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Lowerextremitydeepvenousthrombosis:Initiationofanticoagulation(first10days)

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Lowerextremitydeepvenousthrombosis:Initiationofanticoagulation(first10days)
Authors
GregoryYHLip,MD,FRCPE,
FESC,FACC
RussellDHull,MBBS,MSc

SectionEditors
LawrenceLKLeung,MD
JessMandel,MD

DeputyEditor
GeraldineFinlay,MD

Alltopicsareupdatedasnewevidencebecomesavailableandourpeerreviewprocessiscomplete.
Literaturereviewcurrentthrough:Feb2016.|Thistopiclastupdated:Nov03,2014.
INTRODUCTIONVenousthromboembolism(VTE)iscomprisedoftwoentities,deepvenousthrombosis
(DVT)andpulmonaryembolus(PE).VTEhassignificantmorbidityandmortalityforboththeinpatientand
outpatientpopulation.Theriskofrecurrentthrombosisandembolizationishighestinthefirstfewdaysandweeks
followingdiagnosis.Initialanticoagulationduringthefirst5to10daysiscriticalinthepreventionofrecurrenceand
VTErelateddeath.
Theagentsused,timing,duration,anddosingofinitialanticoagulationforthetreatmentofDVTarediscussedin
thistopic.TheindicationsandoverviewofDVTtreatment,aswellaslongterm(3to12months)andextended
(indefinite)anticoagulationforpatientswithVTEarediscussedseparately.(See"Overviewofthetreatmentof
lowerextremitydeepveinthrombosis(DVT)",sectionon'Patientswithcontraindicationstoanticoagulation'and
"Lowerextremitydeepvenousthrombosis:Longtermanticoagulation(10daystothreemonths)"and"Rationale
andindicationsforindefiniteanticoagulationinpatientswithvenousthromboembolism".)
NOMENCLATUREForthepurposesofdiscussioninthistopic,thefollowingtermsapply:
Initialanticoagulationisadministeredoverthefirst5to10daysfollowingadiagnosisofDVT.Longterm
anticoagulanttherapyistypicallyadministeredforafiniteperiodbeyondtheinitialperiod,usuallythreetosix
monthsandoccasionallyupto12months.Extendedanticoagulationusuallyreferstotherapythatis
administeredindefinitely.(See"Lowerextremitydeepvenousthrombosis:Longtermanticoagulation(10days
tothreemonths)"and"Rationaleandindicationsforindefiniteanticoagulationinpatientswithvenous
thromboembolism".)
FactorXaanddirectthrombininhibitorshaveavarietyofnamesincludingnewer/noveloralanticoagulants,
nonvitaminKantagonistoralanticoagulants(NOAs,NOACs),andtargetspecificoralanticoagulants
(TOACs,TSOACs)[1].Throughoutthistopicwerefertotheseagentsbytheirpharmacologicclass,factor
Xaanddirectthrombininhibitors.(See"AnticoagulationwithdirectthrombininhibitorsanddirectfactorXa
inhibitors".)
INDICATIONSMostpatientswithultrasoundprovenproximalDVT(popliteal,femoral,oriliacveinDVT)and
selectcasesofdistalDVT(belowthekneeandinthecalfveinsperoneal,posterior,andanteriortibialDVT)
shouldbeanticoagulated.TheindicationtoanticoagulateisstrongerforpatientswithproximalDVTthanwith
distalDVTbecausetheriskofcomplications,particularlyembolization,ishigher.Althoughtheefficacyof
anticoagulanttherapyinpatientswithasymptomaticDVT(ie,incidentalDVT)isunknown,weandothersprefer
thatthispopulationofpatientsbemanagedoranticoagulatedinthesamemannerassymptomaticpatients[2].For
eachpatient,thedecisiontoanticoagulatemustweightheriskofmorbidityandmortalitywithoutanticoagulation
againsttheriskofbleedingonanticoagulation.Detailsoftheindicationsforanticoagulationarediscussed
separately.(See"Overviewofthetreatmentoflowerextremitydeepveinthrombosis(DVT)",sectionon
'Indications'.)
BLEEDINGRISKInallpatients,thedecisiontoanticoagulateshouldbeindividualizedandthebenefitsof
venousthromboembolism(VTE)preventioncarefullyweighedagainsttheriskofbleeding(table1).Mostclinicians
agreethatpatientswithathreemonthbleedingrisklessthan2percent(lowrisk)shouldbeanticoagulatedand
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thatthosewithableedingriskmorethan13percent(highrisk)shouldnotbeanticoagulated[3].Forpatientswith
ableedingriskbetweenthesevalues(moderaterisk),thereisnoagreementregardingthepreferredapproachsuch
thatthedecisiontoanticoagulateinthispopulationmustbeindividualizedaccordingtothevaluesandpreferences
ofthepatientaswellastheriskbenefitratio.Toolsareavailableforestimatingtheriskofbleedingin
anticoagulatedindividuals(eg,HASBLEDscore)(calculator1).However,noneofthesetoolshavebeenvalidated
inpatientsanticoagulatedforVTE,andnooneindexcanreliablypredictbleedingriskinaparticularpatientsuch
thatmanycliniciansuseagestaltestimateforassessingbleedingrisk.(See"Rationaleandindicationsfor
indefiniteanticoagulationinpatientswithvenousthromboembolism",sectionon'Assessingtheriskofbleeding'
and"ManagementofwarfarinassociatedbleedingorsupratherapeuticINR",sectionon'Bleedingrisk'.)
Absoluteandrelativecontraindicationstoanticoagulation,forwhichaninferiorvenacavafiltershouldbeplaced,
arediscussedseparately.(See"Overviewofthetreatmentoflowerextremitydeepveinthrombosis(DVT)",
sectionon'Patientswithcontraindicationstoanticoagulation'and"Overviewofthetreatmentoflowerextremity
deepveinthrombosis(DVT)",sectionon'Inferiorvenacavafilter'.)
SELECTIONOFAGENTInitialanticoagulationreferstosystemicanticoagulationadministeredforthefirst5
to10daysfollowingadiagnosisofDVT.WhenthedecisionismadetoanticoagulatepatientswithDVT,
anticoagulanttherapyshouldbestartedimmediatelyasadelaymaypotentiallyincreasetheriskoflifethreatening
embolization[4,5].Thechoiceofinitialanticoagulantisnotaffectedbytheindicationforanticoagulationorthe
absenceofsymptoms.
Optionsforinitialanticoagulationincludethefollowing:

Lowmolecularweight(LMW)heparin(see'Lowmolecularweightheparin'below)
Fondaparinux(see'Fondaparinux'below)
Unfractionatedheparin(UFH)(see'Unfractionatedheparin'below)
OralfactorXainhibitors(eg,rivaroxaban)(see'DirectfactorXaandthrombininhibitors'below)
Oraldirectthrombininhibitors(eg,dabigatran)(see'DirectfactorXaandthrombininhibitors'below)

