NEWORALANTICOAGULANTDRUGS(NOAC)ANDTHEIRUSEINTHEMANAGEMENTOFATRIAL

FIBRILLATIONINSALFORDPATIENTS

Version2
December2012

1.Background

Threeneworalanticoagulants(NOAC)drugsdabigatran,rivaroxabanandapixabanhavebeenlicensedintheUKforthe
managementofpatientswithAtrialFibrillation(AF).

NICEhavereviewedtwoofthecurrentlylicenseddrugs:

Dabigatran(Pradaxa)NICETA249;Dabigatranetexilateforthepreventionofstrokeandsystemic
embolisminatrialfibrillation

Rivaroxaban(Xarelto)NICETA256;Rivaroxabanforthepreventionofstrokeandstrokeandsystemic
embolisminatrialfibrillation

NICEguidanceonApixaban(Eliquis)isdueApril2013.

Thesedrugsarenewtomarketandthepotentiallongtermsideeffectsarenotyetfullyknown.Concernsalsoincludethat
theoptimalmethodofemergencyreversaloftheanticoagulanteffectsoftheseagentsiscurrentlyunclearinthosepatients
whopresentwithmajorbleeding.Therearealsoconcerns,highlightedbytheMHRAregardingdabigatranuseinrenal
insufficiencyasexposureissubstantiallyincreasedinthesepatients.Thebenefitsofdabigatranandrivaroxabanover
warfarindeclineasINRcontrolonwarfarinincreases.Inpatientswherewarfariniswellcontrolled(timeintherapeuticrange
[TTR]>65%),theuseofdabigatranorrivaroxabanmaybelessfavourable.Onthisbasis,theuseofthesedrugsshouldbe
implementedcarefullyandtargetedtothosepatientsthatarelikelytogainthemostbenefitfromthemi.e.patientspoorly
controlledonwarfarinorthoseeligiblefor,butchoosenottobeanticoagulatedwithwarfarin.

2.ImplementationinSalford

TheGreaterManchesterandCheshireCardiacandStrokeNetwork(GMCCSN)haveproducedguidancetoensurethereisa
plannedintroductionforthesedrugs.Guidancedocumentshavebeendevelopedandfulldocumentsareavailableonthe
GMCCSNwebsite.ThisguidancehaswarfarinasfirstlinetreatmentunlesscommencementofaNOACisclinically
appropriateoritisthepatientschoicetocommenceNOAC(withinlicensedindications).ThisisinlinewithNICETA249and
NICETA256.AllpatientscommencinganticoagulanttreatmentmusthaveaCHA2DS2VASC>1.

FurtherclarificationonCHA2DS2VASCof1

ItisadvisedbytheEuropeanSocietyGroupwhodevelopedthe2010ESCguidanceonAFthatscoring1pointforfemalesex
shouldbeappliedonlytofemalesaged65orover.

3.ManagedentryofNewOralAnticoagulants(NOAC)initiatingandswitchinganticoagulanttherapysafely

Toensurethatprescribingofthesenewdrugsiscontrolledandappropriate,allnewinitiationsofNOACwillbemonitoredby
theNHSSalfordCCGlocalitymedicinesmanagementteam.Therewillbenoformalgatekeeperrole,butthesedrugshave
notbeenapprovedforanyofflabeluseinprimarycareexceptinlinewiththecardiacnetworkalgorithm(seefigure1).

3.1Acutesetting(SRFT)

PatientswhoarediagnosedwithAFwhilstaninpatientatSRFT,maybecommencedonwarfarinasperexistingprotocols.If,
afteranindepthdiscussionwiththeconsultant,theyrequestaNOACthenSRFTwillberesponsibleforensuringallelements
oftheprescribingchecklist(appendix4)arecompletedandthatthisiscommunicatedtotheGP.Patientswhoare
commencedonanticoagulationforAFshouldhaveaCHA2DS2VASCscore>1

3.2PatientswithadiagnosisofAFalreadyprescribedwarfarin(underthecareoftheanticoagulantclinic)

Theanticoagulantclinicwillreviewpatientscurrentlyprescribedwarfarin/sinthrometoidentifythosepatientswhoare
currentlyinadequatelycontrolledandmeetthecriteriaasspecifiedbythecardiacnetworkguidance:

