Rationale and Indications For Indefinite Anticoagulation in Patients With Venous Thromboembolism

3/6/2016
Rationaleandindicationsforindefiniteanticoagulationinpatientswithvenousthromboembolism
OfficialreprintfromUpToDate
www.uptodate.com2016UpToDate
Authors
GregoryYHLip,MD,FRCPE,
FESC,FACC
RussellDHull,MBBS,MSc
SectionEditors
JessMandel,MD
LawrenceLKLeung,MD
DeputyEditor
GeraldineFinlay,MD
Alltopicsareupdatedasnewevidencebecomesavailableandourpeerreviewprocessiscomplete.
Literaturereviewcurrentthrough:Feb2016.|Thistopiclastupdated:Oct19,2015.
INTRODUCTIONDeepveinthrombosis(DVT)andacutepulmonaryembolism(PE)aretwomanifestationsof
venousthromboembolism(VTE).AnticoagulationisthemainstayoftherapyforpatientswithVTE.Mostpatients
withVTEareanticoagulatedforafiniteperiod(3to12months)followingafirstepisodeofVTE.Selectpatientsat
increasedriskofrecurrentthrombosisbeyondtheconventionalperiodmaybenefitfromindefiniteanticoagulation.
AnticoagulationisadministeredinthissettingtoreducethelifetimeriskofrecurrentthrombosisandVTE
associateddeath.
Thistopicwilldiscusstherapeuticindefiniteanticoagulationasopposedtoprophylacticanticoagulationfollowing
anepisodeofVTE.Populationsthatarelikelyorunlikelytobenefitfromindefiniteanticoagulationwillbe
discussedalongwiththefactorsthatcontributetomakingthisdecision.Theindicationsfortheinitialandlong
termtreatmentoflowerextremityDVT,aswellasalternatetherapiesforpatientswithDVTandPEarediscussed
indetailseparately.(See"Overviewofthetreatmentoflowerextremitydeepveinthrombosis(DVT)"and
"Overviewofthetreatment,prognosis,andfollowupofacutepulmonaryembolisminadults"and"Anticoagulation
inacutepulmonaryembolism"and"Lowerextremitydeepvenousthrombosis:Initiationofanticoagulation(first10
days)"and"Lowerextremitydeepvenousthrombosis:Longtermanticoagulation(10daystothreemonths)".)
TERMINOLOGYForthepurposesofdiscussioninthistopic,thefollowingtermsapply:
Thetermunprovokedvenousthromboembolism(VTEdeepvenousthrombosisand/orpulmonaryembolism)
impliesthatnoidentifiablecauseorprovokingeventforVTEisevident(alsoknownasspontaneousor
idiopathic).Incontrast,aprovokedVTEisonethatisusuallycausedbyaknownevent(eg,surgery,hospital
admission).ProvokingeventsandriskfactorsassociatedwiththedevelopmentofVTEcanbetransient(ie,
temporaryandreversibleeg,estrogentherapy)orpersistent.Persistentriskfactorsincludereversible
conditions(eg,prolongedimmobilityfollowingsurgery,pregnancy,orcurablemalignancy)andirreversible
conditionssuchasinheritablethrombophilias,andmetastaticendstagemalignancy.(See"Overviewofthe
causesofvenousthrombosis".)
Proximaldeepvenousthrombosis(DVT)isonethatislocatedinthepopliteal,femoral,oriliacveins.
IsolateddistalDVThasnoproximalcomponent,islocatedbelowtheknee,andisconfinedtothecalfveins
(peroneal,posterior,anteriortibial,andmuscularveins)(table1).
Initialanticoagulationisadministeredinthefirst5to10daysfollowingadiagnosisofVTE.Longterm
anticoagulanttherapyistypicallyadministeredforafinitetimebeyondtheinitialperiod,usuallythreetosix
months,andoccasionallyupto12months.Extendedanticoagulationreferstotherapythatisadministered
indefinitely.(See"Lowerextremitydeepvenousthrombosis:Initiationofanticoagulation(first10days)"and
"Lowerextremitydeepvenousthrombosis:Longtermanticoagulation(10daystothreemonths)".)
OralfactorXaanddirectthrombininhibitorshavebeenreferredtousingavarietyofnamesincluding
newer/noveloralanticoagulants,nonvitaminKantagonistoralanticoagulants(NOAs,NOACs),directoral
anticoagulants,(DOACs),andtargetspecificoralanticoagulants(TOACs,TSOACs)[1].Throughoutthis
topic,werefertotheseagentsbytheirpharmacologicclass,factorXa,anddirectthrombininhibitors.(See
"AnticoagulationwithdirectthrombininhibitorsanddirectfactorXainhibitors".)
http://www.uptodate.com/contents/rationaleandindicationsforindefiniteanticoagulationinpatientswithvenousthromboembolism?topicKey=PULM%2F94
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RATIONALEMostpatientswithacutevenousthromboembolism(VTE)requireanticoagulationforaminimum
ofthreemonths,withsomepatientsrequiringlongerfiniteperiodsof6to12months.Therationaleforextending
anticoagulationindefinitelyisbaseduponlongtermepidemiologicstudiesofrecurrenceriskaftercessationofa
conventionalcourseofanticoagulationaswellasrandomizedtrialsandmetaanalysesthatsuggestthat
anticoagulationforprolongedperiodssuccessfullyreducestherateofVTErecurrence.Moststudiesare
inadequatelypoweredtoassessmortality.Cumulatively,datasuggestthatthedecreaseinVTErecurrenceseen
withprolongedperiodsofanticoagulationisachievedattheexpenseofanincreasedriskofbleeding.Thus,
indefiniteanticoagulationismostlikelytobenefitthosewithanincreasedriskofrecurrenceinwhomtheriskof
bleedingislow.Ourapproachtoselectingthoselikelytogainbenefitwhileminimizingharmisdiscussedinthe
sectionsbelow.
PATIENTSLIKELYTOBENEFITWeandothersagreethatindefiniteanticoagulationislikelytobenefitthe
populationslistedbelow,providedtheriskofbleedingislow(algorithm1)[24].(See'Assessingtheriskof
bleeding'below.)
UnprovokedproximalDVTandsymptomaticPEThedecisionregardingtheuseofindefiniteanticoagulation
inapatientwithafirstepisodeofidiopathic(unprovoked)proximalDVToridiopathicsymptomaticPEis
dependentuponthelikelihoodofmajorbleedonanticoagulation.Forthosewithalowbleedingrisk,wesuggest
indefinitetreatmentratherthantreatmentforthreetosixmonths.Forpatientswithamoderateorhighbleeding
risk,thebenefitsofindefiniteanticoagulationarelesscertainanddependheavilyuponpatientspecificbleeding
andthromboticrisksaswellasthepatientsvaluesandpreferences.(See'Makingthedecisiontoindefinitely
anticoagulate'below.)
RecurrencewithandwithoutanticoagulationTherationaleforindefiniteanticoagulationinpatientswith
anunprovokedproximalDVTorsymptomaticPEisbaseduponthehighestimatedlifetimeriskofrecurrentVTE,
whichcanbedramaticallyreducedbyextendinganticoagulationbeyondtheconventionalthreetosixmonths[5
11].Importantly,moststudiesreportariskreductionintherateofVTErecurrenceattheexpenseofanincreased
rateofbleedingandwithoutmortalitybenefit.
Theestimatedriskofrecurrencefollowingcessationofanticoagulationinpatientswithafirstunprovokedepisode
ofVTEis10percentatoneyearand30percentatfiveyears(approximately5percentperyearafterthefirstyear)
[2,3,5,6,12,13].Priordurationoftherapydoesnotaffecttheriskofrecurrenceonceanticoagulanttherapyis
discontinued[8,14].Fullanticoagulationisassociatedwithanover90percentreductionintherateofrecurrence
comparedwithlowintensityanticoagulantregimensandaspirinwhicharelesseffective(approximately60and30
percentratereductioninrecurrencerespectively).Thisdecreaseinrecurrenceoutweighstherateofbleedingwith
fullanticoagulationinmostpatientswhoareestimatedtohavealow(0.8percentperyear)orintermediate(1.6
percentperyear)bleedingrisk[2].(See'Assessingtheriskofbleeding'below.)
TherecurrenceriskfollowingafirstepisodeofunprovokedVTEisillustratedbythefollowingstudies:
Onesystematicreviewof11studiesinpatientswithacuteVTEtreatedforatleastthreemonthsreported
recurrenceratesof7.4percentperpatientyearat24monthsafteranticoagulationwithdrawal[5].Similar
resultswerereportedinamulticenterstudywitharecurrencerateof12percentat26monthsinasimilar
population[14].Theriskwasindependentoftheeffectofage,priordurationofanticoagulation,andthe
presenceorabsenceofsymptomsorinheritedthrombophilias.
