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Warfarin
Updated2015Feb2609:46:00AM:poorerkidneyfunctionassociatedwithincreasingriskof
majorbleeding,especiallyinfirst30days,whenstartingwarfarininelderlypatientswithatrial
fibrillation(BMJ2015Feb3)viewupdate Showmoreupdates
RelatedSummaries:
Anticoagulation(listoftopics)
VitaminKantagonistmanagement
Warnings
GeneralInformation
Description:
Anticoagulantacoumarinderivative.211330
Class:
Class:CoumarinDerivatives
UsesandEfficacy
Uses:
DVTandPE:
Treatmentandsecondarypreventionofvenousthromboembolism(DVTand/orPE).2115001005
Initiateconcomitantlywithaparenteralanticoagulant(e.g.,alowmolecularweightheparin[LMWH],
heparin[referringthroughoutthismonographtounfractionatedheparin],fondaparinux).1005Overlap
parenteralandoralanticoagulanttherapyfor5daysanduntilastableINRof2hasbeen
maintainedfor24hours,thendiscontinueparenteralanticoagulant.10001005
AnticoagulanttherapygenerallynotrecommendedfortreatmentofisolateddistalDVTunless
symptomsaresevereandthereisariskforthrombusextension.1005
TheAmericanCollegeofChestPhysicians(ACCP)recommendsamoderateintensityof
anticoagulation(targetINR2.5,range23)formostpatientswithDVTorPE.10001005
Appropriatedurationoftherapydeterminedbyindividualfactors(e.g.,locationofthrombi,presence
orabsenceofprecipitatingfactors,presenceofcancer,patient'sriskofbleeding).1005Formost
casesofvenousthromboembolism,aminimumof3monthsofanticoagulanttherapyis
recommended.2113301005Longtermanticoagulation(>3months)maybeconsideredinselected
patients(e.g.,thosewithidiopathic[unprovoked]DVTorPEwhoareatlowriskofbleeding,cancer
patientswithDVTorPE).1005(SeeDosageunderDosageandAdministration.)
Warfaringenerallyisthepreferredanticoagulantforlongtermtreatmentofvenous
thromboembolisminpatientswithoutcancerhowever,inpatientswithcancer,ACCPsuggestsuse
ofanLMWHoverwarfarinbecauseofcertainfactorsinsuchpatientsthatmayaffectwarfarin
therapy(e.g.,possiblereducedresponsetowarfarin,druginteractions,needforinvasiveprocedures
thatrequirereversalofanticoagulation).1005
UsedinselectpediatricpatientswithDVTorPE.1013LMWHsorheparingenerallyrecommended
forbothinitialandongoingtreatmentofvenousthromboembolisminchildrenhowever,warfarin
maybeindicatedinsomesituations(e.g.,recurrentidiopathicvenousthromboembolism).1013
Treatmentandsecondarypreventionofvenousthromboemboliceventssecondarytouseofcentral
venousaccessdevices(CVAD)inchildren.1013RemoveaffectedCVADifnolongerfunctioningor
requiredhowever,ifCVADrequired,ACCPsuggestsgivinganticoagulantsuntilcatheterisremoved.
1013
Afterinitial3monthsoftherapy,mayconsideruseofprophylacticdosewarfarin(targetINR
1.51.9)however,therapeuticdosagesmayberequiredifrecurrentthromboembolismoccurs.1013
OrthopedicSurgery:
Preventionofpostoperativevenousthromboembolisminpatientsundergoinghiporknee
replacementsurgeryorhipfracturesurgery.1003
ACCPrecommendsroutinethromboprophylaxis(withapharmacologicand/ormechanicalmethod)in
allpatientsundergoingmajororthopedicsurgery(hiporkneereplacementsurgery,hipfracture
surgery).1003Continuethromboprophylaxisforatleast1014days,andpossiblyforupto35days
aftersurgery.1003
Severalantithromboticagents(e.g.,LMWHs,fondaparinux,lowdoseheparin,warfarin,aspirin)
recommendedbyACCPforpharmacologicthromboprophylaxisinpatientsundergoingmajor
orthopedicsurgery.1003AlthoughLMWHsgenerallypreferred,alternativeagents(e.g.,warfarin)may
beconsideredifanLMWHisnotavailableorcannotbeused(e.g.,inpatientswithheparininduced
thrombocytopenia[HIT]orinthosewhorefuseorareuncooperativewithsubQinjections).1003
Whenselectinganappropriatethromboprophylaxisregimen,considerfactorssuchasrelative
efficacy,bleedingrisk,logistics,andcompliance.1003
EmbolismAssociatedwithAtrialFibrillation:
Preventionofstrokeandsystemicembolisminpatientswithatrialfibrillation.
223 278 279 369 456 459 500 990 999 1007 1017
ACCP,theAmericanCollegeofCardiology(ACC),AmericanHeart
Association(AHA),andotherexpertsrecommendantithrombotictherapy(e.g.,warfarin,aspirin)in
patientswithpersistent,permanent,orparoxysmalatrialfibrillationwhoareconsideredtobeat
increasedriskofstroke.2232782793694564599909929991007
Choiceofantithrombotictherapyisbasedonpatient'sriskforstroke.3413453694599991007Ingeneral,
oralanticoagulanttherapy(traditionallywarfarin)isrecommendedinpatientswithhighriskfor
strokeaspirinisrecommendedinlowriskpatientsandthosewithcontraindicationstooral
anticoagulanttherapy.2113303353413443453494569909991007AHAandASAstatethatoral
anticoagulationisnotrecommendedinwomen65yearsofagewithatrialfibrillationandnoother
riskfactorsinstead,antiplatelettherapyisareasonableoptioninselectedlowriskwomen.1017
Patientsatincreasedriskofstrokegenerallyincludethosewithahistoryofstroke,TIA,orsystemic
embolism,andthosewith2ofthefollowingriskfactors:advancedage(e.g.,75years),history
ofhypertension,diabetesmellitus,orseverelyimpairedleftventricularsystolicfunctionand/orheart
failure.5009991007Inaddition,populationbasedstudiessuggestthatfemalesexisanimportantrisk
factorforstrokeinpatientswithatrialfibrillation,particularlyinpatients75yearsofage.1017
Inpatientswithatrialfibrillationatincreasedriskofstrokewhocannottakeorchoosenottotake
oralanticoagulantsforreasonsotherthanconcernsaboutmajorbleeding(e.g.,thosewithdifficulty
maintainingstableINRs,complianceissues,dietaryrestrictions,costlimitations),combination
therapywithclopidogrelandaspirinratherthanaspirinaloneisrecommended.9981007
Antiplateletagentsmaybeusedincombinationwithwarfarintherapyinselectedpatientswhohave
coexistingconditionsthatwarrantuseofantiplatelettherapy(e.g.,thosewithrecentplacementof
anintracoronarystent,thosewithacutecoronarysyndrome).1007
AHAandASAstatethatapixaban,dabigatran,orrivaroxabanmaybeausefulalternativeto
warfarinforthepreventionofstrokeandsystemicthromboembolisminselectedwomenwith
paroxysmalorpermanentatrialfibrillationandcertainriskfactorswhodonothaveaprosthetic
heartvalveorhemodynamicallyimportantvalvedisease,severerenalfailure(creatinineclearance
<15mL/minute),1038lowerbodyweight(<50kg),oradvancedliverdisease(impairedbaseline
clottingfunction).1017
Expertssuggestmanagingantithrombotictherapyinpatientswithatrialflutterinthesamemanner
asinpatientswithatrialfibrillation.9991007
CardioversionofAtrialFibrillation/AtrialFlutter:
Preventionofembolizationinpatientsundergoingpharmacologicorelectricalcardioversionofatrial
fibrillation.3419991007
ACCPandotherexpertsrecommendthatpatientswithatrialfibrillationlasting>48hoursorof
unknowndurationwhoaretoundergoelectivecardioversionreceivetherapeuticanticoagulation
(e.g.,usuallywithwarfarin)for3weekspriortocardioversionalternatively,atransesophageal
echocardiography(TEE)guidedapproachmaybeused.9991007Aftersuccessfulcardioversion,all
patientsshouldreceivetherapeuticanticoagulationfor4weeks.9991007
EmbolismAssociatedwithValvularHeartDisease:
Preventionofthromboembolismassociatedwithvarioustypesofvalvularheartdisease,in
combinationwithorasanalternativetolowdoseaspirinassessriskofthromboembolismversus
riskofbleedingwhendeterminingchoiceofantithrombotictherapy.3444591008
Warfarinanticoagulation(INR23)isrecommendedinpatientswithrheumaticmitralvalvedisease
andconcurrentatrialfibrillation,leftatrialthrombus,orahistoryofsystemicembolism.10071008
ACCPsuggestswarfarinanticoagulationinpatientswithrheumaticmitralvalvediseaseandnormal
sinusrhythmwhohavealeftatrialdiameter>5.5cmbecauseoftheirhighriskofdevelopingatrial
fibrillation.1008
WarfarinalsorecommendedbyACCandAHAforpreventionofthromboemboliceventsinselected
patientswithmitralvalveprolapseandahistoryofstrokewhohaveconcomitantatrialfibrillation,
mitralvalveregurgitation,orleftatrialthrombus.996
Generallyshouldnotinitiateantithrombotictherapyinpatientswithinfectiveendocarditisinvolvinga
nativevalvebecauseoftheriskofserious(e.g.,intracerebral)hemorrhageandlackofdocumented
efficacy.1008Inpatientswithaprostheticvalvewhoarealreadyreceivingwarfarin,ACCPsuggests
temporarydiscontinuanceofthedrugifinfectiveendocarditisdevelopsandreinitiationoftherapy
onceinvasiveproceduresnolongerrequiredandpatientisstabilizedwithoutsignsofneurologic
complications.1008
Usedinalimitednumberofpatientsundergoingpercutaneousballoonmitralvalvotomytoprevent
leftatrialembolism.1008
ThromboembolismAssociatedwithProstheticHeartValves:
Usedtoreducetheincidenceofthromboembolism(e.g.,stroke)inpatientswithprosthetic
mechanicalorbiologicalheartvalves.2113303413423433701008
Riskofsystemicembolismhigherwithmechanicalversusbioprostheticvalves,higherwithfirst
generationmechanical(e.g.,cagedball,cageddisk)valvesversusnewermechanical(e.g.,bileaflet,
MedtronicHalltiltingdisk)valves,higherwith>1prostheticvalve,andhigherwithprostheticmitral
versusaorticvalvesriskalsoincreasesinthepresenceofatrialfibrillation.3413423433701008
Longtermwarfarintherapyrequiredinallpatientswithmechanicalheartvalvesbecauseof
associatedhighriskofthromboembolism.2113303704599961008
Warfarinanticoagulationalsosuggestedinpatientswithmitralbioprostheticvalves,atleastforthe
first3monthsaftervalveinsertion.1008Inpatientswithaorticbioprostheticvalveswhoareinsinus
rhythmandhavenootherindicationsforwarfarintherapy,aspiringenerallysuggestedforinitial
(e.g.,first3monthsaftervalveinsertion)andlongtermantithrombotictherapy.9961008However,
longtermwarfarintherapy(INR2.5,range23)maybeindicatedinsomepatientswith
bioprostheticheartvalveswhohaveadditionalriskfactorsforthromboembolism(e.g.,atrial
fibrillation,priorthromboembolism,leftventriculardysfunction,hypercoagulablestates).996
Ingeneral,targetINRof2.5(range23)issuggestedinpatientswithanaorticmechanicalvalve,
whiletargetINRof3(range2.53.5)isrecommendedinthosewithamitralmechanicalvalve.
500 1008 996Ahigherintensityofwarfarinanticoagulationalsomaybeconsideredinpatientswithboth
aorticandmitralmechanicalvalves.1008
ACCPrecommendsaddinglowdoseaspirin(e.g.,50100mgdaily)towarfarintherapyinall
patientswithmechanicalheartvalveswhoareatlowriskofbleeding.1008Combinationtherapyalso
maybewarrantedinsomepatientswithbioprostheticvalves(e.g.,thosewithadditionalriskfactors
forthrombosis).996
STSegmentElevationMI(STEMI):
Usedasadjunctivetherapywithantiplateletagents(e.g.,aspirin,clopidogrel)duringandafter
successfulcoronaryarteryreperfusionforthepreventionofearlyreocclusionanddeathinpatients
withacuteSTEMI.2112262422432442452462472482492502512523303504324825009921010
Ingeneral,antiplatelettherapyispreferredtoanticoagulantsforsecondarypreventionandrisk
reductioninpatientswithatherosclerosis,includingthosewithacuteMIhowever,warfarin(in
combinationwithlowdoseaspirin)maybeindicatedinselectedpatients(e.g.,thosewithatrial
fibrillation,prostheticheartvalve,leftventricularthrombus,orconcomitantvenousthromboembolic
disease).9921010
Themanufacturerandotherexpertsrecommendwarfarintherapy(targetINR23)inconjunction
withlowdoseaspirin(100mgdaily)for3monthsfollowingacuteMIinhighriskpatients(e.g.,
thosewithlargeanteriorMI,substantialheartfailure,intracardiacthrombusvisibleontransthoracic
echocardiography,atrialfibrillation,historyofpreviousthromboembolicevent).3505001010Triple
therapywithwarfarin,lowdoseaspirin,andclopidogrelissuggestedinsomepatients(e.g.,those
withanteriorMIandleftventricularthrombus).1010
CerebralEmbolism:
Oralanticoagulationwithwarfarinoroneoftheneweroralanticoagulants(e.g.,apixaban,
dabigatran,rivaroxaban)isrecommendedforsecondarypreventionofcerebralembolisminpatients
withTIAsorischemicstrokeandconcurrentatrialfibrillation,providednocontraindicationsexist.
335 338 349 352 432 999 1009 1017
Warfarinalsoisusedforpreventionofrecurrentstrokeinpatientsathighriskforrecurringcerebral
embolismfromothercardiacsources(e.g.,prostheticmechanicalheartvalves,recentMI,left
ventricularthrombus,dilatedcardiomyopathies,maranticendocarditis,extensivewallmotion
abnormalities).33533834943210081010
Antiplateletagentsgenerallypreferredoveroralanticoagulationforsecondarypreventionof
noncardioembolicstrokeinpatientswithahistoryofischemicstrokeorTIA.1009
ACCP,AHA,andASAgenerallyrecommendoralanticoagulationwithwarfarinfollowinginitialtherapy
withheparinoranLMWHinpatientswithacutecerebralvenoussinusthrombosis.10091017AHA
andASArecommendpostpartumanticoagulationwithwarfarin(targetINRof23)asanalternative
toLMWHforatleast6weeks(foratotalminimumdurationof6monthsofanticoagulanttherapy)
followingLMWHtherapyduringpregnancyinwomenwithcerebralvenoussinusthrombosis.1017
WarfarinissuggestedbyACCPasanoptionforlongtermanticoagulationinchildrenwitharterial
ischemicstrokeassociatedwithdissectionoracardioemboliccause.1013Warfarinalsohasbeen
usedinchildrenwithcerebralvenoussinusthrombosiswhodonothavesubstantialintracranial
hemorrhage.1013
ArterialOcclusiveDisease:
Hasbeenusedincertainpatientswithperipheralarterialocclusivedisease.1011However,ACCP
generallyrecommendsuseofantiplateletagents(aspirinorclopidogrel)forprimaryorsecondary
preventionofcardiovasculareventsinpatientswithperipheralarterialdisease.1011
IndefiniteanticoagulationwithwarfarinrecommendedbyACCPinallpatientswithchronic
thromboembolicpulmonaryhypertension.1005
HeparinInducedThrombocytopenia:
Maybeusedasfollowuptherapyafterinitialtreatmentwithanonheparinanticoagulant(e.g.,
lepirudin,argatroban)inpatientswithHIT.1006Overlaptherapywithwarfarinandnonheparin
anticoagulantfor5daysanduntildesiredINRhasbeenachieved.1006
DonotinitiatewarfarininpatientswithHITuntilsubstantialplateletrecoveryoccurs(e.g.,platelet
count150,000/mm3)inpatientsalreadyreceivingwarfarinatthetimeofHITdiagnosis,ACCP
suggestsadministrationofvitaminK.1006(SeeNecrosisunderCautions.)