WarfarincannotbeadministeredastheonlyinitialanticoagulantforthetreatmentofpatientswithDVT.The
choiceamongavailableagentsmustweighthebenefitsofeachtherapyagainsttherisksofbleedinginthecontext
ofthepatientscomorbidities,preferences,cost,andconvenience.Ingeneral:
Formostpatients,andinparticularforpatientswithactivecancerandpregnantwomen,wepreferLMW
heparinratherthanotheragents(UFH,fondaparinux,oralfactorXa,andoraldirectthrombininhibitors).
Heparinagents(LMWheparin,UFH)aretypicallypreferredovernoveloralanticoagulants(factorXaand
directthrombininhibitors)baseduponthelongerclinicalexperiencewiththemasinitialanticoagulants,as
wellastheiratleastpartialreversibilitywithavailableantidotes.Fondaparinuxisanacceptablealternativeto
LMWheparinfornonpregnantpatients.
Intravenous(IV)UFHisourpreferredagentforpatientswithsevererenalfailure(eg,creatinineclearance
<30mL/min)andforpatientsinwhomthereisahighlikelihoodthatacutereversalofanticoagulationwillbe
needed.Whilethismustbeadministeredintheinpatientsetting,IVUFHallowsforamorerapiddose
adjustmentandreversalthandosubcutaneous(SC)andoraltherapy.
OralanticoagulationwithadirectfactorXa(eg,rivaroxaban)orthrombin(eg,dabigatran)inhibitormaybean
acceptablealternativeforpatientswithnormalrenalfunctionwhowishtoavoidtheburdenofdailyinjections
whoarealsowillingtoaccepttheriskofbleedingonanirreversibleagent.Theiradministrationshouldbein
accordancewiththecriteriainclinicaltrialsthatdemonstratedtheirefficacy.Weprefertoadministerashort
courseofheparin(fivedays)priortotransitioningtodabigatranandedoxaban(dualtherapy),while
rivaroxabanandapixabancanbeusedasthesoleinitialanticoagulant(monotherapy).Inparticular,these
agentsareNOTsuitableforthetreatmentofhemodynamicallyunstablepulmonaryembolus(PE)ormassive
iliofemoralDVT(eg,phlegmasiaceruleadolens)wheretheirefficacyhasnotbeenadequatelystudiedand
theirusemayinterferewithpotentialthrombolytictherapyorsurgicalembolectomy.Similarly,inpatientswith
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cancerorpregnantwomen,theirsafetyandefficacyisunproven,and,assuch,theyshouldnotberoutinely
usedinthesepopulations.
TIMING,DURATION,ANDDOSINGForpatientswithproximalDVT,thegreatestriskofembolizationis
duringthefirstthreemonthsofanticoagulanttherapyand,inparticular,duringthefirstfewdaysfollowingthe
diagnosis.WhenthedecisionismadetoanticoagulatepatientswithDVT,anticoagulanttherapyshouldbestarted
immediatelyasadelaymaypotentiallyincreasetheriskoflifethreateningembolization.Baselinecoagulation
tests(prothrombintime,InternationalNormalizedRatio[INR],activatedpartialthromboplastintime[aPTT])should
bedrawnpriortotheinitiationofanticoagulationtoguidetherapy.Thetiming,duration,anddoseofinitial
anticoagulationvarywiththeagentselectedandarediscussedinthesectionsbelow.
Formostpatients,warfarinandheparinarestartedonthefirstday,andhepariniscontinuedforaminimumoffour
tofivedaysuntiltheINRhasbeenwithintherapeuticrangeforaminimumof24to48hours.Thereisnobenefitto
prolongedcoursesofsystemicheparinbeyondtheachievementofatherapeuticINR.(See'Transitioningto
maintenancetherapy'below.)
LowmolecularweightheparinAsdescribedabove,lowmolecularweight(LMW)heparinisourpreferred
anticoagulantformostpatientswithnewlydiagnosedDVT,inparticularforthosewithactivecancerorpregnancy.
(See'Selectionofagent'above.)
DosingTheinitialtherapeuticdoseofLMWheparin(eg,enoxaparin,dalteparin,tinzaparin)variesby
product.Dosingistypicallyweightbasedandrenallyadjusted,andallareadministeredsubcutaneously(SC).
Typicalstartingdosesare:
Enoxaparin1mg/kgtwicedaily(or1.5mg/kgoncedaily)
Dalteparin200units/kgoncedailyforthefirst30daysfollowedby150units/kgformaintenance
Tinzaparin175units/kgoncedaily(notavailableintheUnitedStates)
Dosingforobesepatientsandpatientswithrenalinsufficiencyislistedinthetables(table2andtable3).(See
"Therapeuticuseofunfractionatedheparinandlowmolecularweightheparin",sectionon'LMWheparin'.)
EfficacyEvidencefromseveralrandomizedtrialsandmetaanalyseshavereportedthat,comparedwith
intravenous(IV)andSCunfractionatedheparin(UFH),SCLMWheparinhashigherratesofthrombusregression
andlowerratesofrecurrentthrombosis,majorbleeding,andmortality[619].However,thedataarefraughtwith
methodologicflaws,includingpublicationbiasinfavorofLMWheparin.Thus,atminimum,LMWheparinappears
tobeassafeandaseffectiveasUFH(IVandSC).
Ina2010metaanalysisof23studiesthatcomparedLMWheparinwithIVorSCUFHinpatientswithacute
venousthromboembolism(VTEDVTand/orpulmonaryembolus[PE]),LMWheparinwasassociatedwith
thefollowing[15]:
Fewerthromboticcomplications(eg,recurrence,extension,embolization)(3.6versus5.3percentodds
ratio[OR]0.70,95%CI0.570.85)
Improvedthrombusregression(53versus45percentofparticipantsOR0.69,95%CI0.590.81)
Reducedratesofmajorhemorrhage(1versus2percentOR0.58,95%CI0.400.83)
Reducedmortality(4versus6percentOR0.77,95%CI0.630.93)
Anoldermetaanalysisof13studiesofpatientswithacuteVTEperformedbetween1980and1994reported
that,comparedwithUFH,LMWheparinwasassociatedwithalowerrateofbothrecurrentVTE(2.7versus
7percent)andmajorbleeding(0.9versus3.2percent)[9].
A1999metaanalysisof11trialsofpatientswithacuteDVTfoundalowermortalityrateatthreetosix
monthsamongpatientstreatedwithLMWheparin,comparedwiththosereceivingUFH(OR0.71,95%CI
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0.530.94)[13].Differencesinrecurrentthromboembolismandbleedingcomplicationswerenotdifferent
betweenthetwotreatments.
OncedailyregimensofLMWheparinappeartobeaseffectiveastwicedailyregimens.Metaanalysesoftrials
directlycomparingonceversustwicedailyadministrationfoundnodifferencesinrecurrentthrombosis,major
hemorrhage,ormortality[11,12,2025].Thelargeststudyof900patientswithsymptomaticDVT,athirdofwhom
alsohadPE,comparedtheLMWheparin,enoxaparin,administeredasastandardtwicedailyregimen(1mg/kg
twicedaily),withaloweroncedailyregimen(1.5mg/kgperday)[11].Althoughratesofrecurrence(3versus4
percent)andhemorrhage(1versus2percent)werelowerwiththetwicedailyregimen,thedifferencewasnot
significantandmayhavebeenexplainedbythelowertotaldailydoseadministeredintheoncedailytreatment
group.Exceptforenoxaparin,weprefer,whenoncedailydosingisbeingconsidered,thatitbeadministeredatthe
sametotaldailydoseasatwicedailyschedule.
TheLMWheparinshaveanumberofadvantagesoverunfractionatedheparin[26,27].(See"Therapeuticuseof
unfractionatedheparinandlowmolecularweightheparin",sectionon'Advantagesandlimitations'.)
GreaterbioavailabilitywhengivenbySCinjection.
Durationoftheanticoagulanteffectislonger,permittingonceortwicedailyadministration.
Fixeddosingisfeasiblebecausetheanticoagulantresponse(antiXaactivity)correlateswellwithbody
weight.
Laboratorymonitoringisnotnecessary(correlationbetweenantiXaactivityandbleedingorrecurrent
thrombosisispoor).
Lowerriskofheparininducedthrombocytopenia(HIT).
Useasanoutpatienttherapy.
DisadvantagesofLMWheparincomparedwithUFHincludethehighercost,and,althoughprotamineisan
antidoteforhemorrhage,itseffectisincomplete.Inaddition,efficacyislesscertainintheobesepopulation,in
patientswithrenalfailure,andinolderpatientswhoareunderweight(<45kg).LMWheparinshouldbeavoidedor
doseadjustmentsmadeinthesecircumstances(table2andtable3).(See"Therapeuticuseofunfractionated
heparinandlowmolecularweightheparin",sectionon'Othercomplications'and"Therapeuticuseofunfractionated
heparinandlowmolecularweightheparin",sectionon'Dosing'.)
LMWheparinalsoappearstobeaseffectiveasoncedailySCfondaparinux.(See'Fondaparinux'below.)
TrialsdirectlycomparingLMWheparinwithoralfactorXaanddirectthrombininhibitorsasinitialtherapiesfor
acuteDVThavenotbeenperformed.(See'DirectfactorXaandthrombininhibitors'belowand"Lowerextremity