Inanothertrialinvolving267patientswithafirstidiopathicDVT,recurrentVTEwassignificantlygreaterin
patientstreatedwithwarfarinforthreemonthscomparedwiththosereceivingtreatmentfor12months(8.3
versus0.7percent)[8].However,theinitialclinicalbenefitoflongertermtreatmentwasnotmaintainedafter
warfarinwasdiscontinued,witharecurrencerateof5percentperpatientyearinbothgroups.
Inarandomizedtrialof371adultpatientswithafirstepisodeofsymptomaticunprovokedPE,allofwhom
weretreatedwithaconventionalcourseofanticoagulation(sixmonths),ratesofVTErecurrencewere
reducedfrom13.5to1.6percentinpatientswhohadextendedcoursesofwarfarin(18months),compared
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withplacebo[11].However,ratesofmajorbleedingwerehigher(4versus0.5percent)andonce
anticoagulationwasdiscontinued,thebenefitwasnotmaintained.Althoughmortalitywasnotdifferent
betweenthegroups,thestudywasnotpoweredtodetectsuchadifference.
ThehighestratesofrecurrenceoccurinthosewithunprovokedproximalDVTandPE[6,7,9,10].As
examples:
Inametaanalysisofsevenstudies,amongpatientswhopresentedwithPEorDVT,therecurrencerateat
fiveyearswas22and26percent,respectively[7].PatientswithproximalDVThadafivefoldhigher
cumulativerecurrenceratethanthosewithdistalDVT.AmongthosewhopresentedwithsymptomaticPE,
theriskofrecurrenceasPEwasthreefoldgreaterthaninpatientswhopresentedwithproximalDVT(HR,
3.195%CI,1.95.1).
InapooledanalysisofsevenrandomizedtrialsofpatientswithVTE,similartwoyearrecurrencerateswere
reportedinthosewithPEandproximalDVT(HR1.19,95%CI0.871.63)[6].Ratesinthoseforisolated
distalDVTwerehalfthatofpatientswithproximalDVTandPE.
Inaprospectivestudythatfollowed1149patientswithDVToffanticoagulationforfourtonineyears,
proximalDVTwasanindependentpredictorofrecurrence(relativerisk[RR],2.40,95%CI,1.483.88)[9].
TheriskofrecurrenceinpatientswithisolateddistalDVTisdiscussedseparately.(See'Unprovokedisolated
distalDVT'below.)
Summarizedinthesectionsbelowarethemajortrialsthatdemonstratedbenefitfromprolongedperiodsof
anticoagulationwiththeoralanticoagulants,warfarinandfactorXaanddirectthrombininhibitors,andfrom
antiplatelettherapywithaspirin.MosttrialspreselectedpatientswithunprovokedVTEandexcludedpatientsat
highriskforbleeding.Treatmentperiodswereuptofouryearsbutonaverageonetothreeyearswithmanytrials
thatwerestoppedearlyforefficacy.Theselectionofagentforindefiniteanticoagulationispresentedseparately.
(See'Agentselection'below.)
WarfarinSeveraltrialshavereportedreducedVTErecurrenceratesfromextendedanticoagulationwith
warfarintherapyforthetreatmentofunprovokedVTE[2,1520].Thesetrialscomparedpatientsreceivingwarfarin
atvariedInternationalNormalizedRatio(INR)targetswithpatientswhostoppedtherapyatthreeorsixmonths
andwerefollowedforonetothreeyears.
Ina2012metaanalysisoffivetrialsofpatientswithunprovokedVTE,extendinganticoagulationbeyond
threeorsixmonthswithfullintensitywarfarin(targetINR2.5)orlowintensitywarfarin(targetINR1.75)
reducedthefiveyearrecurrencerateby90and64percent,respectively(riskratio[RR],0.12,95%CI0.05
0.25forthestudiesthatreportedfullintensityanticoagulation)[2].AreductioninVTErecurrenceforthoseon
fullintensitytherapywasassociatedwitha2.6foldincreaseinmajorbleedingatfiveyears(RR2.63,95%
CI1.026.67).TheestimatedabsolutereductioninVTEeventswasreportedas88and264fewereventsper
1000patientstreatedatoneyearandfiveyears,respectively.
Inarandomizedtrialof162patientswithafirstepisodeofunprovokedVTEwhohadcompletedthree
monthsofanticoagulanttherapy,comparedtoplacebo,anadditional24monthsofwarfarin(targetINR2to
3)resultedinareductioninVTErecurrence(1.3versus27.4percentperpatientyear)[18].Warfarinwas
associatedwithahigherrateofbleeding(3.8versus0percentperpatientyear)thatwaswithoutassociated
fatality.
Inanotherrandomizedtrial(PREVENT)of508patientswithunprovokedVTE(firstorsecond)whohad
receivedamedianofsixmonthsoftherapeuticwarfarin(targetINR2to3),whencomparedwithplacebo,
continuoustreatmentwithlowintensitywarfarin(targetINR1.5to2.0)resultedina64percentreductionin
therateofVTErecurrence(5versus11per100patientyearshazardratio[HR]0.46,95%CI0.200.90)
[15].Theratesofbleedingwerelowinbothgroupswithahigherrateofmajorbleedinginpatientsonwarfarin
thatdidnotreachstatisticalsignificance(2versus0.8percent).
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Athirdrandomizedtrial(ELATE)comparedlowintensitywarfarin(targetINR1.5to1.9)versustherapeutic
warfarin(targetINR2to3)in738patientswhohadreceivedthreeormoremonthsoftherapeuticwarfarin
followinganepisodeofunprovokedVTE[20].Afteramedianfollowupof2.4years,lowintensitywarfarin
wasassociatedwithahigherincidenceofrecurrentVTE(1.9versus0.7per100patientyears,HR2.8,95%
CI1.17.0)withoutasignificantdifferenceinratesofclinicallyimportantbleeding.
FactorXaanddirectthrombininhibitorsOralfactorXaanddirectthrombininhibitorshaveproven
efficacyinrandomizedtrialsasanticoagulantsadministeredbeyondtheconventionalperiodofthreetosixmonths,
anduptotwoyearsforsomeagents(eg,rivaroxaban).Patientsinthesetrialswereconsideredbystudy
investigatorstobeatriskofrecurrence(eg,unprovokedVTE).[12,2125].(See"Lowerextremitydeepvenous
thrombosis:Longtermanticoagulation(10daystothreemonths)",sectionon'Selectionofagent'and'Our
approach'belowand"Lowerextremitydeepvenousthrombosis:Longtermanticoagulation(10daystothree
months)".)
RivaroxabanRivaroxaban,anoralfactorXainhibitor,wasstudiedin1556patients(EINSTEIN)withacute
VTE,whohadcompleted6to12monthsofeitherrivaroxaban(20mgoncedaily)orwarfarin[22].Compared
toplacebo,anadditional6to12monthsofrivaroxabanwassuperiorforthepreventionofrecurrentDVT(1.3
versus7percent).Althoughnonmajorbleedingeventswereincreasedinthosetakingrivaroxaban(5.4versus
1.2percent),theincidenceofnonfatalmajorbleedingwasnodifferentbetweenthegroups(0.7versus0
percent).
ApixabanApixaban,anoralfactorXainhibitor,wasstudiedin2482patients(AMPLIFYEXT)withVTE
whohadalreadycompleted6to12monthsofapixabanorwarfarin[12].Comparedwithplacebo,twelve
monthsofapixabanadministeredataprophylacticortherapeuticdose(2.5or5mg,respectively)resultedin
lowerratesofsymptomaticVTEandVTErelateddeath(1.7and1.7percentversus8.8percent),aswellas
lowerratesofallcausedeath(3.8and4.2versus11.6percent)andnonVTEassociateddeath(0.5and0.6
versus1.3percent).Thebenefitsofapixabanoccurredwithoutanincreasedriskinmajorbleedingevents
(0.2and0.1versus0.5percent).
DabigatranExtendedcourses(6to36months)oftheoraldirectthrombininhibitordabigatranwere
comparedtowarfarin(REMEDY2856patients)orplacebo(RESONATE1343patients),inpatientsatrisk
ofrecurrencewhohadcompletedatleastthreemonthsofeitherdabigatranorwarfarin[25].Comparedwith
warfarin,dabigatranresultedinasimilarrateofrecurrentVTE(1.8versus1.3percent)andasignificantly
lowerrateofmajororclinicallyrelevantbleeding(5.6versus10.2percent),butasignificantlyhigherrateof
acutecoronarysyndrome(0.9versus0.2percent).Comparedtoplacebo,dabigatranresultedinalowerrate
ofrecurrentVTE(0.4versus5.6percent)andahigherrateofmajororclinicallyrelevantbleeding(5.3versus
1.8percent).
AspirinTheantiplateletagentaspirin(100mg/day)hasprovenefficacyinpatientswithafirst
unprovokedepisodeofVTEwhohavecompletedaconventionalcourseofanticoagulation[2630].Inthis
population,ratesofVTErecurrencearereducedbyatleastonethirdwhencomparedtoplaceboorobservation:
Onemulticentertrial(WARFASA)randomlyassigned402patientswithafirstepisodeofunprovokedVTE
whoweretreatedwith6to18monthsofwarfarintherapytoreceiveaspirinorplaceboforanadditionaltwo
years[26].Aspirinwasassociatedwitha40percentreductionintherateofrecurrentVTE(7versus11
percent/yearHR0.5895%CI0.360.93).Bleedingrateswerelowandsimilarbetweenthegroups(0.3
percentperpatientyear).