Efficacy:
TreatmentofVenousThromboembolism:
Warfarinefficacyfortreatmentofvenousthromboembolism:
warfarinfor3monthsaftercalfveinthrombosisassociatedwithreducedrecurrence
riskat3monthsand1year(level2[midlevel]evidence)
basedonsmallrandomizedtrialwithoutblinding
51patientswithsymptomaticcalfveinthrombosisrandomizedtowarfarinfor3monthsvs.no
warfarin
allpatientshadinitialheparinandcompressionstockings
comparingwarfarinvs.nowarfarin
recurrentvenousthromboembolism(VTE)at3monthsin0%vs.29%(p<0.01,NNT4)
recurrentVTEat1yearin4%vs.32%(p<0.02,NNT4)
ReferenceLancet1985Sep72(8454):515
Comparativeefficacyfortreatmentofvenousthromboembolism:
comparisonswithunfractionatedheparin
adjusteddosewarfarinassociatedwithlowerrecurrenceriskbutmorebleeding
comparedtolowdosesubcutaneousheparinafteracutedeepveinthrombosis(DVT)
(level2[midlevel]evidence)
basedonrandomizedtrialwithoutblinding
68patientswithacuteDVTtreatedwithIVheparinandrandomizedtoadjusteddose
warfarinvs.fixedlowdosesubcutaneousheparin
comparingwarfarinvs.lowdoseheparin
recurrentvenousthromboembolismin0%vs.26%(p=0.001,NNT4)
bleedingin20%vs.0%(p<0.005,NNH5)
ReferenceNEnglJMed1979Oct18301(16):855
comparisonswithlowmolecularweightheparin(LMWH)
lowmolecularweightheparinmaybeassafeandeffectiveasvitaminKantagonists
forlongtermmanagementofvenousthromboembolism(level2[midlevel]
evidence)
basedonCochranereviewoftrialswithmethodologiclimitations
systematicreviewof15randomizedtrialscomparinglowmolecularweightheparin(LMWH)
vs.vitaminKantagonistsforlongtermtreatmentofsymptomaticvenousthromboembolism
in3,197patients
alltrialslackedblindingofpatientsandpersonnelandmosthadunclearallocation
concealment
vitaminKantagonistsincludedwarfarin,acenocoumarol,coumarin,andphenprocoumon
LMWHincludedenoxaparin,tinzaparin,dalteparin,bemiparin,nadroparinandreviparin
LMWHassociatedwith
nonsignificantdecreaseinrecurrentsymptomaticvenousthromboembolism(oddsratio
[OR]0.82,95%CI0.591.13)inanalysisof15trials,butresultspossiblyconfoundedby
differencesininitialtreatmentregimen
decreasedmajorbleeding(OR0.5,95%CI0.310.79)inanalysisof15trials,butonly
trendtowarddecreasedmajorbleedinginanalysislimitedtohighqualitytrials
nosignificantdifferenceinmortality(OR1.06,95%CI0.741.54)inanalysisof15trials,but
wideconfidenceintervalcannotexcludeclinicallyrelevantdifferences
ReferenceCochraneDatabaseSystRev2012Oct17(10):CD002001
EBSCOhostFull
Text
longtermtreatmentwithlowmolecularweightheparinmayreduceriskof
recurrentvenousthromboembolismbutnotmortalitycomparedtovitaminK
antagonistsinpatientswithcancerandsymptomaticvenousthromboembolism
basedonCochranereviewoftrialswithunclearornoblinding
systematicreviewof10randomizedtrialscomparinglongtermtreatmentwithlow
molecularweightheparin(LMWH)vs.oralanticoagulants(vitaminKantagonistor
ximelagatran)in1,981patientswithcancerandsymptomaticvenousthromboembolism
(VTE)
comparingLMWH(enoxaparin,tinzaparin,dalteparin,nadroparin)tovitaminKantagonists
LMWHassociatedwithreductioninrecurrentVTEinanalysisof5trialswith1,162
patients
riskratio0.5(95%CI0.350.71)
NNT1125withrecurrentVTEin14%ofvitaminKantagonistgroup
nosignificantdifferencesin
mortalityinanalysisof6trialswith1,310patients
majorandminorbleedinginanalysesof4trialswith<1,000patients(resultsfor
minorbleedinglimitedbysignificantheterogeneity)
ReferenceCochraneDatabaseSystRev2014Jul8(7):CD006650
EBSCOhostFull
Text
longtermtinzaparinhometherapymaybeaseffectiveasinitialtinzaparinfollowed
bywarfarinfordeepveinthrombosis(level2[midlevel]evidence)
480patientswithacuteproximaldeepveinthrombosisrandomizedtotinzaparinhome
therapyvs.usualcare
tinzaparinhometherapywastinzaparin175units/kgsubcutaneouslyoncedailyfor12
weeks
usualcarewastinzaparinfor5daysplusoralwarfarinfor12weeks
legulcersin0.5%oftinzaparinhometherapygroupcomparedto4.1%ofusualcaregroup
(p=0.02,NNT28)
tinzaparinhometherapyassociatedwithsignificantlygreaterpatientsatisfaction
nosignificantdifferencesinmortality,recurrentvenousthromboembolism,orbleeding
ReferenceAmJMed2009Aug122(8):762
comparisonswithdabigatran
dabigatranisaseffectiveaswarfarinwithlowerrateofbleedingfollowing
parenteralanticoagulationfortreatmentofacutevenousthromboembolism(level1
[likelyreliable]evidence)
basedon2randomizednoninferioritytrials
2,564patients(meanage55years)withacutesymptomaticVTEandnormalrenalfunction
randomizedtodabigatran150mgorallytwicedailypluswarfarinlikeplacebovs.warfarin
plusdabigatranlikeplacebofor6months
warfarinwasdoseadjustedtoachieveINR23
allpatientsinitiallygivenparenteralanticoagulationtherapyformedian9days
primaryoutcomewastimetofirstoccurrenceofcompositeofsymptomaticVTEorVTE
relateddeath
noninferioritycriteriondefinedasupperlimitof95%CIforhazardratio<2.75and
upperlimitof95%CIforriskdifference<3.6%
modifiedintentiontotreatanalysisexcluded25(1%)patientsnotstartingstudydrug
comparingdabigatranvs.warfarin
symptomaticVTEorVTErelateddeathat6monthsin2.3%vs.2.2%(noninferiority
met)
symptomaticdeepveinthrombosisin1.3%vs.1.4%(notsignificant)
symptomaticnonfatalpulmonaryembolismin1%vs.0.6%(notsignificant)
deathrelatedtoVTEin0.1%vs.0.2%(notsignificant)
anydeathin1.6%vs.1.7%(notsignificant)
majorbleedingepisodesin1.6%vs.1.9%(notsignificant)
anybleedingepisodesin16.1%vs.21.9%(p<0.05,NNT18)
adverseeventsleadingtodiscontinuationofstudydrugin9%vs.6.8%(p=0.05)
nosignificantdifferencesinacutecoronarysyndromesorabnormalliverfunctiontests
ReferenceRECOVERtrial(NEnglJMed2009Dec10361(24):2342),commentarycan
befoundinNEnglJMed2010Mar18362(11):1050
2,589patients(meanage55years)withacuteVTEwererandomizedtodabigatran150mg
orallytwicedailypluswarfarinlikeplacebovs.warfarinplusdabigatranlikeplacebofor6
months
warfarinwasdoseadjustedtoachieveINR23
allpatientsinitiallygivenparenteralanticoagulationtherapy(unfractionatedheparinor
lowmolecularweightheparin)formean10days
primaryoutcomewastimetofirstoccurrenceofcompositeofsymptomaticVTEorVTE
relateddeath
noninferioritycriteriondefinedasupperlimitof95%CIforhazardratio<2.75and
upperlimitof95%CIforriskdifference<3.6%
387patients(15%)droppedout,but>99%ofpatientswereincludedinmodified
intentiontotreatanalysis
symptomaticVTEorVTErelateddeathat6monthsin2.3%vs.2.2%(noninferiority
met)
majorbleedingin1.2%vs.1.7%(notsignificant)
anybleedingin15.6%vs.22.1%(p<0.05,NNT16)
allcausedeathin2%vs.1.9%(notsignificant)
anyadverseeventin67%vs.71%(nopvaluereported)
adverseeventsleadingtodiscontinuationofstudydrugin7.8%vs.7.8%(not
significant)
acutecoronarysyndromesin0.3%vs.0.2%(nopvaluereported)
ReferenceRECOVERIItrial(Circulation2014Feb18129(7):764)
consistentresultsforrateofrecurrentVTEandrateofanybleedinginpooledanalysisof
RECOVERandRECOVERIItrials(Circulation2014Feb18129(7):764)
extendedtherapywithdabigatranmaybeaseffectiveaswarfarinforpreventionof
recurrentorfatalvenousthromboembolismandmayreduceriskofbleedingin
patientswhocomplete312monthsofinitialanticoagulanttherapy(level2[mid
level]evidence)
basedonrandomizednoninferioritytrialwithbaselinedifferences
2,866patients(meanage55years)withVTEwhocompleted312monthsofinitial
anticoagulanttherapy(withapprovedanticoagulantordabigatraninprevioustrial)were
randomizedto1of2groupsfor636months
dabigatran150mgtwicedailypluswarfarinlikeplacebo
warfarin(doseadjustedtoachieveINR23)plusdabigatranlikeplacebo
significantbaselinedifferencesincludedincreasedprevalenceofcoronaryarterydisease,
diabetesmellitus,andhypertensionindabigatrangroup
noninferioritymarginwas2.85forhazardratiocomparingdabigatrantowarfarinforriskof
recurrentorfatalvenousthromboembolism
recurrentorfatalVTEin1.8%vs.1.3%(hazardratio1.44,95%CI0.782.64)
symptomaticDVTin1.2%vs.0.9%(notsignificant)
symptomaticnonfatalPEin0.7%vs.0.4%(notsignificant)
VTErelatedmortalityin0.1%vs.0.1%(notsignificant)
clinicallyrelevantbleedingin5.6%vs.10.2%(p<0.001,NNT22)
majorbleedingin0.9%vs.1.8%(p=0.06)
acutecoronarysyndromein0.9%vs.0.2%(p=0.02,NNH142)
ReferenceREMEDYtrial(NEnglJMed2013Feb21368(8):709),editorialcanbefoundin
NEnglJMed2013Feb21368(8):767
comparisonswithrivaroxaban
rivaroxabanmayreduceriskofmajorbleedingwithoutincreasingriskof
symptomaticrecurrentvenousthromboembolism(VTE)comparedtoenoxaparin
plusvitaminKantagonistfortreatmentofpulmonaryembolism(PE)(level2[mid
level]evidence)
4,833patients(meanage58years)withacutesymptomaticPE(withorwithoutdeepvein
thrombosis[DVT])randomizedto1of2groups
rivaroxaban(15mgorallytwicedailyfor3weeksfollowedby20mgorallyoncedaily)
standardtherapy
enoxaparin1mg/kgtwicedailyuntilINR2for2consecutivedaysafter5daysof
treatment(medianduration8days)
vitaminKantagonist(warfarinoracenocoumarol)startedwithin48hoursafter
randomization
treatmentduration(3,6,or12months)determinedbytreatingphysicianbefore
randomization
patientsineligibleiftheyreceivedlowmolecularweightheparin(LMWH),fondaparinux,or
unfractionatedheparinfor>48hoursor>1doseofvitaminKantagonistbefore
randomization
prematuretreatmentdiscontinuationin10.7%ofrivaroxabangroupvs.12.3%ofstandard
therapygroup(p=0.07)
majorbleedingdefinedasclinicallyovertbleedingwitheitherhemoglobindecreaseofat
least2g/dLortransfusionofunitsofredcells,intracranialbleeding,retroperitoneal
bleeding,bleedinginanothercriticalsite,orfatalbleeding
clinicallyrelevantnonmajorbleedingdefinedasovertbleedingthatdidnotmeetcriteriafor
majorbleedingbutledtomedicalintervention,unscheduledphysiciancontact,changein
studydrug,discomfort,orimpairmentofactivitiesofdailylife
comparingrivaroxabanvs.standardtherapy
symptomaticrecurrentVTEin2.1%vs.1.8%(notsignificant)
majororclinicallyrelevantnonmajorbleedingin10.3%vs.11.4%(notsignificant)
majorbleedingin1.1%vs.2.2%(p=0.003,NNT91)
mortalityduringintendedtreatmentperiod2.4%vs.2.1%(notsignificant)
ReferenceEINSTEINPEtrial(NEnglJMed2012Apr5366(14):1287)
rivaroxabanappearsaseffectiveasenoxaparinplusvitaminKantagonistfor
treatmentofacutedeepveinthrombosis(DVT)(level2[midlevel]evidence)
3,449patientswithacutesymptomaticDVTrandomizedto1of2treatments
rivaroxaban(15mgorallytwicedailyfor3weeks,then20mgorallyoncedailyfor3,6,
or12months)
standardcare(enoxaparin1mg/kgsubcutaneoustwicedailyandeitherwarfarinor
acenocoumarol48hoursafterrandomization)
patientsineligibleiftheyreceivedlowmolecularweightheparin(LMWH),fondaparinux,or
unfractionatedheparin(UFH)withinlast48hoursor>1doseofvitaminKantagonist
beforerandomization
enoxaparintreatment
discontinuedwhenINR2for2consecutivedaysafter5daysoftreatment
mediantreatmentduration8days
prespecifiednoninferioritymarginof2forupperlimitof95%CIforcomparisonof
symptomaticrecurrentvenousthromboembolism(VTE)
comparingrivaroxabanvs.standardcare
earlytreatmentdiscontinuationin11.3%vs.14.2%(p=0.01)
symptomaticrecurrentVTEin2.1%vs.3%(hazardratio0.68,95%CI0.441.04)
symptomaticrecurrentVTEormajorbleedingin2.9%vs.4.2%(p=0.03,NNT77)
majororclinicallyrelevantnonmajorbleedingin8.1%vs.8.1%(notsignificant)
majorbleedingin0.8%vs.1.2%(notsignificant)
deaththroughendofintendedtreatmentperiodin2.2%vs.2.9%(p=0.06)
nosignificantdifferenceinmajorbleeding,firstmajororclinicallyrelevantnonmajor
bleeding
ReferenceEINSTEINAcuteDVTstudy(NEnglJMed2010Dec23363(26):2499),editorial
canbefoundinNEnglJMed2010Dec23363(26):2559
rivaroxabanmightbesafeandeffectivefortreatmentofdeepveinthrombosis(DVT)
basedonrandomizedtrialwithpartialblinding
613patientswithcompressionultrasoundsymptomaticDVTofpoplitealormoreproximal
veinsrandomizedto1of5groups
rivaroxaban10mgtwicedailyfor12weeks
rivaroxaban40mgoncedailyfor12weeks
standardtherapyofenoxaparin1mg/kgforupto7daysandvitaminKantagonist
treatmentwasdoubleblindedinrivaroxabangroupsandopenlabelinstandardtherapy
group
nosignificantdifferencesinanyreportedoutcomes
Outcomes:
Rivaroxaban Rivaroxaban Rivaroxaban Rivaroxaban Standard
VTErelated
10mg
20mg
30mg
40mg
Therapy
0.9%
0%
0%
0.9%
0%
0.9%
1%
0.9%
0.9%
0.9%
1.7%
1.7%
3.3%
1.7%
0%
mortality
Recurrent
DVT
Major
bleeding
Abbreviations:DVT,deepveinthrombosisVTE,venousthromboembolism.
ReferenceCirculation2007Jul10116(2):180fulltext
Intensitycomparisonsfortreatmentofvenousthromboembolism:
lowintensitywarfarin(targetINR1.52)mayreducerecurrencerisk(level2[mid
level]evidence)butislesseffectivethanfulldosewarfarin(targetINR23)for
extendedanticoagulationaftervenousthromboembolism(VTE)(level1[likelyreliable]
evidence)
basedonrandomizedtrials
lowintensitywarfarin(targetINR1.52)forlongtermusemaypreventVTE
comparedtoplaceboafterinitialfulldosetreatment3months(level2[midlevel]
evidence)
basedonrandomizedtrialwithallocationconcealmentnotstated
578patients>30yearsoldwithobjectivelyconfirmedidiopathicVTEwhohadreceivedfull
dosewarfarin(INR23)foratleast3months(median6.5months)entered28dayopen
labelruninphasetodeterminethatwarfarindosecouldbetitratedtoachievestableINR
levels1.52withoutexceeding10mg/day,andtoexcludepatientswith<85%compliance
508patientswhosatisfiedrunincriteriawererandomizedtowarfarinwithtargetINR1.52
vs.placebo
doseadjustedevery2monthsbasedonINRtoreachtargetrangeof1.52
trialstoppedearlyduetoclearbenefitaftermeanfollowup2.1years
comparinglowintensitywarfarinvs.placebo
medianINR1.7vs.1withoutoverlapofinterquartileranges
recurrentVTEin5.5%vs.14.6%(p<0.001,NNT11,rates2.6vs.7.2per100person
years)
majorbleedingin2%vs.0.8%(notsignificant)
minorbleedingin23.5%vs.13.4%(p=0.002,NNH10,rates12.8vs.6.7per100
personyears)
mortalityrate1.6%vs.3.2%(notsignificant)
compositeendpoint(recurrentVTE,majorbleeding,ordeath)reachedin8.6%vs.
16.2%(p=0.01,NNT14,rates4.1vs.8per100personyears)
ReferenceNEnglJMed2003Apr10348(15):1425fulltext,editorialcanbefoundinN
EnglJMed2003Apr10348(15):1478,MedJAust2003Jul21179(2):68,commentarycan
befoundinCMAJ2003Apr29168(9):1160
EBSCOhostFullTextfulltext,NEnglJ
Med2003Jul24349(4):398,JFamPract2003Aug52(8):588
ACPJClub2003SepOct139(2):44
EBSCOhostFullText,
EBSCOhostFullText
followingatleast3monthsofconventionalintensitywarfarin,ongoingtreatment
withlowintensitywarfarin(targetINR1.52)islesseffectivethanconventional
intensitywarfarin(targetINR23)(level1[likelyreliable]evidence)
basedonrandomizedtrial
738patientswithunprovokedVTEwhocompletedatleast3monthsofconventional
intensitywarfarinwererandomizedtolowvs.conventionalintensitywarfarinformean2.4
years
comparingtargetINR1.52vs.targetINR23
recurrentVTEin4.3%vs.1.6%(p=0.03,NNT37)
nosignificantdifferencesinratesofmajorbleeding(2.4%vs.2.2%,1.1vs.0.9per100
personyears)oroverallbleeding
ReferenceNEnglJMed2003Aug14349(7):631fulltext,editorialcanbefoundinNEngl
JMed2003Aug14349(7):702,commentarycanbefoundinNEnglJMed2003Nov
27349(22):2164,AmFamPhysician2004Mar169(5):1272,ACPJClub2004Mar
Apr140(2):37
EBSCOhostFullText
lowintensitywarfarinmayalsobecalledlowdosewarfarin
INR23isadequateforpreventingthrombosisinpatientswithantiphospholipid
antibodiesandpreviousthrombosis(level1[likelyreliable]evidence)
basedonrandomizedtrial
114patientswithantiphospholipidantibodysyndromeandpreviousthrombosisweregiven
warfarinandrandomizedtotargetINR23(moderateintensity)vs.INR3.14(highintensity)
formean2.7years
comparingINR23vs.INR3.14
recurrentthrombosisin3.4%vs.10.7%(or1.3vs.4.1per100patientyearsoffollowup)
(p=0.15)
majorbleedingin6.9%vs.5.4%(or3vs.2.7per100patientyearsoffollowup)(not
significant)
ReferenceNEnglJMed2003Sep18349(12):1133,correctioncanbefoundinNEnglJMed
2003Dec25349(26):2577,NEnglJMed2004Jul8351(2):200,editorialcanbefoundinN
EnglJMed2003Sep18349(12):1177,commentarycanbefoundinNEnglJMed2003Dec
25349(26):2568,ACPJClub2004MarApr140(2):38
EBSCOhostFullText
PulmonaryArterialHypertension:
warfarinmightdecreasemortalityinpatientswithPAH(level2[midlevel]evidence)
basedonsystematicreviewofobservationalstudies
systematicreviewof9observationalstudiesevaluatingoralanticoagulationtherapyin1,730
patientswithPAH
warfarinassociatedwithdecreasedmortality(hazardratio0.69,95%CI0.570.82)
ReferenceCanJCardiol2014Aug30(8):879
PreventionofCancer:
warfarinmaylowerriskofdiagnosisofcancer
854patientswithfirstepisodeofvenousthromboembolismrandomizedtowarfarinfor6
weeksvs.6months
meanfollowup8.1years
firstcancerdiagnosedin111(13%)
cancerwasdiagnosedin15.8%patientstreatedfor6weeksvs.10.3%patientstreatedfor6
months(oddsratio1.6,95%CI1.12.4)
differencemainlydueto6.7%vs.2.8%incidenceofnewurogenitalcancers(oddsratio2.5,
95%CI1.35)
differenceevidentonlyafter2yearsoffollowup,nodifferenceinincidenceofcancerrelated
deaths
ReferenceNEnglJMed2000Jun29342(26):1953),editorialcanbefoundinNEnglJMed
2000Jun29342(26):1991commentarycanbefoundinNEnglJMed2000Nov
2343(18):1337
DosageandAdministration
RelatedSummaries:
VitaminKantagonistmanagement
INRMonitoring:
DynaMedcommentaryuseofINRrecommendedoverprothrombintime(PT)ratiosfor
individualizingwarfarindosesbecausePTratiosmayvaryacrosslaboratories,reagentsand
batchesofreagent
Administration:
Administerorally.211330AdministerbyIVinjectionwhentherapywithacoumarinderivativeis
indicatedandoraltherapyisnotfeasible.211
IMadministrationnotrecommended.211
OralAdministration:
Administerinasingledailydose.211330Administeratthesametimeeachday,withfoodoronan
emptystomach.453
Ifadoseismissed,contactclinician.445453Administerdoseassoonasrememberedonthesame
daydonottakeadoubledosethenextdaytomakeupforthemisseddose.445453
IVAdministration:
Forsolutionanddrugcompatibilityinformation,seeCompatibilityunderStability.
Reconstitution:
Reconstitutelyophilizedpowderforinjectionwith2.7mLofsterilewaterforinjectiontoafinal
concentrationof2mg/mL.211
RateofAdministration:
Injectslowly(over12minutes)intoaperipheralvein.211
Dosage:
Availableaswarfarinsodiumdosageexpressedintermsofwarfarinsodium.211330
Initialdosagevarieswidelyamongpatientsindividualizedosagebasedonfactorssuchasage,
race,bodyweight,sex,genotype,concomitantdrugs,andthespecificindicationbeingtreated.500
AdjustdosagebasedonINRifapreviouslystablepatientpresentswithasinglesubtherapeuticor
supratherapeuticINR(0.5aboveorbelowthetherapeuticrange),ACCPsuggeststhatcurrent
dosagebecontinuedandINRretestedwithin12weeks.1000
Themanufacturersstatethatusualinitialdosageis25mgdailyinpatientswhoseCYP2C9and
VKORC1genotypesarenotknown.211500ForpatientswithknownCYP2C9andVKORC1genotypes,
themanufacturerssuggestthatinitialdosagemaybedeterminedbyexpectedmaintenance
dosagesobservedinclinicalstudiesofpatientswithvariouscombinationsofthesegenevariants.
211 500(SeeTable.)
Table1.ExpectedDailyMaintenanceDosagesofWarfarinSodiumBasedonCYP2C9and
VKORC1Genotypes211500a:
CYP2C9
VKORC1
*1/*1
GG
AG
AA
57mg
57mg
34mg
*1/*2 *1/*3 *2/*2 *2/*3 *3/*3

57
34
34
34
0.52
mg
mg
mg
mg
mg
34
34
34
0.52
0.52
mg
mg
mg
mg
mg
34
0.52
0.52
0.52
0.52
mg
mg
mg
mg
mg
Manufacturerssuggestusingtheseexpected
maintenancedosagerangestoestimateinitial
dailydosageinpatientswithknownCYP2C9
andVKORC1genotypes.Dosageranges
derivedfrommultiplepublishedclinical
studies.VKORC11639G>A(rs9923231)
variantisusedinthistableothercoinherited
VKORC1variantsalsomaybeimportant
determinantsofwarfarinsodiumdosage.