TheINR%oftimeinthetherapeuticrangeof23lessthat65%(unexplained)(asdeterminedbytheRosendaal
method)and/or

INR>5morethan2time(in12months)(unexplained)and/or
Otherclinicalconsideratione.g.intolerancethatmustbespecifiedinthereferraltotheGP

Followingreview,thesepatientswillbehighlightedandacommunicationletter(seeappendix3)willbesentfromthe
anticoagulantclinictotheGP.ThiswillbetoadvisetheGPto:

1.UndertakeaCHA2DS2VASCscore

2.Followtheappropriatealgorithm(seefigure1below)dependentuponthepatientsscore.

3.IfthepatientsCHA2DS2VASCscoreis>1andwarfarin/sinthrometreatmenthasnotledtoadequatecontrol
(asperGMcriteria),aneworalanticoagulantagent(NOAC)shouldbecommenced.

4.Patientsmedicalhistory(e.g.renalimpairment),concomitantdrugs/interactionse.g.verapamilshouldbe
reviewedpriortocommencingNOAC.

5.Inthemajorityofcases,patientswillalreadybeprescribedwarfarinandwillneedtohavetherapyswitchedover.
Thiswillrequireliaisonwiththeanticoagulantclinicaswarfarin/sinthromeiswithdrawn.

6.ToaidswitchingofanticoagulationtoNOACorcommencementofNOAC,patientinformationleafletsare
availablefordabigatranandrivaroxaban,bothcontainingapatientalertcardthatthepatientisadvisedtokeep
ontheirpersonandshowtohealthcareprofessionalspriortotreatment.Anticoagulantclinicshavestocksof
theseortheycanbeobtaineddirectlyfromthemanufacturer.Inaddition,toensuresafechangeoverof
medicationfromwarfarin/sinthrometoNOAC,asummarychecklistcanbefoundinappendix2.

7.Asummaryoftheoralanticoagulantscurrentlyavailableforthisindicationcanbefoundinappendix5tosupport
treatmentchoice.

3.3PatientswithanewdiagnosisofAF,identifiedbytheGP

PatientswhohaveanewdiagnosisofAF(withaCHA2DS2VASCscore>1)shouldbecommencedonwarfarinifnot
contraindicated,unlessafteranindepthdiscussionwiththeGP,theyrequestaNOAC.IfaNOACistobecommenced,follow
theflowchartinappendix1.

Ifwarfarinistobecommenced,referimmediatelytotheanticoagulantclinicforcommencementofwarfarin.

Ifafter3monthsthepatienthas:

TheINR%oftimeinthetherapeuticrangeof23lessthan65%unexplained(asdeterminedbytheRosendaal
method)and/or

INR>5morethan2timesunexplained(in12months)

Thentheyshouldbereviewedasaboveinsection3.2

3.4PatientswithanewdiagnosisofAF,identifiedbysecondarycareoutpatients

PatientswhohaveanewdiagnosisofAF(withaCHA2DS2VASCscore>1)shouldbecommencedonwarfarinunless
contraindicatedorafteranindepthdiscussionwiththeconsultanttheyrequestaNOAC.Patientsshouldbeinformedthat
theirGPwillneedtoreviewthemforappropriatenessofaNOAC.SecondarycareshouldthenrequestthattheGPreviews
thepatientsand,ifappropriateafterafurtherinformeddiscussioncommencesaNOAC.IfaNOACistobecommenced,
ensuretheprescribingchecklistiscompleted(appendix4).Secondarycaredonotneedtoinformthelocalitymedicines
managementteamattheCCGasthereisnolongeragatekeeperrole.

Ifthepatientistobecommencedonwarfarin,theGPshouldreferthepatientthroughtothenewstartanticoagulationclinic
ASAPandinformthepatientssecondarycareconsultantthatthepatienthasbeenanticoagulated.TheGPwillthen
prescribewarfarinaspercurrentarrangements.Theanticoagulationofthesepatients(witheitherwarfarinoraNOAC)
remainstheresponsibilityoftheGPtoarrangeinatimelymannerwithoutdelay.