Inanothertrial(ASPIRE)of822patients,mostofwhomhadreceivedanticoagulationfor6to12monthsfor
afirstepisodeofunprovokedVTE,comparedwithplacebo,aspirinwasassociatedwithareductioninVTE
recurrenceoverafouryearperiodthatwasNOTstatisticallysignificant(5versus7percentperyear)[27].
Theratesofbleedingandseriousadverseeventsweresimilar.
AprospectivelyplannedcombinedanalysisoftheWARFASAandASPIREtrialsreportedthataspirin,as
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comparedwithplacebo,significantlyreducedtherateofVTErecurrenceby32percent(HR0.6895%CI
0.510.90)withnoexcessriskofbleeding[28,29].
Inametaanalysisof12trials(12,000patients),aspirinwasassociatedwitha30percentriskreductionin
VTErecurrencewhencomparedwithplaceboorobservation[30].
RecurrentunprovokedVTEForpatientswithalowbleedingriskandasecondepisodeofunprovokedVTE,
werecommendindefiniteanticoagulationoverthreemonthsofanticoagulation.Forthosewithmoderateorhigh
bleedingrisk,thebenefitsofindefiniteanticoagulationarelesscertain,anddependheavilyonpatientspecific
thromboticandbleedingriskaswellasthepatientsvaluesandpreferences.(See'Ourapproach'below.)
Therationaleforindefiniteanticoagulationisbasedupontheestimatedhighriskofrecurrentthromboticeventsin
thispopulation.AsecondepisodeofVTEhasa50percenthigherriskofrecurrencewhencomparedwithafirst
event[2,15,21,31].Ratesarehighestinpatientswithtwounprovokedevents,approximately15percentatone
yearand45percentatfiveyears(ie,7.5percentperyearafterthefirstyear)[2,15,21,31,32].Asanexample,one
2012metaanalysisoffiverandomizedtrialsofpatientswithVTEreportedthat,comparedtoathreeorsixmonth
periodofanticoagulation,extendingtherapyinpatientswithasecondunprovokedVTEresultedin132and396
fewereventsper1000patientsatoneyearandfiveyears,respectively[2].
Therecurrencerateassociatedwithapatientthathasaunprovokedfirsteventfollowedbyaprovokedsecond
event,orviceversa,isunknownbutprobablycarriesariskofrecurrencethatissimilartothatofthesingle
unprovokedevent.
PATIENTSWITHPOSSIBLE/UNCLEARBENEFITTheefficacyandsafetyofindefiniteanticoagulationin
populationsotherthanunprovokedproximaldeepvenousthrombosis(DVT)andunprovokedsymptomatic
pulmonaryembolism(PE)arelesswellestablished.ThesepopulationsincludethosewithrecurrentprovokedVTE,
provokedVTEwithpersistentriskfactors,unprovokedisolateddistalDVT,andunprovokedincidentalPE.For
thesepatients,therapyshouldbeindividualizedaftercarefullyweighingpatientspecificbleedingandthrombotic
riskinthecontextofpatientpreferencesandvalues.Forexample,inapatientwithisolateddistalDVT,indefinite
anticoagulationmaybeconsideredinthepresenceofadditional,irreversible,multipleriskfactors(egstrongfamily
historyofDVT,activecancer,antiphospholipidsyndrome)orminortransientriskfactors(eg,travel).Incontrast,a
patientwithanisolatedsmallsubsegmental,incidentalPEmayprefertoavoidtheadverseeffectsofindefinite
anticoagulationthatiswithoutprovenbenefit.(See"Overviewofthetreatmentoflowerextremitydeepvein
thrombosis(DVT)",sectionon'DistalDVT'.)
RecurrentprovokedVTEThebenefitsofindefiniteanticoagulationinpatientswithrecurrentprovokedevents
arelesscertainthanthosewithunprovokedevents,anddependheavilyonpatientspecificrisksaswellasthe
patientsvaluesandpreferences.However,despitethelackofhighqualitydataandthewidevariationin
estimatedriskinthispopulation,cliniciansfrequentlyopttotreatpatientswithasecondepisodeofprovokedVTE
withlifelonganticoagulationprovidedthebleedingriskislow.(See'Makingthedecisiontoindefinitely
anticoagulate'below.)
Thereisawidespectrumofriskforrecurrenteventsinthispopulation,whichlimitstheabilitytoestimateriskfor
anindividual.Asanexample,forpatientswithtwoprovokedevents,theriskofrecurrenceisunknownbut
probablyhigherthanasingleprovokedevent(whichisestimatedtobe1to5percentatoneyearand3to15
percentatfiveyears)butnotashighastwounprovokedevents(15percentatoneyearand45percentatfive
years).
Datatosupportourapproachisderivedfromobservationalcohortsaswellasstudiesthatexaminedrecurrence
riskinpatientswithandwithoutanticoagulationwhohadbothprovokedandunprovokedevents[16,31,32].One
studythatprospectivelyfollowed738patientswithDVTforfourtonineyears,reportedthatthefiveyear
cumulativeincidenceofrecurrentVTEincreasedfrom22percentafterafirstDVTto28percentafterasecond
DVT[31].Inaddition,apriorhistoryofVTEwasanindependentpredictorofrecurrence(relativerisk[RR]1.71,
95%CI1.162.52).Anothermulticentertrialevaluatedtheoutcomeof227patientswithasecondepisodeofVTE
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whowererandomlyassignedtoreceiveeithersixmonthsoforalwarfarinorextendedtherapyforfouryears[16].
Extendedtherapy(targetINR2to2.85)wasassociatedwithalowerrateofrecurrence(3versus21percent,
relativerisk[RR]0.13,95%CI0.040.40)butattheexpenseofahigherriskformajorhemorrhage(9versus3
percentrelativerisk[RR]3.395%CI0.910).Anotherprospectivestudyof131patientswithalatesecond
episodeofVTE(ie,morethanoneyearafterthefirstevent)reportedarecurrencerateof6percentperyear[32].
ProvokedVTEwithpersistentriskfactorsSomepatientswithprovokedthromboemboliceventsare
consideredbytheircliniciantohavehigherthanusualriskofrecurrence.Indefiniteanticoagulationinpatientswith
persistentriskfactors(eg,malignancy,antiphospholipidsyndrome)mustbedecidedonanindividualbasis.The
assessmentofthesefactorsispresentedinmoredetailbelow.(See'Assessadditionalriskfactors'below.)
UnprovokedisolateddistalDVTWeandothersagreethatthreemonthsofanticoagulationissufficientfor
mostpatientswithisolateddistalDVT[2].However,webelievethatasmallproportionofpatientsinthis
populationmaybenefitfromindefiniteanticoagulation[2].
Supportforlimitinganticoagulationtothreemonthsinthispopulationisderivedfromrandomizedtrialsofpatients
withunselectedVTEthatreportedalowerrecurrenceriskfollowingaconventionalcourseofanticoagulationwhen
comparedwiththosewithproximalDVTorPE[6,7,9,10].Asexamples:
InonepooledanalysisofsevenrandomizedtrialsofpatientswithVTE,recurrenceattwoyearsinpatients
withisolateddistalDVTwashalfofthatreportedinpatientswithproximalDVT(hazardratio[HR]0.49,95%
CI0.340.71)[6].Thisstudywasnotpoweredtospecificallycomparetheriskbetweenunprovokedand
provokedepisodesofdistalDVT.
Inametaanalysisofsevenstudies,patientswithproximalDVThadafivefoldhighercumulativerecurrence
ratethanthosewithdistalDVT(HR,4.895%CI,2.111.0)[7].Theriskinunprovokedversusprovoked
VTEpopulationswasnotcompared.
Weagreewithotherexpertsthatthereareasmallproportionofpatientsinthispopulationthatmaybenefitfrom
indefiniteanticoagulation[2].Asexamples,manyexpertsindefinitelyanticoagulatepatientswithanunprovoked
isolateddistalDVTwhoalsohaveastrongfamilyhistoryofvenousthromboembolism,orwhohavepersistent,
multiple,orminorriskfactors.Despitethelackofrandomizedtrialsexaminingtheefficacyofindefinite
anticoagulationinthispopulation,therationaleforthisapproachisbaseduponthehighlikelihoodofrecurrentVTE
overalifetimeperiod.
UnprovokedincidentalPETheefficacyandsafetyofindefiniteanticoagulationinpatientswithasmall
incidentalunprovokedPE(ie,asymptomaticorsmallsubsegmentalPE)isunknown.Anydecisiontoanticoagulate
indefinitelywilldependheavilyuponanindividualassessmentofthepotentialrisksandbenefitsaswellaspatient
preferencesandvalues.(See'Makingthedecisiontoindefinitelyanticoagulate'below.)