Routineuseofwarfarinloadingdosesnotrecommendedbymanufacturer211500however,some
evidencesuggeststhatuseofa10mgloadingdosemayreducetimetotherapeuticINR.1000
PediatricPatients:
Warfarindosageinpediatricpatientsvariesbasedonageinfantsgenerallyhavethehighest,and
adolescentshavethelowestdosagerequirements.211500ACCPgenerallysuggestsatargetINR
rangeof23formostindicationsinchildrenexceptinthesettingofprostheticcardiacvalveswhere
adherencetoadultrecommendationsissuggested.1013
Adults:
TreatmentofDVTandPE:
OralorIV:
AdjustdosagetoachieveandmaintaintargetINRof2.5(range23).3325001005
PatientswithaproximalDVTorPEprovokedbysurgeryorothertransientriskfactor:ACCPstates
that3monthsofanticoagulationusuallysufficient.1005
Patientswithanunprovoked(idiopathic)thromboembolicevent:Continueanticoagulanttherapyfor
3monthsafter3months,evaluaterisksandbenefitsofextendedtherapy.1005Ingeneral,
extendedanticoagulanttherapyisrecommendedinpatientswithlowriskofbleeding.1005
Cancerpatientswithacutevenousthromboembolism:Extendedanticoagulanttherapy
recommended.1005
PatientswithacuteupperextremityDVTinvolvingtheaxillaryormoreproximalveins:Continue
anticoagulanttherapy3months.1005IfupperextremityDVTassociatedwithacentralvenous
catheter,continueanticoagulationaslongasthecatheterremainsinplaceifcatheterisremoved,
3monthsofanticoagulationissufficient.1005
PreventionofDVTandPE:
HipReplacement,KneeReplacement,orHipfractureSurgery:
OralorIV:
AdjustdosagetoINRrangeof23.5001000
ACCPrecommendscontinuingthromboprophylaxisforatleast1014days,andpossiblyforupto35
daysaftersurgery.1003
EmbolismAssociatedwithAtrialFibrillation:
OralorIV:
MaintaintargetINRof2.5(range23)longterm.2113303353443453493699909991007
CardioversionofAtrialFibrillation:
OralorIV:
Patientswithatrialfibrillationlasting>48hoursorofunknownduration:Initiatewarfarin3weeks
priortocardioversion(targetINR23)andcontinueaftertheprocedureuntilnormalsinusrhythm
maintainedfor4weeks.9991007
EmbolismAssociatedwithValvularHeartDisease:
OralorIV:
Patientswithrheumaticmitralvalvediseaseandconcurrentatrialfibrillation,leftatrialthrombus,or
ahistoryofsystemicembolism:MaintaintargetINRof2.5(range23).1008
Patientswithrheumaticmitralvalvediseaseinnormalsinusrhythm,butwithleftatrialhypertrophy
(leftatrialdiameter>5.5cm):TargetINRof2.5(range23)suggestedbyACCP.1008
Patientsbeingconsideredforpercutaneousmitralvalvotomywithevidenceofleftatrialthrombus
(confirmedbyTEE):Treatwithwarfarin(targetINRof3range2.53.5)andpostponeprocedure
untilthrombusresolution.1008
ThromboembolismAssociatedwithProstheticHeartValves:
Prophylaxis:
OralorIV:
Baseintensityofanticoagulationonthetypeofvalveprosthesis.2113309961008Ingeneral,targetINR
of2.5(range23)suggestedinpatientswithamechanicalaorticvalvetargetINRof3(range2.5
3.5)recommendedinthosewithamechanicalmitralvalve.5001008996Higherintensityof
anticoagulationalsomaybeconsideredinpatientswithmechanicalheartvalvesinbothaorticand
mitralpositions.1008
Patientswithmechanicalheartvalvesinanyposition:Longtermoralanticoagulationrequired.
996 1008
ACCPrecommendsaddinganantiplateletagentsuchaslowdoseaspirin(e.g.,50100mg
daily)towarfarintherapyinpatientsatlowriskofbleeding.1008
Patientswithbioprostheticmitralvalves:3monthsofwarfarintherapysuggestedaftervalve
insertionafter3months,mayswitchtoaspirintherapy,providedpatientisinnormalsinusrhythm.
1008
Patientswithbioprostheticheartvalvesandadditionalriskfactorsforthromboembolism(e.g.,atrial
fibrillation,priorthromboembolism,leftventriculardysfunction,hypercoagulablestates):Longterm
warfarintherapymaybewarrantedmayconsideraddingaspirintherapy.996
STEMI:
TreatmentandSecondaryPrevention:
OralorIV:
Patientsathighriskofsystemicorpulmonaryembolism(e.g.,largeanteriorMI,ahistoryofprevious
thromboembolism,intracardiacthrombus,atrialfibrillation,orsubstantialheartfailure):Longterm
(3months)warfarin(INR23)andaspirintherapy(100mgdaily)recommendedfollowingacute
MI.5001010
CerebralThromboembolism:
SecondaryPrevention:
OralorIV:
PatientswithTIAsorischemicstrokeandconcurrentatrialfibrillation:MaintaintargetINRof2.5
(range23)longterm,providednocontraindicationstotherapyexist.3353383493524329901009
Patientswithriskofrecurrentstrokefromothercardiacsources(e.g.,mechanicalprostheticheart
valves,recentMI,leftventricularthrombus,dilatedcardiomyopathies,maranticendocarditis,
extensivewallmotionabnormalities):MaintaintargetINRof2.5(range23)withconcomitantlow
doseaspirin.335338349432
Patientswithacutecerebralvenoussinusthrombosisprovokedbyatransientriskfactor:AHA,
ASA,andotherexpertssuggestcontinuationofanticoagulationwithwarfarin(afterinitialheparinor
lowmolecularweightheparintherapy)for36months,10091017withdosageadjustedtomaintaina
targetINRof23.1017
Patientswithunprovokedcerebralvenoussinusthrombosis:AHAandASAsuggestcontinuing
warfarintherapyfor612months(targetINRof23).1017
Patientswithseverethrombophilia,recurrentcerebralvenoussinusthrombosis,venousthrombosis
occurringafteracutecerebralvenoussinusthrombosis,orotherpermanentriskfactorsfor
recurrentthrombosis:Considerindefiniteanticoagulationwithwarfarin(targetINRof23)following
aninitialepisodeofcerebralvenoussinusthrombosis.10091017
PatientswithapatentforamenovaleandcryptogenicstrokewhohaveevidenceofDVT:Target
INR2.5(range23)recommended.1008
HIT:
ConversiontoWarfarinTherapy:
OralorIV:
InitiatewarfarinonlyaftersubstantialrecoveryfromacuteHIThasoccurred(i.e.,plateletcounts
150,000/mm3).3924424434441006
Overlaptherapywithanonheparinanticoagulantfor5daysuntildesiredINRisachieved.
387 392 393 1006
General:
Carefullyindividualizedosagebasedonclinicalandlaboratoryfindings(i.e.,INR).211330
Determineoptimumdosageanddurationoftherapybytheconditionbeingtreated.500
Adjustdosageinsmallincrementsandcarefullymonitorpatientresponse.211330
Dosageofwarfarindoesnotvarywiththerouteofadministration.211
Administrationoflargeloadingdoses(i.e.,>10mg)notrecommended211330possibleincreased
riskofhemorrhageornecrosis.211330(SeeHemorrhageunderCautions.)
Factorssuchasconcomitanttherapywithdrugsordietaryorherbalsupplements,changesin
diet,environment(prolongedhotweather),physicalstate,andgeneticvariationsinwarfarin
metabolismand/orsensitivitymayalteranindividualsresponsetowarfarintherapy.
211 330 462 463 464 465 468 472 474(SeeFactorsInfluencingResponseunderCautionsandsee
Interactions.)
LaboratoryMonitoringofTherapy:
DetermineINRregularlyinallpatientsreceivingwarfarin.211330MonitorINRdailyfollowing
initiationoftherapyuntilitstabilizesinthetherapeuticrange.211330Frequencyofsubsequent
INRdeterminationsbasedonclinicaljudgmentandpatientresponse,butgenerallyevery14
weeks.500
InpatientswithconsistentlystableINRs,ACCPhassuggestedanINRtestingintervalofupto12
weeks.1000
PerformadditionalINRtestingwhendifferentwarfarinpreparations(e.g.,proprietaryversus
generic)areinterchanged,andwhenconcomitantdrugtherapyisadded,discontinued,ortaken
irregularly.211330
Safetyandefficacymaybeimprovedbyincreasingthequalityoflaboratorycontrol.211330
ProportionoftimeinthetherapeuticINRrangeisincreasedinpatientsmanagedby
anticoagulationclinicsandinpatientsmanagedwiththeassistanceofcomputerprograms.
211 330 452 462
ACCPsuggeststhatselfmanagementbeconsideredasanalternativetooutpatientmonitoringin
appropriatelyselected,motivatedpatientswhocandemonstratecompetencyinselfmanagement
strategiesandtechniques.1000
Pharmacogenomics:
Variationsingenesresponsibleforwarfarinmetabolismorpharmacodynamicresponsemay
affectdosagerequirements.211330378462463464465466467468469470471
Lowerdosagesmayberequiredtoavoidexcessiveanticoagulation(e.g.,INR>3)andbleedingin
patientswithvariationsin2genes(CYP2C9andVKORC1).211330462464465466467469470474
CurrentlackofevidencetosupportbenefitofroutinegenetictestingACCPcurrently
recommendsagainstroutineuseofgenetictestingtoguideinitialdosageselection.1000
TransferringfromParenteralAnticoagulantstoWarfarin:
Whenwarfarinisindicatedforfollowuptherapyafterinitialtherapywithaparenteral
anticoagulant(e.g.,heparin,LMWH),overlaptherapywithparenteralanticoagulantandwarfarin
untiladequateoralanticoagulationobtainedasindicatedbyINRmonitoring.10001005
Manufacturersrecommendthatheparinandwarfarinbeusedconcurrentlyfor45daysuntil
thedesiredINRhasbeenachieved.211330500
InadultswithacuteDVTorPE,ACCPrecommendsthatheparin,anLMWH,orfondaparinuxbe
usedconcurrentlywithwarfarinfor5daysanduntilINRis2for24hours.1005
Inchildrenwithvenousthromboembolisminwhomlongtermwarfarintherapyisbeing
considered,ACCPrecommendsthatwarfarinbeinitiatedonthesamedayasheparinoran
LMWHoverlapsuchtherapyfor5daysanduntiltheINRistherapeutic.1013
Whenwarfarinisusedforfollowuptherapyafteranonheparinanticoagulant(e.g.,argatroban,
lepirudin)inpatientswithHIT,overlaptherapywithwarfarinandthenonheparinanticoagulant
for5daysuntilanadequateresponsetowarfarinisobtainedasindicatedbyINR.1006Initiate
warfarintherapyonlyaftersubstantialrecoveryfromacuteHIThasoccurred(i.e.,plateletcounts
150,000/mm3).1006
Conversionfromargatrobantowarfarinismorecomplexthanwithothernonheparin
anticoagulantssincecombinedtherapywithargatrobanandwarfarinprolongsthePT/INRbeyond
thatproducedbywarfarinalone.392Consultmanufacturer'sprescribinginformationforspecific
guidelinesforconversion.392MonitorINRdailyduringconcurrentargatrobanandwarfarin
therapy.392
InterruptionofTherapyforInvasiveProcedures:
Temporaryinterruptionofwarfarintherapymayberequiredinpatientsundergoingsurgeryor
otherinvasiveprocedurestominimizeriskofperioperativebleeding.1004
Assessriskofthromboembolismversusriskofperioperativebleedingtodeterminewhether
interruptionoftherapyisnecessary.1004Temporaryinterruptionoftherapyusuallyrequiredfor
majorsurgicalorinvasiveprocedures,butmaynotbenecessaryforminorproceduresassociated
withalowbleedingrisk(e.g.,minordentalprocedures,minordermatologicprocedures,cataract
surgery).1004
Iftemporaryinterruptionofwarfarinnecessarypriortosurgery,discontinueapproximately5days
priortoprocedure.1004Mayresumeapproximately1224hourspostoperativelywhenadequate
hemostasisisachieved.1004
Mayconsiderbridginganticoagulation(administrationofanLMWHorIVheparinduringtheperiod
ofwarfarininterruption)inpatientsatparticularlyhighriskofthromboembolism.1004ACCPstates
thatbridgingtherapygenerallyunnecessaryforpatientsotherthanthoseathighestriskfor
strokeand/orvenousthromboembolism(e.g.,patientswithmechanicalheartvalves,atrial
fibrillation,oravenousthromboemboliceventwithadditionalriskfactorsforvenous
thromboembolism).1004
SpecialPopulations:
HepaticImpairment:
Possibleincreasedanticoagulanteffect.211330Mayrequirelowerinitialandmaintenancedosages.
211 330
RenalImpairment:
Possibleincreasedanticoagulanteffectinmoderatetosevererenalimpairment.aNodosage
adjustmentsrequired.211330
GeriatricPatients:
Possibleincreasedanticoagulanteffect.211330Considerlowinitialdosages.500Adjustdosageto
maintainINRatthelowerendoftherangeof23.211330344
DebilitatedPatients:
Possibleincreasedanticoagulanteffect.211330Considerlowinitialdosages.500
AsianPatients:
Possibleincreasedanticoagulanteffect.211330378Mayrequirelowerinitialandmaintenancedosages.
211 330 378
(SeePharmacogenomicsunderDosageandAdministration.)
DosingSupportStrategies:
GenotypeguidedDosing:
inconsistentevidenceforefficacyofgenotypeguidedvitaminKantagonistdosingalgorithms
genotypeguideddosingalgorithmsforinitiationofwarfarinmaynotbeassociated
withimprovedanticoagulationresponseorreductioninmajorbleedingor
thromboemboliceventscomparedtoclinicaldosingalgorithms(level2[midlevel]
evidence)
basedonsystematicreviewlimitedbyclinicalheterogeneity
systematicreviewof9randomizedtrialsevaluatinggenotypeguidedinitialdosingof
warfarinanditsanalogs(acenocoumarolandphenprocoumon)vs.clinicaldosingin2,812
adultsrequiringanticoagulationfollowedformedian12weeks(range4weeksto6months)
studiesvariedingenotypebasedandclinicalwarfarindosingalgorithms,outcome
definitions,anddurationsofwarfarindoseinitiationandfollowup
nosignificantdifferencesin
percentageoftimeINRwithintherapeuticrangeinanalysisof9trials,resultslimitedby
significantheterogeneity
percentageofpatientswithINR>4inanalysisof8trials
incidenceofmajorbleedinginanalysisof7trials
incidenceofthromboemboliceventsinanalysisof7trials
ReferenceJAMAInternMed2014Aug1174(8):1330
EBSCOhostFullText,editorial
canbefoundinJAMAInternMed2014Aug1174(8):1338
EBSCOhostFullText
Thissystematicreviewincludesthefollowing4referencesinitsanalysis:
genotypeguideddosingalgorithmforinitiationofwarfarinmayimproveresponse
comparedtostandarddosinginpatientswithatrialfibrillationorvenous
thromboembolism(level3[lackingdirect]evidence)
basedonnonclinicaloutcomefromsingleblindrandomizedtrial
455patients(meanage67years)withatrialfibrillationorvenousthromboembolism
initiatingwarfarinwithtargetINR23wererandomizedtogenotypeguideddosingalgorithm
vs.standarddosingandfollowedfor12weeks
genotypeguideddosingalgorithm(usingCYP2C9*2,CYP2C9*3,andVKORC1variant
genotypedata)wasappliedondays13anddoserevisionalgorithmappliedonday4,5,
orboth
standarddosingconsistedof3dayloadingdoseregimenofwarfarin510mg/day
dependingonage
94%wereincludedinanalysesfortargetINR
comparingpharmacogeneticdosingalgorithmvs.standarddosing
meanpercenttimeintherapeuticrange67.4%vs.60.3%(p<0.001)
mediantimetotherapeuticINR21daysvs.29days(p<0.001)
mediantimetostabledose44daysvs.59days(p=0.003)
anyINR4in27%vs.36.6%(p=0.03)
bleedingin37%vs.38%(notsignificant)
ReferenceEUPACTtrial(NEnglJMed2013Dec12369(24):2294),editorialcanbefound
inNEnglJMed2013Dec12369(24):2345
genotypeguidedwarfarindosingalgorithmmaynotimproveanticoagulation
responsecomparedtoclinicaldosingalgorithm(level3[lackingdirect]evidence)
basedonnonclinicaloutcomefromrandomizedtrial
1,015adultsinitiatingwarfarinwithtargetINR23wererandomizedtogenotypeguided
dosingalgorithmvs.clinicaldosingalgorithmduringfirst5daysoftreatmentandfollowed
to28days
bothgroupshaddoseinitiationalgorithmappliedondays13anddoserevisionalgorithm
appliedonday4,5,orboth
genotypeguideddosingalgorithmusedCYP2C9andVKORC1genotypedataandclinical
variablestodeterminedosing
56%wereinitiatingwarfarinforvenousthromboembolism,23%foratrialfibrillation,and
remainingpatientshadotherormultipleindications
61%had1geneticvariant(CYP2C9*2,CYP2C9*3,andVKORC1)
comparinggenotypeguideddosingalgorithmvs.clinicaldosingalgorithm
meanpercenttimeintherapeuticrangefrom428days45.2%vs.45.4%(not
significant)
anyINR4in19%vs.18%(notsignificant)
majorbleedingin1%vs.2%(notsignificant)
thromboembolismin1%vs.1%(notsignificant)
ReferenceCOAGtrial(NEnglJMed2013Dec12369(24):2283),editorialcanbefoundin
NEnglJMed2013Dec12369(24):2345
genotypeguidedalgorithmforvitaminKagonistsmaynotimproveresponse
comparedtoclinicaldosingalgorithminadultswithatrialfibrillationorvenous
thromboembolism(level3[lackingdirect]evidence)
basedonnonclinicaloutcomefrompooledanalysisof2randomizedtrials
548patients(meanage68years)withatrialfibrillationorvenousthromboembolism
initiatingeitheracenocoumarolorphenprocoumonwithtargetINR23wererandomizedin2
trialstogenotypeguideddosingalgorithmvs.clinicaldosingalgorithmandfollowedfor12
weeks
bothdosingsappliedduringfirst57daysoftreatment
genotypeguidedalgorithmusedCYP2C9andVKORC1variantgenotypedataandclinical
variabletodeterminedosing
comparinggenotypeguideddosingalgorithmvs.clinicaldosingalgorithm
meanpercenttimeintherapeuticrange61.6%vs.60.2%(notsignificant)
mediantimetoreachtherapeuticINR22daysvs.22days(notsignificant)
nosignificantdifferencesinincidenceofbleedingorthromboembolicevents
ReferenceNEnglJMed2013Dec12369(24):2304,editorialcanbefoundinNEnglJ
Med2013Dec12369(24):2345
pharmacogeneticguidedalgorithmmayimproveaccuracyandefficiencyoforal
warfarindosing(level3[lackingdirect]evidence)
basedonsubgroupanalysisinrandomizedtrialwithoutclinicaloutcomes
206patientsstartingwarfarinwererandomizedtopharmacogeneticguidedvs.empiric
protocolguideddosingfor3months
forpharmacogeneticguideddosing
genotypesCYP2C9*2andCYP2C9*3andVKORC1C1173Tdeterminedbybuccalswab
DNA
dosingalgorithmfollowedregressionequationincluding3geneticvariants,age,sex,and
weight
prothrombintimeINRmeasuredondays0,3,5,21,60,and90
pharmacogeneticguideddosingmoreaccuratelyapproximatedstabledoses(p<0.001),
resultinginsmallerdoses(p=0.002),fewerdosingchanges(p=0.03),andfewerINRs
(notsignificant)
nosignificantdifferenceinprimaryendpoint(percentoutofrangeINRs)
primaryendpointreducedwithpharmacogeneticguideddosing(29%vs.39%,NNT10)in
subgroupofwildtypeandmultiplevariantcarriers
ReferenceCirculation2007Nov27116(22):2563,commentarycanbefoundinACPJClub
2008MarApr148(2):45
EBSCOhostFullText
pharmacogeneticalgorithmassociatedwithimprovedwarfarindoseprediction
comparedtogenotypemeandosetable,warfarinlabel,clinicalalgorithm,andempiric
dosing(level3[lackingdirect]evidence)
basedonretrospectivecohortstudywithoutclinicaloutcome
1,378patientsfrom3anticoagulationcentershadwarfarindosecalculatedusing
pharmacogeneticalgorithm,genotypemeandosetable,warfarinlabel,clinicalalgorithm,and
empiricdosing
percentofpatientswhosepredictedwarfarindosewaswithin20%oftheirstabletherapeutic
doses
52%withpharmacogeneticalgorithm(p<0.001vs.othermethods)
44%withgenotypemeandosetable
43%withwarfarinlabel
39%withclinicalalgorithm
37%withempiricdosing
ReferenceJAmCollCardiol2011Feb157(5):612fulltext
pharmacogeneticalgorithmappearstopredictappropriatewarfarindosemore
accuratelythanclinicalalgorithm(level3[lackingdirect]evidence)
basedonvalidationcohortstudy
1,009patientsinitiatingwarfarinanalyzedusingpharmacogeneticalgorithmorclinical
algorithmtoestimateappropriatewarfarindose
algorithmcalculatedpercentageofpatientswhosepredictedwarfarindosewaswithin20%of
actualstabletherapeuticdose
algorithmcreatedinpreviouscohortstudyof4,043patientscombininggeneticinformationand
clinicalvariables
age
height
weight
race
geneticvariant
presenceofenzymeinhibitor
useofamiodarone
comparingaccurateidentificationwithpharmacogeneticalgorithmvs.clinicalalgorithm
patientsrequiring21mgweeklytoachievetargetINR49.4%vs.33.3%(p<0.001)
patientsrequiring49mgweeklytoachievetargetINR24.8%vs.7.2%(p<0.001)
ReferenceNEnglJMed2009Feb19360(8):753,correctioncanbefoundinNEnglJMed
2009Oct15316(16):1613,editorialcanbefoundinNEnglJMed2009Feb19360(8):811,
commentarycanbefoundinNEnglJMed2009Jun4360(23):2474
pharmacogeneticguideddosingmaybecosteffectiveforpatientswithhigh
hemorrhageriskbutnotforpatientswithtypicalnonvalvularatrialfibrillation
basedonMarkovdecisionmodelanalysis
estimatedcostofpharmacogeneticguideddosingexceededcostofstandardwarfarindosing
by>$170,000(2007dollars)perqualityadjustedlifeyeargainedfortypicalcase(male,69
yearsoldwithnowarfarincontraindications)
costofpharmacogeneticguideddosing<$50,000/qualityadjustedlifeyearwhenlimitedto
patientswithhighhemorrhagerisk
ReferenceAnnInternMed2009Jan20150(2):73
foundinAnnInternMed2009Jan20150(2):139
EBSCOhostFullText,editorialcanbe
EBSCOhostFullText
discussionofpharmacogenetictestingcanbefoundinJFamPract2007Aug56(8):621
EBSCOhostFullText
DosingSupportStrategies:
InteractiveDosingSupport:
freewebsitefromBarnesJewishHospitalatWashingtonUniversityMedicalCentertoestimate
therapeuticwarfarindosecanbefoundatWarfarinDosing.org
NomogramforWarfarinDosingBasedonGenetics:
nomogramsfordailywarfarindosebasedonage,genderandCYP2C9andVKORC1genotypes
canbefoundinClinMedRes2007Mar5(1):8
EBSCOhostFullTextfulltext
CautionsandAdverseEffects
Contraindications:
Pregnancy.211330
Hemorrhagictendenciesorblooddyscrasias.211330
Recentorcontemplatedeye,brain,orspinalcordsurgery.211330
Recentorcontemplatedtraumaticsurgeryresultinginopensurgicalwounds.211330
ActiveulcerationorbleedingoftheGI,respiratory,orGUtracts.211330
Cerebrovascularhemorrhage.211330
Aneurysms(cerebral,dissectingaorta).211330
Pericarditisandpericardialeffusions.211330
Bacterialendocarditis.211330
Eclampsia,preeclampsia,orthreatenedabortion.211330
Spinalpunctureorotherdiagnosticortherapeuticprocedureswithpotentialforuncontrolled
bleeding.211330
Majorregionalorlumbarblockanesthesia.211330
Severe,uncontrolled,ormalignanthypertension.211330
Unsupervisedpatientswithsenility,alcoholism,orpsychosisorotherlackofpatientcooperation.