deepvenousthrombosis:Longtermanticoagulation(10daystothreemonths)",sectionon'Directthrombinand
factorXainhibitors'.)
FondaparinuxAsdescribedabove,fondaparinuxisanacceptableanticoagulantchoiceformostnonpregnant
patientswithnewlydiagnosedDVT.(See'Selectionofagent'above.)
DosingFondaparinuxistypicallydosedaccordingtopatientweightas5mgoncedaily(<50kg),7.5mg
oncedaily(50to100kg),and10mg(>100kg).(See"Therapeuticuseoffondaparinux",sectionon
'Pharmacology'.)
EfficacyAlthoughSCfondaparinuxislesswellstudiedthaneitherLMWheparinorUFHinthissetting,
fondaparinuxappearstohaveasimilarefficacyandsafetyprofiletoLMWheparin[28].Onemulticentertrialof
2205patientswithacuteDVTwererandomizedtoreceivefondaparinux,7.5mgSConcedaily(5mginpatients
weighing<50kg10mg>100kg),orenoxaparin1mg/kgSCtwicedailywithwarfarin,foratleastfivedays.There
wasnodifferenceintherateofrecurrentthromboembolism(4percent),majorbleeding(1percent),ormortality
rates(3versus4percent)betweenthetwotreatments.Baseduponthistrial,the2012AmericanCollegeofChest
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PhysiciansAnticoagulationGuidelinesfortheinitialtreatmentofDVTsuggestfondaparinuxratherthanIVorSC
UFHasanalternativetoLMWheparin[3].(See'Selectionofagent'above.)
Thetherapeuticuseoffondaparinuxisdiscussedindetailseparately[28].(See"Therapeuticuseoffondaparinux",
sectionon'VTEinitialtreatment'.)
UnfractionatedheparinAsdescribedabove,UFHisourpreferredanticoagulantforpatientswithsevererenal
failure(eg,creatinineclearance<30mL/min)andforpatientsinwhomthereisahighlikelihoodthatacutereversal
ofanticoagulationwillbeneeded.(See'Selectionofagent'above.)
DosingInitialdosingofSCandIVUFHisalsoweightbased,butunaffectedbyrenalinsufficiency.We
preferweightbasedprotocols(table4)ratherthanfixeddoseprotocols(table5AB)becausetheymake
pharmacologicsenseandimprovetimespentwithinthetherapeuticrangefortheaPTT(targetrange1.5to2.5
timesthecontrol)[2931].
TheuseofheparinprotocolsmayincreasethetimespentinthetherapeuticrangefortheaPTT.Achievingand
maintainingatherapeuticaPTTrangecanbechallenging[3235].Asanexample,oneobservationalstudyreported
that60percentoftreatedpatientsfailedtoachieveanadequateaPTTresponseduringtheinitial24hoursof
therapyandthat30to40percentofpatientsremainedsubtherapeuticoverthenextthreetofourdays[33].These
observationsledtoprotocolsdesignedtoefficientlyachieveandmaintaintargetaPTTgoals.Commonlyused
protocolsare:
Weightbased(table4)[30]
Nonweightbased(table5AB)[31]
Thepreferenceforweightbasedprotocolsisprimarilybaseduponarandomizedtrialofamixedpopulationof
patientsrequiringIVUFHforseveraldifferentindications(venousandarterialthrombosis,unstableangina).Inthat
trial,aweightbasedheparindosingnomogram(table5AB)wascomparedwithanonweightbasednomogramto
maintainanaPTTratioof1.5to2.3timescontrolvalues(table4)[30].Patientstreatedwiththeweightadjusted
regimenreceivedastartingbolusdoseof80units/kgfollowedbyan18units/kgperhourinfusionsubsequent
adjustmentsweremadeeverysixhours.Patientsinthestandardcaregroupreceivedabolusof5000units
followedbya1000units/hourinfusionsubsequentfixeddoseadjustmentsweremadeeverysixhours.Ahigher
percentageofpatientsintheweightadjustedgroupachievedatherapeuticaPTTwithin24hours(97versus77
percent)withoutanincreaseinmajorbleeding.Recurrentthromboembolismwasmorefrequentinthenonweight
basedgroup(relativerisk5.0,95%CI1.121.9).Thisprotocolisgeneralizableandwidelyusedroutinelyinclinical
practice.
Althoughnotroutine,weightadjustedSCUFHhasbeenusedanecdotallyforpatientswhodeclineIVaccessand
haveacontraindicationtoLMWheparin.Onemetaanalysisof15randomizedtrialsofpatientswithDVTandPE
comparedSCUFHwithcontinuousIVUFHorSCLMWheparinforinitialanticoagulation[36].SCUFHwasas
effectiveandassafeasIVUFHandLMWheparin,althoughthisstudywasterminatedearlyduetopoorpatient
accrual.Typically,SCUFHisgivenasaweightbaseddosingof333units/kgloadingdosefollowedby250
units/kgevery12hours[37].
OptimaldosingofUFHinobesepatientsisunknown.Mostphysiciansuseidealbodyweighttoguidedosing
andincreasetheaPTTaccordinglytothetarget.Theclinicalefficacyofthisapproachisunknown.(See
"Bariatricsurgery:Intensivecareunitmanagementofthecomplicatedpostoperativepatient",sectionon
'Anticoagulantdosing'.)
AdditionaltherapeuticusesofUFHarediscussedindetailseparately.(See"Therapeuticuseofunfractionated
heparinandlowmolecularweightheparin",sectionon'Unfractionatedheparin'.)
EfficacyInthepast,IVUFHwasthegoldstandardforinitialanticoagulationinpatientswithDVTuntil
LMWheparinbecameavailable.ComparedwithLMWheparin,useofIVUFHisassociatedwithslightlyhigher
ratesofrecurrentthrombosisandmajorbleeding.ComparativestudiesbetweenLMWheparinandIVUFHare
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discussedindetailseparately.(See'Selectionofagent'aboveand'Lowmolecularweightheparin'above.)
TheefficacyofIVUFHdependsuponachievingacriticaltherapeuticlevelassoonaspossible,preferablywithin
thefirst24hoursoftreatment,usuallyviaacontinuousIVinfusion[14,30,3842].Thecriticaltherapeuticlevelof
heparin,asmeasuredbytheaPTT,isatargetaPTTratiorangeof1.5to2.5timesthecontrol.Thiscorrespondsto
aheparinlevelof0.3to0.7units/mL,whenmeasuredbyanantiXaassay[43,44].Studiesthatsupportthistarget
rangeincludethefollowing:
OneolderprospectivestudyofpatientswithacuteDVTreportedthat,comparedwithanaPTTratio>1.5,
patientswhohadanaPTTratio<1.5timesthecontrolforthreedayshadathreefoldincreaseintheriskof
recurrentthrombosis[38].
ApooledanalysisofthreerandomizedtrialsexaminedtherapeuticorsubtherapeuticUFH(mostlyIVUFH)
foracuteproximalDVT[42].ComparedwithpatientswhoseaPTTexceededthetherapeuticthresholdby24
hours,failuretoachieveatherapeuticaPTTduringthattimewasassociatedwithanincreasedrateof
recurrentthrombosis(23percentversus4percent).
AlthoughthereisastrongcorrelationbetweensubtherapeuticaPTTvaluesandrecurrentthromboembolism,the
relationshipbetweensupratherapeuticaPTT(ie,anaPTTratio2.5ormore)andbleedingislessdefinite[31].
Nonetheless,aimingforatherapeuticrangewiththeavoidanceofperiodsofbothsubtherapeuticand
supratherapeuticlevelsisprudent.
TheadvantagesofUFHcomparedwithLMWheparinincludeitslowercostanditssafeuseinthosewithrenal
insufficiency.AnadditionaladvantageoftheIVformulationisitsshorthalflife,particularlyforpatientsinwhom
thereisapotentialneedforacutediscontinuation(eg,surgery).DisadvantagesincludethatinfusionsofUFH
requirehospitaladmission,andbothSCandIVUFHareassociatedwithahigherpotentialforHIT.(See
"Therapeuticuseofunfractionatedheparinandlowmolecularweightheparin",sectionon'Othercomplications'.)
DirectfactorXaandthrombininhibitors
DosingWeadvocatefortheuseoforalfactorXa(rivaroxaban,apixaban,edoxaban)ordirectthrombin
inhibitors(dabigatran)inaccordancewithcriteriainclinicaltrialsthatdemonstratedtheirefficacy.Theseagents
areattractivecandidatesasinitialanticoagulantsinpatientswithacuteDVTduetotheirquickonsetofaction
(peakefficacyonetofourhoursafteringestion).Intrialsthatevaluateddabigatranandedoxaban,allpatientswere
treatedwithfivedaysofheparinpriortotheiradministration(ie,"dualtherapy"initialanticoagulation)assuch,we
preferthatashortcourseofheparinbeadministeredbeforetransitioningtoeitherdabigatranoredoxaban.In
contrast,rivaroxabanandapixabanwereevaluatedasanticoagulantswithoutprioradministrationofheparin(ie,
monotherapy)ourclinicalexperienceisinkeepingwiththedatathatsupporttheiruseasthesoleinitial
anticoagulant.Importantly,anticoagulanttherapywithheparinshouldnotbedelayedwhilethedecisionisbeing
madetotreatwithoneoftheseneweroralagents.(See'Selectionofagent'above.)
Manyoftheseagentsarerenallyexcreted,andpatientswithacreatinineclearanceof<25to30mL/minutewere
excludedfrommanyofthetrialsthattestedtheirsafety.Assuch,webelievethatpatientswiththisdegreeof
