioperativeaspirinuseinpatientsun-dergoingCABG,ifaspirintherapyhasbeeninter-ruptedbeforesurgery,itshouldbeadministered

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earlyaftersurgery,alwayswithin48hafterCABGand,preferably,within6haftersurgery.141InpatientswhoarereceivingclopidogrelandrequireCABG,therearenodatatosuggestbenefitfromtheadministrationofclopidogrelintheperiop-erativeperiodwhereastherearepreliminarydatasuggestingharmwiththisapproach.142IntheCanRapidriskstratificationofUnstableAnginaPatientsSupressAdverseOutcomesWithEarlyImplemen-tationoftheAmericanCollegeofCardiology/Amer-icanHeartAssociationguidelines(CRUSADE)studythatincluded2,855patientswithanon-STelevationmyocardialinfarction,87%ofpatientsun-derwentCABGwithin5daysofpriorclopidogrelexposure.143Suchpatientshada70%higherlikeli-hoodforatransfusionrequirementof4UormoreofRBCs.ThemostcompellingdataabouttheriskofbleedingamongpatientsundergoingCABGwhoarereceivingclopidogrelcomefromtheClopidogrelinUnstableanginatopreventRecurrentEvents(CURE)trial.144Inapostrandomizationsubgroupanalysisofthistrial,exposuretoclopidogrelwithin5dayspriortoCABGwasassociatedwithanapprox-imately50%increaseinmajorbleeding.Otherret-rospectivestudieshaveconfirmedtheincreasedriskforbleedingwithpriorclopidogrelexposureinpa-tientsundergoingCABGsurgery.145–148Anin-creasedriskofbleedingappearstooccurevenwhenCABGisperformedinanoff-pumpmanner.149Mitigatingtheriskforperioperativebleedingandtransfusionwithantifibrinolyticdrugs,suchasapro-tinin,orplatelettransfusionisproblematicbecausebothtreatmentsareassociatedwithadverseeffects.Althoughtworandomizedtrialssuggestedareduc-tionintheneedfortransfusionamongpatientstreatedwithaprotininundergoingsurgerywhileonclopidogrelwithoutraisingconcernsofexcessiveriskofthrombosis,aprotininappearstobeassociatedwithanincreasedriskforthromboticandotheradverseeffects,150,151andisnolongeravailableforclinicaluseintheUnitedStates.Inoneobservationalstudyinvolving4,374patientsundergoingCABGsurgeryforST-segmentelevationmyocardialinfarc-tion,aprotininusewasassociatedwitha55%in-creasedriskformyocardialinfarctionorcongestiveheartfailureanda181%increasedriskforstrokeorencephalopathy.152Similarly,pre-CABGplatelettransfusionisassociatedwithlongersurgeryand,par-adoxically,morebleedingandreoperationforbleedingcomplications.153Alternativeantifibrinolyticagentsthatcanbeusedinlieuofaprotonintoreduceperioperativebleedinginpatientsundergoingcardiacsurgeryincludeepsilon-aminocaproicacidandtranexamicacid,whichhavebeenshowntoreducetransfusionrequire-ments.154,155Theefficacyof1-deamino-8-D-arginine

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vasopressin(DDAVP)inpatientsundergoingcardiacsurgerywhohavebeenexposedtoaspirinislessclear.15.5.3PCIs

Randomizedtrialshavecompareda325-mgdoseofaspirintoplaceboamongpatientsundergoingaballoonangioplastytypeofPCI.ThereductioninriskassociatedwithaspirinadministrationinthesestudieshasledtotherecommendationthataspirinbeadministeredinallpatientspriortoanyPCIprocedure.17Clopidogrelhasbeencomparedtoplaceboamongpatientswithacutecoronarysyndromesandfoundtoreducetheriskofprocedure-relatedevents.157,158Inpostrandomizationsubgroupanalysesofpatientsun-dergoingPCIinthesetrials,clopidogrelwaspartic-ularlybeneficialamongpatientsundergoingPCIandthebenefitseemstoapplynotonlytopatientswhoreceivedstentsbuttothoseundergoingballoonangioplastyandothertypesofPCIproceduresaswell.PretreatmentwithclopidogrelisrecommendedbeforeanytypeofPCIprocedurewheneveritcanbeaccomplishedandsuchtreatmentshouldbecontin-uedduringtheperiproceduralperiod.Amongpa-tientsonlong-termclopidogreltherapy,onestudyshowedthatperiproceduraladministrationofa600-mgloadingdoseofclopidogreltosuchpatientsresultedinagreaterinhibitionofplateletaggregationthannotreceivingaloadingdose.159Otherstudieshavesug-gestedthatclinicaloutcomesareimprovedifPCIisperformedaftera600-mgloadingdoseofclopidogrelhasbeenadministered;fewpatientsinthosestudieswerereceivinglong-termclopidogrelanditisnotknownwhetherchronicallyadministeredclopidogrelachievesthesameeffect.160–162Recommendation

4.5.Forpatientswhoarenotathighriskforcardiacevents,werecommendinterruptionofantiplateletdrugs(Grade1C).Forpatientsathighriskofcardiacevents(exclusiveofcoro-narystents)scheduledfornoncardiacsurgery,wesuggestcontinuingaspirinuptoandbeyondthetimeofsurgery(Grade2C);ifpatientsarereceivingclopidogrel,wesuggestinterruptingclopidogrelatleast5daysand,preferably,within10dayspriortosurgery(Grade2C).InpatientsscheduledforCABG,werecommendcontinuingaspirinuptoandbeyondthetimeofCABG(Grade1C);ifaspirinisinterrupted,werecommenditbereinitiatedbetween6hand48hafterCABG(Grade1C).Inpatientssched-uledforCABG,werecommendinterrupting

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clopidogrelatleast5daysand,preferably,10dayspriortosurgery(Grade1C).InpatientsscheduledforPCI,wesuggestcontinuingaspi-rinuptoandbeyondthetimeoftheprocedure;ifclopidogrelisinterruptedpriortoPCI,wesuggestresumingclopidogrelafterPCIwithaloadingdoseof300to600mg(Grade2C).4.6SurgeryinPatientsWithCoronaryStentsPatientswhoarereceivingantiplatelettherapybecauseofabaremetalordrug-elutingstentinthecoronaryarteriesdeservespecialconsiderationbe-causeofthehighthromboticriskifantiplateletdrugtherapyisinterrupted.Insuchpatientswhoareundergoingnoncardiacsurgery,thereisamarkedlyincreasedriskofcoronarystentthrombosisinthepostoperativeperiod,especiallyifsurgeryisunder-takenincloseproximitytostentplacement.163–172Furthermore,theclinicalimpactofstentthrombosisinthisclinicalsettingisconsiderable,asitwillbefatalorassociatedwithalargemyocardialinfarctioninϾ50%ofaffectedpatients.107,163,173–175Aretro-spectivecohortstudyassessed40consecutivepa-tientswhohadelectivenoncardiacsurgeryϽ6weeksaftercoronaryarterystenting.163Inthisstudy,eightpatients(20%)diedpostoperatively,inwhomallbutonehadperioperativeinterruptionofclopi-dogreloraspirin.