PATIENTSUNLIKELYTOBENEFITWeandothersagreethatindefiniteanticoagulationisunlikelytobenefit
thepopulationsdescribedbelow,providedthatpersistentriskfactors,whichwouldelevatetheriskofrecurrence,
areabsent[24].(See'Assessadditionalriskfactors'below.)
ProvokedVTEwithtransientriskfactorFormostpatientswhohaveaprovokedVTEwithtransientmedical
orsurgicalriskfactors,werecommendanticoagulationforthreetosixmonthsratherthanperiodsoflongeror
shorterduration.ForthosewithaVTEprovokedbyatransientsurgicalriskfactor,theriskofVTErecurrenceis
estimatedtobe1percentatoneyearand3percentatfiveyears(approximately0.5percentperyearafterthefirst
year)[26].ForthosewithaVTEprovokedbyanonsurgicaltrigger(eg,oralcontraceptivepill,longflight,
pregnancy),theriskofVTErecurrenceisestimatedto5percentatoneyearand15percentatfiveyears
(approximately2.5percentperyearafterthefirstyear)[26].
Studiesthatsupportalowrecurrenceriskinthispopulationincludethefollowing:
Inonesystematicreviewof11studiescomprising2268patients,therateofVTErecurrencewasreportedas
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3.3percentperpatientyearforallpatientswithatransientriskfactor,0.7percentperpatientyearinthe
subgroupwithVTEprovokedbysurgery,and4.2percentperpatientyearinthesubgroupwithanonsurgical
transientevent(eg,estrogentherapy)[5].
InapooledanalysisofsevenrandomizedtrialsofpatientswithVTE,recurrenceattwoyearsinpatients
whosethromboticeventwasprovokedbyatemporaryriskfactorwasunderhalfthatcomparedtothosewith
unprovokedVTE(hazardratio[HR]0.55,95%CI0.410.74).
PatientswithahighriskofbleedingIndefiniteanticoagulationshouldnotbeofferedtopatientswithahigh
riskofbleeding.However,shouldtheriskforbleedingresolve(eg,recoveryfromtrauma),indefinite
anticoagulationmaybereconsidered.Forthoseinwhomtheriskofbleedingismoderate,theoptimaldurationof
anticoagulationisunknownandindividualizingtherapyaftercarefulassessmenttheriskbenefitratioshouldbe
performed.Assessingtheriskofbleedingisdiscussedseparately.(See'Assessingtheriskofbleeding'below.)
MAKINGTHEDECISIONTOINDEFINITELYANTICOAGULATE
OurapproachWhilethereisgeneralconsensusthatsomepatientsbenefitfromindefiniteanticoagulation,
thereisdisagreementregardingthespecificpatientpopulationsthatshouldbeincludedinthisgroup[2,33,34].
Mostexpertsagreethatindefiniteanticoagulationlikelybenefitspatientswithafirst,unprovokedepisodeof
proximaldeepvenousthrombosis(DVT)and/orunprovokedsymptomaticpulmonaryembolism(PE)aswellthose
withrecurrentunprovokedvenousthromboembolism(VTE).Whilemorecontroversial,someexpertsalsopromote
indefiniteanticoagulationinthesettingofrecurrentprovokedVTE,provokedVTEwithpersistent,irreversible,or
multiplemajorriskfactors(eg,activecancer,antiphospholipidsyndrome),orforthosewithunprovokedisolated
distalDVT.Thebenefitisuncertaininthosewithsmallasymptomaticincidental/subsegmentalPE.Incontrast,
indefiniteanticoagulationshouldNOTberoutinelyadministeredtomostpatientswithaprovokedepisodeofVTE
wheretheriskfactorsaretransient(eg,surgery,cessationofhormonaltherapy),orforanypatientwithahighrisk
ofbleeding.
Thefinaldecisiontoanticoagulateindefinitelyshouldbeindividualizedandbaseduponanassessmentofthe
following:
RiskofVTErecurrenceAllpatientsshouldhaveaninitialassessmentforriskofrecurrencebasedupon
theclinicalnatureandcontextoftheepisodeofVTE(eg,provokedorunprovokedVTE,reversibleor
irreversibleriskfactors,firstepisodeversusrecurrentepisode).(See'Riskassociatedwiththeclinicalnature
ofVTE'below.)
Thisinitialassessmentmaybefurthermodifiedbytheconsiderationofadditionalfactors,whichare
particularlyimportantforthosewithapossible/unclearbenefitfromindefiniteanticoagulation.Asexamples
(see'Assessingtheriskofrecurrence'below):
InfavorofcontinuedanticoagulationAdditionalfactorsthatsignificantlyincreasetheriskof
recurrenceincludeactiveormetastaticmalignancy,antiphospholipidsyndrome,andhighrisk
thrombophilias(eg,congenitalantithrombinIIIdeficiency).Weakerfactorsassociatedwithanincrease
intheriskofrecurrenceorriskofseverecomplicationsshouldarecurrenceoccurincludemalegender,
moderatetoseverepostthromboticsyndrome,poorcardiorespiratoryreserve(ie,patientsinwhoma
recurrentPEmaybelifethreatening),andelevatedDdimerwithinthreemonthsafterstopping
anticoagulation.
InfavorofstoppinganticoagulationAnormalDdimerlevelwithinthreemonthsafteranticoagulant
withdrawalisassociatedwithalowerrecurrencerisk.
RiskofbleedingThepatientshouldalsobeassessedandinformedoftheestimatedincidenceofmajor
bleedingshouldanticoagulationbecontinued.Inalargemetaanalysis,therateofmajorbleedingassociated
withextendedperiodsofanticoagulationwas2.7per100patientyears,withacasefatalityrateof9.1
percent(95%CI2.522)[35].(See'Assessingtheriskofbleeding'below.)
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PatientvaluesandpreferencesPhysiciansshoulddiscussindetailwithpatientstheirvaluesand
preferencesincludingtheimportanceoftheiroccupationandhobbiesinthecontextoflifeexpectancyand
thepotentialburdensoftherapy.Thepatient'sageandcomorbidities,individualbleedingrisk,comfortwith
thedifficultiesofcontinuinganticoagulation(eg,costs,frequencyofINRtesting),needforcloserfollowup,
andotherqualityoflifeissuesshouldbereviewedatthistime[3640].(See'Patientvaluesandpreferences'
below.)
ThisapproachisconsistentwithguidelinessetoutbytheAmericanCollegeofChestPhysicians(table2),the
InternationalSocietyonThrombosisandHemostasis,andtheInternationalConsensusStatementonthe
PreventionandTreatmentofVenousThromboembolism[24].Whiletheseguidelineshaveattemptedtomeasure
ariskbenefitratiotohelpidentifythosepatientsinwhomthebenefitofanticoagulationisoutweighedbytherisk
ofbleedinganddeath,noneshouldsubstituteforclinicaljudgement.Strictlyadheringtotheguidelinesisnot
practicalornecessary.
Evidencethatsupportsourapproachisbaseduponseveralrandomizedtrialsthatstudiedextended
anticoagulationforlimitedperiods(uptothreeyears),aswellasfromepidemiologicstudiesthatestimatedlong
termriskinaperiodofonetofouryearsfollowingcessationofaconventionalcourseofthreetosixmonthsof
anticoagulation.Studieswereheterogeneouswithrespecttorandomization,lengthoffollowupforVTEand
bleeding,aswellasagentselectedandintensityofanticoagulation.Additionallimitationstothesestudiesinclude
poordefinitionsofwhatconstitutesaprovokedorunprovokedVTEaswellasthehighdegreeofclinicalvariation
amongpatientsincludingthepresenceofmultipleriskfactors,manyofwhichareilldefined.Importantly,few
studiesreportamortalitybenefit.Thesestudiesarediscussedindetailseparately.(See'Recurrencewithand
withoutanticoagulation'above.)
Assessingtheriskofrecurrence
RiskassociatedwiththeclinicalnatureofVTEBaseduponavailabledatafromrandomizedtrialsand
metaanalyses,TheAmericanCollegeofChestPhysicianshasestimatedtheriskofrecurrenceinthefollowing
populations,whichprovidethebasisforourapproach[2](see'Ourapproach'above):
FirstepisodeofunprovokedVTE10percentforthefirstyear5percent/yearthereafter
SecondepisodeofunprovokedVTE15percentforthefirstyear7.5percent/yearthereafter
FirstVTEprovokedbysurgery1percentforthefirstyear0.5percent/yearthereafter
FirstVTEprovokedbynonsurgicalfactor5percentforthefirstyear2.5percent/yearthereafter
Althoughseveralotherclinicalpredictionruleshavebeendevelopedtoestimatetheriskofrecurrenceinpatients
withunprovokedVTEfollowingcessationofaconventionalthreetosixmonthcourseofanticoagulation,noneof
thesemodelshavebeenadequatelyvalidatedforroutineuseinclinicalpractice[4143].