211 330
Inadequatelaboratoryfacilitiesformonitoringanticoagulation.211330
Knownhypersensitivitytowarfarinoranyingredientintheformulation.211330
Warnings/Precautions:
Warnings:
Hemorrhage:
PossiblemassivehemorrhageinvolvingtheGItract,spinalcord,GU,cerebral,pericardial,pulmonary,
adrenal,orhepaticsites.a(SeeBoxedWarning.)Hemorrhagiccomplicationsmaybemanifestedby
signsorsymptomsthatdonotindicateobviousbleeding,suchasparalysisheadachepaininthe
chest,abdomen,joints,muscles,orotherareasdizzinessshortnessofbreathdifficultybreathing
orswallowingunexplainedswellingweaknesshypotensionorunexplainedshock.211330Results
principallyfromoverdosageorexcessivePT/INRprolongationhowever,mayoccurwhenthe
PT/INRisintheusualtherapeuticrangeandfrequentlyresultsfromthepresenceofoccultlesions.
a 211 330
Morelikelytooccurduringtheinitiationoftherapyandwithhigherdosages,resultingin
higherINRs.211330
IncreasedriskofpostoperativehemorrhageassociatedwithanaPTT>50secondsevenifPT/INRin
desiredrange.211330a
Carefulclinicalmanagement,includingfrequentPT/INRdeterminations,isrequired.211330(See
GeneralunderDosageandAdministration.)Immediatecriticalevaluationrecommendedifany
unexpectedbleedingoccurs(e.g.,microscopicorgrosshematuria,melena,excessiveuterineor
menstrualbleeding,petechiae,ecchymoses,bleedingfromgumsorothermucousmembranes,
oozingfromshavingnicks).a211330
Inpatientswithmajorbleedingassociatedwithwarfarintherapy,ACCPsuggeststheuseof4factor
prothrombincomplexconcentrateratherthanfreshfrozenplasmaforrapidreversalof
anticoagulationadditionaluseofphytonadione(510mgbyslowIVinfusion)recommended.1000
Adrenalhemorrhageresultinginacuteadrenalinsufficiencyreportedwithanticoagulanttherapy.
409 410 411 417Inpatientswithmanifestationsofacuteadrenalhemorrhageorinsufficiency,
discontinueanticoagulanttherapy,measureplasmacortisolconcentrationsimmediately,andinstitute
prompt,vigoroustherapywithIVcorticosteroidsdelayininitiatingtherapymayresultindeath.a
TissueNecrosis:
Rarely,possiblepotentiallyfatalnecrosisand/organgreneofskinorothertissues.
203 211 215 290 291 292 293 298 330
Appearsearly(e.g.,110days)afterinitiationoftherapyprincipallyat
sitesoffattissue(e.g.,abdomen,breasts,buttocks,thighs).290293298Increasedriskinpatientswith
hereditary,familial,orclinicaldeficienciesofproteinCoritscofactor,proteinS.211213290330
Discontinuetherapyifwarfarininducednecrosisissuspected211213215290330354andadminister
vitaminK(phytonadione)orfreshfrozenplasma.213215290291ConsiderheparinorLMWHtherapyto
treattheunderlyingthromboembolicdiseaseandpossiblypreventadditionalmicrovascular
thrombosis.211213215290298330Inseverecases,surgicaldebridement,skingrafting,oramputation
maybenecessary.203211215290292293330
Possiblelimbischemia,necrosis,andgangrenemayoccurinpatientswithHITwhenwarfarinis
substitutedfororcontinuedafterheparinorLMWHtreatment.387388389395Usewithcaution.
211 330 391
Ifwarfarinusenecessary,delayinitiationoftherapyuntilthrombingenerationis
adequatelycontrolledandthrombocytopeniahasresolved(i.e.,plateletcounts150,000/mm3).
354 442 443 444 1006
Initiationofanticoagulanttherapywithheparinfor45daysbeforeinitiationofwarfarin211330or
overlappingtherapywiththe2drugsfor56days203291292mayminimizetheriskofwarfarin
inducednecrosis.203211330
PurpleToesSyndromeandCholesterolMicroembolization:
Purpletoessyndromemayresultfrompossibleincreasedreleaseofatheromatousplaquefragments
fromsystemiccholesterolmicroemboli.211216221284285286287288330Mayoccur310weeksorlater
followinginitiationofwarfarintherapy.203211216284289330
Discontinuanceofwarfarintherapyisrecommendedsomecasesofpurpletoessyndromehave
progressedtogangreneornecrosis,requiringdebridementand/oramputation.211284288330
Otherpossiblemanifestationsofsystemicatheroembolismincludelivedoreticularis,rash,gangrene,
abruptandintensepainintheleg,foot,ortoes,footulcers,myalgia,penilegangrene,abdominal
pain,flankorbackpain,hematuria,renalinsufficiency,hypertension,cerebralischemia,spinalcord
infarction,pancreatitis,andsymptomssimulatingpolyarteritis.211216221285287288330
Fetal/NeonatalMorbidityandMortality:
Possibleteratogenicity,fetalorneonatalhemorrhage,andintrauterinedeath.2113301012aDetectable
infetalplasmaatconcentrationsapproachingmaternalconcentrations.211330Generally
contraindicatedduringpregnancy,exceptincertainpregnantwomen(e.g.,thosewithmechanical
heartvalves)consideredtobeathighriskforthrombosis.2113303413423433865001012
ACCP,ACC,andAHAsuggestthatwarfarinmightnotbefetopathicwhenadministeredduringthe
first6weeksofpregnancy.3411012Ifdecisionmadetousewarfarinduringpregnancy,ACCP
recommendsavoidingadministrationduringweeks612ofgestationandclosetoterm(toavoid
anticoagulationofthefetus).1012
GeneralPrecautions:
AdequatePatientEvaluationandMonitoring:
Closelysuperviseallpatientsmedicallyandensureavailabilityofadequatelaboratoryfacilitiesfor
monitoringtherapy(e.g.,usingPT/INR)andtreatinghemorrhage.211330
FactorsInfluencingResponse:
Possibleincreasedanticoagulantresponse(increasedPT/INRandriskofhemorrhage)dueto
vitaminKdeficiency,scurvy,malnutritionorcachexia,smallbodysize,hepaticdysfunction,moderate
tosevererenalimpairment,fever,hyperthyroidism,infectiousdisease,carcinoma,collagendisease,
CHF,diarrhea,biliaryobstruction,oldage,debility,menstruationandmenstrualdisorders,radiation
therapy,initialhypoprothrombinemia,anddecreasedclearanceofwarfarinasaresultofvariations
ingenesresponsibleforwarfarinmetabolism.211330462463464465466467468469470473(See
PharmacogenomicsunderDosageandAdministration.)
PossibleincreasedsensitivitytoanticoagulanteffectinAsianpatients.211378465469(SeeAsian
PatientsunderDosageandAdministration.)
Possibledecreasedresponse(decreasedPT/INR)duetoincreasedintakeorGIabsorptionof
vitaminK,diabetesmellitus,edema,hyperlipidemia,hypothyroidism,andvisceralcarcinoma.211a
Rarely,inheritedfamilialcoumarinresistanceduetovariationsintheanticoagulantvitaminK
receptorsite.aMayrequire1020timestheusualdosagetoachievetherapeuticeffects.a
Resistancealsomayresultfromanincreasedrateofdrugmetabolismandexcretion.aConsider
acquiredorinheritedwarfarinresistanceiflargedailydosesarerequiredtomaintainthePT
ratio/INRwithinanormaltherapeuticrange.211330
SurgeryorOtherInvasiveProcedures:
GenerallycontraindicatedinpatientswithrecentorcontemplatedsurgeryoftheeyeorCNSandin
thoseundergoingtraumaticsurgeryresultinginlargeopensurfaces.211
Limittheoperativesitesufficientlytopermiteffectiveuseoflocalproceduresforhemostasis(e.g.,
absorbablehemostaticagents,sutures,pressuredressings)ifnecessary.211Maintainmeticulous
surgicalhemostasis(e.g.,absorbablehemostaticagents,sutures,pressuredressings)ifminor
dentalandsurgicalproceduresareperformed.211a
AdministerIMinjectionsofconcomitantlyadministeredtherapyinanupperextremitytopermiteasy
accessformanualcompression,inspectionforbleeding,and/oruseofpressurebandages.211
SpecificPopulations:
Pregnancy:
CategoryX.211(SeeFetal/NeonatalMorbidityandMortalityunderCautions.)
Lactation:
Limiteddataindicatethatwarfarinisnotdistributedintobreastmilkordetectableinplasmaof
nursinginfantsprolongedPT/INRsreportedinsomeinfants,butsubstantialcoagulation
abnormalitiesnotobserved.211330414420421422423424Althoughthemanufacturerstatestoexercise
caution,500expertsgenerallyconsiderwarfarintherapycompatiblewithbreastfeeding.
341 414 420 421 422 423 424 1012
NeonatesareparticularlysensitivetotheeffectsofwarfarinasaresultofvitaminKdeficiency.a
MonitorinfantsatriskforbleedingwithcoagulationtestsandevaluatetheirvitaminKstatusbefore
breastfeeding.211
PediatricUse:
Safetyandefficacynotestablishedinchildren<18yearsofage.211330Hasbeenusedinpediatric
patientsforpreventionandtreatmentofthromboembolicevents.211330Morefrequent
determinationsofINRarerecommendedinpediatricpatients.2113301013
ACCPstatesexperiencewithwarfarininthepediatricpopulationismostlybasedonuseinchildren
>3monthsofage.1013
GeriatricUse:
Increasedanticoagulantresponse.a211Lesswarfarinrequiredtoproduceatherapeuticlevelof
anticoagulation.aCautioususerecommended,particularlywhentheriskofhemorrhageispresent.
211 330 335Increasedriskforhemorrhageinpatients75yearswithatrialfibrillationwhoareathigh
riskforthromboembolism.335ClosemonitoringofINRrecommended.335
HepaticImpairment:
Increasedanticoagulantresponseduetodecreasedsynthesisofcoagulationfactorsanddecreased
metabolismofwarfarin.211Weighrisksversusbenefitsofanticoagulanttherapyinpatientswith
moderatetoseverehepaticimpairment.211
RenalImpairment:
Increasedanticoagulantresponseinpatientswithmoderateorsevererenalimpairment.aWeigh
risksversusbenefitsofanticoagulanttherapyinpatientswithmoderatetosevererenalimpairment.
211
CommonAdverseEffects:
Hemorrhage.211
AdverseEffects:
Bleeding:
majorbleedingoccursin>2%ofpatientstakinganticoagulationtherapy(level1
[likelyreliable]evidence)
systematicreviewof29randomizedtrialsand4prospectivecohortstudieswith10,757
patientstakingcoumarinderivative(targetINR23)foratleast3months(4,374patientyears
ofanticoagulanttherapy)
majorbleedingoccurredin276patients(2.6%,NNH39)
overallrateof7.22per100patientyears(NNH14peryear),13.4%ofwhichwerefatal
fatalbleedingatrateof1.31per100patientyears(NNH76peryear)
intracranialbleedingatrateof1.15per100patientyears(NNH87peryear)
among2,422patientswhoreceivedwarfarin>3monthsin9studies
rateofmajorbleedingwas2.2%duringfirst3months(55patients,NNH44)and1.8%
after3months(44patients,NNH55),9%ofmajorbleedingcaseswerefatal
fatalbleedingrateafter3monthswas0.63(NNH159peryear)
intracranialbleedingrateafter3monthswas0.65per100patientyears(NNH154per
year)
ReferenceAnnInternMed2003Dec2139(11):893
EBSCOhostFullText,summarycan
befoundinAmFamPhysician2004Aug1570(4):770
vitaminKantagonistsassociatedwithincreasedriskofsubduralhematomacompared
toantiplateletmonotherapy,factorXainhibitors,ordirectthrombininhibitors(level2
[midlevel]evidence)
basedonsystematicreviewwithincompleteassessmentoftrialquality
systematicreviewof19randomizedtrialsevaluatingvitaminKantagonists,antiplatelet
therapy,ordirectactingoralanticoagulantsin92,156patients
trialqualityassessmentdidnotincludeallocationconcealment
275subduralhematomaswerereported
vitaminKagonistsassociatedwithincreasedriskofsubduralhematomacomparedto
antiplatelettherapyinanalysisof9trialswith11,603patients
oddsratio(OR)3(95%CI1.56.1)
NNH1521541withsubduralhematomain0.13%ofcontrols
factorXainhibitorsinanalysisof5trialswith49,687patients
OR2.9(95%CI2.14.1)
NNH180507withsubduralhematomain0.18%ofcontrols
directthrombininhibitorsinanalysisof5trialswith30,866patients
OR1.8(95%CI1.22.7)
NNH2462,089withsubduralhematomain0.24%ofcontrols
ReferenceStroke2014Jun45(6):1672
riskofhemorrhageassociatedwithwarfarinusehighestwithinfirst30daysinelderly
patientswithatrialfibrillation(level2[midlevel]evidence)
basedonretrospectivecohortstudy
125,195patients66yearsoldwithatrialfibrillationwhobeganwarfarintherapybetween
1997and2008werefollowedupto5years
10,840patientshadmajorhemorrhage(definedashospitalvisitforhemorrhage)with18.1%
mortalityeitherinhospitalorwithin7daysofdischarge
overallhemorrhagerate
3.8%perpersonyearduringentirefollowupperiod
11.8%perpersonyearduringfirst30daysoffollowup
3.4%perpersonyearduring31daysto5yearsoffollowup
ReferenceCMAJ2013Feb5185(2):E121
poorerkidneyfunctionassociatedwithincreasingriskofmajorbleeding,especiallyin
first30days,whenstartingwarfarininelderlypatientswithatrialfibrillation(level2
[midlevel]evidence)
12,403patients66yearsoldwithatrialfibrillationwhobeganwarfarinwereanalyzed
medianfollowup2.1years
adjustedincidenceper100personyearsofmajorbleedingwithinfirst30daysofstarting
warfarin(pfortrend=0.001)
6.1in581patientswithestimatedglomerularfiltrationrate(GFR)90mL/minute/1.73m2
12.7in3,221patientswithestimatedGFR4559mL/minute/1.73m2
19.8in586patientswithestimatedGFR1529mL/minute/1.73m2
63.4in55patientswithestimatedGFR<15mL/minute/1.73m2
similartrend(withlowerincidence)at>30daysafterstartingwarfarin
ReferenceBMJ2015Feb3350:h246fulltext
warfarintherapyassociatedwithincreasedmortalityinpatientswithfirstprimary
intracerebralhemorrhage
982patientswithfirsteverprimaryintracerebralhemorrhageduring19932008
18.5%wereonwarfarintherapy
comparingintracerebralhemorrhageoutcomesforwarfarintherapyvs.nowarfarintherapy
28daymortalityin54.4%vs.23.4%(p<0.001,NNH3)
1yearmortalityin64.8%vs.32.1%(p<0.001,NNH3)
onscenemortalityin3.8%vs.0%(nopvaluereported)
warfarinuseingeneralpopulationincreasedfrom0.68%in1993to2.28%in2008
ReferenceStroke2011Sep42(9):2431fulltext,editorialcanbefoundinStroke2011
Sep42(9):2383fulltext
warfarinassociatedintracerebralhemorrhagemayrecurinabout22%afterrestarting
warfarin
basedoncohortstudy
48patientswhosurvivedepisodeofwarfarinassociatedintracerebralhemorrhageevaluated
23patientsrestartedwarfarin
22%hadrecurrentwarfarinassociatedintracerebralhemorrhage,3fatalepisodes
13%hadfatalrecurrence
thromboemboliceventsin20%of25patientswhodidnotrestartwarfarin
ReferenceArchNeurol2008Oct65(10):1313
EBSCOhostFullText
inpatientswithmajorbleeding,warfarinassociatedwithincreasedmortalityat7days
andlongerstayinintensivecareunitcomparedtodabigatran(level2[midlevel]
evidence)
basedoncohortanalysisofdatafromrandomizedtrials
5randomizedtrialscomparingwarfarinvs.dabigatranin27,419patientswithvenous
thromboembolismoratrialfibrillationwereanalyzed
majorbleedingin4.1%withwarfarinvs.3.7%withdabigatran(nopvaluereported)
comparingwarfarinvs.dabigatraninpatientswithmajorbleeding
7daymortality8.4%vs.5.3%(p=0.045,NNH32)
30daymortality13%vs.9.1%(p=0.057)
meanlengthofstayinintensivecareunitorcriticalcareunit2.7daysvs.1.6days(p=
0.01)
meanlengthofstayinhospital8.9daysvs.8.4days(notsignificant)
surgeryrequiredin15%vs.12.1%(notsignificant)
consistentresultsfordifferenceinriskofmortalityat30daysafteradjustmentforsex,age,
weight,renalfunction,andconcomitantantithrombotictherapy
ReferenceCirculation2013Nov19128(21):2325
Riskfactorsforbleeding:
riskfactorsforhemorrhageonwarfarinincludealcoholabuse,chronicrenal
insufficiencyandhistoryofgastrointestinalbleedingbasedonretrospectivecohortstudy
of579patientsidentifiedfromVAMedicalCenterpharmacydatabase,concomitantaspirinnot
associatedwithincreasedriskofbleeding(JGenInternMed1998May13(5):311
EBSCOhostFullTextinAmFamPhysician1998Oct1558(6):1427)
increasingageassociatedwithincreasingriskformajorhemorrhage
basedoncohortof13,559adultswithatrialfibrillation
age>80yearsassociatedwithincreasedriskforintracranialhemorrhage
ReferenceJAmGeriatrSoc2006Aug54(8):1231
EBSCOhostFullText
age80yearsassociatedwithincreaseriskformajorhemorrhage
basedoncohortof472consecutivepatients65yearsoldstartingwarfarintherapyand
followedfor1year
32%were80yearsold
cumulativeincidenceofmajorhemorrhage
13.1per100personyearsinpatients80yearsold
4.7per100personyearsinpatients<80yearsold(p=0.009)
riskfactorsformajorhemorrhage
first90daysofwarfarin
age80years
INR4
26%patients80yearsoldstoppedtakingwarfarinwithinfirstyear
ReferenceCirculation2007May29115(21):2689,commentarycanbefoundinJFamPract
2007Sep56(9):709
EBSCOhostFullText
riskfactorsformajorbleedinginoldestpatientsareinadequatepatienteducationand
polypharmacy
cohortstudyof323patients>80yearsoldtakinganticoagulants,rateofmajorbleeding2.4
eventsper1,000personmonths
independentriskfactorswereinsufficienteducationonoralanticoagulanttherapyasperceived
bypatientorcaregiver(oddsratio[OR]8.83),polypharmacy(OR6.41)andINRabove
therapeuticrange(OR1.08)
ReferenceArchInternMed2004Oct11164(18):2044
riskfactorsforintracranialhemorrhageincludeage>85yearsandINR>3.5
casecontrolstudycompared170patientswithintracranialhemorrhageduringwarfarin
therapyand1,020matchedcontrols
riskforintracranialhemorrhagewashigheratage85yearsandolder(OR2.5,95%CI1.34.7
comparedwithage7074years)andwithINR3.53.9(OR4.6[95%CI2.39.4]compared
withINR23)
ReferenceAnnInternMed2004Nov16141(10):745
EBSCOhostFullTextPDF,
commentarycanbefoundinAnnInternMed2005Apr19142(8):676