renalinsufficiencyshouldnotbeconsideredfortheseagents.Thedistributionofagentandanticoagulanteffectin
theobesepopulationisunknown.(See"AnticoagulationwithdirectthrombininhibitorsanddirectfactorXa
inhibitors"and"Managementofbleedinginpatientsreceivingdirectoralanticoagulants"and"Lowerextremitydeep
venousthrombosis:Longtermanticoagulation(10daystothreemonths)",sectionon'Directthrombinandfactor
Xainhibitors'.)
Typicalinitialdosesare:
Rivaroxaban15mgtwicedaily(forthefirstthreeweeks)
Apixaban10mgtwicedaily(forfirstsevendays)
Edoxaban60mgoncedaily(and30mgoncedailyinpatientswithacreatinine30to50mL/minuteorabody
weightbelow60kg)
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Dabigatran150mgtwicedaily
Maintenancedosesforlongtermanticoagulationarediscussedseparately.(See"Anticoagulationwithdirect
thrombininhibitorsanddirectfactorXainhibitors"and"Lowerextremitydeepvenousthrombosis:Longterm
anticoagulation(10daystothreemonths)",sectionon'DirectthrombinandfactorXainhibitors'.)
Inkeepingwiththeclinicaltrialsthatdemonstratedtheirefficacy,inpatientswhoarereceivingheparinasthe
initialanticoagulant,wepreferthatoralfactorXaordirectthrombininhibitorsbegivenwithin6to12hours
followingthelastdoseofSCLMWheparinwhenadministeredasatwicedailyregimen,orwithin12to24hours
foroncedailyregimens.InfusionsofUFHcanbeimmediatelydiscontinuedfollowingtheadministrationofthese
oralagents.(See"Lowerextremitydeepvenousthrombosis:Longtermanticoagulation(10daystothreemonths)",
sectionon'Transitioningtolongtermtherapy'.)
TheefficacyandsafetyoffactorXaanddirectthrombininhibitorsasanticoagulantsforextensiveDVT(eg,
patientswithphlegmasiaceruleadolens)orhemodynamicallysignificantpulmonaryembolusareunknown,and,as
such,theyshouldNOTbeusedinthesepatientpopulationswheretheirusemayinterferewiththepotential
administrationofthrombolytictherapy.Similarly,becausetheirsafetyandefficacyisunproven,wepreferthat
theseagentsNOTbeadministeredinpatientswhoarepregnantorinpatientswithactivemalignancy.(See
"Overviewofthetreatmentoflowerextremitydeepveinthrombosis(DVT)",sectionon'Phlegmasiacerulea
dolens'and"Fibrinolytic(thrombolytic)therapyinacutepulmonaryembolismandlowerextremitydeepvein
thrombosis"and"Deepveinthrombosisandpulmonaryembolisminpregnancy:Treatment"and"Treatmentof
venousthromboembolisminpatientswithmalignancy".)
EfficacyRandomizedtrialsoftheseoralagentsinpatientswithacuteDVTexaminedefficacyandsafetyin
thecontextoflongtermanticoagulationwiththesameoralagentforthreemonthsormore.Whencomparedwith
conventionalcoursesofLMWheparinorIVUFHfollowedbylongtermanticoagulationwithwarfarin,theseagents
hadsimilarratesofrecurrentthrombosisandmajorhemorrhage[4548].However,trialsthatreportedefficacyfor
dabigatran(directthrombininhibitor)andedoxaban(factorXainhibitor)usedaminimumoffivedaysof
anticoagulationwithLMWheparinorUFHpriortotheiradministrationforlongtermoraltherapy(ie,dualtherapy)
[47,48].Incontrast,trialsofrivaroxabanandapixabanreportedefficacyofbothagentsasthesoleinitial
anticoagulant(monotherapy).Althoughshortperiods(<48hours)ofheparinwereallowedpriortorandomization,
ourexperiencewiththeseagentsisinkeepingwiththedatathatsuggestmonotherapywiththeseagentsissafe
andeffective.Detailsofthetrialsthatreportedthesafetyandefficacyoftheseagentsforthelongtermtreatment
ofVTEarediscussedseparately.(See"Lowerextremitydeepvenousthrombosis:Longtermanticoagulation(10
daystothreemonths)",sectionon'DirectthrombinandfactorXainhibitors'.)
DurationoftherapyforheparinWhenadministeredtogetherwithwarfarinonday1,thereisnobenefitto
prolongedcoursesofsystemicheparinbeyondatherapeuticINR.Randomizedtrialshavereportedthatshorter
coursesofheparintherapy(typicallyfourtofivedays)plusinitiationofwarfarinonday1isaseffectiveaslonger
coursesofheparin(10to14days)withthedelayedinitiationofwarfarin(eg,startingday5to10)[2,29,49].Asan
example,inonerandomizedtrialofpatientstreatedwithparenteralheparinforproximalDVT,theinitiationof
warfarinonday1oftherapywasassociatedwithanequivalentthreemonthrateofrecurrentVTEwhencompared
withwarfarinstartedonday5to10oftherapy(7percenteach)[2].Thisapproachhastheaddedadvantageof
minimizingthetotalnumberofdaysthatapatientrequiresanticoagulationwithheparin,therebyreducingtherisk
ofHIT[26].Inclinicalpractice,thesameapproachisacceptableforpatientstakingSCLMWheparin,UFH,and
fondaparinux.
Detailsoftransitioningtolongtermmaintenancetherapyarediscussedseparately.(See'Transitioningto
maintenancetherapy'below.)
EMPIRICANTICOAGULATIONThedecisiontoempiricallyanticoagulatewhilewaitingfordiagnostictest
resultsdependsupontheclinicalsuspicionforDVT(table6)andtheexpectedtimingofdiagnostictests.In
general,empiricanticoagulationisadministeredtothoseinwhomthesuspicionforDVTishighandissafeto
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withholdwhenthesuspicionislow,providedtestingisnotdelayedfor>24hours[3].Empiricanticoagulationmay
beconsideredforthoseinwhomthesuspicionisassessedasintermediate,particularlywhentestingisexpected
tobedelayedformorethanfourhours.Forempiricanticoagulation,weprefertherapeuticlowmolecularweight
(LMW)orunfractionatedheparin(UFH)forasshortaperiodasisfeasible,providedtherearenocontraindications.
ThediagnosisofDVTisdiscussedseparately.(See"Diagnosisofsuspecteddeepveinthrombosisofthelower
extremity".)
SPECIALPOPULATIONSWhenchoosinganinitialanticoagulant,patientswithmalignancy,pregnantwomen,
outpatients,andthosewithahistoryofheparininducedthrombocytopenia(HIT)deservespecialconsideration.
MalignancyFormostpatientswithmalignancyandDVTwhohaveareasonablelifeexpectancyandadequate
renalfunction(creatinineclearance30mL/min),lowmolecularweight(LMW)heparinisthepreferredagentfor
initialanticoagulation,ratherthanotheragents.ThereisinsufficientevidencetosupporttheuseoffactorXaand
directthrombininhibitorsinpatientswithmalignancyatthistime.Thisisdiscussedinmoredetailseparately.(See
"Treatmentofvenousthromboembolisminpatientswithmalignancy".)
PregnancyForpregnantwomenwithacuteDVT,adjusteddosesubcutaneous(SC)LMWheparinisthe
preferredagentforinitialanticoagulationbecauseithasamorefavorablesafetyprofile,especiallywhencompared
withwarfarin.Warfarinfreelycrossestheplacentalbarrierandcanproduceanembryopathywhengivenbetween
thesixthandninthweeksofpregnancy.Intravenous(IV)andSCformsofunfractionatedheparin(UFH)are
alternativestoLMWheparin.FactorXaanddirectthrombininhibitorshavenotbeenadequatelytestedinpregnant
womenwithacuteDVTandshouldnotbeadministered.(See"Deepveinthrombosisandpulmonaryembolismin
pregnancy:Treatment"and"Useofanticoagulantsduringpregnancyandpostpartum".)
OutpatientsNotallpatientswhohaveacuteDVTneedtobeadmittedtothehospitalforinitialanticoagulation.
SeveralrandomizedtrialsandmetaanalysesthathavecomparedoutpatienttherapywithSCLMWheparinwith
inpatienttherapywithIVUFHsuggestthat,inselectpopulations,treatmentathomewithLMWheparinissafe
andeffective.MostcliniciansagreethatoutpatienttherapywithLMWheparincanbeconsideredin
hemodynamicallystablepatientswithalowbleedingrisk,whohaveapracticalsysteminplaceforthe
administrationandsurveillanceofanticoagulanttherapy,whoarealsowithoutrenalinsufficiency,massiveDVT,
concurrentpulmonaryembolism,orothercomorbidconditionsthatrequireinpatientcare(table7).Thedecisionto
anticoagulateasanoutpatientshouldbemadeinthecontextofthepatientsunderstandingoftheriskbenefitratio,
preferences,andclinicalcondition.TheoutpatienttreatmentofDVTandpulmonaryembolismarediscussed
separately.(See"Overviewofthetreatmentoflowerextremitydeepveinthrombosis(DVT)",sectionon
'Outpatienttherapy'and"Overviewofthetreatment,prognosis,andfollowupofacutepulmonaryembolismin
adults",sectionon'Outpatientanticoagulation'.)