VTEhasthehighestriskofrecurrenceinthefirstsixmonthstooneyearfollowingtheinitialeventandalthough
theannualratedeclines,itiscumulativeformanyyearsbeyondthat.Bestillustratingthisisapopulationbased
cohortstudyof1719patientsdiagnosedwithVTEthatestimatedcumulativepercentagesofVTErecurrenceas
thefollowing:7days(0.2percent),30days(1percent),and180days(4percent),1year(6percent),and10years
(18percent)[44].
AssessadditionalriskfactorsThepresenceofadditionalriskfactorsmayfacilitatethedecisionto
proceedwithorwithholdindefiniteanticoagulationfollowingafirstepisodeofprovokedorunprovokedVTE.
Factorsthatincreasetheriskarediscussedinthesectionsbelow.
ActivemalignancyActivemalignancyisariskfactorforVTEwithratesofrecurrenceestimatedtobe
ashighas15percentperyear[2,4446].However,theriskvariesconsiderablyaccordingtowhetherthecanceris
active,progressive,metastatic,beingtreated,orcured.Inaddition,ratesofbleedingarehigherinpatientswith
activecancer.Thus,thedecisiontoextendtherapyindefinitelyinthispopulationshouldcarefullyweighthebenefit
ofpreventingVTErecurrenceagainsttheriskofbleeding,whilealsotakingintoconsideration,thetypeofcancer,
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burdenofdisease,treatmentreceived,patientpreference,andlifeexpectancy.Theseissuesarediscussedin
detailseparately.(See"Treatmentofvenousthromboembolisminpatientswithmalignancy".)
AntiphospholipidsyndromePatientswithantiphospholipidsyndrome(APL)areatincreasedriskof
recurrentVTE.Typically,mostclinicianswillindefinitelyanticoagulatemostpatientswithserologicallyproven
antiphospholipidsyndrome(APL)followingafirstepisodeofVTE(provokedorunprovoked).Detailsonthe
durationofanticoagulationandagentselectionforpatientswithAPLarediscussedseparately.(See"Treatmentof
theantiphospholipidsyndrome",sectionon'Venousthromboembolism'.)
InheritedthrombophiliasPatientswiththehighriskinheritedthrombophilias(proteinS,proteinC,
antithrombinIIIdeficiency,homozygousfactorVLeidenandhomozygousprothrombingenemutations)areat
increasedriskofrecurrentVTEandmostclinicianswillindefinitelyanticoagulatethispopulation.Incontrast,most
cliniciansdoNOTindefinitelyanticoagulatepatientswhohaveafirstepisodeofprovokedVTEandlowerrisk
thrombophilias(eg,factorVLeiden).Theriskofrecurrentthrombosisandmanagementofpatientswithinherited
thrombophiliasandVTEarediscussedseparately.(See"Managementofinheritedthrombophilia",sectionon
'Longtermtherapytopreventrecurrence'and"FactorVLeidenandactivatedproteinCresistance:Clinical
manifestationsanddiagnosis",sectionon'RiskofrecurrentDVT'and"Antithrombindeficiency",sectionon
'Thrombosis'.)
MalegenderMalegenderisafrequentlycitedriskfactorforrecurrencefollowingafirstepisodeofVTE.
However,studiesareconflictinginregardtotheeffectofgenderontherateofrecurrence.Severalrandomized
trialsandmetaanalyseshavereportedincreasedriskofrecurrenceamongmenaftercessationoforal
anticoagulanttherapy,withrelativerisksvaryingfrom1.3to3.6[14,21,4752].Incontrast,anumberofother
studieshavesuggestednosexdifferenceinVTErecurrence[15,53].Apossibleexplanationforthiscontradiction
isthepresenceofinfluencingfactorsincludinghormonalfactorsandage[41,5456].Asexamples:
HormonalInaposthocanalysisofarandomizedstudyoflowintensitywarfarin,higherratesofrecurrent
VTEwerereportedwhenmenwerecomparedtowomenwithhormonalrelatedthrombosis(eg,estrogen
therapy18versus5percent)[56].Incontrast,ratesofrecurrenceweresimilarwhenwomenwithhormone
relatedthromboticeventswereremovedfromtheanalysis(18versus14percent).
AgeInasubgroupanalysisofoneretrospectivestudy(PROLONG),recurrencerateswerehigherinmen
thaninwomen(7.4versus4.3eventsper100patientyearshazardratio[HR]1.7)[54].Whileratesin
womenandmenolderthan65yearsweresimilar(6.6versus8.1eventsper100patientyears),recurrence
ratesinthoseyoungerthan65yearsweresignificantlyhigherinmalesthaninfemales(5.1versus0.4
eventsper100patientyearsHR,10.6).
OtherOnemulticenterprospectivecohortstudyof646patientsreportedthatmenhada14percentannual
riskofVTErecurrence,inwhichnohighorlowrisksubgroupswereidentified[41].Incontrast,variablerisk
wasidentifiedinwomenaccordingtothefollowingcharacteristics:hyperpigmentation,edema,orrednessof
eitherleg,Ddimer250mcg/Lwhilestilltakingwarfarin,bodymassindex30kg/m2,andage65years.
Comparedtowomenwithfewerofthelistedfeatures,womenwithtwoormorehadanannualriskof
recurrentVTEthatapproachedthatofmen(14versus2percent).
ElevatedDdimerWesuggestnotroutinelymeasuringDdimerlevelstodeterminewhoshouldor
shouldnotreceiveindefiniteanticoagulation.WhileelevatedDdimerlevelscanidentifypatientsatriskofVTE
recurrencefollowingcessationoforalanticoagulants,theyhavelowspecificity[17,52,5764].Inaddition,the
optimaltimingofDdimertestingandtheefficacyofindefiniteanticoagulationinpatientswithelevatedDdimer
levelsareuncertain.
MetaanalysesofobservationalstudieshaveconsistentlyreportedanelevatedrateofVTErecurrenceinpatients
withanelevatedDdimer(>500ng/mL)atthreetofourweeksfollowingcessationofanticoagulationcompared
withpatientswithanormalDDimer(9to17percentversus3to7percent)[6264].Inaddition,anobservational
study(PROLONGII)suggestedthatmeasurementatthreemonthsinpatientswithunprovokedVTEcanalso
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predictthoseatincreasedriskofrecurrence[65].InPROLONGII,5and32percentofpatientshadanabnormalD
dimerondayzeroafteranticoagulationwithdrawalandday30,respectively,allofwhomwereanticoagulated.In
theremaininggroup,comparedtopatientsinwhomtheDdimerwasnormalforthefirst12monthsafter
anticoagulationwithdrawal,patientswithalateandpersistentlyelevatedDdimerat(3to12months)hadahigh
riskofrecurrentVTE(27versus3episodesofVTEper100patientyearshazardratio7.995%CI2.130).
PatientsinwhomtheDdimerwasnormalatthethirdmonthbutbecameabnormalthereafterhadanintermediate
riskofrecurrentVTE(11.1eventsper100patientyears).
TheDULCISstudyassessedtheabilityofDDimerlevelsandimagingforresidualveinthrombosistopredict
patientswithalowriskofrecurrencefollowingafirstepisodeofVTE[66].Patientswhohadpersistently
negativeDdimerlevelsbythreemonthstogetherwithnoorstableresidualveinthrombosishadalow
recurrencerateofthreeeventsper100patientyearsoveratwoyearperiod.Amongthosewhohadelevated
Ddimerlevelsatthreemonths,anticoagulationreducedtherateofrecurrencefrom9to0.7eventsper100
patientyears.
AlthoughanelevatedDdimermaybevaluableinselectingthoseathighriskofrecurrence,anegativeDDimer
doesnotappeartoidentifythoseatlowriskofrecurrence.Inaprospectivestudy,VTErecurrenceratewas
measuredin319patientswithafirstepisodeofunprovokedVTEwhohadtwoconsecutivenegativeDdimer
levelsthefirstfollowingcompletionofastandardcourseofanticoagulanttherapyandthesecondatonemonthoff
anticoagulanttherapy[52].Inthispopulation,thetwoyearrecurrenceratewas7percentperpatientyear(10
percentinmen,5percentinwomen),suggestingthatnegativeDdimerlevelsinthispopulationarenotusefuland
donotjustifythecessationofanticoagulanttherapy.
Residualveinobstruction(RVO)Dataareconflictingregardingtheabilityofresidualveinobstruction
(RVO)onimaging(eg,impedanceplethysmographyorultrasound)toreliablypredictrecurrence[6772].While
imagingtodetectresolutionofclotorRVOmaybeusefulasabaselinetesttohelpinterpretimagingfor
suspectedfuturerecurrences[73],wedonotadvocatetheuseofroutineimagingtofacilitatethedecisionof
whethertocontinueordiscontinueanticoagulationattheendofafiniteperiod(eg,threemonths).(See"Lower
extremitydeepvenousthrombosis:Longtermanticoagulation(10daystothreemonths)",sectionon'Durationof
treatment'.)