3.5PatientswithadiagnosisofAFwhoarenotanticoagulated

GPsshouldreviewallpatientsontheirAFregistersandidentifythosepatientswhoarenotonanytreatmentorwhohave
chosentotakeaspirin.ThesepatientsshouldbereviewedandiftheirCHA2DS2VASC>1andtheydecidethattheydonot
wishtotakewarfarinthentheoptiontotakeaNOACshouldbediscussedwiththepatient,bearinginmindseveralofthe
contraindicationstowarfarinalsoapplytotheNOACdrugs(seeappendix5).

4.Miscellaneousinformation

4.1NOACgeneralsafetyinformation

TheMHRAissuedadrugsafetyupdateforDabigatraninDecember2011afteranumberofserousandfatalhaemorrhages
werereportedinelderlypatientswithrenalimpairment.TheyalsoreleasedafurtherdrugsafetyupdateinJuly2012which
clarifiesthetypeofclinicalconditionsandmedicinesthatarecontraindicatedforusewithdabigatran,tohelpminimisethe
knownriskofhaemorrhage.

Dabigatranisalsonowcontraindicatedwithdronedarone,andwiththeuseofotheranticoagulantagents,exceptwhen
switchingtherapytoorfromdabigatran,orwiththeuseofunfractionatedheparinformaintenanceofvenousorarterial
catheterpatency.Italsoremindsprescribersabouttheimportanceofmonitoringrenalfunctioninpatientswhoreceive
dabigatran.

CardiologyhaveadvisedthatduetoalackofdataitisadvisabletoavoidtheuseofNOACsincombinationwithaspirin
>100mganddualantiplatelettherapy.Inaddition,coumarinsratherthenNOACsshouldbeusedinallpatientswith
rheumaticheartdiseasecausinganydegreeofmitralstenosisandthosewithsevereaorticstenosisofanycause.

4.2NOACuseinpatientswithreducedrenalorhepaticfunction

Theyrecommendedthatrenalfunctionshouldbeassessedinallpatientsbeforecommencingdabigatrantreatmentandat
leastonceayearinpatientsolderthan75orthosewithsuspecteddeclineinrenalfunction.Dabigatraniscontraindicatedin
patientswithsevererenalimpairment(CRCl<30ml/min).Patientswithelevatedliverenzymes>2ULNwereexcludedfrom
thestudyinvestigatingthepreventionofstrokeandSEEassociatedwithatrialfibrillation.Notreatmentexperienceis
availableforthissubpopulationofpatients,andthereforetheuseofdabigatranisnotrecommendedinthispopulation.

Forrivaroxaban,cautionisrequiredinpatientswithsevererenalimpairment(creatinineclearance<30mL/min)ormoderate
hepaticimpairment.Itisnotrecommendedinpatientswithacreatinineclearanceoflessthan15mL/min.Limitedclinical
dataforpatientswithsevererenalimpairment(creatinineclearance1529ml/min)indicatethatrivaroxabanplasma
concentrationsaresignificantlyincreasedtherefore,rivaroxabantobeusedwithcautioninthesepatients.Rivaroxabanis
alsocontraindicatedinpatientswithhepaticdiseaseassociatedwithcoagulopathyandclinicallyrelevantbleedingrisk,andis
notrecommendedinthosealsotakingstronginhibitorsofcytochromeP3A4enzymeorPglycoprotein,suchastheazole
antimycotics(eg,ketoconazole)orHIVproteaseinhibitors(eg,ritonavir).

4.3NOACsinmonitoreddosingsystems(MDS)

Dabigatranmustremaininitsoriginalpackingupuntilitistakentoprotectitfrommoisture.IfitwastogointoanMDS,then
thewholeblisterwouldneedtogoinandthepatientwouldhavetopeelthebackingoffpriortotaking(notpushitthrough
asthismaydamagethecoating).InpracticethisisnotworkableandthesizewouldlimititgoingintomostoftheMDS
systemsthatcommunitypharmacistsuse.

RivaroxabandoesnothaveanyspecificstoragerequirementsandsomaybeanoptionifthepatientrequiresanMDS.