HeparininducedthrombocytopeniaForpatientswithaDVTandapriordiagnosisofHIT,anyformofheparin
iscontraindicated.ThisincludessystemicUFH,LMWheparin,heparinflushes,heparinbondedcatheters,and
heparincontainingmedications.Immediateanticoagulationwithanonheparinanticoagulant(eg,argatroban,
danaparoid,fondaparinux,bivalirudin)isindicated(table8).ThediagnosisandmanagementofpatientswithHIT
arediscussedindetailseparately.(See"Clinicalpresentationanddiagnosisofheparininducedthrombocytopenia"
and"Managementofheparininducedthrombocytopenia".)
TRANSITIONINGTOMAINTENANCETHERAPYTherapeuticanticoagulationshouldbeensuredduringthe
transitionfrominitialtolongterm(maintenance)therapy.Theoptimaltransitionstrategyvarieswiththelongterm
anticoagulantchosen.
Whenwarfarinischosenastheagentforlongtermanticoagulation,itistypicallystartedonthesamedaywith
lowmolecularweight(LMW)heparin,unfractionatedheparin(UFH),orfondaparinuxanddoseadjusteduntilthe
InternationalNormalizedRatio(INR)iswithinthetherapeuticrange(2to3target2.5)foraminimumof24to48
hours[50].Typicalstartingdosesofwarfarinare5mg/dayfortwodays(range2mgto10mg/day)(table9).Initial
dosesatthelowerrange(2to5mg/day)maybeconsideredinthoseassessedathighbleedingrisk(eg,older
adults),anddosesinthehigherrange(5to10mg/day)maybeselectedinhealthyindividualswhoarewithout
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obviousriskforbleeding.SubsequentdoseadjustmentsaremadetotargetanINRof2to3.Initialdosingand
maintenancetherapyforwarfarinarediscussedseparately.(See"TherapeuticuseofwarfarinandothervitaminK
antagonists",sectionon'Warfarinadministration'and"Lowerextremitydeepvenousthrombosis:Longterm
anticoagulation(10daystothreemonths)",sectionon'Warfarin'.)
WhensubcutaneousLMWheparinandfondaparinuxarechosenforlongtermanticoagulationandtheyhavenot
beenchosenastheinitialanticoagulant,theycanbeadministeredsubcutaneously(SC)andintravenous(IV)UFH
immediatelydiscontinued.OralfactorXaordirectthrombininhibitorsaregenerallygivenwithin6to12hours
followingthelastdoseofatwicedailyregimenofSCLMWheparin,within12to24hoursforoncedailyregimens,
anduponthediscontinuationoftheIVUFHinfusion.Transitioningfrominitialtomaintenancetherapyand
switchinganticoagulantsduringtherapyarediscussedindetailseparately.(See"Lowerextremitydeepvenous
thrombosis:Longtermanticoagulation(10daystothreemonths)",sectionon'Transitioningtolongtermtherapy'
and"Lowerextremitydeepvenousthrombosis:Longtermanticoagulation(10daystothreemonths)",sectionon
'Transitioningduringtherapy'.)
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(DVT)(BeyondtheBasics)".)
BeyondtheBasicstopics(see"Patientinformation:Deepveinthrombosis(DVT)(BeyondtheBasics)"and
"Patientinformation:Warfarin(Coumadin)(BeyondtheBasics)")
SUMMARYANDRECOMMENDATIONS
Initialanticoagulationreferstosystemicanticoagulationadministeredforthefirst5to10daysfollowinga
diagnosisofdeepvenousthrombosis(DVT).Anticoagulationshouldbestartedimmediatelyasadelay
increasestheriskofembolizationanddeath.Thechoiceofinitialanticoagulationisthesameforpatients
withproximal,distal,symptomatic,andasymptomaticDVT.(See'Nomenclature'above.)
EverypatientwithacuteDVTshouldbeassessedfortheriskofbleedingpriortoanticoagulation.Most
cliniciansagreethatanticoagulationshouldbeadministeredtopatientswithalowriskofbleedingand
avoidedinthoseathighrisk.Forpatientswithamoderateriskofbleeding,thedecisiontoanticoagulate
mustbeindividualizedaccordingtothevaluesandpreferencesofthepatientaswellastheriskbenefitratio
asassessedbytheclinician.(See'Bleedingrisk'aboveand"Overviewofthetreatmentoflowerextremity
deepveinthrombosis(DVT)",sectionon'Assessingbleedingrisk'and"Managementofwarfarinassociated
bleedingorsupratherapeuticINR",sectionon'Bleedingrisk'.)
ForpatientswithacuteDVT,treatmentoptionsforinitialanticoagulationincludethefollowing:lowmolecular
weight(LMW)heparin,fondaparinux,unfractionatedheparin(UFH),andoralfactorXaanddirectthrombin
inhibitors.Ingeneral:
Formostpatients,wesuggestLMWheparinratherthanotheragents(fondaparinux,intravenous[IV]
UFH,factorXaordirectthrombininhibitors)(Grade2B).Fondaparinuxisanacceptablealternativefor
nonpregnantpatients.AdecisionbetweenLMWheparinandfondaparinuxisusuallymadebasedon
clinicianexperienceandavailability.Dosingisindividualizedforeachproduct.(See'Selectionofagent'
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aboveand'Lowmolecularweightheparin'aboveand'Fondaparinux'above.)
Forpatientswithsevererenalfailure(eg,creatinineclearance<30mL/min),orforpatientsinwhom
thereisahighlikelihoodofneedingtoacutelydiscontinueorreverseanticoagulation,wesuggestIV
UFHratherthanLMWheparin(Grade2C).Aweightbasedprotocolispreferablyusedtoadminister
UFHatadosesufficienttoprolongtheactivatedpartialthromboplastintime(aPTT),withatargetaPTT
ratioof1.5to2.5overthecontrol(table4).(See'Selectionofagent'aboveand'Unfractionatedheparin'
above.)
OralfactorXa(rivaroxaban,apixaban,edoxaban)anddirectthrombininhibitors(dabigatran)are
alternativeagentsinpatientswithnormalrenalfunctionwhowishtoavoidtheburdenofdaily
injections,whoarewillingtoaccepttheriskofirreversiblebleeding.Wepreferthattheiradministration
beinaccordancewiththecriteriainclinicaltrialsthatdemonstratedtheirefficacy.Ourpreferenceisto
administerashortcourseofheparin(fivedays)priortotransitioningtodabigatranandedoxaban(dual
therapy),whilerivaroxabanandapixabancanbeusedassoleinitialanticoagulants(monotherapy).
Dosingisindividualizedforeachproduct.(See'Selectionofagent'aboveand'DirectfactorXaand
thrombininhibitors'above.)
Fullanticoagulationshouldbeensuredduringthetransitionfrominitialtolongterm(maintenance)therapy.
Formostpatients,warfarinandheparinarestartedonthefirstday,andhepariniscontinuedforaminimum
offourtofivedaysuntiltheInternationalNormalizedRatio(INR)hasbeenwithintherapeuticrange(2to3
target2.5)foraminimumof24to48hours.LMWheparinandfondaparinuxcanbeadministered
subcutaneously(SC)andIVUFHimmediatelydiscontinued.OralfactorXaordirectthrombininhibitorsare
generallygivenwithin6to12hoursfollowingthelastdoseofatwicedailyregimenofSCLMWheparin,
within12to24hoursforoncedailyregimens,anduponthediscontinuationofIVUFHinfusion.(See
'Transitioningtomaintenancetherapy'above.)
Specificinitialanticoagulantsforuseinspecialpopulationsincludethefollowing:
Forpatientswithmalignancyandpregnantwomen,wesuggestthatLMWheparinbeselectedasthe
initialanticoagulantratherthanotheragents(Grade2C).FactorXaanddirectthrombininhibitorshave
notbeenadequatelytestedinthesepopulationsand,assuch,shouldnotbeadministered.(See
"Treatmentofvenousthromboembolisminpatientswithmalignancy"and"Deepveinthrombosisand
pulmonaryembolisminpregnancy:Treatment".)
Outpatientanticoagulationratherthaninpatienttherapycanbeconsideredwhenpatientsare
hemodynamicallystable,havealowriskofbleeding,donothaverenalinsufficiency,andhavea
practicalsysteminplaceathomefortheadministrationandsurveillanceofanticoagulanttherapy(table
7).ItisnotappropriateinpatientswithmassiveDVT(eg,iliofemoralDVT,phlegmasiaceruleadolens),
concurrentpulmonaryembolism,ahighriskofbleedingonanticoagulanttherapy,comorbidconditions,
orotherfactorsthatwarrantinhospitalcare.(See"Overviewofthetreatmentoflowerextremitydeep
veinthrombosis(DVT)",sectionon'Outpatienttherapy'.)
ForpatientswithaDVTandapriordiagnosisofheparininducedthrombocytopenia(HIT),heparinis
contraindicated,andimmediateanticoagulationwithanonheparinanticoagulant(eg,argatroban,
danaparoid,fondaparinux,bivalirudin)isindicated(table8).(See"Managementofheparininduced
thrombocytopenia".)
UseofUpToDateissubjecttotheSubscriptionandLicenseAgreement.
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Topic95336Version7.0