Conflictingstudiesregardingtheabilityofimagingtopredictrecurrencesincludethefollowing:
A2011systematicreviewof11randomizedstudies(2302patients)reportedthatthepresenceofRVOatthe
timeofcessationofanticoagulationpositivelycorrelatedwithrecurrentVTE,particularlyinpatientswith
malignancy[74].However,thisanalysiswaslimitedbysignificantheterogeneityduetodifferencesinstudy
population,timing,anddifferencesintheRVOdefinitionsusedintheincludedstudies.
Aseparate2011systematicreviewofnineprospectivecohortstudiesandfiverandomizedcontrolledtrials
reportedthatRVOdidnotpredictrecurrenceinpatientswithunprovokedVTEfollowinganticoagulation
discontinuation[75].
Inanobservationalstudyof296patientswithafirstepisodeofsymptomaticprovokedDVT,RVOwas
presentin45percentofpatientsatthetimeofcessationoforalanticoagulation[76].However,RVOwasnot
significantlyassociatedwithVTErecurrence.
IncreasedthrombingenerationThegenerationofthrombinisnotroutinelymeasuredfollowingan
episodeofVTE.However,anumberofobservationalstudieshavesuggestedthatitmaybeassociatedwithan
increasedriskofrecurrence.Asexamples:
Inonestudyof254patientswithafirstepisodeofunprovokedVTEwhowerefollowedfor2.7yearsafter
discontinuationofwarfarin,thosewithhighervaluesforthrombingenerationmeasuredonemonthafter
discontinuationoftreatmenthadathreetosixfoldhigherrateofVTErecurrencethanthosewithlesser
valuesofthrombingeneration[77].
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Alargerstudyof914patientswithafirstepisodeofunprovokedVTEwhoweretreatedwithoral
anticoagulantsforaminimumofthreemonthsreportedthat,comparedtopatientswithlowerlevelsof
thrombingeneration,patientswithincreasedlevels>400nMhadahigherrateofVTErecurrenceatfour
years(20versus7percentrelativerisk2.5,95%CI1.73.7)[78].
Postthromboticsyndrome(PTS)Patientswithpostthromboticsyndrome(PTS)areatincreasedrisk
ofrecurrentVTE.InaprospectivecohortstudyofpatientswithacuteDVT,thosewithPTShada2.6fold
increaseinrecurrence[79].(See"Postthrombotic(postphlebitic)syndrome".)
AssessingtheriskofbleedingMostexpertsandsocietalguidelinesagreethatpatientsinwhomtheriskof
bleedingisassessedashighshouldnotreceiveindefiniteanticoagulation.However,shouldtheriskforbleeding
resolve(eg,recoveryfromtrauma),anticoagulationmaybeinitiated.(See"Managementofwarfarinassociated
bleedingorsupratherapeuticINR",sectionon'Riskfactors'.)
Majorbleedingisvariablydefinedamongstudies.However,manystudiesdefinedmajorbleedingasovertbleeding
associatedwithadecreaseinthehemoglobinlevelof2gperdeciliterormore,bleedingthatarequiredablood
transfusionoftwoormoreunitsofblood,occurredintoacriticalsite,orcontributedtodeath.Intwolargemeta
analyses,therateofmajorbleedingwasincreased2.6foldifanticoagulationwascontinuedbeyondthreemonths
withanabsoluterateof2.7per100patientyears,andacasefatalityrateof9.1percent(95%CI2.522)[2,35].
Anothermetaanalysisof11studiesthatincluded3965patientsreportedamajorbleedingrateof0.45per100
patientyears(95%CI0.290.64)andafatalbleedingrateof0.14per100patientyears(95%CI0.0570.26)[80].
Usingableedingriskmodelcontainingacomprehensivelistof17riskfactors,therateofmajorbleedingwas
estimated,bytheAmericanCollegeofChestPhysiciansasfollows[2]:
Lowrisk(noriskfactorspresent)1.6percentduringthefirstthreemonths0.8percent/yearthereafter
Intermediaterisk(oneriskfactorpresent)3.2percentduringthefirstthreemonths1.6percent/year
thereafter
Highrisk(twoormoreriskfactors)12.8percentduringthefirstthreemonths6.5percent/yearthereafter
Riskfactorsassociatedwithbleedingduringanticoagulanttherapyincludethefollowing(table3)[2,81]:
Olderage(>65yearsassessedastworiskfactorsif>75years)
Priorbleeding(especiallyifnotcorrectable)
Cancer(assessedastworiskfactorsifmetastaticorhighlyvascular)
Renalinsufficiency
Liverfailure
Diabetesmellitus
Thrombocytopenia
Priorstroke(especiallyifhemorrhagic)
Anemia
Concomitantantiplateletornonsteroidalantiinflammatorytherapy
Recentsurgery
Frequentfalls
Alcoholabuse
Reducedfunctionalcapacity
Poorcontrolofwarfarintherapy
Theriskofbleedingisproportionatetothenumberofriskfactorspresent.Forexample,youngpatientswithout
additionalrisksforbleedingwhohavebeenwellcontrolledonwarfarintherapyhavealowriskofbleeding(eg,1
percent)whereasolderpatientswithmultipleriskfactorsandatriskoffallinghaveahighriskofbleeding(>4
percent).
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Althoughanumberoftoolsareavailabletopredictapatientsriskofbleedingwhileonanticoagulation(eg,HAS
BLEDbleedingriskscore,(calculator1)),nonehavebeenvalidatedforpatientswithVTE[2,8185].Thus,when
consideringindefiniteanticoagulation,wesuggesttheuseofgestaltestimatestoweightheriskofbleeding
againstthebenefitofpreventingrecurrence[33,86].(See"Managementofwarfarinassociatedbleedingor
supratherapeuticINR",sectionon'Scoringsystems'.)
PatientvaluesandpreferencesItiscriticalthattherisksandbenefitsofindefiniteanticoagulationbe
discussedinthecontextofpatientspersonalvaluesandpreferences.Individualpatientsattachavariabledegree
ofvalueonissuessuchasclinicalandlaboratorymonitoringofwarfarin(eg,medicationadjustments,telephone
calls,frequencyofofficevisits),inconvenienceoforpainassociatedwithinjections(forlowmolecularweight
heparin),andavailabilityofreversalagents(forfactorXaanddirectthrombininhibitors)ifbleedingweretooccur
[3640].Inaddition,patientsweighbenefitsandharmsdifferentlydependingontheiroccupation,hobbies,
comorbidities,andlifeexpectancy.Forexample,ayoungpatientwhoisamountainclimbermayprefertostop
anticoagulationafteranunprovokedeventratherthanincreasetheirriskofbleedingfromaccidentalfalls.In
contrast,anolderpatientwithactivecancermaychoosetoremainonanticoagulationandacceptthehigherriskof
bleeding.Theimpactofpatientvalueswasillustratedinanobservationalstudythatreportedthat10percentof
patientsdeclinedindefiniteanticoagulationdespitebeingcandidatesforit[66].
AgentselectionIngeneral,patientswhochooseindefiniteanticoagulationplantocontinuetheircurrent
anticoagulantratherthanswitchtoanewagent.Therelativeefficacyandsafetyisexpectedtobesimilarduring
bothphasesofanticoagulation[2]:
Formostpatients,warfarinistheagentofchoicebecausethisisthepreferredagentforlongterm
anticoagulationwithavailabledatathatsupportitsefficacyandsafetyforuptofouryears.(See'Warfarin'
above.)
OralfactorXaanddirectthrombininhibitorsareconvenient,fixeddoseagentsthatdonotrequireroutine
laboratorymonitoringordoseadjustments.However,thereareconcernsregardingreversibilityforthese
agentsforbleedingevents.Managementofbleedingandagentsunderinvestigationforbleedinginthis
populationarediscussedseparately.(See'FactorXaanddirectthrombininhibitors'aboveand"Lower
extremitydeepvenousthrombosis:Longtermanticoagulation(10daystothreemonths)"and"Management
ofbleedinginpatientsreceivingdirectoralanticoagulants".)
Lowmolecularweight(LMW)heparinandfondaparinuxarepotentialagentsofvalueforindefinite
anticoagulation.However,onlyindirectevidencefromtrialsusingshorterdurationsoftherapy(eg,six
months)areavailableandthepotentialfordruginducedosteoporosismaybeincreasedwhenLMWheparin
isadministeredforprolongedperiods(eg,years)[87].(See"Lowerextremitydeepvenousthrombosis:Long
termanticoagulation(10daystothreemonths)",sectionon'Lowmolecularweightheparin'.)
AspirinisgenerallyconsideredtobelesseffectiveatpreventingVTErecurrence(30percentriskreduction)
thanroutineanticoagulation(90percentriskreduction)[30].Itmaybepreferredinthoseunwillingtoaccept
theriskofbleedingontherapeuticanticoagulation.(See'Aspirin'above.)
Datathatsupporttheuseoftheseagentsaslongtermanticoagulantsarediscussedseparately.(See"Lower
extremitydeepvenousthrombosis:Longtermanticoagulation(10daystothreemonths)",sectionon'Transitioning
tolongtermtherapy'.)