Tomitigatetheriskforperioperativestentthrombosis,electivenoncardiacsurgeryshouldbeavoidedduringtheperiodafterstentplacementwhenstentendothelializationisongoingasthisisthetimewhencoronarystentsaremostsuscepti-bletothrombosis.Inpatientswithabaremetalstent,theaforementionedstudysuggestedthattheriskofthrombosiswithsurgerywashigherinpatientswhohadsurgerywithin2weeksofstent-ingcomparedtomorethan2weeksafterstenting(pϭ0.15).163Alargerstudysuggestedthattheriskofbaremetalstentthrombosisandotheradverseeventsisincreasedifnoncardiacsurgeryisperformedwithin6weeksofstentplacement,1whichisconsistentwiththeapproximatetimerequiredforendothelializationaroundthebaremetalstents.176,177Arelevant,butpoorlystudied,issueintheman-agementofpatientswithcoronarystentswhorequiresurgeryiswhetherbridgingtherapyiswarrantedforpatientsinwhominterruptionofantiplatelettherapyisrequiredbecauseofahighbleedingriskassociatedwiththeplannedsurgery.Insuchpatients,bridgingtherapymightconsistofadministeringLMWHorUFHinamannersimilartothatinpatientswhorequiretemporaryinterruptionofVKAs,thoughthisapproachhasnotbeenformallystudiedtoassess

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efficacyandshouldbeweighedagainstapotentialincreasedriskforpostoperativebleeding.Analter-nativeapproachmightbetheuseofbridgingtherapywithshort-actingantiplateletdrugssuchasthegly-coproteinIIb/IIIaantagoniststirofibanoreptifi-batide,whichhavebeenstudiedinpatientsunder-goingPCI.17Theseagentshaveeliminationhalf-livesofapproximately2handtheirinterruption10hbeforesurgerywouldallowrestorationofplateletfunctionbythetimeofsurgery.108Emergingshort-actingantiplateletdrugsthattargetplateletP2re-ceptors,suchascangrelor,mayhaveclinicalutilityintheperioperativesettingbecauseofrapidreversalofantiplateletactivityaftertreatmentisstopped.178Studiesareneededtoassesstheefficacyandsafetyofbridgingtherapyinpatientswhoarereceivingantiplateletdrugsand,untilrelevantdataareavail-able,clinicaljudgmentandcautionareurgedinregardtotheuseofshort-actingantithromboticagentsinpatientswhorequiretemporaryinterrup-tionofaspirinand/orclopidogrel.

Lessisknownaboutthetimingofnoncardiacsurgeryinpatientswithasirolimus-orpaclitaxel-elutingcoronarystent,inwhomalongertimeisrequiredforcoronaryreendothelializationthanpa-tientswithabaremetalstent.Therehavebeenseveralreportsofthrombosisofsuchdrug-elutingstentsduringtheintraoperativeandpostoperativeperiod,insomecasesevenwhensurgeryisper-formedyearsafterstentplacement.165–170Thoughaspirinisrecommendedindefinitelyafterplacementofadrug-elutingstentandclopidogrelisrecom-mendedforatleast3monthsafterplacementofasirolimus-elutingstentand6monthsafterplacementofapaclitaxel-elutingstent,mostpatientsarereceiv-ingcombinedaspirin-clopidogreltherapyforatleast12monthsafterplacementofadrug-elutingstent.179,180Consequently,electivesurgeryshouldbedelayedfor12monthsafterplacementofadrug-elutingstentwheneverpossible.Recommendation

4.6.Inpatientswithabaremetalcoronarystentwhorequiresurgerywithin6weeksofstentplacement,werecommendcontinuingaspirinandclopidogrelintheperioperativeperiod(Grade1C).Inpatientswithadrug-elutingcor-onarystentwhorequiresurgerywithin12monthsofstentplacement,werecommendcontinuingaspirinandclopidogrelintheperioperativeperiod(Grade1C).Inpatientswithacoronarystentwhohaveinterruptionofantiplatelettherapybeforesurgery,wesuggestagainsttheroutineuseofbridgingtherapywithUFH,LMWH,directthrombin

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inhibitors,orglycoproteinIIb/IIIainhibitors,(Grade2C).

Valuesandpreferences:Theserecommendationsreflectarelativelyhighvalueplacedonpreventingstent-relatedcoronarythrombosis,andaconsider-ationofcomplexityandcostsofadministeringbridgingtherapyintheabsenceofefficacyandsafetydatainthisclinicalsetting,andarelativelylowvalueonavoidingtheunknownbutpotentiallylargeincreaseinbleedingriskassociatedwiththeconcomitantadministrationofaspirinandclopidogrelduringsurgery.

5.0PerioperativeManagementof

AntithromboticTherapyinPatientsWho

RequireDental,Dermatologic,or

OphthalmologicProceduresMinordental,dermatologic,andophthalmologicprocedurescancompriseupto20%ofallsurgicalandnonsurgicalproceduresperformedinpatientswhoarereceivingantithrombotictherapy.21,55Astheseproceduresaretypicallyassociatedwithrela-tivelylittlebloodloss,akeyquestionrelatestothesafetyofcontinuingantithrombotictherapyaroundthetimeoftheprocedureandwhethercontinuingtreatmentconfersanincreasedriskofclinicallyimportantbleeding.Apracticalissuethatalsorelatestothemanagementofsuchpatientsisthatmost,ifnotall,minorproceduresareundertakeninaclinicorotherout-of-hospitalsetting.Consequently,bleed-ingthatmayoccuraftertheprocedurewilloccurwhilethepatientishomeandmaygenerateconcernandanxietyforthepatient.Patientsshould,there-fore,begiveninstructionstodealwithpotentialbleeding,whichusuallyrequiresprolongedlocalpressureoverthesiteofadentalordermatologicprocedure.Inaddition,patientsshouldbeadvisedwhenbleedingisexcessiveandwarrantsmedicalattention.