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GRAPHICS
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(%)
Moderaterisk (1
riskfactor)

Highrisk (2risk
factors)

0.6

1.2

4.8

Increasedrisk
(%)

Totalrisk(%)

1.6

3.2

12.8

0.3

0.6

2.5

0.5

0.8**

1.6**

6.5

Categorizationof
riskofbleeding

Lowrisk (0risk
factors)

Anticoagulation0to3months

Baselinerisk
(%)

Anticoagulationafterfirst3months

Baselinerisk
(%/years)
Increasedrisk
(%/years)
Totalrisk
(%/years)

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*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.
Graphic97160Version2.0

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Suggesteddosesoflowmolecularweightheparinsinobesepatients

Enoxaparin*

VTE
treatment

Acute
coronary
syndromes

VTE
prophylaxis

Official
prescribing
information
onusein
obese
patients

Usestandard
treatmentdosing

Unstableangina
ornonSTEMI:

BMI30to39
kg/m 2:Use

Marginalincrease
observedinmean

(ie,1mg/kgevery
12hoursbasedon
ABW).

Usestandard
treatmentdosing
(ie,1mg/kgevery

Inpatientswitha
BMI40kg/m 2,a
lowerdose(ie,
0.74mg/kgevery
12hours,based

12hoursbasedon
ABW)as
alternativetoUFH
forpatientsnot
undergoingan

standard
prophylaxisdosing
(ie,30mgevery
12hoursor40
mgoncedaily).

antifactorXa
activityusing
actualbodyweight
[ABW]andonce
dailydosingin

BMI40
kg/m 2:
Empirically

onABW),was
suggestedina
smallcaseseries
basedonpeak
antifactorXa
levels,buthasnot

earlyinvasive
approach.

healthyobese
persons(BMI30
to48kg/m 2)
comparedwith
nonobese
persons. [3]

beenclinically
evaluated. [1]
Oncedailydosing
regimensof
enoxaparinare
not
recommended.

increasestandard
prophylaxisdose
by30percent(ie,
to40mgevery12
hours).

STEMI(for
patientsnot
managedwith
PCI):

HighVTErisk
bariatricsurgery
withBMI50

Age<75years:
Usestandard
dosing(ie,1
mg/kgevery12
hoursbasedon
ABWaftersingle

kg/m 2:40mg
every12hours.
[4,5]
HighVTErisk

intravenousbolus
of30mg
maximumdoseof
100mgforfirst
twosubcutaneous
dosesonly).

[2,3]

bariatricsurgery
withBMI>50
kg/m 2:60mg
every12hours.
[5]

Age75years:
Usereduced
dosing(ie,0.75
mg/kgevery12
hoursbasedon
ABWmaximum
doseof75mgfor
firsttwodoses
only). [2,3]
Dalteparin

Approvedbythe

Unstableangina

BMI30to39
2

UseABWbased

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USFDAonlyfor
extended

ornonSTEMI:

treatmentof
cancerassociated
VTE.Usestandard
treatmentdosing
(ie,200units/kg
oncedailybased

treatmentdosing
(ie,120units/kg
every12hours
basedonABW).

Usestandard

onABWforthe
firstmonth,
followedby150
units/kgoncedaily
forsubsequent

kg/m 2:Use
standard

dosingforpatients

prophylaxisdosing
(ie,2500or5000

kg(acutecoronary
syndromes)or99
kg(cancer
associatedVTE).
Useamaximum

unitsoncedaily).
BMI40
kg/m 2:
Empirically
increasestandard
prophylaxisdose
by30percent(ie,
increaseto3250
or6500units
oncedaily). [2]

months).

Considerusing
100units/kg
every12hours
basedonABWfor
patientsweighing
>100kg. [4]
Tinzaparin
(not
availablein
theUnited
States)

Usestandard
treatmentdosing
(ie,175units/kg
oncedailybased
onABW).

Notindicated.

weighingupto90

doseof10,000
unitsperdosefor
patientsweighing
>90kg(acute
coronary
syndromes)or
18,000unitsper
dayforpatients
weighing>99kg
(cancerassociated
VTE). [7]

BMI30to39
kg/m 2:For
orthopedicsurgery
usestandard
prophylaxisdosing

Safetyandefficacy
inpatients
weighing>120kg
hasnotbeenfully
determined.

(ie,50or75anti
factorXaunits/kg
basedonABW
oncedaily)for
generalsurgery

Individualized
clinicaland
laboratory
monitoringis
recommended

usestandardfixed
dosing(ie,3500
antifactorXa
unitsoncedaily).

(Canadaproduct
monograph). [8]

BMI40
kg/m 2:For
orthopedicsurgery
usestandard
prophylaxisdosing
(ie,50or75anti
factorXaunits/kg
basedonABW
oncedaily)for
generalsurgery
empirically
increasefixeddose
by30percent(ie,
increaseto4500
antifactorXa
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unitsonce
daily). [2]

Alldosesshownareforpatientswithnormalrenalfunctionandareforsubcutaneous
administration(exceptinitialintravenousbolusofenoxaparinfortreatmentofSTEMIin
patients<75yearsold).Fordoseadjustmentduetorenalimpairment,refertoindividual
Lexicompmonograph.
AntifactorXatesting:Clinicallystablepatientsweighingupto144kg(enoxaparin)or190
kg(dalteparin )or165kg(tinzaparin)withBMI<40kg/m 2 mayreceivelowmolecularweight
heparinforVTEtreatmentadjustedaccordingtoABWwithoutantifactorXatesting [6].
Generally,antifactorXamonitoringisnotrecommended,butitcanbeconsideredforpatients
withBMI40kg/m 2 whoareunstable,experienceunexpectedthromboembolicorbleeding
complications,orrequireprolongedVTEtreatment.
VTE:venousthromboembolismABW:actual(total)bodyweightSTEMI:STelevationmyocardial
infarctionUFH:unfractionatedheparinUSFDA:USFoodandDrugAdministration.
*Conversion:1mgenoxaparin100internationalunitsenoxaparin.
Accordingtothedalteparinprescribinginformation,afixeddoseof18,000unitsperdayis
recommendedforpatientsweighing>99kgwhoarebeingtreatedforcancerassociatedVTE.However,
guidelinessuggestthatdalteparindoseshouldbebasedonactualbodyweight [2] .Cappeddalteparindose
of18,000unitsperdayisnotrecommended.
Empiricdoseadjustmentisapproximateandroundingofdosemaybeneededdependingonproduct
detail.RefertoLexicompmonographincludedwithUpToDate.
Anempiricdoseincreaseof30percentforfixedprophylacticofdosesoflowmolecularweightheparin
forVTEprophylaxisforpatientswhoaremorbidlyobeseisbasedonexpertopinionandanalysisof
pharmacodynamicandclinicaloutcomesdata [2] .
References:
1.DealEN,HollandsJM,RineyJN,etal.Evaluationoftherapeuticanticoagulationwithenoxaparin
andassociatedantiXamonitoringinpatientswithmorbidobesity:acaseseries.JThromb
Thrombolysis201132:188.
2.NutescuEA,SpinlerSA,WittkowskyA,etal.Lowmolecularweightheparinsinrenalimpairment
andobesity:availableevidenceandclinicalpracticerecommendationsacrossmedicalandsurgical
settings.AnnPharmacother200943:1064.
3.Lovenox(enoxaparinsodium)injectionUSprescribinginformationJune,2013revisionavailableat
USNIHDailyMedwebsitehttp://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=5017a927
2a244f2789f927c805bf7d59(AccessedOctober15,2013).
4.ScholtenDJ,HoedemaRM,ScholtenSE.Acomparisonoftwodifferentprophylacticdoseregimens
oflowmolecularweightheparininbariatricsurgery.ObesSurg2002,12:19.
5.BorkgrenOkonekMJ,HartRW,PantanoJE,etal.Enoxaparinthromboprophylaxisingastric
bypasspatients:extendedduration,dosestratification,andantifactorXaactivity.SurgObesRelat
Dis20084:625.
6.GarciaDA,BaglinTP,WeitzJI,etal.Parenteralanticoagulants:AmericanCollegeofChest
PhysiciansEvidenceBasedClinicalPracticeGuidelines(9thEdition).Chest2012141:e24S.
7.Fragmin(dalteparinsodiuminjection)USprescribinginformationOctober,2010revisionavailable
atUSNIHDailyMedwebsitehttp://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=c5cd4a8e
14c0440bb4539f3d3250c951(AccessedOctober15,2013).
8.Innohep(tinzaparinsodium)CanadaproductmonographApril,2011revisionavailableatHealth
Canadawebsitehttp://webprod5.hcsc.gc.ca/dpdbdpp/indexeng.jsp(AccessedOctober15,
2013).
Graphic65464Version12.0
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Suggesteddoseadjustmentsoflowmolecularweightheparinsin
renalinsufficiencyforadults