Ingeneral,prophylacticorlowdoseanticoagulantregimensarelesseffectivethantherapeuticanticoagulationin
reducingrecurrenceoverextendedperiodsandassuch,arenotroutinelyadministered.
Occasionally,alternateagentsneedtobeswitchedorarestarteddenovofollowingaperiodoffanticoagulation
(eg,highriskofbleedingthathassinceresolved).Reasonsforswitchingagentsandsuggestedtransition
strategiesarediscussedseparately.(See'Patientvaluesandpreferences'aboveand"Lowerextremitydeep
venousthrombosis:Longtermanticoagulation(10daystothreemonths)",sectionon'Transitioningduring
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therapy'.)
FOLLOWUPAlthoughtheoptimalperiodoffollowupforpatientsonindefiniteanticoagulationisunknown,
mostcliniciansandsocietalguidelinessuggestregularreview(eg,annually)[2,3].Duringfollowuppatientsshould
beassessedforrecurrence,thedevelopmentofcontraindicationstoanticoagulation,alteredbleedingrisk,and
chronichemorrhage,aswellasforchangesinagentpreference.
INFORMATIONFORPATIENTSUpToDateofferstwotypesofpatienteducationmaterials,TheBasicsand
BeyondtheBasics.TheBasicspatienteducationpiecesarewritteninplainlanguage,atthe5thto6thgrade
readinglevel,andtheyanswerthefourorfivekeyquestionsapatientmighthaveaboutagivencondition.These
articlesarebestforpatientswhowantageneraloverviewandwhoprefershort,easytoreadmaterials.Beyond
theBasicspatienteducationpiecesarelonger,moresophisticated,andmoredetailed.Thesearticlesarewritten
atthe10thto12thgradereadinglevelandarebestforpatientswhowantindepthinformationandarecomfortable
withsomemedicaljargon.
Herearethepatienteducationarticlesthatarerelevanttothistopic.Weencourageyoutoprintoremailthese
topicstoyourpatients.(Youcanalsolocatepatienteducationarticlesonavarietyofsubjectsbysearchingon
patientinfoandthekeyword(s)ofinterest.)
Basicstopics(see"Patientinformation:Deepveinthrombosis(bloodclotsinthelegs)(TheBasics)")
BeyondtheBasicstopics(see"Patientinformation:Deepveinthrombosis(DVT)(BeyondtheBasics)"and
"Patientinformation:Warfarin(Coumadin)(BeyondtheBasics)")
SUMMARYANDRECOMMENDATIONS
Mostpatientswithafirstepisodeofvenousthromboembolism(VTEproximaldeepvenousthrombosis
[DVT]and/orpulmonaryembolus[PE])areanticoagulatedforafiniteperiodof3to12months.Select
patientsbenefitfromindefiniteanticoagulationwhichisadministeredwiththeprimarygoalofreducingthe
lifetimeriskofrecurrentthrombosisandVTEassociateddeath.(See'Terminology'above.)
Thedecisiontoanticoagulateindefinitelyshouldbeindividualizedandbaseduponanestimateoftheriskof
recurrenceandbleedinginthecontextofthepatientsvaluesandpreferences.Ingeneral,forpatientsin
whomtheriskofbleedingislow,thefollowingapplies(see'Makingthedecisiontoindefinitelyanticoagulate'
above):
FormostpatientswithafirstepisodeofunprovokedproximalDVTand/orunprovokedsymptomatic
PE,wesuggestindefiniteanticoagulationratherthanstoppingtherapyafter3to12months(Grade2B).
InpatientswitharecurrentepisodeofunprovokedVTE,werecommendindefiniteanticoagulationrather
thanstoppingtherapyafter3to12months(Grade1B).(See'Patientslikelytobenefit'above.)
Indefiniteanticoagulationshouldnotberoutinelyadministeredtopatientswithaprovokedepisodeof
VTEwithmajortransientriskfactors(eg,surgery,cessationofhormonaltherapy)(Grade1B).We
alsoavoidindefiniteanticoagulationinthosewithahighbleedingrisk,andcarefullyassesstherisk
benefitratiointhosewithamoderateriskofbleeding.(See'Patientsunlikelytobenefit'above.)
FormostpatientswithrecurrentprovokedVTEorafirstepisodeofprovokedVTEwithirreversible,
multiple,orminorriskfactors,afirstepisodeofunprovokedisolateddistalDVToranunprovoked
episodeofincidentalPE,therapymustbeindividualizedbaseduponacarefulassessmentofpatient
specificrisksofbleedingandthrombosis.Therearewidevariationsinboththerecurrenceriskand
benefitinthesepopulations.(See'Patientswithpossible/unclearbenefit'above.)
Foreverypatientinwhomindefiniteanticoagulationisbeingconsidered,theinitialassessmentshould
evaluatethebaselineriskofrecurrencethatisassociatedwiththeclinicalnatureoftheevent(eg,provoked,
unprovoked,presenceandtypeofriskfactors).(See'RiskassociatedwiththeclinicalnatureofVTE'
above.)
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Thepresenceofoneormoreadditionalmajorriskfactors(eg,activemalignancy)orminorriskfactors
(eg,malegender)mayfavorcontinuedanticoagulationafteraconventionalperiodof3to12months.
(See'Assessadditionalriskfactors'above.)
Factorsthataffectbleedingrisk(eg,olderage>75years,frequentfalls)andpatientvaluesand
preferences(eg,burdenoftherapeuticmonitoring)stronglyimpactthedecisiontocontinueor
discontinueanticoagulationbeyondtheconventionalperiod.Indefiniteanticoagulationshouldnotbe
offeredtopatientswithahighriskofbleeding.However,shouldtheriskforbleedingresolve(eg,
recoveryfromtrauma),indefiniteanticoagulationmaybereconsidered.(See'Assessingtheriskof
bleeding'aboveand'Patientvaluesandpreferences'above.)
Mostpatientswhochooseindefiniteanticoagulationplantocontinuetheircurrentanticoagulant(usually
warfarin)ratherthanswitchtoanewagent.Alternateagentsmayneedtobeinitiated(eg,factorXaand
directthrombininhibitors,lowmolecularweightheparinandaspirin)inthosewithapreferencetoavoidthe
burdenofInternationalNormalizedRatio(INR)monitoringorwithpoorINRcontrol.Formostpatients,we
suggestfullintensityanticoagulation(eg,warfarinwithINRtarget2to3)ratherthanlowintensityregimens
oraspirin(Grade2B).(See'Agentselection'above.)
Patientsreceivingindefiniteanticoagulationareseenatleastannually.Duringfollowuppatientsshouldbe
assessedforrecurrence,adequacyoftherapeuticcontrol,thedevelopmentofcontraindicationsto
anticoagulation,alteredbleedingrisk,andchronichemorrhage,aswellasforchangesinagentpreference.
(See'Followup'above.)
UseofUpToDateissubjecttotheSubscriptionandLicenseAgreement.
REFERENCES
1.HustedS,deCaterinaR,AndreottiF,etal.NonvitaminKantagonistoralanticoagulants(NOACs):No
longernewornovel.ThrombHaemost2014111:781.
2.KearonC,AklEA,ComerotaAJ,etal.AntithrombotictherapyforVTEdisease:AntithromboticTherapyand
PreventionofThrombosis,9thed:AmericanCollegeofChestPhysiciansEvidenceBasedClinicalPractice
Guidelines.Chest2012141:e419S.
3.BaglinT,BauerK,DouketisJ,etal.Durationofanticoagulanttherapyafterafirstepisodeofanunprovoked
pulmonaryembolusordeepveinthrombosis:guidancefromtheSSCoftheISTH.JThrombHaemost2012
10:698.
4.NicolaidesAN,FareedJ,KakkarAK,etal.Preventionandtreatmentofvenousthromboembolism
InternationalConsensusStatement.IntAngiol201332:111.
5.IorioA,KearonC,FilippucciE,etal.Riskofrecurrenceafterafirstepisodeofsymptomaticvenous
thromboembolismprovokedbyatransientriskfactor:asystematicreview.ArchInternMed2010170:1710.
6.BoutitieF,PinedeL,SchulmanS,etal.Influenceofprecedinglengthofanticoagulanttreatmentandinitial
presentationofvenousthromboembolismonriskofrecurrenceafterstoppingtreatment:analysisof
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Thrombosis,9thed:AmericanCollegeofChestPhysiciansEvidenceBasedClinicalPracticeGuidelines.
Chest2012141:e24S.
Topic94740Version12.0
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GRAPHICS
Lowerextremity(CEAP)veinlist
Superficialveins
Deepveins
Perforator
veins
Telangiectasiasorreticular
veins
Inferiorvenacava
Thigh
Commoniliacvein
Calf
Greatsaphenousveinabove
Internaliliacvein
theknee
Greatsaphenousveinbelow
theknee
Smallsaphenousvein
Nonsaphenousveins
Externaliliacvein
Pelvic:gonadal,broadligamentveins,other
Commonfemoralvein
Deepfemoralvein
Femoralvein*
Poplitealvein
Crural:anteriortibial,posteriortibial,peroneal
veins(allpaired)
Muscular:gastrocnemial,solealveins,other
CEAP:ClinicalEtiologyAnatomyPathophysiologyclassificationoflowerextremitychronicvenous
disorders.