InourreviewofrandomizedandnonrandomizedprospectivestudiesthatassessedtheriskofbleedinginpatientswhocontinueVKAsorantiplateletdrugsduringminorprocedures,whicharesummarizedinTables4–8,wehavefocusedonpostproceduralbleeding.Todistinguishbleedingthatisclinicallyimportantandrequiresmedicalattention,frombleedingthatdoesnotrequiremedicalattentionandis,typically,self-limiting,weclassifiedbleedingintothreecategories:(1)majorbleeding,whichreferstobleedingthatrequirestransfusionofՆ2UpackedRBCs181;(2)clinicallyrelevantnonmajorbleeding,whichreferstobleedingthatisnotmajorbutrequiresmedicalattention(eg,applicationofwounddressingoradditionalsutures);and(3)minorbleed-ing,whichreferstobleedingthatisself-limiting,

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5759d1561e///e0502/600l15062Bt:/t:/t:/t:/n0n0n0n0reee:enjoml:oml:omloml:oatrttrtrtroatiMaatatenenenentrrorrpTCoTCTCoTCoircs59e175561Dytr/llg5//6/alnoj1aaani12266/402/5ltcvt:aid2)t:/t:0t:/)n0n1)n)cTonemenlieneei/.l%l:%e)e):e%2)3noCRolNBmt7or.m%l:m%l%o2m1l:.o.5ort3tt2r.tr%iaa.ta.t5a1t0lNe(6n(1e(3ne(9n(1e2(n(1C,rsTCorrrTCoTCoTCo:esemg7ro59uctn5i/tdud1/31/e1512noeOe1t00c:5::2ll:t/t/ot/oaBn)n))tdn0rc%0:e%7%nendeette:irePnm7lm8l:.o5rl:.oormloilnot6or.tttrliaa2r3mtproataCe2t(n1atpeerneentMe(6nrrrorronTCoTCo(TCTCeDmsgilnoibomstgenre0000ebovdmEnUrohsTtneddipeetiiffau-iiP*cc)wd0eden1lop0pl1s1si.5ottyFoopnNNaoritecheedeeunuϩuniTSnciAanAdri)ni(ltiottiKKieitpcanacgVnVAKϩcassonaisrnpttuoucorimipV)cAdoolriapocxooei-cpbuditesncrot:t:t:d:otmeevGnetss2tsKomae3ts7eϩnn:dxeVcnoRrorpemAa:lertoAlϪne-eg:uϪen:lϪlnlrittrmthdraKKroldtymtunaoroymiritroeVϩtnaVnarpteaptytnenroeodaef(tsnro(daesanaditaPITCrTCrroTCTCn.Ao5N157152569566102.fonloineatenextorls,eaiusnrpnllltdsneuoiaenodts)xismdopiir(icitbucoiifxnsniott(ucm)fnrccssae,eosiiyoaoeliParrrnts,arprctraittternfxeongmxeerutooxeegictoimtrrooldaCellucametpaaucitsraryosresttcfodndcϭlrogytnlanenFnTneeaxsnferadapAiDDreionOO;scsite,os9bsT3,AA1ymrϭtsoyϭre,rolft0hap0F,rFr0tiina3dA9a35e1rorAa21tyϭnTiethϭet,hr6ϭ,aano1ϭrae6raeϭdcTpli,ϭVϭnseϭoaestdVerHusaverekznnETosoirAiHtElasimeIiTcdts;tMoNTMvdVVeoavldPtanfnvaoentiRemAAArria—ptpeyaKKKsTerVVVAhl4Taceinl.bo0919a3033haN11cTe////mr234y888/111n90yl3l2la2ϭdil0aa9saka0Vuet9n0t0oa60et0treaect0So1v2ce2de2HrBEaSAM*CHEST/133/6/JUNE,2008SUPPLEMENT

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PeriproceduralInterventionClinicalOutcomes,No./TotalTypeofProcedureDentalextractions1515Atleast10d0No.GroupFollow-upThromboembolismEventsMinorBleedingTreatment:0/15Control:0/15ClinicallyRelevantNonmajorBleedingTreatment:0/15Control:5/15(33.3%)Treatment:0/43Control:0/52MajorBleedTreatment:0/15Control:0/15Treatment:surgicalglueControl:gelatinspongeNotspecified0Dentalextractions5243Treatment:0/43Control:0/52Treatment:dayϪ2tranexamicacidControl:dayϪ5tranexamicacid10d0Treatment:2/43(4.6%)Control:1/52(1.9%)Treatment:0/23Control:0/26Dentalextractions2623Treatment:surgicalglueControl:dayϪ7tranexamicacidTreatment:surgicalglue(Beriplast)Control:surgicalglue(Surgicel)Notspecified0NotspecifiedTreatment:2/23(8.7%)Control:0/26Treatment:0/23Control:0/26Dentalextractions26200Treatment:0/20Control:0/26Treatment:2/20(10%)Control:1/26(3.8%)Treatment:0/44Control:10/45(22.2%)Treatment:0/20Control:0/2445Treatment:0/44Control:0/45Oralsurgeries(dentalextractions,endodonticsurgery)Treatment:tranexamicacidControl:salinemouthwashTreatment:2/44(4.5%)Control:2/45(4.4%)Table5—RandomizedTrialsAssessingProhemostaticInterventionsinPatientsUndergoingDentalProcedures:ClinicalDescriptionandResults(Section5.1)PatientsStudy/yrNo.TypeofTreatmentIndicationforATTherapyAl-BelasyandAmer185/200330VKACarterandGoss186/200385VKACarteretal187/200349VKAHalfpennyetal188/200146VKADownloaded from chestjournal.chestpubs.org at Charlesworth on April 22, 2011

Ramströmetal1/1993VKAVTEϭ11,AFϭ7,Strokeϭ4,MHVϭ3,VHDϭ5VTEϭ20,AFϭ14,CADϭ10,VHDϭ33,strokeϭ1VTEϭ8,AFϭ12,CADϭ5,strokeϭ5,VHDϭ19VTEϭ16,AFϭ12,CADϭ3,strokeϭ2,MHVϭ9,VHDϭ3VTEϭ29,AFϭ9,CADϭ6,strokeϭ15,MHVϭ29,VHDϭ6AntithromboticandThrombolyticTherapy8thEd:ACCPGuidelines