EBSCOhostFull
Text
challengesamongtheelderlyonanticoagulantsinclude
loweredserumalbuminduringacuteillnessescausingincreaseinINR
erraticdietscausingfluctuationsinvegetableintakeandeffectonINR
concurrentuseofNSAIDsleadingtoincreasedriskofgastrointestinalbleeding
comorbidmedicalconditionsormedicationsthatcanaffecttheINR
riskoffalling
ReferenceCurrOpinPulmMed2001Sep7(5):365
riskofbleedingandriskofthromboembolismbothappearincreasedwitholderage
cohortofall4,202patientsofLeidenAnticoagulationClinic(theNetherlands)treated1994
1998becauseofmechanicalheartvalveprostheses(targetINR3.5),atrialfibrillation(target
INR3)orpostmyocardialinfarction(targetINR3)
incidenceratesper100patientyearsofmajorhemorrhagewere1.5in842patients<60
yearsold,2.1in1,200patientsaged6070years,2.5in1,464patientsaged7180years,and
4.2in696patients>80yearsold
incidenceratesper100patientyearsofmajorthromboembolismwas1forage<60years,
1.4forage6070years,1.6forage7180yearsand2.4forage>80years
ReferenceArchInternMed2005Jul11165(13):1527
EBSCOhostFullText
minorheadtraumamaybeassociatedwithsignificantmorbidityandmortalityin
patientstakingwarfarin
basedonretroactivechartreview
caserecordsof13patientstakingwarfarin(meanage69years)presentingtoanAustralian
hospitalbetween19942000withaheadinjurywerereviewed
medianINR2.4(range1.810)
5patientsdied
causesofheadinjury
9slippedandfell
2involvedinmotorvehicleaccident(bothdied)
2foundlyingonfloor
patientsymptomsatpresentation
confusionin4
neurologicdeficitin4
seizurein3
headachein2
nauseaandvomitingin1
11patientshadbrainCT
9hadCTfindingsofintracerebralhemorrhage
2patientshadnormalCTscans
1patientwithoutCThadINRof10anddied
1patienthadminorscalplacerationandnoCTperformed
ReferenceSingaporeMedJ2006Aug47(8):676
increasedthrombomodulinconcentrationassociatedwithwarfarinrelatedbleeding
basedonprospectivecohortstudy
719patients(meanage70years,63%male)withplannedwarfarintreatmentfor3months
hadthrombomodulinconcentrationmeasuredwithenzymelinkedimmunosorbentassayat
baseline
clinicallyrelevantbleedingdefinedasovertbleedingeventcausingadmissiontohospitalor
prolongedhospitalcare
113clinicallyrelevantbleedingeventsand73majorbleedingeventsinmean4.2yearsfollow
up
bleedingincidenceper100treatmentyearsforpatientsstratifiedbythrombomodulin
concentration
ThrombomodulinConcentrationandBleeding:
Thrombomodulin
ClinicallyRelevant
MajorBleeding
Concentration
Bleeding
5ng/mL
2.4
1.5
5.16.1ng/mL
4.5
2.7
>6.1ng/mL
5.6
3.7
thrombomodulinconcentrationnotassociatedwithcardiovasculareventsorallcausemortality
ReferenceArchInternMed2009Jul13169(13):1210
EBSCOhostFullText,
commentarycanbefoundinArchInternMed2009Nov23169(21):2031
EBSCOhostFull
Text
riskofanticoagulationrelatedhemorrhageincreasedwithadditionaluseof
antiplateletagentsinpatientsreceivingwarfarintherapy(level2[midlevel]
evidence)
4,183patientsreceivingwarfarinandwithdocumenteduseornonuseofantiplateletagents
followedfor6months
indicationsfortreatmentincludedatrialfibrillation,venousthromboembolism,heartvalve
disorders,andothercardiovascularconditions
abouthalfthepatientswerereceivingtreatmentduetoatrialfibrillation
comparingusevs.nonuseofantiplateletagents
anticoagulationrelatedhemorrhagesin4.2%vs.2%(p<0.001)
coronaryeventsin0.9%vs.0.3%(p=0.009,notsignificantafteradjustment)
deathin0.1%vs.0.2%(notsignificant)
thromboticeventsin0.3%vs.0.4%(notsignificant)
ReferenceChest2008Apr133(4):948fulltext
resumptionofwarfarintherapyassociatedwithdecreasedriskofmortalityand
thrombosiswithoutsignificantincreasedriskofrecurrenthemorrhageinpatientswith
gastrointestinalbleeding(level2[midlevel]evidence)
442patients(meanage74years)withgastrointestinaltractbleedingduringwarfarintherapy
evaluatedforresumptionofwarfarintherapyandfollowedfor90days
58.8%resumedwarfarintherapy
comparingresumptionvs.noresumptionofwarfarintherapy
thrombosisin0.4%vs.5.5%(p<0.001)
mortalityin5.8%vs.20.3%(p<0.001)
recurrentgastrointestinalbleedingin10%vs.5.5%(p=0.09)
ReferenceArchInternMed2012Oct22172(19):1484
EBSCOhostFullText,editorial
canbefoundinArchInternMed2012Oct22172(19):1492
EBSCOhostFullText
increaseinINRbeforewarfarinassociatedbleedingmaybesubtle
cohortof2,391patientstreatedbyanticoagulationserviceinBoston,eachof32patients
(1.3%)withwarfarinrelatedhemorrhagewerematchedwith2controls
meanINRattimeofbleedingwas5.9vs.2.3(p<0.001),lastINRbeforebleedingevent
obtainedmean11.6vs.18.3dayspriorandwas3vs.2.1(p<0.001)
ReferenceArchInternMed2004Oct25164(19):2176,commentarycanbefoundinArch
InternMed2005Mar28165(6):703
EBSCOhostFullText
reviewofbleedingriskswithwarfarinandaspirincanbefoundinBMJ2002Oct
12325(7368):828
adjusteddosewarfarinwithtargetINR23associatedwith1.1%annualrateofmajorbleeding
and41.1%cumulaterateofanybleedingafter3yearsinelderlypatients,basedonrandomized
trialin677patientsaged6789yearswithatrialfibrillation,increasingINRvalueandprior
myocardialinfarctionwereindependentriskfactorsforbleedingbutincreasingagewasnot(Arch
InternMed1999Jun28159(12):1322
EBSCOhostFullText)
cerebralischemiaofarterialorigindoesNOTappeartosubstantiallyincreaseriskofintracranial
hemorrhagewithINR23,basedoninterimanalysisofongoingrandomizedtrial(Stroke2003
Jun34(6):e45)
casereportsofunusualbleedinginpatientstakingwarfarin
casereportofsevereintestinalbleedinginwomanwithoveruseofsennabasedlaxatives
whiletakingwarfarincanbefoundinLancet2008Mar1371(9614):784
intramedullaryspinalcordhematomareportedinpatienttakingwarfarin(level3
[lackingdirect]evidence)
basedoncasereport
patientpresentedwithacutepainlessprogressivequadriplegia
initialCTscannegative,subsequentMRIlocatedcervicalhematoma
ReferenceJAmGeriatrSoc2007May55(5):799
EBSCOhostFullText
Predictionrulesforbleeding:
ATRIAscorepredictsriskforwarfarinassociatedmajorhemorrhageinpatientswith
atrialfibrillation(level1[likelyreliable]evidence)
basedonderivationandvalidationcohortstudy
9,186patientswithatrialfibrillationtreatedwithwarfarinfromAnticoagulationandRisk
FactorsinAtrialFibrillation(ATRIA)studywererandomlydividedinto
derivationcohortof6,123patients
validationcohortof3,063patients
totalwarfarinexposure32,888personyears(medianwarfarinexposure3.5years)
majorhemorrhage(definedasfatal,requiringtransfusionof2unitspackedbloodcells,or
hemorrhageintocriticalanatomicsite[intracranial,retroperitoneal])in
307(5%)patientsinderivationcohort
154(5%)patientsinvalidationcohort
riskfactorsidentifiedinderivationcohortandpointsassignedtoderiveATRIAscore(total
score010points)
anemia3points
severerenaldisease(estimatedglomerularfiltrationrate<30mL/minuteordialysis
dependent)3points
age75yearsold2points
priorbleeding1point
hypertension1point
observedmajorbleedingbyATRIAscore
Results:
TotalScore
DerivationCohort
ValidationCohort
(Events/100Person
(Events/100Person
years)
years)
03points
0.72
0.83
4points
2.71
2.41
510points
5.99
5.32
ATRIAscoreperformedbetterthan6otherriskscoresinthiscohort
ReferenceJAmCollCardiol2011Jul1958(4):395,commentarycanbefoundinNatRev
Cardiol2011Aug28(9):481,AnnInternMed2011Nov15155(10):JC5
EBSCOhostFull
Text
7differentriskscoresdonotappearusefulforpredictionofmajorbleedinginadults
receivingvitaminKantagonists(level2[midlevel]evidence)
basedonvalidationcohortstudywithloweventrate
515adultsreceivingoralvitaminKantagonists(acenocoumarolorphenprocoumon)were
followedfor12monthsandassessedwith7clinicalpredictionscoresforriskofmajorbleeding
all7riskscores(includingATRIA,HASBLED,HEMORR2HAGES,RIETE,OBRIscores)stratified
patientsintolow,intermediate,andhighbleedingriskcategories
majorbleedingin6.8%
majorbleedingbyriskcategory
3%6%forlowrisk
7%10%forintermediaterisk
7%15%forhighrisk
overallperformancewasclosetochanceforeachscore
nosignificantdifferencesinpredictionofmajorbleedingriskamongthe7scoresorcomparing
scorestophysician'ssubjectiveriskassessment
ReferenceAmJMed2012Nov125(11):1095fulltext
DynaMedcommentaryacenocoumarolorphenprocoumonavailableinSwitzerlandand
comparabletowarfarin
HEMORR2HAGESmaybemoreaccuratethan3otherschemesforpredicting
hospitalizationforhemorrhage(level2[midlevel]evidence)
3,791Medicarebeneficiarieswithatrialfibrillationidentifiedfromqualityimprovementregistries
in7states
162(4.3%)werehospitalizedforhemorrhage
HEMORR2HAGESscorederivedfrom
2pointsforpriorbleed
1pointforhepaticorrenaldisease
1pointforethanolabuse
1pointformalignancy
1pointforage>75years
1pointforreducedplateletcountorfunction
1pointforuncontrolledhypertension
1pointforanemia
1pointforgeneticfactors
1pointforexcessivefallrisk
1pointforstroke
rateofbleedingper100patientyearsofwarfarin
1.9for0points
2.5for1point
5.3for2points
8.4for3points
10.4for4points
12.3for5ormorepoints
ReferenceAmHeartJ2006Mar151(3):713
bleedingriskpredictionscore(BRPS)simpleenoughtouseatbedsideandvalidatedin
onestudytohelppredictriskofbleedingwhenstaringwarfarin
predictionrulebasedonage,sexandpresenceofmalignancyandderivedfrom241patients
withvenousthromboembolismstartingwarfarinandfollowedfor3months
predictionrulevalidatedin780suchpatients
BRPS=1.6ifage>60yearsPLUS1.3iffemalePLUS2.2ifmalignancy,lowriskif0,
moderateriskif13,highriskif>3
invalidationgroup,thosewithhighriskhad17%riskforanybleedingand7%riskformajor
bleedingcomplication,thosewithmoderateriskhad8%riskforanybleedingand2%riskfor
majorbleedingcomplication,thosewithhighriskhad4%riskforanybleedingand1%riskfor
majorbleedingcomplication
ReferenceArchInternMed1999Mar8159(5):457
EBSCOhostFullTextinJFamPract
1999Jun48(6):413
simplerversionofthisrulewouldbehighriskifcancerinfemaleorpatient>60yearsold
moderateriskinmale<60yearsoldwithcancer,femaleorpatient>60yearsoldwithout
cancerlowriskinmale<60yearsoldwithoutcancer(DynaMedcommentary)
OutpatientBleedingRiskIndex
riskindexcanpredictriskformajorbleedinginoutpatientsonwarfarin
seriesof820patientswithmajorbleedingoccurringin87atrateof6.5%/year
556wereevaluatedretrospectivelytodevelopriskindex
264followedprospectivelyfor7yearsafterhospitaldischarge
4independentriskfactorsformajorbleedingwere
age>65years
historyofGIbleeding
historyofstroke
atleast1ofrecentmyocardialinfarction,hematocrit<30%,creatinine>1.5mg/dL
(132.6mol/L),ordiabetesmellitus
riskofbleedingat48months
3%withnoriskfactors
12%with12riskfactors
53%with34riskfactors
ReferenceAmJMed1998Aug105:91inQuickScanReviewsinFamPract1999
Mar23(12):25
riskindexdistinguishedlowfrommoderateriskinprospectivestudy
222patientswithDVTorPEtreatedwithLMWHfor5daysandwarfarin(targetINR2.5)
for3months,meanfollowup18.5months
only2patientshadhighrisk(34riskfactors)
158patients(58%)whowerelowrisk(0riskfactors)had7(5.5%)minorhemorrhages
andnomajorhemorrhages
92(41%)whoweremoderaterisk(12riskfactors)had5(5.4%)majorhemorrhages
ReferenceArchInternMed2003Apr28163(8):917
EBSCOhostFullText
riskindexdistinguishedintermediatefromhighriskinveteranpopulation
retrospectiveanalysisofall1,269patientsmanagedbyaVApharmacistrunoutpatient
warfarinmanagementclinic20012002
majorbleeddefinedashemodynamicinstability,transfusion,intracranialhemorrhageor
death
minorbleeddefinedasrequiringhospitalizationorphysicianevaluation
130lowriskpatients(noriskfactors)had1majorbleed(0.8%)and11minorbleeds
(8.5%)
943intermediateriskpatients(12riskfactors)had25majorbleeds(2.6%)and50
minorbleeds(5.3%)
196highriskpatients(34riskfactors)had19majorbleeds(9.7%)and12minorbleeds
(6.1%)
ReferenceJGenInternMed2005Nov20(11):1008
EBSCOhostFullText,
commentarycanbefoundinEvidenceBasedMedicine2006JulAug11(4):120
Bleedingprevention:
pharmacistparticipationinwarfarinmanagementmayreduceriskofbleeding(level2
[midlevel]evidence)
basedonsystematicreviewofmostlyobservationalstudies
systematicreviewof24studies(5randomizedtrialswithoutblinding,19observationalstudies)
comparingwarfarinmanagementwithpharmacistparticipationvs.usualcarein728,377
patients
pharmacistparticipationinwarfarinmanagementassociatedwithreduced
riskoftotalbleeding(riskratio[RR]0.51,95%CI0.280.94)inanalysisof4randomized
trialswith736patients
riskofmajorbleeding(RR0.49,95%CI0.260.93)inanalysisof12observationalstudies
with9,214patients,resultslimitedbyheterogeneity(p=0.044)
riskofthromboembolicevents(RR0.37,95%CI0.260.53)inanalysisof15observational
studieswith10,585patients
nosignificantdifferencesinallcauseandwarfarinrelatedmortality
ReferenceJThrombHaemost2010Nov8(11):2418
EBSCOhostFullText
OtherAdverseEffectsofWarfarin:
systemiccholesterolmicroembolization
purpletoessyndrome
vasculitis
hepaticdisorders
fever
dermatitis
urticaria
abdominalpain
asthenia
GIupset
headache
pruritus
alopecia
paresthesias
raresideeffectofskinnecrosisduetotemporaryhypercoagulablestatebyloweredlevelsof
proteinC(increasedriskifproteinCdeficiency)
trachealcalcification(pictureinCMAJ2008Jul29179(3):291
EBSCOhostFullTextfulltext)
possibleincreasedriskofosteoporosiswithlongtermuse
longtermexposuretooralanticoagulationassociatedwithincreasedriskof
vertebralandribfracturesinstudyof572women>35yearsoldwhodeveloped480
fracturesover6,314personyearsoffollowup,reasonsforassociationunclear(ArchIntern
Med1999Aug9/23159(15):1750
EBSCOhostFullText)
longtermuseofwarfarinassociatedwithosteoporoticfracturesinmenwithatrial
fibrillation
retrospectivestudyof13,881Medicarebeneficiarieswithatrialfibrillationwhowere
hospitalizedinUnitedStates19981999
7,587werenotprescribedwarfarin,1,833usedwarfarinfor<1year,4,461usedwarfarin
>1year
nosignificantassociationbetweenosteoporoticfractureanduseofwarfarin<1year
nosignificantassociationbetweenosteoporoticfractureandwarfarinuse>1yearin
women
ReferenceArchInternMed2006Jan23166(2):241
EBSCOhostFullText,
commentarycanbefoundinArchInternMed2006Jul24166(14):1525
EBSCOhost
FullText
PregnancyandBreastfeeding:
AvoidUseinPregnancy(WarfarinTeratogenic):
warfarinshouldnotbeusedduringpregnancy
warfarinembryopathyifgiveninfirsttrimesterat69weeks,nasalhypoplasia,stippledepiphyses
ofbones,phenotypicallychondrodysplasiapunctata
complicationsatanytimeduringpregnancybleeding,opticatrophy,agenesisofcorpus
callosum,mentalretardation,upto50%blindness,DandyWalkermalformation,midlinecerebellar
atrophy
useofheparinfor612weeksgestationinsteadofwarfarinhasbeenrecommendedfor
pregnantwomenwhorequireanticoagulation,forexample,mechanicalheartvalves
systematicreviewsuggeststhatthisapproachavoids6.4%riskoffetalembryopathyatexpense
ofincreasingriskofvalvethrombosisfrom3.9%to9.2%,basedoncaseseriesandcohort
studieslargeprospectivetrialsrecommended(ArchInternMed2000Jan24160(2):191
EBSCOhostFullText)noanticoagulationregimenoffersoptimaloutcomesforbothmother
andfetus(JWatch2000Mar120(5):39)
inuteroexposuretocoumarinsnotassociatedwithanylargesignificanteffectsoncognitive
functionatage814yearsinstudycomparing291exposedand253unexposedchildren
(Pediatrics2001Jan107(1):123
EBSCOhostFullText)
UseDuringBreastfeeding:
warfarinappearssafeduringlactationbutdataverylimited
reviewofsafetyoforalanticoagulantsduringlactation2smallcaseserieswithwarfarinupto
12mg/dayfoundnowarfarininbreastmilkorinfants'bloodandnoneonataladversebleeding
dicumarolrecommendedasalternativeoralanticoagulantifwarfarinnottolerated
phenindioneandanisindioneareanticoagulantswhichareexcretedinbreastmilk,butonly1
casereportofinfantbleedinghasbeenreported
ReferenceObstetGynecol2000Jun95:938inAmFamPhysician2000Dec1562(12):2669
Interactions
Metabolism:
Druginteractionswithwarfarinandothercoumarinderivativescanoccurviapharmacodynamic
interactions(e.g.,impairedhemostasisincreasedordecreasedintestinalsynthesisorabsorptionof
vitaminKaltereddistributionormetabolismofvitaminKincreasedwarfarinaffinityforreceptor
sitesdecreasedsynthesisand/orincreasedcatabolismoffunctionalbloodcoagulationfactorsII,
VII,IX,andXinterferencewithplateletfunctionorfibrinolysisulcerogeniceffects)or
pharmacokineticinteractions(e.g.,increasedordecreasedrateofwarfarinmetabolismincreasedor
decreasedproteinbinding).211aSuchinteractionsmayincreaseordecreaseresponsetocoumarin
derivatives.(SeeTables2and3.)