Dalteparin

VTEtreatment
Cl cr 30mL/min:Noadjustment

VTEprophylaxis*
Cl cr 20mL/min:Noadjustment

Cl cr 20to29mL/min:Dueto
variableresponse,adjustdosebased
uponantifactorXalevels
Enoxaparin

Cl cr 30mL/min:Noadjustment

Cl cr 30mL/min:Noadjustment

Cl cr 20to29mL/min:Reduceto1
mg/kgoncedaily

Cl cr 20to29mL/min:Reduceto
30mgoncedaily(medicalorsurgical
patients)

Nadroparin

Cl cr 50mL/min:Noadjustment

Cl cr 50mL/min:Noadjustment

(notavailablein
US)

Cl cr 30to50mL/min:Reducedose
by25to33percent(optional)

Cl cr 30to50mL/min:Reducedose
by25to33percent(optional)

Cl cr <30mL/min:Contraindicated

Cl cr 20to29mL/min:Reducedose
by25to33percent

Tinzaparin

Cl cr 30mL/min:Noadjustment

Cl cr 30mL/min:Noadjustment

(notavailablein
US)

Cl cr 20to29mL/min:Not
adequatelystudied.Patientsage70
yearsseematelevatedmortalityrisk.
Ifused,adjustmentofdosebased
uponantifactorXalevelsisadvised.

SuggesteddoseadjustmentofLMWheparinsforreducedrenalfunction.Alldosinginthis
tablereferstosubcutaneousdosing.Cautionshouldbeusedinallpatientswithrenal
insufficiency,andpatientsshouldbeobservedforsignsofbleeding.RepeateddosesofLMW
heparintopatientswithrenalinsufficiencymayleadtoaccumulationandincreasedriskof
bleedingtovaryingdegrees.Incontrast,unfractionatedheparinisnotdependentprimarily
uponrenalfunctionforclearanceandmaybeapreferredoptionforpatientswithCl cr <20
mL/min,kidneyfailure,orreceivingdialysis.UseofLMWheparininpatientswithrenal
insufficiencyhasbeenassociatedwithhyperkalemia.RefertotheUpToDatetopicsontheuse
ofheparinandLMWheparininspecificclinicalconditionsforspecificindications.Dose
adjustmentforrenalinsufficiencyinacutecoronarysyndromesandmyocardialinfarctionis
discussedinUpToDatetablesonthoseconditions.RefertoUpToDatecontentoninfantsand
childrenfordosinginthesegroups.
LMWheparin:lowmolecularweightheparinVTE:venousthromboembolismCl cr :creatinineclearance

asdeterminedbyCockcroftGaultequation,acalculatorisavailableinUpToDate.
*ForshorttermVTEprophylaxis(ie,upto10days).Forlongtermuse,periodicantifactorXaactivity
testingmaybeusefultoruleoutdrugaccumulation.
AntifactorXaactivitylevelsshouldbemeasuredfourtosixhoursafterdosing,afterthethirdorfourth
dose.Thefollowingtargetrangeshavebeensuggested:
Dalteparin:0.5to1.5antifactorXaunits/mL(target1.05)inoncedailyuse
Nadroparin:0.6to1antifactorXaunits/mLintwicedailyuse1.3antiXaunits/mLinoncedailyuse
Tinzaparin:0.85antifactorXaunits/mLinoncedailyuse
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(Garciaetal.Chest2012141:e24S)
Dosingsuggestedinprescribinginformationotherapproachesincludingdoseadjustmentbasedon
antifactorXaactivityarediscussedinUpToDatetopicsonuseofLMWheparin.
Datafrom:
1.Dalteparinsodiuminjection.USFDAapprovedprescribinginformation(revisedJanuary,2015).
Availableathttp://www.accessdata.fda.gov/drugsatfda_docs/label/2015/020287s062lbl.pdf
2.Enoxaparinsodiuminjection.USFDAapprovedprescribinginformation(revisedOctober,2013).
Availableat:at:http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/020164s102lbl.pdf
3.Nadroparincalciuminjection.Canadaproductmonograph(revisedFebruary,2015).Availableat
http://webprod5.hcsc.gc.ca/dpdbdpp/indexeng.jsp
4.Tinzaparinsodiuminjection.Canadaproductmonograph(revisedMay,2014).Availableat
http://webprod5.hcsc.gc.ca/dpdbdpp/indexeng.jsp
Graphic90258Version3.0

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Exampleofaweightbasednomogramforintravenous
unfractionatedheparininfusionfortreatmentofvenous
thromboembolismand/orpulmonaryembolism
Initialdose

80units/kgbolus,then18units/kgperhour*

aPTTresult

Action

NextaPTT

aPTT<35seconds
(<1.2xcontrol)

80units/kgbolus,then
increaseinfusionrateby4
units/kgperhour

6hours

aPTT35to45
seconds(1.2to1.5
xcontrol)

40units/kgbolus,then
increaseinfusionrateby2
units/kgperhour

6hours

aPTT46to70
seconds (1.5to
2.3xcontrol)

Nochange(therapeuticrange)

6hours(whentwoconsecutivevaluesare
withintherapeuticrange,thennextaPTT
inmorning)

aPTT71to90

Decreaseinfusionrateby2

6hours

seconds(2.3to3.0
xcontrol)

units/kgperhour

aPTT>90seconds
(>3.0xcontrol)

Holdinfusion1hour,then
decreaseinfusionrateby3

6hours

units/kgperhour

aPTT:activatedpartialthromboplastintime.
Thistableisprovidedasanexampleofalocallydevelopedandvalidated
unfractionatedheparinweightbaseddoseadjustmentnomogram.Itreflectsthe
originalaPTTranges,bolussizes,andsuggestedchangesininfusionratethatwerepresentat
thetimethestudywasperformed. [1]Thetherapeuticranges(ie,relationshipbetweenthe
aPTTandantifactorXaactivity),initialandsubsequentbolussizes,andsizesoftheinfusion
ratechanges,aswellasdosingdifferencesdependingonthedisorderundertreatment(eg,
venousthromboembolism,stroke,acutecoronarysyndrome)shouldbeestablishedseparately
foreachinstitution.
*Useoftotalbodyweight(TBW)issuggestedforcalculatingtheinitialbolusdoseandinfusionratefor
mostobesepatients.Foradditionalinformationreferto"Managementofthecriticallyillobesepatient",
section"Anticoagulants".
TherapeuticaPTTrangeof46to70secondscorrespondedtoantiXaactivityof0.3to0.7units/mL.
ThetargetaPTTrangeinaparticularinstitutionshouldreflectwhatisknownaboutthelocalreagents
andequipmenttoperformtheassay [2] .
ThefirstaPTTshouldbeobtained4to6hoursaftertheinitialheparinbolus.
References:
1.RaschkeRA,ReillyBM,GuidryJR,etal.Theweightbasedheparindosingnomogramcompared
witha"standardcare"nomogram.Arandomizedcontrolledtrial.AnnInternMed1993119:874.
2.GarciaDA,BaglinTP,WeitzJIA,etal.ParenteralAnticoagulants:Antithrombotictherapyand
PreventionofThrombosis,AmericanCollegeofChestPhysiciansEvidenceBasedClinicalPractice
Guidelines(9thEdition).Chest2012141:e24Se43S.
Graphic58483Version8.0
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Exampleofanonweightbasedintravenousheparinprotocol:PartI
Initialintravenousheparinbolus:5000units.
Continuousintravenousheparininfusion:commenceat42mL/hourof20,000units(1680
units/hour)in500mLoftwothirdsdextroseandonethirdsaline(a24hourheparindoseof
40,320units),exceptinthefollowingpatients,inwhomheparininfusionwillbecommencedata
rateof31mL/hour(1240units/hour)(ie,a24hourdoseof29,760units).
Patientswhohaveundergonesurgerywithintheprevioustwoweeks.
Patientswithaprevioushistoryofpepticulcerdisease,gastrointestinalorgenitourinarybleeding.
Patientswith(thrombotic)strokewithintheprevioustwoweeks.
Patientswithaplateletcount<150,000/microL.
Patientswithmiscellaneousreasonsforahighriskofbleeding(eg,hepaticfailure,renalfailure,or
vitaminKdeficiency).