*VHDϭvalvularheartdisease;CADϭcoronaryarterydisease;seeTable4forexpansionofabbreviations.0d92503210e11343354////////e090352500slB:5:1000301::tt/t/:3/::/:/ttln0n0tttn0nn0tn0nnuroe:e:::eesjamlomleeele:lomlommoommeMtrtrtrttrmrttatatataattataaReneneneeneneerorororrororrdTCTCTCTTCTCTTnan2503210/y1343354otr7)///////logi2%90352250llnjtaaaani:25:10:3203:10:ptcvt./t/t/::/t/:toin43)n0n0ttn)n0n)1t)nniTnemdlie1:er/lene%e:::lelele:c.oCRoelm(lo1momo%eom%l%e2o7mmt0r.rrm0mrtsNNBa9t5ttt.r.atatt.tta6t6taaee1n(enena5ane(n(eeDrororoe(errororr,seTCTCTCTTCTCTTlamocctg00iun92543210n/Oid11363354///////il1351121le09Cae:53::3051:12::l/tt/:1:ct)/t3t/ttin)n)1)n0n)n):nBt/n0e%2)n:%:le)neesire:leComlom3le%m%e%n3o4.m)7o%:l%e:l0m%5trr6ot0m.r1mom%0t.r5t.t.trt.t.riata8t1t.a5a4ta3a2uMenn8e(e(n3ata2e(ne(roo(rro(ene(ro(e(rrorrdTCTCTCTTCTCTTecomrsPilolbamsttennoe00000000ebvDmEorghnTiogrpdddeueeeiiid-fffiinwcddicdddcoe15e4eUlpp50pl1oss1ssFttttooonNNNeit*yya)ae;yynauaP1o20.ededlAadl.ituuKeedeen5nϾ2–5nAnAgVuAuuorulnnAntnoeiiiiniritKitKϩtKtKtttnvpR.1rnnnnocnnyooVnVspooVeuN,oVooolpitoIRcp4ocpertsocpcpconr::oour:o:oncc:atcIGtNttϪ:tt:ttttt:nInstsutnnnnsnstn;torlae:e:o:soe:ennn:ieemAltelelrchSumloo;mAomAlere;i(trtr2otKr2tpmATdataKor3mAmtttteeneVtnϪaKnϪananϪaKor3mtsteVeVnϪtaaaKeVcroroeVoerrroroerrcoTCTCTCTTCTCTTritpiorbe.o0923550322510PN9511334333154m1orlhteatriunsttdnetssssosneodfonnnnnn(soooo(oAciiiiiiotcs,ttttstresccccecPaiaaaai)farrnrrrrrrotfxeoittttedtoegtxxxxgeixnrc)eeeerfeeluaelllluiclopasrusttsaaaattteaitynlxstlptTeaeitnnnnasnareeeereuDODDDDODni,t,,,ln302,oT51136ai2ϭrmCArϭϭϭϭesioyDtl5rogfpFF,,F,nnaAdA26A2,Vbϭ,Aa,r,211,18,161H4,2m,8,3C4eD181,,e,,,ioiesth371tr593ϭoAsa221o1ϭϭϭϭ041ϭϭϭϭ1Mϭϭ,8ϭbP,ϭ,e1ecTiϭϭϭpsdeϭDekVDϭϭDekVϭ2km,7ϭϭϭroDDeko5ϭVr3HDDekssnEDDtEAorHHVEAorHDEϭrAϭortHhAtInTAoTCtsMVHTCtsMHVTFsVCEtTstϭETMHAorVCtsVCHVNVMVVAVVseietaidPtufnoenitSemptAAAAAAriAyaKKKKKKpsKtrTerVVVVVVAVoThoC.o95005710427454—N26/e70///913/30l10902909l0119brya2d1091rll2l/aaazt1/a/ytiTdel0nl9ame2/all8tttra9ew99ur1e17e5o1lte0blna3V1l9n0naSd0paoh0ai8e9a0itn2mtennD0an9r2lta9alv1p1dia2traelaaeeesaBCCDDGMMwww.chestjournal.org

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o./Totaltment:1/30.3%)ClinicallyRelevantNonmajorBleedingMajorBleedTreatment:0/30tment:2/104.9%)tment:4/250.6%)rol:3/250.2%)tment:3/233%)tment:0/229Control:0/250Treatment:0/23tment:2/40.0%)Treatment:0/40tment:0/40Treatment:0/40tment:3/96.1%)Treatment:0/96tment:0/156Control:0/240Treatment:0/12Control:0/2rol:2/240.8%)tment:1/12.3%)rol:0/2Treatment:0/104Treatment:0/250Treatment:1/229(0.4%)Treatment:0/156N,semoctuOlacinilCdeunniotintnoeCvr—etnI6laerulbdeacTorpirePstneitaP326S

a3a1a1t1a1aa5aa3at8te(e(e(nee(ee(en0anrrro(e(rrrrrro(e(roTTTCTTTTTTCTCg4096n0053200652id312244911///02//////0/e30051000040e:::21:::::2:2l/:/Btttttttt/tnnn0tn)n)nnnn0n0::re)eeleeeeee:elom%mmom%%on3mmmmlomt0ttrm9tt.t.ttttrtria1aaa4aaaatatMe(eena7e(eeeenenrrroe(rrrrrroroTTTCTTTTTTCTCmsilobmstenoe0000000000bvmEorhTpdddddddueeeeeeeoiiiiiii-ffffffiiiiiiwmficccccccodeeeelpppdeeelo03pssss4pppsssF1tttt1tttoooooooNNNNNNN.esl,daeAoneee,eeϩuoelKrteeeiuslul†ueuuϩinoVnuulltu;lanoeno†nodnnnAddironAnouo,iirnrdiirdiiriiiiittpctKttitgirittgttttcttKcpnnonVnntncarnnnnncannaentn2nayuootoooonoorioooooooooVroccsncpccccciccceiccculicocϪcpcit,ssr::;:o:::::orGtottttotome:lto,totomg,tiy:tmnnn2nsnnnnarannmannasndatsasae;ee:e;e;xucnnse;xe;xedn::xlmAmϪmAlmAmAesie;ensgmAemAeernumAlAeAleerarttytttrmArutttaKaaaKoraKaKaerruttaKuaKnaeraKatruaKorKmtKornuateVedeVtneVeVtpseVseVteVtseVtnhrrrorrrrrroVaeVtnrusrotTTTCTTTTTTCTCpirep.o0400350066022N305522449541122112ϭDAeyyPsrrr;u,,,essssseselnssndnesnnngngpoiinneornoo,ororttoooiciuoiieiuiulciitottttststtcditccgcrecaccuaccrPaaaryalalmrtaarcarrraraxatortttetrtrrrffxrxxvmxoxodettoepxeeeeonltnlxxrereeiellllloelpaaaaatleleaatlltttttoetahahenaaaiynnnnnosttttlettTeeeeeroneoneognnndeedDDDDDDDriSDDacoy,,,T97,,EmA,5,9251212TrϭϭϭϭϭVϭ()IoyϭfpF,0,,F,,0e6,4k9MnaF0r4A59,3218V,A8V,10,1,71,,,,o3oA20224H5V6315H2,,6r.tieth,143ϭ74H11ϭϭϭϭMϭ55ϭϭ2MϭϭϭϭM15ss,ϭna1ϭcTϭϭ3eikVr,ϭ1eϭϭϭϭϭ,kV3DDDr,e6ϭ,D93VoidϭDtnVFϭoDe5DrHhIϭoDDDreVAaIEHTVHAEtHDAtϭHsMVCoErHtAHAhϭAHAhEtϭTHCϭHivVMTFVMTsMPVCtoFCVCoFVVAVAAMFMAerbbtnaifnrfoeipoemsptanya,TerAAAAAAAAAAoiTKKKKKKKKKKsnVVVVVVVVVVapx.o04035006eN30022449911513roftlu/es05d2//3a//0he9,rb01620gn3/94.y09l2k5lc0an041h/sl3/A0221alae0l2t0e095esylatte/ddnaao0r2/1l9launteei4M2a6ad1b/tamt0e3n25D02tngaw-le4anSh5eii00ao2B0-2lrkala0n02aaThtir9tumR0o0n0e00ilt2ss2oalcteuiareu9eeaun2m99s1rr2s`eao1eLeRRauaeeiZZBCKGartSMoSS*†AntithromboticandThrombolyticTherapy8thEd:ACCPGuidelines