Table2.DrugsThatMayIncreaseResponsetoCoumarinDerivatives(e.g.,Warfarin)211a:
acetaminophen
ezetimibe
pantoprazole
*alcohol(acuteintoxication)
fenofibrate
*pentoxifylline
allopurinol
fenoprofencalcium
phenylbutazone
aminosalicylicacid
fluoroquinoloneanti
pravastatin
infectives
*amiodarone
fluoxetine
propafenone
anabolicsteroids
flutamide
propoxyphene
argatroban
fluvastatin
propylthiouracil
aspirin
fluvoxamine
quinidine
atenolol
gefitinib
quinine
atorvastatin
gemfibrozil
*rabeprazole
azithromycin
glucagon
salicylates
bivalirudin
ibuprofen
sertraline
capecitabine
indomethacin
streptokinase
cefixime
influenzavirusvaccine
sulfinpyrazone
celecoxib
isoniazid
sulfonamides
chloralhydrate
ketoprofen
sulindac
chloramphenicol
lansoprazole
tamoxifen
cimetidine
lepirudin
tetracycline
cisapride
lovastatin
thiazides
cotrimoxazole
meclofenamate
thyroiddrugs
danazol
mefenamicacid
tramadol
diazoxide
methylthiouracil
tricyclic
antidepressants
diflunisal
*metronidazole
*urokinase
*disulfiram
miconazole
valdecoxib
erythromycin
nalidixicacid
vitaminE
esomeprazole
neomycin(oral)
zafirlukast
ethacrynicacid
oxandrolone
zileuton
concurrentuseprobablyshouldbeavoided,if
possible
Table3.DrugsthatMayDecreaseResponsetoCoumarinDerivatives(e.g.,Warfarin):
*alcohol(chronicalcoholism)
ethchlorvynol
raloxifene
aminoglutethimide
glutethimide
rifampin
atorvastatin
griseofulvin
spironolactone
*barbiturates
mercaptopurine
sucralfate
carbamazepine
methaqualone
trazodone
clozapine
nafcillin
vitaminK
corticosteroids
*oralcontraceptivescontaining
estrogen
corticotropin
*
concurrentuseprobablyshouldbeavoided,if
possible
pravastatin
DrugsAffectingHepaticMicrosomalEnzymes:
PotentialpharmacokineticinteractionwithinhibitorsorinducersofCYP2C9,1A2,or3A4(increased
warfarinexposurewithconcomitantinhibitors,decreasedwarfarinexposurewithconcomitant
inducers).211(SeeTable4.)CloselymonitorINRinpatientswhoinitiate,discontinue,orchange
dosagesoftheseconcomitantdrugs.211
Table4.CYPInteractionswithWarfarin211:
Enzyme
Inhibitors*
Inducers*
CYP2C9
amiodarone
aprepitant
capecitabine
bosentan
cotrimoxazole
carbamazepine
etravirine
phenobarbital
fluconazole
rifampin
fluvastatin
fluvoxamine
metronidazole
miconazole
oxandrolone
sulfinpyrazone
tigecycline
voriconazole
zafirlukast
CYP1A2
acyclovir
montelukast
allopurinol
moricizine
caffeine
omeprazole
cimetidine
phenobarbital
ciprofloxacin
phenytoin
disulfiram
cigarettesmoking
enoxacin
famotidine
fluvoxamine
methoxsalen
mexiletine
norfloxacin
oralcontraceptives
phenylpropanolamine
propafenone
propranolol
terbinafine
thiabendazole
ticlopidine
verapamil
zileuton
CYP3A4
alprazolam
armodafinil
amiodarone
amprenavir
amlodipine
aprepitant
amprenavir
bosentan
aprepitant
carbamazepine
atorvastatin
efavirenz
atazanavir
etravirine
bicalutamide
modafinil
cilostazol
nafcillin
cimetidine
phenytoin
ciprofloxacin
pioglitazone
clarithromycin
prednisone
conivaptan
rifampin
cyclosporine
rufinamide
darunavir/ritonavir
diltiazem
erythromycin
fluconazole
fluoxetine
fluvoxamine
fosamprenavir
imatinib
indinavir
isoniazid
itraconazole
ketoconazole
lopinavir/ritonavir
nefazodone
nelfinavir
nilotinib
oralcontraceptives
posaconazole
ranitidine
ranolazine
ritonavir
saquinavir
telithromycin
tipranavir
voriconazole
zileuton
listofdrugsisnotallinclusive
DrugsthatIncreaseRiskofBleeding:
Possibleincreasedriskofbleedingwithconcomitantuseofantiplateletagents,NSAIAs,SSRIs,and
anticoagulantsotherthanwarfarin.211(SeeTable5.)
Monitorclosely.211WhilethemanufacturersofwarfarinstatethatNSAIAs,includingselective
cyclooxygenase2(COX2)inhibitors,maybeusedwithclosemonitoringinpatientsreceiving
warfarin,211500someexperts(ACCP)suggestthatsuchconcomitanttherapybeavoided.1000
Table5.DrugsthatCanIncreaseBleedingRisk:
DrugClass
SpecificDrugs
Anticoagulants argatroban,dabigatran,bivalirudin,desirudin,heparin,lepirudin
Antiplatelet
aspirin,cilostazol,clopidogrel,dipyridamole,prasugrel,ticlopidine
agents
NSAIAs
celecoxib,diclofenac,diflunisal,fenoprofen,ibuprofen,indomethacin,ketoprofen,
ketorolac,mefenamicacid,naproxen,oxaprozin,piroxicam,sulindac
Serotonin
citalopram,desvenlafaxine,duloxetine,escitalopram,fluoxetine,fluvoxamine,
reuptake
milnacipran,paroxetine,sertraline,venlafaxine,vilazodone
inhibitors
AntibioticsorAntifungalAgents:
PotentialalterationinINRwithconcomitantuseofcertainantibioticsorantifungalagentshowever,
studieshavenotshownconsistenteffectsonplasmawarfarinconcentrations.211
MonitorINRcloselywheninitiatingordiscontinuinganyantibioticorantifungalagentinpatients
receivingwarfarin.211
DietaryorHerbalSupplements:
Concomitanttherapywithdietaryorherbal(botanical)supplementsmayalteranindividuals
responsetowarfarintherapy.211(SeeTables6and7.)Limitedinformationisavailableregardingthe
interactionpotentialofdietaryandherbalproducts.211Exercisecautionandperformadditional
PT/INRdeterminationswhenevertheseproductsareaddedordiscontinued.211
Table6.DietaryorHerbalSupplementsthatMayIncreaseResponseto
CoumarinDerivatives(e.g.,Warfarin)211a:
agrimony
chamomile(GermanandRoman) parsley
alfalfa
clove
passionflower
aloegel
*cranberry
paudarco
Angelicasinensis(dongquai) dandelion
policosanol
aniseed
fenugreek
poplar
arnica
feverfew
pricklyash(Northern)
asafoetida
garlic
quassia
aspen
Germansarsaparilla
redclover
blackcohosh
ginger
senega
blackhaw
Ginkgobiloba
sweetclover
bladderwrack(Fucus)
ginseng(Panax)
sweetwoodruff
bogbean
horsechestnut
tamarind
boldo
horseradish
tonkabeans
bromelains
inositolnicotinate
wildcarrot
buchu
licorice
wildlettuce
capsicum
meadowsweet
willow
cassia
nettle
wintergreen
celery
onion
Table7.DietaryorHerbalSupplementsthatMay
DecreaseResponsetoCoumarinDerivatives(e.g.,
Warfarin)211a:
agrimony
goldenseal St.Johnswort
coenzymeQ10(ubidecarenone) mistletoe
yarrow
ginseng(Panax)
Somebotanicalproducts(e.g.,garlic,Gingkobiloba)increaseriskofbleedingwhenusedalone
additiveanticoagulanteffectsarepossiblewhenusedconcomitantly.211
Possibleinteractionbetweenwarfarinandcranberryjuice(i.e.,increasedeffectandpossible
increasedriskofbleeding).501502503504505506510However,evidencemostlyfromcasereports
prospectivecontrolledstudiesgenerallyhavenotbeenabletoconfirmthisinteraction.
501 502 504 505 507 508 509 510 511
Althoughclinicallyimportantinteractionnotlikely,monitorcloselyfor
changesinINRandbleeding.501502507508509510
SystematicReviewsandOtherEvidence:
systematicoverviewofdruginteractionswithwarfarin
181articlesidentifiedwithoriginalreportson120drugsorfoods,84%ofreportswereofpoor
quality(mostlysinglecasereports),31casesofclinicallysignificantbleedingwereallsingle
casereports
drugswithconsistentreportsofinteractionswithwarfarinincludeazoleantibiotics,macrolides,
quinolones,nonsteroidalantiinflammatorydrugs(NSAIDs)includingselectivecyclooxygenase
2inhibitors(COX2inhibitors),selectiveserotoninreuptakeinhibitors(SSRIs),omeprazole,
lipidloweringagents,amiodarone,andfluorouracil
ReferenceArchInternMed2005May23165(10):1095
EBSCOhostFullText,
commentarycanbefoundinArchInternMed2005Nov28165(21):2540
EBSCOhostFull
Text
additionofaspirintooralanticoagulanttherapymayreduceriskforarterial
thromboembolismbutincreaseriskformajorbleedinginpatientswithmechanical
heartvalves(level2[midlevel]evidence),insufficientevidenceinotherpatients
basedonsystematicreviewofvariableevidence
systematicreviewandmetaanalysisof10randomizedtrialsofaspirinvs.noaspirinin4,180
patientsreceivingsimilardosesoforalanticoagulantsandfollowedforatleast3months
4trialswerehighquality,6trialswerelowquality
patientsstudiedincludedmechanicalheartvalves(5trials),atrialfibrillation(2trials),coronary
arterydisease(2trials)andhighriskforcardiovasculardisease(1trial)
aspirindose100mg/dayorlessin6trialsand2001,000mg/dayin4trials
comparingaspirinvs.noaspiringinoverallmetaanalysis
6.3%vs.8.8%arterialthromboembolism(p<0.001,NNT40),thisanalysislimitedby
heterogeneity
3.8%vs.2.8%majorbleeding(p=0.05,NNH100)
6.7%vs.6.7%allcausemortality(notsignificant)
statisticallysignificantdifferenceslimitedtopatientswithmechanicalvalves
insufficientevidenceinotherpatientgroupstodemonstrateorexcludeclinicallysignificant
differences
ReferenceArchInternMed2007Jan22167(2):117
canbefoundinJFamPract2007Jun56(6):430
EBSCOhostFullText,commentary
EBSCOhostFullText
gemfibrozil,simvastatinandatorvastatinassociatedwithincreasedriskof
gastrointestinalbleedinginpatientstakingwarfarin(level2[midlevel]evidence)
basedoncasecontrolstudy
12,193patientstakingwarfarinandhospitalizedforgastrointestinalbleedingwerematchedto
609,650warfarinuserswithnogastrointestinalbleeding
increasedriskofgastrointestinalbleedinginpatientstakingwarfarinassociatedwithfirst
prescriptionfor
gemfibrozil(oddsratio[OR]1.88,95%CI13.54)
simvastatin(OR1.46,95%CI1.032.07)
atorvastatin(OR1.39,95%CI1.071.81)
pravastatinnotassociatedwithincreasedriskofgastrointestinalbleeding
ReferenceAmJMed2010Feb123(2):151
drugswhichincreaseriskofbleedingonwarfarin
highlyprobablealcohol(ifliverdisease),amiodarone,anabolicsteroids,cimetidine,clofibrate,
erythromycin,fluconazole,isoniazid,metronidazole,miconazole(eventopical),omeprazole,
phenylbutazone,piroxicam,propafenone,propranolol,sulfinpyrazone(biphasicwithlater
inhibition),trimethoprimsulfamethoxazole
probableacetaminophen,chloralhydrate,ciprofloxacin,dextropropoxyphene,disulfiram,
itraconazole,quinidine,phenytoin(biphasicwithlaterinhibition),tamoxifen,tetracycline,
influenzavaccine
possibleaspirin,disopyramide,fluorouracil,ifosfamide,ketoprofen,lovastatin,metolazone,
moricizine,nalidixicacid,norfloxacin,ofloxacin,propoxyphene,sulindac,tolmetin,topical
salicylates
ReferenceChest1998114(5suppl):445SPDFinJAmBoardFamPract1999Nov
Dec12(6):486
acuteupperrespiratoryinfectionandantibioticuseassociatedwithincreasedriskof
excessiveanticoagulationinpatientsonstablewarfarintherapy(level3[lacking
direct]evidence)
basedonretrospectivelongitudinalcohortstudywithoutclinicaloutcomes
12,006patients(meanage68years)onstablewarfarintherapycategorizedintothefollowing
groups
purchasinganantibiotic(antibioticgroup)
upperrespiratorytractinfectionbutnotreceivinganantibiotic(sickcontrols)
purchasingawarfarinrefillonly(stablecontrols)
proportionofpatientswithfollowupINR(3to15daysafterprescriptionpurchaseor
correspondingindexdate)5
3.2%forantibioticgroup(p<0.001vs.stablecontrols,notsignificantvs.sickcontrols)
2.6%forsickcontrols(p<0.017vs.stablecontrols)
1.2%forstablecontrols
ReferenceJAMAInternMed2014Mar1174(3):409
EBSCOhostFullText
inconsistenteffectsonINRwithfluoroquinolones
basedonsystematicreviewof22studiesandreports
ReferenceAnnPharmacother2008May42(5):680
acetaminophenisassociatedwithoveranticoagulationinpatientstakingwarfarin
93casepatientswithINR>6.0and196controlswithINR1.73.3inoutpatient
anticoagulationclinicinterviewedtoassessriskfactors
acetaminopheningestionindependentlyassociatedindosedependentmannerwithhavingINR
>6
otherfactorsindependentlyassociatedwithINR>6werenewmedicationknownto
potentiatewarfarin,advancedmalignancy,recentdiarrhealillness,decreasedoralintakeand
takingmorewarfarinthanprescribed
ReferenceJAMA1998Mar4279(9):657
EBSCOhostFullTextfulltext,commentarycan
befoundinJAMA1998Aug26280(8):695,696,JAMA1998Mar4279(9):702
EBSCOhost
FullText
occasionaluseofacetaminophendidnotincreaserisk,butpatientstaking>2,275mg/week
shouldbemonitoredcloselyforelevatedINR(inJFamPract1998Jun46(6):456)
GeneralConcepts:
Concomitanttherapywithdrugsordietaryorherbalsupplementsmayalteranindividualsresponse
towarfarintherapy.211330aForadequateanticoagulationcontrol,performadditionalPT/INR
determinationswhenconcomitantdrugtherapyisadded,discontinued,ortakenirregularly.211330
DrugsorSupplementsIncreasingAnticoagulantResponse:
Potentialpharmacodynamicinteraction(e.g.,decreasedintestinalsynthesisorabsorptionofvitamin
KaltereddistributionormetabolismofvitaminKincreasedwarfarinaffinityforreceptorsites
decreasedsynthesisand/orincreasedcatabolismoffunctionalbloodcoagulationfactorsII,VII,IX,
andXinterferencewithplateletfunctionorfibrinolysisulcerogeniceffects).211aPotential
pharmacokineticinteraction(e.g.,decreasedrateofwarfarinmetabolismdecreasedprotein
binding).211a
DrugsThatMayIncreaseResponse
acetaminophen
alcohol(acuteintoxication)a
allopurinol
aminosalicylicacid
amiodaronea
anabolicsteroids
argatroban
aspirin
atenolol
atorvastatin
azithromycin
bivalirudin
capecitabine
cefixime
celecoxib
chloralhydrate
chloramphenicol
cimetidine
cisapride
cotrimoxazole
danazol
diazoxide
diflunisal
disulfirama
erythromycin
esomeprazole
ethacrynicacid
ezetimibe
fenofibrate
fenoprofencalcium
fluoroquinoloneantiinfectives
fluoxetine
flutamide
fluvastatin
fluvoxamine
gefitinib
gemfibrozil
glucagon
heparin
ibuprofen
indomethacin
influenzavirusvaccine
isoniazid
ketoprofen
lansoprazole
lepirudin
lovastatin
meclofenamate
mefenamicacid
methylthiouracil
metronidazolea
miconazole
nalidixicacid
neomycin(oral)
oxandrolone
pantoprazole
pentoxifyllinea
phenylbutazone
pravastatin
propafenone
propoxyphene
propylthiouracil
quinidine
quinine
rabeprazolea
salicylates
sertraline
streptokinase
sulfinpyrazone
sulfonamides
sulindac
tamoxifen
tetracyclines
thiazides
thyroiddrugs
tramadol
tricyclicantidepressants
urokinasea
valdecoxib
vitaminE
zafirlukast
zileuton
aConcurrentuseprobablyshouldbeavoided,ifpossible
DietaryorHerbalSupplementsThatMayIncreaseResponse
agrimony
alfalfa
aloegel
Angelicasinensis(dongquai)
aniseed
arnica
asafoetida
aspen
blackcohosh
blackhaw
bladderwrack(Fucus)
bogbean
boldo
bromelains
buchu
capsicum
cassia
celery
chamomile(GermanandRoman)
clove
cranberrya
dandelion
fenugreek
feverfew
garlic
Germansarsparilla
ginger
Ginkgobiloba
ginseng(Panax)
horsechestnut
horseradish
inositolnicotinate
licorice
meadowsweet
nettle
onion
parsley
passionflower
paudarco
policosanol
poplar
pricklyash(Northern)
quassia
redclover
senega
sweetclover
sweetwoodruff
tamarind
tonkabeans
wildcarrot
wildlettuce
willow
wintergreen
DrugsorSupplementsDecreasingAnticoagulantResponse:
Potentialpharmacodynamicinteraction(e.g.,increasedsynthesisoffunctionalbloodcoagulation
factorsII,VII,IX,andX).211aPotentialpharmacokineticinteraction(decreasedabsorption,
inductionofhepaticmicrosomalenzymes[e.g.,St.Johnswort]).381aPotentialpharmacodynamic
interaction(procoagulanteffects[e.g.,coenzymeQ10]).380
DrugsthatMayDecreaseResponse
alcohol(chronicalcoholism)a
aminoglutethimide
atorvastatin
barbituratesa
carbamazepine
clozapine
corticosteroids
corticotropin
ethchlorvynol
glutethimide
griseofulvin
mercaptopurine
methaqualone
nafcillin
oralcontraceptivescontainingestrogena
pravastatin
raloxifene
rifampin
spironolactone
sucralfate
trazodone
vitaminK
HerbalorDietarySupplementsthatMayDecreaseResponse
agrimony
coenzymeQ10(ubidecarenone)
ginseng(Panax)
goldenseal
mistletoe
St.Johnswort
yarrow
SpecificDrugs:
Drug
Interaction
Comments
Acetaminophen Potentialforincreasedanticoagulanteffects307310
312 313 1014
however,conflictingdataexistregarding
90 304 305 306 308 309 311
clinicalimportance
MonitoringofINR
recommendedfollowing
initiationof,andduring
sustainedtherapywith
large(>1.5gdaily)
acetaminophendoses211318
319 320 322 330 1014
Alcohol
Moderateamounts(300600mLwinedaily)didnot Somecliniciansrecommend
alterwarfarinplasmaconcentrationsor
avoidanceofconcomitant
hypoprothrombinemiceffectinhealthyyoungmen
alcoholingestion485486
492 493
Otherclinicianssuggest
drinksdaily)486inpatientsreceivinglongterm
limitingalcoholconsumption
therapeuticanticoagulationnotwellstudied486490
tosmallamounts(e.g.,12
491 495
drinksoccasionally)487
warfarinhypoprothrombinemia486490494495long
duringwarfarintherapy487
termalcoholuse(e.g.,chronicalcoholism)
488
associatedwithreducedwarfarineffectthrough
chronicheavyconsumption
effectsofmoderateconsumption(e.g.,12
Acuteingestionofalcoholmayenhance
andrecommendagainst
increasedmetabolism486490494Antiplateleteffectof (e.g.,>720mLbeer,>300
alcoholmayincreasebleedingriskwithouteffects
onINR
Antiplatelet
487
mLwine,>60mLliquor
daily)489
Increasedriskofbleeding1000
agents
ACCPsuggestsavoiding
concomitantuseunless
benefitisknownorishighly
likelytoexceedpotential
harmfrombleeding1000
Capecitabine
InhibitsCYP2C9isoenzymeanddecreaseswarfarin
Useconcomitantlywith
metabolism383384Possibleincreasedanticoagulant
caution382383Frequent
response,increasedPT/INR,and/orpotentiallyfatal monitoringofPT/INR
bleedingepisodes,especiallyinpatients>60years
recommendedtofacilitate
ofagewithcancer382383
anticoagulantdosage
adjustments382383384
Cholestyramine Potentialfordecreasedwarfarinabsorptionand
a
Concurrentuseof
decreasedwarfarinhalflife Potentialdecreased
cholestyramineand
vitaminKabsorptiona
warfarinprobablyshouldbe
avoided,ifpossiblea
Lomitapide
IncreasedexposuretowarfarinandincreasedINR
Manufactureroflomitapide
1015
suggestsmonitoringINR
regularly,particularly
followingadjustmentsin
lomitapidedosage,and
adjustingwarfarindosage
asclinicallyindicated1015
Miconazole
PotentialforincreasedPT/INRand/orbleeding211
MonitoringPT/INRand
(Vaginal)
330 362 363 364
appropriatedosage
adjustmentsrecommended
withconcomitant
intravaginalmiconazole
therapy363364
NSAIAs
Oxandrolone
Potentialforplateletaggregationinhibition,GI
Manufacturerrecommends
bleedingandpepticulcerationand/orperforation,
cautioususe500ACCP
alteredPT/INR211330
suggestsavoidance1000
PotentialforincreasedwarfarinhalflifeandAUC418 Whenoxandrolonetherapy
419
PotentialincreasedPT/INRandbleeding418419
isinitiated,changed,or
discontinued,close
monitoringofPT/INRand
clinicalresponse
recommendedtofacilitate
anticoagulantdosage
adjustmentsandreduce