HeparindoseadjustedusingtheaPTT.TheaPTTisperformedinallpatientsasoutlinedbelow:
4to6hoursaftercommencingheparintheheparindoseisthenadjustedaccordingtothenomogram
showninHeparinProtocolIIuntiltheaPTTiswithinthetherapeuticrange.
Thereafter,theaPTTwillbeperformedoncedaily.Ifthevalueisoutsidethetherapeuticrange,the
heparindoseisthenadjustedaccordingtothenomogramshowninHeparinProtocolIIuntiltheaPTT
iswithinthetherapeuticrange.

Adaptedfrom:HullRD,RaskobGE,RosenbloomD,etal.Optimaltherapeuticlevelofheparintherapyin
patientswithvenousthrombosis.ArchInternMed1992152:1589.
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Exampleofanonweightbasedintravenousheparinprotocol:Part
IItitrationbasedupontheactivatedpartialthromboplastintime
IVinfusion
Ratechange,
mL/hour*

aPTT

Dosechange,
units/24hour

Additionalaction

45

+6

+5760

RepeatedaPTT in4
to6hours

46to54

+3

+2880

RepeatedaPTTin4to
6hours

55to85

None

86to110

2880

Stopheparinsodium
treatmentfor1hour
repeatedaPTT4to6
hoursafterrestarting
heparintreatment

>110

5760

Stopheparin
treatmentfor1hour
repeatedaPTT4to6
hoursafterrestarting
heparintreatment

NOTE:ThistablereflectstheoriginalaPTTranges,bolussizes,andsuggestedchangesin
infusionratethatwerepresentatthetimethisstudywasperformed.Thetherapeuticranges
(ie,relationshipbetweentheaPTTandantifactorXaactivity),initialandsubsequentbolus
sizes,andsizesoftheinfusionratechanges,aswellasdosingdifferencesdependingonthe
disorderundertreatment(eg,venousthromboembolism,stroke,acutecoronarysyndrome)
shouldbeestablishedseparatelyforeachinstitution.
aPTT:activatedpartialthromboplastintimeIV:intravenous.
*Heparinsodiumconcentration,20,000unitsin500mL=40units/mL.
WiththeuseofActinFSthromboplastinreagent(Dade,Mississauga,Ontario).
Duringthefirst24hours,repeatedaPTTin4to6hours.Thereafter,theaPTTwillbedeterminedonce
daily,unlesssubtherapeutic.
Redrawnfrom:HullRD,RaskobGE,RosenbloomD,etal.Optimaltherapeuticlevelofheparintherapyin
patientswithvenousthrombosis.ArchInternMed1992152:1589.
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Pretestprobabilityofdeepveinthrombosis(Wellsscore)
Clinicalfeature

Score

Activecancer(treatmentongoingorwithintheprevioussixmonthsorpalliative)

Paralysis,paresis,orrecentplasterimmobilizationofthelowerextremities

Recentlybedriddenformorethanthreedaysormajorsurgery,withinfourweeks

Localizedtendernessalongthedistributionofthedeepvenoussystem

Entirelegswollen

Calfswellingbymorethan3cmwhencomparedtotheasymptomaticleg(measured
belowtibialtuberosity)

Pittingedema(greaterinthesymptomaticleg)

Collateralsuperficialveins(nonvaricose)

Alternativediagnosisaslikelyormorelikelythanthatofdeepvenousthrombosis

Score
Highprobability

3or
greater

Moderateprobability

1or2

Lowprobability

0orless

Modification:
Thisclinicalmodelhasbeenmodifiedtotakeoneotherclinicalfeatureintoaccount:apreviously
documenteddeepveinthrombosis(DVT)isgiventhescoreof1.Usingthismodifiedscoring
system,DVTiseitherlikelyorunlikely,asfollows:
DVTlikely

2or
greater

DVTunlikely

1orless

Adaptedfrom:
1.WellsPS,AndersonDR,BormanisJ,etal.Valueofassessmentofpretestprobabilityofdeepvein
thrombosisinclinicalmanagement.Lancet1997350:1795
2.WellsPS,Anderson,DR,RodgerM,etal.EvaluationofDdimerinthediagnosisofsuspecteddeep
veinthrombosis.NEnglJMed2003349:1227.
Graphic75871Version2.0

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Minimalrequirementsforearlyhospitaldischargeoroutpatient
therapyofvenousthromboembolicdisease
Theresponsiblephysicianmustensurethatallofthefollowing
conditionsapply:
Thepatientisambulatoryandinstablecondition,withnormalvitalsigns
Thereisalowaprioririskofbleedinginthepatient
Severerenalinsufficiencyisnotpresent
Thereisapracticalsysteminplaceforthefollowing:
AdministrationofLMWheparinand/orwarfarinwithappropriatemonitoring,and
SurveillanceandtreatmentofrecurrentVTEandbleedingcomplications

VTE:venousthromboembolismLMWheparin:lowmolecularweightheparin.

AdaptedfromHyers,TM,Agnelli,G,Hull,RD,etal.Antithrombotictherapyforvenousthromboembolic
disease.Chest2001119:176S.(SixthACCPConsensusConferenceonAntithromboticTherapy).
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2012ACCPrecommendedtreatmentofheparininduced
thrombocytopenia(HIT)
ThefollowingnonheparinagentsarerecommendedforuseinacuteHITwhetherornot
complicatedbythrombosis:argatrobanordanaparoid.Argatrobanissuggestedoverdanaparoid
inthosewithrenalinsufficiency.(Editor'snote:Lepirudinisnolongeravailable).
InpregnantpatientswithHIT,theuseofdanaparoidissuggestedoverothernonheparin
anticoagulants.Theuseoffondaparinuxissuggestedonlyifdanaparoidisnotavailable.
InpatientswithantibodypositiveHITwhorequireurgentcardiacsurgery,theuseofbivalirudinis
suggestedoverothernonheparinanticoagulants.InpatientswithantibodypositiveHITwho
requirepercutaneouscoronaryinterventions,theuseofbivalirudinorargatrobanissuggestedover
othernonheparinanticoagulants.
WarfarinaloneshouldnotbeusedtotreatHITbecauseoftheriskofcausingvenouslimb
gangreneand/orskinnecrosis.
Warfarinissafetousewhenitisgiventoapatientadequatelyandstablyanticoagulatedwitha
drugthatreducesthrombingeneration(eg,danaparoid,argatroban)itisprudenttodelayuseof
warfarinuntiltheplateletcountis>150,000/microL.
LMWHshouldnotbegiventopatientswithHIT,whetherornotcomplicatedbythrombosis.
ProphylacticplatelettransfusionsshouldnotbeadministeredforthetreatmentofpatientswithHIT
whodonothaveactivebleeding.
ACCP:AmericanCollegeofChestPhysiciansDVT:deepvenousthrombosisLMWH:lowmolecularweight
heparin.
AdaptedfromLinkinsLA,etal.Treatmentandpreventionofheparininducedthrombocytopenia:
Antithrombotictherapyandpreventionofthrombosis,9thedition:AmericanCollegeofChestPhysicians
Evidencebasedclinicalpracticeguidelines.Chest2012141:e495S.
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Suggestedprotocolforinitiatingwarfarintherapy
Daysofwarfarintreatment

INR<1.5

INR1.5
to1.9

INR2.0
to3.0

INR>3.0

Suggestedinitialdosefordays1and2
Normaladult

5mg*

n/a

n/a

n/a

Frailadult,malnourished,elderly,
liverdisease

2.5mg*

n/a

n/a

n/a

Day3

5to10mg

2.5to5mg

0to2.5mg

Nodose

Day4

10mg

5to7.5mg

0to5mg

Nodose

Day5

10mg

7.5to10
mg

0to5mg

Nodose

Day6

7.5to12.5
mg

5to10mg

0to7.5mg

Nodose

Dosingforday3andbeyond

Inthisprotocol,whichisprovidedforguidanceonly,suggesteddosesofwarfarinafterday2
aregivenasranges.TheclinicianmustjudgetherapidityandmagnitudeofINRchangesfor
theindividualpatientandmakedosageadjustmentsaccordingly.Analgorithmformonitoring
andadjustmentofmaintenancewarfarinispresentedseparately.RefertoUpToDatetopicson
useofwarfarinandtableonsuggestedprotocolforadjustmentofmaintenancewarfarin.
n/a:notapplicable.
*ThistableassumesthatthepatienthasstartedwithanINRinthenormalrange.
Seetextfordetailsconcerningthesourceforthisprotocolandrelevantreferences.
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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)].LawrenceLKLeung,MDNothingtodisclose.JessMandel,MDNothingtodisclose.GeraldineFinlay,MD
Nothingtodisclose.
Contributordisclosuresarereviewedforconflictsofinterestbytheeditorialgroup.Whenfound,theseareaddressedbyvettingthrougha
multilevelreviewprocess,andthroughrequirementsforreferencestobeprovidedtosupportthecontent.Appropriatelyreferenced
contentisrequiredofallauthorsandmustconformtoUpToDatestandardsofevidence.
Conflictofinterestpolicy

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