*Formerlyreferredtoasthesuperficialfemoralvein,amisnomersinceitisadeepvein.
Graphic77469Version4.0
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3/6/2016
Algorithmforthetreatmentoflowerextremitydeepvenousthrombosis(DVT
ThisalgorithmonlyappliestopatientswithafirstepisodeofDVT.
*PleaserefertotheUpToDatetopicondeepvenousthrombosis:longtermanticoagulation(threetosixmonths).
PatientswithanunprovokeddistalDVTshouldreceiveatleastthreemonthsofanticoagulation.Asmallproportion
PleaserefertotheUpToDatetopiconrationaleandindicationsforindefiniteanticoagulationinpatientswithvenoust
PleaserefertotheUpToDatetopiconrationaleandindicationsforindefiniteanticoagulationinpatientswithvenous
20/24
3/6/2016
2012ACCPguidelinesforcontinuationordiscontinuationof
anticoagulationafterthefirstthreemonths
Thrombotic
recurrencerisk
group
FirstVTEprovokedby
Bleedingriskgroup*
Low
Intermediate
High
Discontinue(strong)
Discontinue(strong)
Discontinue(strong)
Discontinue(weak)
Discontinue(weak)
Discontinue(strong)
Firstunprovoked
proximalDVTorPE
Continue(weak)
Continue(weak)
Discontinue(strong)
Secondunprovoked
VTE
Continue(strong)
Continue(weak)
Discontinue(weak)
surgery
FirstVTEprovokedby
nonsurgicalfactoror
firstunprovokeddistal
DVT
Thestrengthoftherecommendationtocontinueordiscontinueisnotedinparentheses.
VTE:venousthromboembolismDVT:deepveinthrombosisPE:pulmonaryembolism.
*The2012ACCPbleedingriskmodelassumesriskofmajorbleedingafterthefirstthreemonthsof
anticoagulationas0.8,1.6,and6.5percentforthelow,intermediate,andhighriskgroups,
respectively.
Modifiedfrom:KearonC,AklEA,ComerotaAJ,etal.AntithrombotictherapyforVTEdisease:
AntithromboticTherapyandPreventionofThrombosis,9thed:AmericanCollegeofChestPhysicians
EvidenceBasedClinicalPracticeGuidelines.Chest2012141:e419S.
21/24
3/6/2016
Riskfactorsforbleedingwithanticoagulanttherapyandestimated
riskofmajorbleedinginlow,moderate,andhighriskcategories
Riskfactors*
Age>65years
Age>75years
Previousbleeding
Cancer
Metastaticcancer
Renalfailure
Liverfailure
Thrombocytopenia
Previousstroke
Diabetes
Anemia
Antiplatelettherapy
Pooranticoagulantcontrol
Comorbidityandreducedfunctionalcapacity
Recentsurgery
Frequentfalls
Alcoholabuse
Estimatedabsoluteriskofmajorbleeding(%)
Categorizationof
riskofbleeding
Lowrisk (0risk
factors)
Moderaterisk (1
riskfactor)
Highrisk (2risk
factors)
0.6
1.2
4.8
1.6
3.2
12.8
0.3
0.6
2.5
0.5
0.8**
1.6**
6.5
Anticoagulation0to3months
Baselinerisk
(%)
Increasedrisk
(%)
Totalrisk(%)
Anticoagulationafterfirst3months
Baselinerisk
(%/years)
Increasedrisk
(%/years)
Totalrisk
(%/years)
22/24
3/6/2016
*Theincreaseinbleedingassociatedwithariskfactorwillvarywith(1)severityoftheriskfactor(eg,
locationandextentofmetastaticdisease,plateletcount),(2)temporalrelationships(eg,intervalfrom
surgeryorapreviousbleedingepisode),and(3)howeffectivelyapreviouscauseofbleedingwas
corrected(eg,upperGIbleeding).
Importantforparenteralanticoagulation(eg,first10days),butlessimportantforlongtermor
extendedanticoagulation.
Althoughthereisevidencethatriskofbleedingincreaseswiththeprevalenceofriskfactors,this
categorizationschemehasnotbeenvalidated.Furthermore,asingleriskfactor,whensevere,willresult
inahighriskofbleeding(eg,majorsurgerywithinthepasttwodays,severethrombocytopenia).
Comparedwithlowriskpatients,moderateriskpatientsareassumedtohaveatwofoldriskandhigh
riskpatientsaneightfoldriskofmajorbleeding.
The1.6%correspondstotheaverageofmajorbleedingwithinitialUFHorLMWHtherapyfollowedby
VKAtherapy.Weestimatedbaselineriskbyassuminga2.6relativeriskofmajorbleedingwith
anticoagulation(refertofootnote).
ConsistentwithfrequencyofmajorbleedingobservedbyHulletalinhighriskpatients [1] .
Weestimatethatanticoagulationisassociatedwitha2.6foldincreaseinmajorbleedingbasedon
comparisonofextendedanticoagulationwithnoextendedanticoagulation.Therelativeriskofmajor
bleedingduringthefirstthreemonthsoftherapymaybegreaterthanduringextendedVKAtherapy
because(1)theintensityofanticoagulationwithinitialparenteraltherapymaybegreaterthanwithVKA
therapy(2)anticoagulantcontrolwillbelessstableduringthefirstthreemonthsand(3)
predispositionstoanticoagulantinducedbleedingmaybeuncoveredduringthefirstthreemonthsof
therapy.However,studiesofpatientswithacutecoronarysyndromesdonotsuggesta2.6relativerisk
ofmajorbleedingwithparenteralanticoagulation(eg,UFHorLMWH)comparedwithcontrol.
Ourestimatedbaselineriskofmajorbleedingforlowriskpatients(andadjustedupformoderateand
highriskgroupsasperfootnote).
**Consistentwithfrequencyofmajorbleedingduringprospectivestudiesofextendedanticoagulation
forVTE.
Reference:
1.HullRD,RaskobGE,RosenbloomD,etal.Heparinfor5daysascomparedwith10daysinthe
initialtreatmentofproximalvenousthrombosis.NEnglJMed1990322:1260.
Reproducedfrom:KearonC,AklEA,ComerotaAJ,etal.AntithrombotictherapyforVTEdisease:
AntithromboticTherapyandPreventionofThrombosis,9thed:AmericanCollegeofChestPhysicians
EvidenceBasedClinicalPracticeGuidelines.Chest2012141:e419S.Tableusedwiththepermissionof
ElsevierInc.Allrightsreserved.
23/24
3/6/2016
Disclosures
Disclosures:GregoryYHLip,MD,FRCPE,FESC,FACCSpeaker'sBureau:Bayer[Atrialfibrillationandthrombosis(rivaroxaban)]
BMS/Pfizer[Atrialfibrillationandthrombosis(apixaban)]BoehringerIngelheim[Atrialfibrillationandthrombosis(dabigatran)]Daiichi
Sankyo[Atrialfibrillationandthrombosis(edoxaban)]Medtronic[Atrialfibrillationandthrombosis]SanofiAventis[Atrialfibrillationand
thrombosis].Consultant/AdvisoryBoards:Bayer/Janssen[Atrialfibrillationandthrombosis(rivaroxaban)]BMS/Pfizer[Atrialfibrillationand
thrombosis(apixaban)]BoehringerIngelheim[Atrialfibrillationandthrombosis(dabigatran)]DaiichiSankyo[Atrialfibrillationand
thrombosis(edoxaban)]Merck[Atrialfibrillationandthrombosis]Sanofi[Atrialfibrillationandthrombosis]Biotronik[Atrialfibrillationand
thrombosis]Medtronic[Atrialfibrillationandthrombosis]Portola[Atrialfibrillationandthrombosis].RussellDHull,MBBS,MSc
Grant/Research/ClinicalTrialSupport:LEOPharma[VTE(Tinzaparin)]Sanofi[VTE(Enoxaparin)]Portola[VTE(Betrixaban)]Bayer
[VTE(Rivaroxaban)].JessMandel,MDNothingtodisclose.LawrenceLKLeung,MDNothingtodisclose.GeraldineFinlay,MD
Nothingtodisclose.
Contributordisclosuresarereviewedforconflictsofinterestbytheeditorialgroup.Whenfound,theseareaddressedbyvettingthrougha
multilevelreviewprocess,andthroughrequirementsforreferencestobeprovidedtosupportthecontent.Appropriatelyreferenced
contentisrequiredofallauthorsandmustconformtoUpToDatestandardsofevidence.
Conflictofinterestpolicy
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Rationale and Indications For Indefinite Anticoagulation in Patients With Venous Thromboembolism

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