bleedingrisk419
EvidenceforSpecificInteractions:
Antimicrobials:
someoralantibiotics(azithromycin,levofloxacin,trimethoprimsulfamethoxazole)
associatedwithincreasedINR(level3[lackingdirect]evidence)
retrospectivecohortstudyofpatientstakingwarfarinwhoreceivedprescriptionsforterazosin
(comparatordrug),azithromycin,levofloxacinortrimethoprimsulfamethoxazole
meanchangeinINRwas0.15forterazosin,0.51forazithromycin,0.85forlevofloxacinand
1.76fortrimethoprimsulfamethoxazole
incidenceofsupratherapeuticINRwas5%forterazosin,31%forazithromycin(NNH3.8),
33%forlevofloxacin(NNH3.5)and69%fortrimethoprimsulfamethoxazole(NNH1.5)
incidenceofINR>4was0%forterazosin,16%forazithromycin(NNH6.2),19%for
levofloxacin(NNH5.2)and44%fortrimethoprimsulfamethoxazole(NNH2.2)
ReferenceJGenInternMed2005Jul20(7):653
EBSCOhostFullText
fluconazolemayincreaseriskofbleedingwithwarfarin(level2[midlevel]evidence)
6womenonwarfarinforatleast6monthsandINR23tookonedoseoffluconazole150mg
orallymeanprothrombintimewas27.7secondsatbaseline(INR2.6)andincreased11%at2
days,34%at5daysand2%at8days,butnoneofthesedifferenceswerestatistically
significant3womenhadINR>4orbleedingthatrequiredwarfarindosereduction(Obstet
Gynecol2006Feb107(2):310)
cotrimoxazoleandciprofloxacinassociatedwithhemorrhageinolderpatientstaking
warfarin(level2[midlevel]evidence)
2,151patientstakingwarfarinwhowerehospitalizedforuppergastrointestinaltract
hemorrhagewerecomparedwithupto10matchedcontrolsperpatientforexposurein
previous14daystoantibioticscommonlyusedforurinarytractinfection
riskofhemorrhageassociatedwith
cotrimoxazole(adjustedoddsratio[OR]3.84,95%CI2.336.33)
ciprofloxacin(adjustedOR1.94,95%CI1.282.95)
nosignificantassociationbetweenhemorrhageandamoxicillin,ampicillin,nitrofurantoinor
norfloxacin
EBSCOhostFullText
warfarinandantibiotics
antibioticswhichdecreasewarfarinactivitydicloxacillin,griseofulvin,nafcillin,rifampin
antibioticswhichincreasewarfarinactivitymetronidazole,macrolides(erythromycin,
clarithromycin),fluoroquinolones,azoleantifungals,sulfonamides(includingTMP/SMX),some
parenteralcephalosporins(cefoperazone,cefamandole,cefotetan,cefmetazole)
ReferencePrescriber'sLetter2002Mar9(3):14
NSAIDs:
bothcoxibsandnonselectiveNSAIDsappeartosimilarlyincreaseriskofhospitalization
forupperGIbleedinginpatientstakingwarfarin(level2[midlevel]evidence)within
cohortof98,821patients>66yearsoldcontinuouslytakingwarfarin,361(0.3%)were
hospitalizedforupperGIbleedingall361casescomparedwith4timesasmanyageandsex
matchedcontrolscasepatientsweresignificantlymorelikelythancontrolstobetakingrofecoxib
(oddsratio[OR]2.4),nonselectiveNSAIDs(OR1.9)andcelecoxib(OR1.7)(ArchInternMed
2005Jan24165(2):189
EBSCOhostFullText),editorialcanbefoundinArchInternMed
2005Jan24165(2):158
Corticosteroids:
corticosteroidsreportedtoincreaseINRwithwarfarin(level3[lackingdirect]
evidence)
basedonretrospectivemedicalrecordreviewof387patientsfromananticoagulationclinic
32patientencountersmetinclusioncriteriawhichwere
stableanticoagulationtherapy
shorttermoralcorticosteroidtherapy
INRrecordedwithin30dayspriortocorticosteroidinitiation
INRrecordedduringcorticosteroidtherapyorwithin14daysofdiscontinuation
NOTonantibioticorotherdrugwithprobableinteractionwithwarfarin
meandifferenceinpreandpostINRwas1.24(95%CI0.861.62)
97%patientencountersresultedinchangeinpostINRvalue
62.5%patientshadsupratherapeuticpostINRvalues
50%(16patients)requiredanticoagulationtherapymodificationduringcorticosteroid
treatment
onlyadverseeventreportedwas1caseofminorepistaxis
ReferenceAnnPharmacother2006Dec40(12):2101
methylprednisoloneIVreportedtoincreasemeanINRfrom2.75to8.04in10consecutive
patientstakingstabledosesoforalanticoagulants(AnnInternMed2000Apr18132(8):631
EBSCOhostFullText)
Acetaminophen:
acetaminophen4g/daypotentiateswarfarin'santicoagulantresponse(level3[lacking
direct]evidence)
basedonrandomizedcrossovertrialwithoutclinicaloutcomes
20patients>18yearsoldonstablewarfarindosefor1monthwererandomizedto
acetaminophen1gvs.placebo4timesdailyfor14daysthencrossedovertoalternate
treatmentafter2weekwashoutperiod
comparingacetaminophenvs.placebo
meanmaximumINR3.45vs.2.66(p=0.03)
meanincreaseinINRfrombaseline1.2vs.0.37(p<0.001)
significantlyincreasedmeanINRwithin1week(p=0.0002)
significantreductionsinvitaminKdependentclottingfactorsII,VII,IX,X
ReferenceHaematologica2006Dec91(12):1621PDF
acetaminophenmaybeanunderrecognizedcauseofoveranticoagulation(level3
[lackingdirect]evidence)
basedoncasecontrolstudywithoutclinicaloutcomes
studyof93casepatientswithINR>6and196controlswithINR1.73.3inoutpatient
anticoagulationclinic
acetaminopheningestionindependentlyassociatedindosedependentmannerwithhavingINR
>6
otherfactorsindependentlyassociatedwithINR>6werenewmedicationknownto
potentiatewarfarin,advancedmalignancy,recentdiarrhealillness,decreasedoralintakeand
takingmorewarfarinthanprescribed
ReferenceJAMA1998Mar4279(9):657
EBSCOhostFullText,commentarycanbe
foundinJAMA1998Aug26280(8):696
occasionaluseofacetaminophendidnotincreaserisk,butpatientstaking>2,275mg/week
shouldbemonitoredcloselyforelevatedINR(JFamPract1998Jun46(6):456)
DynaMedcommentarycasesandcontrolsdifferedforuseofvitaminK,alcoholconsumption,
fever,diarrhea,advancedmalignancy,andrecenthospitaldischargesomultipleconfounding
factorslimitconclusionstohypothesisgenerating
acenocoumaroleffectvariedwithacetaminophenuseincasereport(AnnPharmacother1999
Apr33(4):506)
acetaminophenisconsideredanalgesicofchoiceinpatientstakingwarfarin,butprolonged
administrationandexcessiveamountsnotrecommended(Pharmacotherapy1999
Oct19(10):1153)
OtherDrugs:
interactionwithamiodaronedependsonamiodaronedose
studyof43patientstakingwarfarinwhostartedamiodaronetherapyandhadINRfollowed
weekly,peakeffectofamiodaroneonINRat7weeks
authorsrecommendreductionsinwarfarindoseof25%withamiodarone100mg/day,30%
with200mg/day,35%with300mg/dayand40%with400mg/day
ReferenceChest2002121(1):19
EBSCOhostFullTextfulltextinAmFamPhysician
2002Apr1565(8):1669
influenzavaccinationdoesnotappeartointeractwithwarfarintreatment
basedonrandomizedcrossovertrial
104patientsonstablevitaminKantagonistregimen(primarilywarfarin)withindicationfor
influenzavaccinationrandomizedtoplacebovs.placeboplussubsequentvaccine
nosignificantdifferencesinbleedingevents,warfarintreatmentortimeintherapeuticINR
range
EBSCOhostFullText
clinicallyimportantdruginteractionoccurswithcapecitabine(Xeloda)andwarfarin(Coumadin),
resultinginincreasedanticoagulantresponse(Medwatch2001Nov1)
leflunomideassociatedwithasignificantincreaseinwarfarinanticoagulanteffectincasereport
(BMJ2002Dec7325(7376):1333
EBSCOhostFullTextfulltext),correctioncanbefoundin
BMJ2003Feb22326(7386):432
lopinavir/ritonavirassociatedwithsignificantdecreaseinINRinpatienttakingwarfarinincase
report(CMAJ2007Aug14177(4):357
rosuvastatin(Crestor)mayincreaseINRwithwarfarin,basedoncasereportofclinically
significantinteractionandunpublishedstudies(Lancet2004Jan24363(9405):328
EBSCOhostFullText),commentarycanbefoundinLancet2004Mar13363(9412):897
EBSCOhostFullText
duloxetineassociatedwithsevereelevationofINRinpatienttakingwarfarinincasereport(JAMA
2006Apr5295(13):1517)
topicalazole(econazoleorbifonazole)associatedwithincreasedINRin6elderlypatients(Ann
InternMed2008Apr15148(8):633
EBSCOhostFullText),correctioncanbefoundinAnn
InternMed2008May20148(10):795
omeprazoleassociatedwithincreasedINRin2casereportsofpatientstakingphenprocoumon
(BMCGastroenterology2001Apr61:2)
levonorgestrelforemergencycontraceptionassociatedwithoveranticoagulationwithwarfarinin
casereport(BMJ2000Dec2321(7273):1382)
oxandrolone(Oxandrin),asynthetictestosteronederivative,maycauseunexpectedlarge
increasesinINRwithwarfarin(FDAMedWatch2004May5),casereportcanbefoundinArch
InternMed2006Jan9166(1):125
EBSCOhostFullText
OtherPotentialInteractions:
warfarinalsoaffectedbydiet,smokingandmultiplediseasestates
foodsrichinvitaminK(suchascauliflower,broccoli,spinach,kale,greentea,cheddarand
Camembertcheese,Brusselssprouts,greenpeas,lettuce,watercress,springgreens,liver)
decreasetheeffectsofwarfarin
dietaryvitaminKintakeaffectsINRduringstablewarfarindosing
12patientswiththerapeuticINRonwarfarininanticoagulationclinichaddietaryvitaminK
intakedeterminedandwererandomizedtodietrichinvitaminK(500%increase)vs.poorin
vitaminK(80%decrease)for4dayseachincrossovertrialwith12weekwashout,allmeals
preparedbydietitian
meanINRincreasedfrom2.6to3.3atday7withpoorvitaminKdietanddecreasedfrom3.1
to2.8byday4withrichvitaminKdiet
ReferenceAmJMed2004May15116(10):651inAmFamPhysician2005Mar171(5):980
fulltext
cranberryjuicedoesnotclearlyaffectwarfarinmetabolism
cranberryjuicemayhavenoeffectonwarfarinmetabolism(level3[lackingdirect]
evidence)
basedonsystematicreviewoflimitedevidenceandrandomizedtrialwithoutclinical
outcomes
systematicreviewfound7clinicaltrialsand15casereportswithverylimitedevidenceof
effectsofcranberryjuiceonwarfarinmetabolism(AmJMed2010May123(5):384)
basedonrandomizedtrialwithoutclinicaloutcomes
30anticoagulationclinicpatientsonwarfarinforvarietyofindicationswererandomized
tocranberryjuice8ouncesvs.placebowith2weekleadinphase(withweeklyINRsin
range),2weektreatmentphaseand1weekfollowup(total35days)
28.6%(4of14)cranberryjuicevs.25%(4of16)placebogroupdevelopedminimally
elevatedINR
1cranberryjuiceparticipant(7.1%)developedlowINRduringtreatmentphase
nosignificantdifferenceinmeanINRsbetweengroupsoneachday,exceptday11
(higherINRwithcranberryjuice)
ReferenceJThrombThrombolysis2008Feb25(1):112
cranberryjuicemaynotaffectprothrombintime/INR(level3[lackingdirect]
evidence)
basedonrandomizedplacebocontrolledcrossovertrialin7patientswithatrialfibrillation
andstablewarfarindosingfor3months
ReferenceJAmDietAssoc2006Dec106(12):2057
cranberryjuicereportedtointeractwithwarfarinincasereports(level3[lacking
direct]evidence)
1casereportofsuspectedinteractioninvolvingwarfarinandcranberryjuicepatienthad
profoundhypoprothrombinemiaandbleeding(AmJTher2006MayJun13(3):283)
12casesofsuspectedinteractionsinvolvingwarfarinandcranberryjuicereportedtoBritish
drugregulatoryagencies(AmFamPhysician2005Sep1572(6):1000
EBSCOhostFull
Textfulltext)
7casereportsofinteractionsbetweencranberryjuiceandwarfarindetailslimited,but1
patientdiedfromhemorrhagewithINR>50othercasereportsincludedincreased,
decreasedandunstableINRs(Prescriber'sLetter2003Nov10(11):63,BMJ2003Dec
20327(7429):1454
cranberrycontainsflavonoids(whichmayinhibitwarfarinmetabolismbycytochromeP450
2C9)andsalicylicacid(whichhasantiplateleteffect)(ChemBiolInteract2002Jan
22139(1):1,JAmDietAssoc2001Dec101(12):1406,JClinPathol2001Jul54(7):553
EBSCOhostFullTextPDF)
nocasereportsinvolvedcranberryextracttablets
Gojitropicalfruitjuicemightinhibitwarfarinmetabolism(Prescriber'sLetter2006Dec13(12):70)
soymilkassociatedwithsubtherapeuticINRinsinglecasereport(AnnPharmacother2002
Dec36(12):1893)
highprotein(lowcarbohydrate)dietsmayincreasealbuminlevelswhichmaybindwarfarinand
lowerINR,basedontheoreticalandanecdotalconcerns(Prescriber'sLetter2005May12(5):26)
smokingmaytheoreticallyincreasewarfarineffect
12smokerstookwarfarin0.032mg/kg/dayfor2weekswhilesmokingatleast1pack/dayand
thentookwarfarinfor2weeksafterabstainingfromsmokingfor1month,3droppedout
duringabstentionfromsmoking,steadystatewarfarinconcentrationsincreased13%,warfarin
halflifeincreased23%andwarfarinclearancedecreased13%
noclinicallysignificantchangesinprothrombintime
notethisstudywasdonewithclinicallyineffectivedosesofwarfarin
ReferenceClinPharmacolTher1979Mar25(3):309
diseasestatesmayaffectresponsetowarfarin
liverdiseaseandhyperthyroidismincreaseresponsetowarfarin,hypothyroidismdecreases
responsetowarfarin
otherdiseasesthatmayaffectresponsetowarfarinincluderenaldisease,heartfailure,
cancerandfeverbutstudiesarelimited
ReferenceSouthMedJMay200093:448inAmFamPhysician2000Nov1568(10):2318
DrugherbInteractions:
warfarinmayinteractwithherbalproductsdongquaimaydoubleINRincreasedriskofbleeding
mayoccurwithgarlic,ginger,ginkgo,feverfew,fishoils,vitaminEwarfarinmaybelesseffective
withvitaminK,alfalfa,parsley,stingingnettle,greatplantain,largeamountsofgreentea
(Prescriber'sLetter1999Sep6(9):51)
herbswhichmayincreasebleedingtimethroughantiplateletoranticoagulanteffectinclude
bilberry(highdoses),chamomile(theoretical),danshen,dongquai,feverfew,garlic,ginger,
ginkgo,ginseng,kava(theoretical),andsawpalmetto(theoretical)allofthesearebasedon
casereportsunlessotherwisenoted(AlternativeMedicineAlert2003Apr6(4):37)
chamomile(Matricariachamomilla)reportedtobeassociatedwithincreasedINRandinternal
bleedingincasereportofpatienttakingwarfarin(CMAJ2006Apr25174(9):1281
AmericanginsengmodestlyreducedINRlevelswithwarfarin,basedon2weekrandomized
placebocontrolledtrialin20healthyvolunteerstakingwarfarinmedianreductioninpeakINR
0.16withAmericanginsengvs.0.02withplacebo(AnnInternMed2004Jul6141(1):23
EBSCOhostFullText),commentarycanbefoundinAnnInternMed2004Dec7141(11):893,
commentarycanbefoundinAmFamPhysician2005May171(9):1802
St.John'swortmaylowerINRbasedoncasereports(Lancet2000Feb12355(9203):576inThe
MedicalLetter2000Jun2642(1081):56)andinducedclearanceofwarfarinincontrolledtrialof
12healthyvolunteers(BrJClinPharmacol2004May57(5):592
EBSCOhostFullTextin
Prescriber'sLetter2004Oct11(10):59)
glucosaminereportedtoincreaseINRinpatienttakingwarfarin(level3[lacking
direct]evidence)
basedoncasereport
reviewofFDAMedWatchdatabasefound20reportsofglucosamine(withorwithout
chondroitinsulfate)usewithwarfarinassociatedwithincreasedINRorincreasedbleedingor
bruising
ReferencePharmacotherapy2008Apr28(4):540
highdosesofglucosamine/chondroitin(CosaminDS)associatedwithelevatedINRincase
report(AmJHealthSystPharm2004Feb161(3):306
EBSCOhostFullTextin
Prescriber'sLetter2004Mar11(3):17)
Curbicin,anherbaldrugusedformicturitiondifficulties,containsvitaminEand2casesof
increasedanticoagulanteffecthavebeenreported(JAmGeriatrSoc2001Jun49(6):838)
warfarinmayinteractwithdanshen,aChineseherbusedforcardiacdiseases(HospPract1999
Sep34(10):23)
coenzymeQ10mayreducewarfarinactivitybasedonreportof4casescoenzymeQ10is
chemicallysimilartovitaminK(AlternativeMedicineAlert2003Dec6(12):133)
coenzymeQ10reportedtoreduceanticoagulanteffectofwarfarin,butnoclinicallyimportant
differenceinrandomizedplacebocontrolledtrialof24patientstakingwarfarinandcoenzyme
Q10100mg/day(TheMedicalLetter2006Feb2748(1229):19)
theselistsarenotcomprehensive
reviewofpotentialcoagulationeffectsofpreoperativealternativemedicines,manyofwhichare
plateletaggregationinhibitors,canbefoundinAlternTherHealthMed2001NovDec7(6):58
EBSCOhostFullText
MechanismofAction/Pharmacokinetics
Actions:
Acoumarinderivativeanticoagulantasynthetic3substitutedderivativeof4hydroxycoumarin.
211 330 a
Aracemicmixtureofthe2opticalisomersofthedrug.211330a
AnindirectactinganticoagulantinterfereswiththehepaticsynthesisofvitaminKdependent
coagulationfactorsII(prothrombin),VII(proconvertin),IX(Christmasfactororplasma
thromboplastincomponent),andX(StuartProwerfactor).211330aAlsoinhibitstheanticoagulant
proteinsCandS.211330
InterfereswiththeactionofreducedvitaminK,whichisnecessaryforthecarboxylationof
severalglutamicacidresiduesintheprecursorproteinsofthesecoagulationfactors.211330
InhibitsclottingfactorsynthesisbyinhibitingtheregenerationofreducedvitaminKfromvitamin
KepoxideviainhibitionofvitaminKepoxidereductase.464
SequentialdepletionofcirculatingfunctionalcoagulationfactorVII,proteinC,factorIX,protein
S,factorX,andfinallyfactorII.211330a
VitaminKdependentcoagulationfactorsphysiologicallydecreasedinneonatescomparedwith
adultsthrombingenerationafterwarfarintherapydelayedandreducedinchildrencompared
withadults.4964971013
AntithrombogeniceffectsgenerallyoccuronlyafterfunctionalcoagulationfactorsIXandXare
diminished(usually27daysfollowinginitiationoftherapy).a
Doesnotaltercatabolismofbloodcoagulationfactors.a
Inhibitsthrombusformationwhenstasisisinducedmaypreventextensionofexistingthrombi.
211 330 a
Nodirecteffectonestablishedthrombi.aLittleifanyeffectonplateletricharterial
thrombiadheringtoanabnormalvesselwall.a
ProlongsPT/INRandaPTT.211330a
Phytonadione(vitaminK1)reversestheanticoagulanteffect.211330a
Pharmacokinetics:
Absorption:
Bioavailability:
Essentiallycompletelyabsorbedafteroraladministrationpeakplasmaconcentrationusually
attainedwithin4hours.211
Onset:
SynthesisofvitaminKdependentcoagulationfactorsisaffectedsoonafterabsorption(e.g.,within
24hours).211aDepletionofcirculatingfunctionalcoagulationfactorsmustoccurbeforetherapeutic
effectsofthedrugbecomeapparent.a
Duration:
25daysafterasingledose.211
Food:
Decreasedrate,butnotextent,ofabsorptioninthepresenceoffood.211
Distribution:
Extent:
Theapparentvolumeofdistributionisabout0.14L/kg.211
Crossestheplacentalbarrierhowever,thedrughasnotbeendetectedinhumanbreastmilk.211
PlasmaProteinBinding:
Approximately99%.211
Elimination:
Metabolism:
Almostentirelyintheliver.211PrincipallybyCYP2C9CYP2C19,2C8,2C18,1A2,and3A4involvedto
alesserdegree.211
EliminationRoute:
Excretedprincipallyinurineasmetabolitesandtoalesserextentinbile.211
Halflife:
Effectivehalflifeaverages40hours(range:2060hours).211
SpecialPopulations:
SlightlydecreasedclearanceofRwarfariningeriatricpatientscomparedwiththatinyounger
individuals.211330However,similarpharmacokineticsofracemicwarfarinandSwarfariningeriatric
andyoungerindividuals.211
Decreasedmetabolisminpatientswithhepaticdysfunction.211
StabilityandCompatibility
Storage:
Oral:
Tablets:
1530C.211
Parenteral:
PowderforInjection:
1530C.211
Compatibility:
Forinformationonsystemicinteractionsresultingfromconcomitantuse,seeInteractions.