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*PADϭperipheralarterydisease;Treatmentϭtreatmentgroup;VHDϭvalvularheartdisease;-vecontrolϭpatientsnotreceivingantithrombotictherapy.SeeTables4,5forexpansionofabbreviations..Treatment1:0/50Treatment2:0/50Table7—CohortStudiesAssessingProhemostaticInterventionsinPatientsUndergoingDentalProcedures:ClinicalDescriptionandResults(Section5.1)*Control:3/50(6%)Control:0/50Treatment:0/69Treatment:0/69MajorBleedusuallywithpressureatthebleedingsite,anddoes

notrequiremedicalattention.5.1DentalProcedures

Minordentalproceduresassessedconsistofsingleormultipletoothextractionsandendodontic(rootcanal)procedures.Thestudiesassessingperiproce-duralantithrombotictherapyinpatientshavingden-talproceduresaresummarizedinTables4–7.5.1.1PatientsWhoAreReceivingVKAs

Threerandomizedtrials,summarizedinTable4,involvingatotalof270patientscomparedcontinuingVKAtherapywithinterruptingtreatmentpriortoadentalprocedure.182–184Inthesestudies,therewerenoepisodesofthromboembolismormajorbleedingwitheitherperioperativemanagementstrategy.InonetrialthatcomparedcontinuingVKAvsstoppingtreatment2daysbeforetheprocedure,thereweremoreclinicallyrelevantnonmajorbleedsinpatientswhocontinuedVKAtherapy(26.3%vs13.5%).183InanothertrialthatcomparedcontinuingVKAtherapyinconjunctionwithcoadministeredtranexamicacidmouthwashvsstoppingVKAtherapy3daysbeforetheprocedure,therewerefewerclinicallyrelevantnonmajorbleedsinpatientswhocontinuedVKAtherapy(9.2%vs15.2%).184Fiverandomizedtrials,summarizedinTable5,compareddifferentprohemostaticdrugsinatotalof299patientswhocontinuedVKAtherapyaroundthetimeofadentalprocedure.185–1Inthesestudies,therewerenoepisodesofthromboembolismormajorbleeding.Inonetrialwhichcomparedtranex-amicacidmouthwashtosalinemouthwashinpa-tientswhocontinuedVKAtherapy,therewerefewerclinicallyrelevantnonmajorbleedsinpatientswhoreceivedtranexamicacid(0%vs22.2%).1Anothertrialcomparedtreatmentwith2or5daysoftranex-amicacidmouthwashbeforetheprocedure.186Inthisstudy,therewasalowerincidenceofclinicallyrelevantnonmajorbleedinginpatientswhoreceived5daysoftranexamicacid(1.9%vs4.6%).Intheothertrials,continuingVKAtherapywhilecoadmin-isteringaprohemostaticagentwasassociatedwithnoepisodesofmajorbleedingalthoughtheincidenceofclinicallyrelevantnonmajorbleedingvariedacrossstudies.185,187,188Sevenprospectivecohortstudies,summarizedinTable6,assessedbleedinginpatientswhocontinuedVKAtherapyduringdentalextractionandinacontrolgroupofpatientswhointerruptedVKAtherapybeforetheprocedure.190–196Inonestudyinvolving396patients,ofwhom156continuedVKAtherapyand240discontinuedthistreatment,therewerenomajorbleedsandtheincidenceofclinically

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ClinicalOutcomes,No./TotalTreatment1:4/50(8%)Treatment2:2/50(4%)0MinorBleedingTreatment1:2/50(4%)Treatment2:2/50(4%)ClinicallyRelevantNonmajorBleedingThromboembolismEventsFollow-up,d10IndicationforATTherapyTypeofProcedureNo.VTEϭ5,DentalextractionsAFϭ26,CADϭ29,VHDϭ7050Treatment1:tranexamicacid50Treatment2:50control:surgicalglueVKA150Blinderetal207/1999PatientsTypeofTreatmentNo.Bodneretal1998Study208/69VKAVTEϭ14,AFϭ23,MHVϭ32Dentalextractions69Treatment:continueVKA;nocontrolPeriproceduralInterventionGroup100-vecontrol0/50Treatment:3/69(4%)www.chestjournal.org327S

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PeriproceduralInterventionClinicalOutcomes,No./TotalTypeofProcedureNo.1677Cutaneoussurgeries119Cutaneoussurgeries12213Cutaneoussurgeries2144Cutaneoussurgeries212Cutaneoussurgeries494741Treatmentϭcontinuedaspirin-vecontrolTreatmentϭcontinuedVKA-vecontrol376–10d811d052Treatment:continueaspirin-vecontrol5–10d0-vecontrolControl:0/77Control:0/77Treatment:continueVKANotspecified0Treatment:0/16GroupFollow-upMinorBleedingCutaneoussurgeriesThromboembolismEvents,%ClinicallyRelevantNonmajorBleedingTreatment:0/16Control:0/77Treatment:0/52Control:0/119Treatment1:0/81Treatment2:0/12Control:0/2130Treatment1:0/37Treatment2:5/21(23.8%)Control:0/443–6mo0Treatment:0/41Control:0/212Notspecified0Treatment2:0/21Control:0/44Treatment:0/41Control:0/212Treatment:0/47Control:0/49Control:0/49Treatment:12/47(25.5%)Control:3/49(6.1%)MajorBleedTreatment:0/16Treatment1:continueaspirinTreatment2:continueVKA-vecontrolTreatment:2/52(3.8%)Control:4/119(3.4%)Treatment1:1/81(1%)Treatment2:1/12(8%)Control:1/213(0.5%)Treatment1:0/37Treatment1:continueaspirinTreatment2:continueVKA-vecontrolTreatment:1/52(2%)Control:5/119(4.2%)Treatment1:17/81(21%)Treatment2:6/12(50%)Control:28/213(13.1%)Treatment1:8/37(21.6%)Treatment2:7/21(33.3%)Control:6/44(13.6%)Treatment-0/41Control:3/212(1.4%)Treatment:0/47Table8—CohortStudiesAssessingContinuationofAntithromboticTherapyinPatientsUndergoingDermatologicProcedures:ClinicalDescriptionandResults(Section5.2)*PatientsStudyNo.IndicationforTypeofAntithromboticTreatmentTherapyAlcalay212/200193VKABartlett216/1999171AspirinAFϭ10,CADϭ1,MHVϭ3,otherϭ2NotreportedBillingsleyandMaloney213/1997306NotreportedVKA,aspirinKargietal214/2002102NotreportedVKA,aspirinShalomandWong217/2003253AspirinNotreportedDownloaded from chestjournal.chestpubs.org at Charlesworth on April 22, 2011

Syedetal215/200496VKANotreportedAntithromboticandThrombolyticTherapy8thEd:ACCPGuidelines