Parenteral:
SolutionCompatibilityHID:
Compatible
Dextrose5%inRingersinjection,lactated
Dextrose5%insodiumchloride0.45or0.9%
Dextrose5or10%inwater
Incompatible
Ringersinjection
Variable
Ringersinjection,lactated
Sodiumchloride0.9%
DrugCompatibility:
YSiteCompatibility
HID
:
Compatible
Amikacinsulfate
Ascorbicacidinjection
Cefazolinsodium
Ceftriaxonesodium
DopamineHCl
EpinephrineHCl
Heparinsodium
LidocaineHCl
Metaraminoltartrate
Morphinesulfate
Nitroglycerin
Oxytocin
Potassiumchloride
RanitidineHCl
Incompatible
Aminophylline
Bretyliumtosylate
Ceftazidime
CimetidineHCl
Ciprofloxacin
DobutamineHCl
EsmololHCl
Gentamicinsulfate
LabetalolHCl
MetronidazoleHCl
Ringersinjection
Variable
Ammoniumchloride
VancomycinHCl
Preparations
TablesofPreparations:
WarfarinSodium:
Routes
Oral
DosageForms
Tablets
Strengths
1mg
BrandNames
Coumadin(scored)
Manufacturer
BristolMyers
Squibb
Jantoven(scored)
USL
WarfarinSodiumTablets
(scored)
2mg
Coumadin(scored)
BristolMyers
Squibb
Jantoven(scored)
USL
(scored)
2.5mg
Coumadin(scored)
BristolMyers
Squibb
Jantoven(scored)
USL
(scored)
3mg
Coumadin(scored)
BristolMyers
Squibb
Jantoven(scored)
USL
(scored)
4mg
Coumadin(scored)
BristolMyers
Squibb
Jantoven(scored)
USL
(scored)
5mg
Coumadin(scored)
BristolMyers
Squibb
Jantoven(scored)
USL
(scored)
6mg
Coumadin(scored)
BristolMyers
Squibb
Jantoven(scored)
USL
(scored)
7.5mg
Coumadin(scored)
BristolMyers
Squibb
Jantoven(scored)
USL
(scored)
10mg
Coumadin(scored)
BristolMyers
Squibb
Jantoven(scored)
USL
(scored)
Parenteral Forinjection,forIVuse
5mg
Coumadin
only
BristolMyers
Squibb
ComparativePricing:
ThispricinginformationissubjecttochangeatthesolediscretionofDSPharmacy.Thispricing
informationwasupdated02/2015.Forthemostcurrentanduptodatepricinginformation,please
visitwww.drugstore.com.Actualcoststopatientswillvarydependingontheuseofspecificretailor
mailorderlocationsandhealthinsurancecopays.
Coumadin1MGTablets(BMSQUIBBU.S.(PRIMARYCARE)):30/$46.99or90/$116.97
Coumadin2.5MGTablets(BMSQUIBBU.S.(PRIMARYCARE)):30/$52.99or90/$130.97
Coumadin7.5MGTablets(BMSQUIBBU.S.(PRIMARYCARE)):30/$62.99or90/$165.98
Jantoven2MGTablets(UPSHERSMITH):30/$17.99or90/$39.97
WarfarinSodium1MGTablets(TARO):30/$13.99or90/$30.99
WarfarinSodium10MGTablets(TEVAPHARMACEUTICALSUSA):30/$24.99or90/$63.97
WarfarinSodium2.5MGTablets(TARO):30/$14.99or90/$33.97
WarfarinSodium7.5MGTablets(TARO):30/$23.99or90/$61.97
AdditionalInformation:
GenericWarfarinAppearsBioequivalenttoCoumadin:
Coumadinandgenericformulationsappeartobepharmacokineticallyequivalent,therapeutically
equivalentinsmalltrialsinstablepatients,notrialsinpatientswhorequirefrequentchangesin
warfarindoses(TheMedicalLetter1999May2141(1053):47)
genericwarfarin(fromBarrLaboratories)hasefficacyandsafetysimilartoCoumadin
57patientswithchronicatrialfibrillationonstabledosesofCoumadinwithINR23
randomizedtoCoumadinfor4weeksthengenericwarfarin(BarrLaboratories)for8weeks
vs.genericwarfarinfor4weeksthenCoumadinfor8weeks
withCoumadinvs.genericwarfarin,pooledaverageINR2.45vs.2.33,intrasubjectvariability
0.098vs.0.083(lesswithgeneric),nodifferenceinadversereactions
ReferencePrevCardiol1998Fall4:13inQuickScanReviewsinFamPract1999Jul24(4):5
switchtogenericwarfarinNOTassociatedwithchangesinratesofINRtestingor
hospitalizationformajorhemorrhageorcerebralthromboembolism(level2[midlevel]
evidence)
basedonpopulationbasedstudyofallpersons>66yearsoldinOntario19972002
genericwarfarinsubstitutionpolicyimplementedJune7,2001
ReferenceJAMA2006Oct25296(16):1969
EBSCOhostFullText
needforadditionalINRtestingwithswitchtogenericwarfariniscontroversial
FDAdoesnotrecommendneedforadditionalINRtestingwhenswitchingfromCoumadinto
ABratedgenericwarfarin
HOWEVER,genericproductsmayhave80%to125%bioavailabilitycomparedtobrand
products,andFDAdoesnothaveseparatestandardsforbioequivalencefordrugswithnarrow
therapeuticindex
additionalINRtestingmaybewarrantedthoughnotproventobebeneficialcohort
of2,299patientsswitchedfromCoumadintoBarrgenericwarfarin,72%hadINRchange>
10%(33%havingbetterINRcontrol,39%havingworseINRcontrol),13%hadINRchange>
50%,nodifferenceinadverseeventsduring90daysbeforeandaftertheswitch
(Pharmacotherapy2003Mar23(3):360)
ReferencePrescriber'sLetter2003Sep10(9):50
ColorsofCoumadinTablets:
1mgpink
2mglavender
2.5mggreen
3mgtan
4mgblue
5mgpeach
6mgteal
7.5mgyellow
10mgwhite
PatientInformation
AdvicetoPatients:
Importanceofprovidingpatientacopyofmanufacturerspatientmedicationguide.211330445453
Importanceofstrictadherencetoprescribeddosageandschedule.211330Importanceoftaking
tabletsatthesametimeeachday.453Ifadoseismissed,takeassoonaspossibleonthesame
daydonottakeadoubledosethenextdaytomakeupforthemisseddose.453
Importanceofinformingclinicianifadoseismissedoranextradoseistaken.453
ImportanceofcloselaboratorymonitoringtodetermineINRandregularvisitstoclinician.211330
Importanceofinformingclinicianofcoexistingconditionssuchashepaticorrenaldysfunction,
highBP,CHF,diabetesmellitus,propensityforfalling,andalcoholabuse.453
Importanceofinformingclinicianifdiarrhea,infections,orfeveroccursduringtherapy.453
Importanceofpatientscarryinganoticestatingthattheyareundergoinganticoagulanttherapy.
211 330
Importanceofavoidingalcohol211330445453485486orlimitingusetosmallamountsconsultand
informclinicianaboutalcoholuseandabuse.211330445453(SeeInteractions.)
Importanceofavoidingdrasticchangesindietandofeatingabalanceddietwithaconstant
amountofvitaminK.211330Avoidingestionoflargequantitiesoffoodsthatcontainalarge
amountofvitaminK(e.g.,leafygreenvegetables,certainvegetableoils).453Importanceof
informingclinicianbeforeattemptingtodietduringwarfarintherapy.453
Importanceofavoiding211330445453orusingonlysmallamounts488ofcranberryproductsandof
informingclinicianiftheseproductsarepartofthediet.211330445453
Importanceofavoidingactivitiesorsportsthatcouldcausetraumaticinjury.211330Importanceof
informingclinicianaboutfallsorinjuries,especiallyheadinjuries,duringtherapy.453
Importanceofpatientsreportinganysignsofbleeding(e.g.,pain,swellingordiscomfort,
prolongedbleedingfromcuts,increasedmenstrualfloworvaginalbleeding,nosebleeds,bleeding
ofgumsfrombrushing,unusualbleedingorbruising,redordarkbrownurine,redortarblack
stools,headache,dizziness,orweakness)tocliniciansimmediately.211330418
Importanceofpatientsreportingsymptomsofbloodclots(e.g.,pain,color,ortemperature
changestoanyareaofthebody).453Importanceofreportingsymptomsofpurpletoessyndrome
(e.g.,painintoes,purpleordarktoes)toclinicianimmediately.453
Importanceofpatientsinformingclinicianofexistingorcontemplatedconcomitanttherapy,
includingprescriptionandOTCdrugsanddietaryandherbalsupplements.211330418Importanceof
nottakingOTCdrugsordrugsprescribedbyotherclinicianswithoutfirstinformingprimary
clinicianorpharmacist.211330
Importanceofwomeninformingclinicianiftheyareorplantobecomepregnantorplanto
breastfeed.211330
Importanceofinformingpatientsofotherimportantprecautionaryinformation.211330(See
Cautions.)
PatientInformation:
MedicationGuideforCoumadinPDFrequiredtobeprovidedwitheachprescriptionbyFDA(FDA
MedWatch2006Oct6)
patientguidetoCoumadin/warfarintherapycanbefoundatAHRQBloodThinnerPills2010
AugPDForinSpanishPDF
handoutonatrialfibrillationandwarfarinfromPatientUK
WarfarinDoseReminderChartforpatientscanbefoundinFamPractManag2005May12(5):77
GuidelinesandResources
Guidelines:
UnitedStatesGuidelines:
ClinicalPharmacogeneticsImplementationConsortium(CPIC)guidelineonCYP2C9andVKORC1
genotypesandwarfarindosingcanbefoundinClinPharmacolTher2011Oct90(4):625
AmericanHeartAssociation/AmericanCollegeofCardiology(AHA/ACC)scientificstatementon
warfarincanbefoundinCirculation2003Apr1107(12):1692
AmericanHeartAssociation(AHA)policystatementongeneticsandcardiovasculardiseasecan
befoundinCirculation2012Jul3126(1):142157fulltext
UnitedKingdomGuidelines:
ScottishIntercollegiateGuidelinesNetwork(SIGN)nationalclinicalguidelineonantithrombotics
indicationsandmanagementcanbefoundatSIGN2013JunPDF,previousversioncanbefound
atNationalGuidelineClearinghouse2013Jan7:38367
Canadianguidelines:
CanadianAgencyforDrugsandTechnologiesinHealth(CADTH)recommendationsonoptimal
warfarinmanagementforpreventionofthromboemboliceventsinpatientswithatrialfibrillation
canbefoundatCADTH2011NovPDForatNationalGuidelineClearinghouse2013Apr22:38697
ReviewArticles:
reviewofwarfarincanbefoundinAmFamPhysician1999Feb159(3):635,commentarycanbe
foundinAmFamPhysician1999Sep160(3):764,correctioncanbefoundinAmFamPhysician
2002Jan1565(2):172,correctioncanbefoundinAmFamPhysician2006Mar1573(6):974
reviewofwarfarincanbefoundinAmJMed2000Oct15109(6):481inAmFamPhysician2001
Apr1563(8):1628,commentarycanbefoundinAmJMed2001Jun1110(8):672andinAmJ
Med2001Sep111(4):332
reviewcanbefoundinClinicalAdvisor2004Jun7(6):49,commentarycanbefoundinClinical
Advisor2004Aug7(8):9
reviewofdrugdruginteractionsbetweenwarfarinandpsychotropicscanbefoundin
Pharmacotherapy2012Sep5earlyonline
reviewof"reducingrisksforpatientsreceivingwarfarin"canbefoundinFamPractManag2002
JulAug9(7):35
reviewofpreventionandtreatmentofbleedingcomplicationsinpatientsreceivingvitaminK
antagonists,Part1:preventioncanbefoundinAmJHematol2009Sep84(9):579,commentary
canbefoundinAmJHematol2009Sep84(9):546
reviewofherbalanddietarysupplementdruginteractionsinpatientswithchronicillnessescan
befoundinAmFamPhysician2008Jan177(1):73
EBSCOhostFullTextfulltext,correction
canbefoundinAmFamPhysician2008Oct178(7):808
reviewoforalanticoagulanttherapyfromAmericanCollegeofChestPhysicians(ACCP)
EvidenceBasedClinicalPracticeGuidelinesforAntithromboticandThrombolyticTherapy(Ninth
Edition)canbefoundinChest2012Feb141(2Suppl):e44Sfulltext
reviewoflongtermanticoagulanttherapycanbefoundinNEnglJMed2003Aug
14349(7):675,commentarycanbefoundinNEnglJMed2003Nov13349(20):1976
casepresentationofanticoagulationinahighrisknursinghomeresidentcanbefoundinAnnals
ofLongTermCare2005Oct13(10):36
MEDLINESearch:
tosearchMEDLINEfor(Warfarin)withtargetedsearch(ClinicalQueriesfortherapyarticles),click
here
NinthACCPGuidelinesonVitaminKAntagonists:
initiationofvitaminKantagonist(VKA)
warfarininitialdosemayrangefrom2mgto10mg
suggestedinitialdosewarfarin10mgoncedailyfor2days,thendosingbasedonINR
measurementmaybeconsideredinpatientssufficientlyhealthytobetreatedas
outpatients(ACCPGrade2C)
startingdose5mgdailymaybeconsideredinpatientswith
advancedage
impairednutrition
liverdisease
heartfailure
highbleedingrisk
considerstartingdose2mgto3mginpatientswhohaveheartvalvereplacement
subsequentdosingbasedonINRresponse(ACCPGrade2C)
donotusepharmacogeneticbasedinitialdosingtoindividualizewarfarindosing(ACCPGrade
1B)
forpatientswithacutevenousthromboembolism,startingVKAearly(samedayasparenteral
anticoagulation)recommendedoverdelayedstartofVKA(ACCPGrade1B)
formostpatientstreatedwithVKA,therapeuticINRrange23(targetINR2.5)recommended
ratherthanlower(INR<2)orhigher(INR35)range(ACCPGrade1B)
monitoringofVKA
whenINRconsistentlystable,monitorINRatleastevery12weeks(suggestedratherthan
every4weeks)(ACCPGrade2B)
ifpreviouslystabletherapeuticINRswithsingleoutofrangeINR0.5beloworabove
therapeuticrange,continuingcurrentdoseandrecheckingINRwithin12weekssuggested
(ACCPGrade2C)
patientselfmanagementstrategy(ratherthanusualoutpatientINRmonitoring)suggestedfor
patientswhoaremotivatedandcandemonstratecompetencyinselfmanagementstrategies,
includingselftestingequipment(ACCPGrade2B)
forallotherpatients,oralanticoagulationtherapyshouldbemanagedinsystematicand
coordinatedfashion,incorporatingpatienteducation,systematicINRtesting,tracking,follow
up,andgoodpatientcommunicationofresultsanddosingdecisions(AmericanCollegeof
ChestPhysicians[ACCP]BestPracticesStatement)
fordosingdecisionsduringmaintenanceVKAtherapy,usingvalidateddecisionsupporttools
(papernomogramsorcomputerizeddosingprograms)suggestedratherthannodecision
support(ACCPGrade2C)
drugsforwhichavoidingconcomitanttreatmentissuggested
nonsteroidalantiinflammatorydrugs(NSAIDs),includingcyclooxygenase2selectiveNSAIDs
(ACCPGrade2C)
certainantibiotics(ACCPGrade2C)
amoxicillin(withorwithoutclavulanicacid)
cephalosporinsincludingcephalexin,cefradine
cotrimoxazole
ciprofloxacin,levofloxacin,norfloxacin
metronidazole
doxycycline
fluconazole
antiplateletagents(exceptinsituationswherebenefitisknownorishighlylikelytobegreater
thanharmfrombleeding,suchaspatientswithmechanicalvalves,acutecoronarysyndrome,
orrecentcoronarystentsorbypasssurgery)(ACCPGrade2C)
otherdrugsandcomplementarymedicineswhichmayincreaseriskofbleeding(butdatanot
confirmed)include
acetaminophen
selectiveserotoninreuptakeinhibitors(SSRIs)
tramadol
coenzymeQ10
ginger
clinicalpredictionsrulesforbleedingsuggestednottobeusedassolecriterionforwithholding
VKAtherapy(ACCPGrade2C)
discontinuationofVKAtherapy
forpatientseligibletodiscontinueVKAtherapy,abruptdiscontinuationsuggestedratherthan
gradualtaperingofdosetodiscontinuation(ACCPGrade2C)
ReferenceChest2012Feb141(2Suppl):e152SfulltextoratNationalGuidelineClearinghouse
2012Jun4:35262
References
GeneralReferencesUsed:
Unlessotherwisestated,sourcematerialderivedfromAHFSDrugInformationEssentials.
TheAHFSDrugInformationEssentialsdatabaseiscopyrightedbytheAmericanSocietyof
HealthSystemPharmacists,Inc.2010ASHP,Bethesda,Maryland20814.AllRightsReserved.
DuplicationmustbeexpresslyauthorizedbyASHP,unlesssuchduplicationconsistsofprintingor
downloadingportionsofthedatainherentintheprogramfornoncommercialuse.Usedwith
permission.
TheAmericanSocietyofHealthSystemPharmacists,Inc.representsthatthedatabaseprovided
hereunderwasformulatedwithareasonablestandardofcare,andinconformitywith
professionalstandardsinthefield.TheAmericanSocietyofHealthSystemPharmacists,Inc.
makesnorepresentationsorwarranties,expressorimplied,including,butnotlimitedto,any
impliedwarrantyofmerchantabilityand/orfitnessforaparticularpurpose,withrespecttosuch
databaseandspecificallydisclaimsallsuchwarrantiesandrepresentations.Usersareadvised
thatdecisionsregardingdrugtherapyarecomplexmedicaldecisionsrequiringtheindependent,
informeddecisionofanappropriatehealthcareprofessional,andthedatabaseisprovidedfor
informationalpurposesonly.Theentiremonographforadrugshouldbereviewedforathorough
understandingofthedrugsactions,usesandsideeffects.TheAmericanSocietyofHealth
SystemPharmacists,Inc.doesnotendorseorrecommendtheuseofanydruginthedatabase.
Theinformationcontainedinthedatabaseisnotasubstituteformedicalcare.
RecommendationGradingSystemsUsed:
AmericanCollegeofChestPhysicians(ACCP)grades
Grade1strongrecommendationbasedonclearrisk/benefitbalance
Grade2weakrecommendationbasedonunclearorcloserisk/benefitbalance
GradeAhighqualityevidencebasedonconsistentevidencefromrandomizedtrialswithout
importantlimitationsorexceptionallystrongevidencefromobservationalstudies
GradeBmoderatequalityevidencebasedonrandomizedtrialswithimportantlimitations
(inconsistentresults,methodologicflaws,indirectorimpreciseresults)orverystrongevidence
fromobservationalstudies
GradeCloworverylowqualityevidencebasedonobservationalstudies,caseseries,or
randomizedtrialswithseriousflawsorindirectevidence
ReferenceACCPEvidenceBasedClinicalPracticeGuidelines(NinthEdition)Methodologyfor
theDevelopmentofAntithromboticTherapyandPreventionofThrombosisGuidelines(Chest
2012Feb141(2Suppl):53Sfulltext)
DynaMedEditorialProcess:
DynaMedtopicsarecreatedandmaintainedbytheDynaMedEditorialTeam.
Over500journalsandevidencebasedsources(DynaMedContentSources)aremonitored
directlyorindirectlyusinga7Stepevidencebasedmethodforsystematicliteraturesurveillance.
DynaMedtopicsareupdateddailyasnewlydiscoveredbestavailableevidenceisidentified.
TheparticipatingmembersoftheDynaMedEditorialTeamhavedeclaredthattheyhaveno
financialorothercompetinginterestsrelatedtothistopic.
Theparticipatingreviewershavedeclaredthattheyhavenofinancialorothercompeting
interestsrelatedtothistopic,unlessotherwiseindicated.
McMasterUniversityisapartnerthatprovidessupportinidentifyingPracticeChangingDynaMed
Updates.Over1,000practicingphysiciansfrom61disciplinesin77countriesratethesearticles
tohelpyoufindthemostusefulnewevidenceaffectingyourpractice.
F1000isapartnerthatprovidessupportinidentifyingPracticeChangingDynaMedUpdates.Over
2,000practicingcliniciansfrom20disciplinesin60countriesratethesearticlestohelpyoufind
themostusefulnewevidenceaffectingyourpractice.
HowtoCite:
ForattributioninotherpublicationsseeHowtoCiteInformationfromDynaMed.
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