*SeeTables4–7forexpansionofabbreviations.relevantnonmajororminorbleedingwaslowinpatientswhocontinuedandinterruptedVKAther-apy,at0%and0.8%,respectively.194Inanotherstudythatassessedbleedingin250patientswhounderwentdentalextractionsduringVKAtherapyandacontrolgroupof250patientswhohaddentalextractionsbutwerenotreceivingaVKA,therewerenomajorbleedsreported,andtheincidenceofclinicallyrelevantnonmajorbleedingwassimilarintheVKAandnoVKAgroups,of1.6%and1.2%,respectively.196Fiveadditionalsmallerstudiesin-volvingbetween14and249patientsprovidedsimilarresults,withnomajorbleedsreported.However,thesestudiesreportedincidencesofminorbleedingof0to8.3%.In11prospectivecohortstudies,summarizedinTable6,thatassessedcontinuationofVKAtherapybutwithoutacontrolgroup,therewerenomajorbleedsreported.196–206Twoothercohortstudieswithatotalof211patients,summarizedinTable7,assesseddifferentprohemostaticagentsinpatientsundergoingdentalextractionandreceivingaVKA.207,208Therewerenomajorbleedsreported,andtheincidenceofclinicallyrelevantnonmajorandminorbleedingwas0to8%.

Takentogether,thesestudiesindicatethatcon-tinuingVKAtherapyaroundthetimeofaminordentalproceduredoesnotconferanincreaseinclinicallyimportantmajorbleeding.However,thesestudieswerenotadequatelypoweredtoexcludethepossibilitythatundertakingdentalproceduresdur-ingVKAtherapyconfersanincreasedriskforclini-callyrelevantnonmajororminorbleeding.Untilsuchstudiesareundertaken,itisreasonabletoconsidercoadministrationofalocalprohemostaticagent,whichappearstodecreasetheriskforclini-callyrelevantnonmajorandminorbleeding.5.1.2PatientsWhoAreReceivingAntiplateletDrugs

Inonesmallrandomizedtrialof39patientsthatcomparedcontinuingorinterruptingaspirinbeforeadentalprocedure,therewerenomajorbleedsinbothtreatmentarmsbuttheincidenceofclinicallyrelevantnonmajorbleedingwashigherinpatientswhocontinuedaspirintherapy(21%vs10%).209Inacohortstudyinvolving51patientswhocontinuedaspirintherapyaroundthetimeofadentalprocedure,therewerenomajorbleedsandclinicallyrelevantnonmajorbleedingoccurredinonepatient.210Studiesarelackinginregardtopatientswhoarereceivingclopidogrelandrequireadentalproce-dure,althoughitisprobablethatthecontinuationofclopidogrelandaspirininpatientsundergoingdentalprocedureswillincreasetheriskofbleedingabovethatseenwithaspirinalone.211Inhigh-riskpatients

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withacoronarystentimplantedwithinthepastyear,orperhapsatanytimeinthepastinthecaseofadrug-elutingstent,theriskofstentthrombosiswithclopidogrelinterruptionprobablyoutweighstheriskofprocedure-relatedbleedingassociatedwithcon-tinuationoftreatment.Inlower-riskpatientswithoutacoronarystent,periproceduralmanagementisuncertain,althoughitisprobablyreasonabletointerruptclopidogreltherapyandtocontinueaspiringiventhatcombinedantiplatelettreatmentwillin-creasebleedingriskabovethatoftheriskwitheitherdrugalone.Recommendation

5.2DermatologicProcedures

Minordermatologicproceduresassessedincludeexcisionsofbasalandsquamouscellcarcinomas,actinickeratoses,andmalignantorpremalignantnevi.Studiesofperiproceduralantithromboticman-agementaresummarizedinTable8.5.2.1PatientsWhoAreReceivingVKAs

FourcohortstudiesassessedcontinuingVKAther-apyaroundthetimeofadermatologicprocedureinatotalof96patients.212–215Inonestudythatas-sessed47patientswhocontinuedVKAtherapy(and49controlpatientswhowerenotreceivingVKAtherapyatthetimeofprocedure),therewerenomajorbleedsbuttheincidenceofclinicallyrele-vantnonmajorbleedingwashigherinpatientswhocontinuedVKAtherapy(25.5%vs6.1%).215Thereweresimilarfindingsintwoothercohortstudies,213,214whereasnobleedswerereportedinathirdstudyinvolving16patientswhocontinuedVKAtherapy.2125.2.2PatientsWhoAreReceivingAntiplateletDrugs

Fourcohortstudiesassessedcontinuingaspirintherapyaroundthetimeofadermatologicprocedure

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inatotalof211patients.213,214,216,217Therewerenomajorbleedsassociatedwithcontinuingaspirin.Intwostudies,minorbleedingwasmorefrequentinpatientswhocontinuedaspirinaroundthetimeoftheprocedurecomparedtopatientswhowerenotreceiv-ingaspirin(21%vs13%,respectively;21.6%vs13.6%,respectively).213,214However,intwoothercohortstud-iestheincidenceofminorbleedingappearedcompa-rableinpatientswhoreceivedorwhodidnotreceiveaspirinaroundthetimeoftheprocedure(1.9%vs4.2%,respectively;0%vs1.4%,respectively).216,217Dataforpatientswhoarereceivingclopidogrelandrequiredermatologicproceduresarelimitedtocasereportsofpatientswhodevelopedthromboem-boliceventsduringantiplatelettherapyinterrup-tion.218Periproceduralmanagementinsuchpatientscanfollowthatinpatientsundergoingdentalorotherminorprocedures.Recommendation

5.2.Inpatientswhoareundergoingminorder-matologicproceduresandarereceivingVKAs,werecommendcontinuingVKAsaroundthetimeoftheprocedure(Grade1C).Inpatientswhoareundergoingminordermatologicproceduresandarereceivingaspirin,werecommendcontinuingaspirinaroundthetimeoftheprocedure(Grade1C).Inpatientswhoareundergoingminorder-matologicproceduresandarereceivingclopi-dogrel,pleaserefertotherecommendationsout-linedinSection4.5andSection4.6.5.3OphthalmologicProcedures

Minorophthalmologicproceduresassessedaredominatedbycataractextraction,whichwasunder-takeninϾ90%ofpatientsstudied.Asmallminorityofpatientsstudiedhadvitreoretinalorotheroph-thalmologicprocedures.Ourrecommendations,therefore,pertaintopatientsundergoingcataractextraction.ThesestudiesaresummarizedinTable9.5.3.1PatientsWhoAreReceivingVKAs

SixprospectivecohortstudiesassessedbleedinginpatientswhocontinuedVKAtherapyduringoph-thalmologicsurgeryandinacontrolgroupofpa-tientswhowereeithernotreceivingVKAtherapyorwhointerruptedVKAtherapybeforesurgery.219–224Twootherprospectivecohortstudiesassessedbleed-inginpatientswhocontinuedVKAtherapyduringophthalmologicsurgerybutdidnothaveacontrolgroup.225,226Inoneprospectivecohortstudyassess-ingpatientswhohadcataractsurgery,therewasnoapparentincreaseinarterialthromboembolicevents

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in208patientswhodiscontinuedVKAscomparedto526patientswhocontinuedVKAsandtheincidenceofsucheventsappearedhigherinpatientswhocontinuedVKAs(1.14%vs0.48%).221Inthesepa-tients,therewerenomajororclinicallyrelevantnonmajorbleeds.Inanothercohortstudyinvolving639patientswhocontinuedVKAsand1,203controlswhowerenottakingVKAsaroundthetimeofcataractsurgery,therewerenoarterialthromboem-bolicevents.219Thereappearedtobeahigherincidenceofclinicallyrelevantnonmajorbleeding(0.16%vs0.08%)andminorbleeding(1.41%vs0.67%)inpatientswhocontinuedVKAsalthoughtherewerenomajorbleedsreported.Whileothersmallercohortstudiesdemonstratedsimilarre-sults,225,226onecohortstudyinvolving125patientswhohadcataractsurgeryreportedahighrateofmajorbleeding(8.7%).2245.3.2PatientsWhoAreReceivingAntiplateletDrugs

Aprospectivecohortstudyassessingpatientswhounderwentcataractsurgeryfoundnoimportantin-creaseinarterialthromboemboliceventsin977patientswhointerruptedaspirincomparedto3,363patientswhocontinuedaspirin(0.20%vs0.65%).221Inthesepatients,therewerenomajororclinicallyrelevantnonmajorbleedsandmarginallyhigherclinicallyrelevantnonmajorbleedsinpatientswhocontinuedaspirin(0.06%vs0%).Otherstudiesreportedsimilarresultsinpatientsundergoingcata-ractorvitreoretinalsurgery.222,223Therearefewdatainregardtothesafetyofcontinuingclopidogrelinpatientsundergoingoph-thalmologicsurgery.Onestudyofpatientsundergo-ingcataractsurgeryfoundthatalthoughsubconjunc-tivalhemorrhagewasmorecommoninpatientswhowerereceivingeitherclopidogrelorwarfarinthanaspirinornoantithromboticdrugs,therewerenosight-threateningbleedingcomplications.227Onestudydescribedapatientwhowasreceivingaspirinandclopidogrelandunderwentanintracapsularextractionandanteriorvitrectomyinwhomthepostoperativecoursewascomplicatedbyextensivehyphemaandvitreoushemorrhagethatclearedwithin3months.228Aswithotherminorprocedures,perioperativemanagementwillbedrivenbythrom-boembolicrisk.Recommendation

5.3.InpatientswhoareundergoingcataractremovalandarereceivingVKAs,werecom-mendcontinuingVKAsaroundthetimeoftheprocedure(Grade1C).Inpatientswhoareun-AntithromboticandThrombolyticTherapy8thEd:ACCPGuidelines

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Table9—CohortStudiesAssessingContinuationofAntithromboticTherapyinPatientsUndergoingOphthalmologicSurgery:ClinicalDescriptionandResults(Section5.3)*PeriproceduralInterventionClinicalOutcomes,No./Total(%)www.chestjournal.org

IndicationforAntithromboticTherapyTypeofProcedureNo.6391,203NotreportedCataractsurgery(Ͼ80%)76Cataractsurgery97714,322VTEϭ206,CADϭ793,strokeϭ738,VHDϭ248,CADϭ2,040,otherϭ16952620818,215Notreported17208VTEϭ1,AFϭ2,474Cataractsurgery317Vitreoretinalsurgery60-vecontrolTreatment1:continueaspirinTreatment2:stopVKA-vecontrolTreatment:continueVKA;nocontrolNotspecified0Cataractsurgery54Treatment1:continueaspirinTreatment2:stopVKA-vecontrolVKAAtleast3dTreatment3:continueVKATreatment4:stopVKA3,363Treatment1:continueaspirinTreatment2:stopaspirin-vecontrolaspirin10d482Treatment1:stopaspirindayϪ3ltreatment2:stopVKAdayϪ2-vecontrolNotspecified0Treatment:continueVKA-vecontrol10d0GroupFollow-upMinorBleedingCataractsurgeryThromboembolismEventsNotreportedClinicallyRelevantNonmajorBleedingMajorBleedTreatment:0/639Control:0/1203Treatment:1/63(0.16%)Control:1/1203(0.08%)Treatment1:0/482;treatment2:0/76Control:0/609Control:0/609Treatment1:0/3,363Treatment2:0/977Controlaspirin:0/14,322Treatment1:22/3,363(0.65%)Treatment2:2/977(0.20%)Controlaspirin:33/14,322(0.23%)Treatment4:6/526(1.14%)Treatment5:1/208(0.48%)ControlVKA:52/18,215(0.29%)0Treatment-9/639ϭ1.4%Control:8/1203(0.7%)Treatment1:18/482(3.7%);treatment2:3/76(3.9%)Control:25/609(4.1%)Treatment1:0/3,363Treatment2:0/977Controlaspirin:3/14,322(0.02%)Treatment4:0/526Treatment5:0/208ControlVKA:3/18,215(0.02%)Treatment1:6/54(11.1%)Treatment2:0/17Treatment1:2/3,363(0.06%)Treatment2:0/977Controlaspirin:5/14,322(0.03%)Treatment4:0/526Treatment5:0/208ControlVKA:7/18,215(0.04%)Treatment1:0/54Treatment2:3/17(17.6%)Control:0/208Control:21/208(10.1%)Treatment1:0/60Treatment2:1/7(14.3%)Control:0/4740Treatment:0/31Treatment1:2/60(3.3%)Treatment2-1/7ϭ14.3%Control:0/474Treatment2:1/7(14.3%)Control:10/474(2.1%)2moTreatment:1/31(3.2%)Control-0/208MHVϭ3,Otherϭ1NotreportedTreatment-0/31VTEϭ4,AFϭ27,VHDϭ4Cataractsurgery35Treatment:continueVKA;nocontrol30d0Treatment:2/35(5.7%)Treatment:0/35Treatment:0/35PatientsStudyNo.TypeofTreatmentHirschmanandMorby219/20061,842VKAKallioetal220/20001,167VKA,aspirinTreatment1:0/482;treatment2:0/76Katzetal221/200337,611VKA,aspirinLummeandLaatikainen222/1994351VKA,aspirinTreatment4:0/526Treatment5:0/208ControlVKA:0/18,215Treatment1-0/54Treatment2-0/17Downloaded from chestjournal.chestpubs.org at Charlesworth on April 22, 2011

NarendranandWilliamson223/2003541VKA,aspirinTreatment1-0/60CHEST/133/6/JUNE,2008SUPPLEMENT

Robertsetal225/199131Rotenstreichetal226/200135VKA,aspirin,dipyridamole,sulfin-pyrazoneVKA331S

ClinicallyRelevantNonmajorBleedingClinicalOutcomes,No./Total(%)Treatment:0/103Control:0/19dergoingcataractremovalandarereceivingaspirin,werecommendcontinuingaspirinaroundthetimeoftheprocedure(Grade1C).Inpatientswhoareundergoingcataractremovalandarereceivingclopidogrel,pleaserefertotherecommendationsoutlinedinSection4.5andSection4.6.

6.0PerioperativeManagementofAntithromboticTherapyPatientsWhoRequireUrgentSurgicalorOther

InvasiveProcedures6.1PatientsWhoAreReceivingVKAs

Inthenonbleedingpatientwhorequiresrapid(within12h)reversaloftheanticoagulanteffectofVKAsbecauseofanurgentsurgicalorotherinvasiveprocedure,treatmentoptionsthathavebeenas-sessedinobservationalstudiesincludefresh-frozenplasma,prothrombinconcentrates,andrecombinantfactorVIIa.229Norandomizedtrials,todateandtoourknowledge,havecomparedthesetreatmentsinpatientswhorequireurgentreversalofanticoagula-tion.230Inadditiontothesetreatmentoptions,allpatientsshouldreceivevitaminK,atadoseof2.5to5.0mgpoorbyslowIVinfusion.231Administeringfresh-frozenplasma,prothrombinconcentrates,orrecombinantfactorVIIaalonewilltemporarilyover-ridebutwillnoteliminatetheanticoagulanteffectofVKAs,whichpersistuntilVKAsareendogenouslymetabolizedorneutralizedbyvitaminK.Forexam-ple,asfresh-frozenplasmahasaneliminationhalf-lifeof4to6h,notadministeringvitaminKwillleadtoreemergenceofaVKA-associatedanticoagulanteffectwithin12to24h.Ifsurgeryisurgentbutcanbedelayedfor18to24h,theanticoagulanteffectofVKAsislikelytobeneutralizedbyIVvitaminK,atadoseof2.5to5.0mgwithouttheneedforbloodproductorrecombinantfactorVIIadministra-tion.230,232Recommendation

*SeeTables4–7forexpansionofabbreviations.MinorBleedingTreatment:0/103103CataractsurgeryNotspecified0Table9—ContinuedFollow-upThromboembolismEventsPeriproceduralInterventionNo.TypeofProcedureVTEϭ9,AFϭ11,MHVϭ14,CADϭ17,VHDϭ15,otherϭ26IndicationforAntithromboticTherapy19Treatment:continueVKAControl:stopVKA16dpriorGroupControl:0/19Treatment:9/103ϭ8.7%Control:0/19MajorBleed6.1.InpatientswhoarereceivingVKAsandrequirereversaloftheanticoagulanteffectforanurgentsurgicalorotherinvasiveprocedure,wesuggesttreatmentwithlow-dose(2.5to5.0mg)IVororalvitaminK(Grade1C).Formoreimmediatereversaloftheanticoagulanteffect,wesuggesttreatmentwithfresh-frozenplasmaoranotherprothrombinconcentrateinadditiontolow-doseIVororalvitaminK(Grade2C).6.2PatientsWhoAreReceivingAntiplateletDrugsThereisnopharmacologicagentthatcanreversetheantithromboticeffectofaspirin,clopidogrel,or

AntithromboticandThrombolyticTherapy8thEd:ACCPGuidelines

PatientsTypeofTreatmentNo.Study332S

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Wirbelaueretal224/2004128VKAticlopidine,whichirreversiblyinhibitplateletfunc-tion.Consequently,patientswhorequireanurgentsurgicalorotherinvasiveprocedurethatrequiresnormalizedplateletfunctionmayreceivetransfusedplatelets,whichwouldnotbeaffectedbyprioradministrationofantiplateletdrugs.233However,theefficacyandsafetyofplatelettransfusioninpatientswhoarenotthrombocytopenicandwhorequireanurgentsurgicalorotherinvasiveprocedurearenotknown.Onerandomizedtrialin11healthyvolun-teerswhoreceivedaspirin(325mgloadingdose,81mgmaintenancedose)andclopidogrel(300-mgor600-mgloadingdose,75-mgmaintenancedose)foundthatsubsequenttransfusionof12.5Uplateletsledtonormalizedplateletfunctionasdeterminedbyplateletfunctionassays.234However,studiestoas-sesstheefficacyandsafetyofaplatelettransfusiontoneutralizetheantiplateleteffectsofaspirinorclopi-dogrelintheperioperativesettingarelacking.Untilsuchstudiesaredone,itisreasonabletolimitplatelettransfusiontothosepatientswhohaveex-cessiveorlife-threateningbleedingintheperioper-ativeperiod.

Potentialalternativestoplatelettransfusioninpatientswhohavebeenexposedtoantiplateletdrugsareprohemostaticagents.Theseincludeε-aminocaproicacidandtranexamicacid,whichareantifibrinolyticagents,and1-deamino-8-D-argininevasopressin,whichincreasesplasmalevelsofvonWillebrandfactorandassociatedcoagulationfactorVIII.Theseagentsmayimproveplateletfunctioninpatientswhohavebeenexposedtoantiplateletdrugs.235However,outsideofthesettingofcardiacsurgery,thesedrugshavenotbeenwidelystud-ied113,236andshouldbelimitedtopatientswhohaveexcessiveorlife-threateningperioperativebleedingbecauseofpotentialprothromboticeffects.Recommendation

6.2.Forpatientsreceivingaspirin,clopidogrel,orboth,areundergoingsurgeryandhaveex-cessiveorlife-threateningperioperativebleed-ing,wesuggesttransfusionofplateletsorad-ministrationofotherprohemostaticagents(Grade2C).

Dr.DunndisclosesthathereceivedgrantmoniesfromandisonthespeakersbureauforSanofi-Aventis.HehasalsoservedonadvisorycommitteesforSanofi-Aventis,Eisai,andRocheDiag-nostics.

Dr.JafferdisclosesthathehasreceivedconsultantfeesfromSanofi-AventisandAstraZeneca,andthatheisonthespeakersbureauforSanofi-Aventis.

Dr.Beckerrevealsnorealorpotentialconflictsofinterestorcommitment.

Dr.SpyropoulosdisclosesthathehasreceivedconsultantfeesfromBoehringerIngelheim,andhasservedonthespeakersbureauforSanofi-AventisandEisai.

Dr.BergerdisclosesthathehasspokenatCouncilonMedicalEducation-approvedscientificsymposiasupportedbyBristol-MyersSquibb,Sanofi-Aventis,theMedicinesCompany,Astra-Zeneca,Medtronic,Schering-Plough,Lilly,andDaiichiSankyo.HehasservedasaconsultantforPlaCor,Lilly,DaiichiSankyo,MolecularInsightPharmaceuticals,andCVTherapeutics.Dr.BergeralsoownsequityinLumen,Inc(acompanythatisdevelopinganembolicprotectiondevice).

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