4.3OpeningofDabigatrancapsules

Theoralbioavailabilitymaybeincreasedby75%comparedtothereferencecapsuleformulationwhenthepelletsaretaken
withouttheHydroxypropylmethylcellulose(HPMC)capsuleshell.Hence,theintegrityoftheHPMCcapsulesshouldalwaysbe
preservedinclinicalusetoavoidunintentionallyincreasedbioavailabilityofdabigatranetexilate.Therefore,patientsshould
beadvisednottoopenthecapsulesandtotakethepelletsalone(e.g.notsprinkledoverfoodorintobeverages).

4.5NOACdiscontinuation

IntheRELYstudymoredabigatransubjectsdiscontinuedstudymedicationduetoadverseeffectscomparedwithwarfarin
subjects.Gastrointestinaladverseevents(e.g.,dyspepsia,gastrointestinalhaemorrhage,nausea)occurredmorefrequently
withdabigatranvs.warfarin(35%vs.24%)andwerethemostfrequentlyreportedadverseeventsresultingintreatment
discontinuation.Theriskofdyspepsiawithdabigatranwashighestwithinthefirstfewweeksoftreatment.Dyspepsiacanbe
reducedbytakingdabigatranwithfood,butitisnotimprovedbyaddingaPPI.

Forrivaroxaban,inROCKETAFthetotalnumberofsubjectswhopermanentlydiscontinuedstudydrugwassimilarbetween
thetwotreatmentgroups:rivaroxabansubjects35.44%andwarfarinsubjects34.64%.TheKaplanMeierestimated
cumulativediscontinuationratesat1and2yearswere21.83%and34.72%forrivaroxabanand21.12%and33.52%for
warfarin,respectively.

Thenumberofsubjectsreceivingrivaroxabanwhopermanentlydiscontinuedstudydrugforbleedingadverseevents:304
(4.28%)subjectsintherivaroxabangroupcomparedwith219(3.07%)subjectsinthewarfaringroup.

Patientsondabigatranorrivaroxabanshouldtherefore,beadvisedtotakethesemedicationswithfood,toincrease
absorptionandreduceheartburn.

4.6Misseddoses

Dabigatranistakentwiceadayandtheadviceonmisseddosesis;aforgottendosecanstillbetakenupto6hourspriorto
thenextduedose.Amisseddoseshouldbeomittediftheremainingtimeisbelow6hourspriortothenextduedose.Donot
takeadoubledosetomakeupformissedindividualdoses.

Rivaroxabanistakenoncedailyandpatientsareadvisediftheyhavemissedadose,takeitassoonastheyremember.Do
nottakemorethanonetabletinasingledaytomakeupforaforgottendose.Takethenexttabletonthefollowingdayand
thencarryontakingonetabletonceaday.

4.7PreoperativemanagementofpatientstakingNOACs

Dabigatran
ThetimetostoppingtreatmentpriortosurgerydependsonthepatientsrenalfunctionandisdetailedintheSPCandis
summarisedbelow.

Renalfunction(CrClin Estimatedhalflife Highriskofbleedingor Standardrisk

mls/min majorsurgery
>80 Approx13hrs 2daysbefore 24hoursbefore
>50<80 Approx15hrs 23daysbefore 12daysbefore
>30<50 Approx18hrs 4daysbefore 23daysbefore

Rivaroxaban
Ifaninvasiveprocedureorsurgicalinterventionisrequired,rivaroxabanshouldbestoppedatleast24hoursbeforethe
interventionifpossibleandbasedontheclinicaljudgementofthephysician.Iftheprocedurecannotbedelayed,the
increasedriskofbleedingshouldbeassessedagainsttheurgencyoftheintervention.Rivaroxabanshouldberestartedafter
theinvasiveprocedureorsurgicalinterventionassoonaspossible,providedtheclinicalsituationallowsandadequate
haemostasishasbeenestablished.

Bridgingtherapy
OccasionallysomepatientsmayrequirebridgingtherapywithLMWH.Secondarycarewilladviseregardingthisonacaseby
casebasis.

4.8SwitchingpatientsfromNOACsbacktowarfarin
SomepatientsmaynotbeabletotolerateaNOACandsomayhavetoconvertbacktowarfarin

Dabigatrantowarfarin
Whenconvertingfromdabigatrantowarfarin,adjustthestartingtimeofwarfarinbasedoncreatinineclearanceasfollows:
CrCL 50ml/min,startwarfarin3daysbeforediscontinuingdabigatran.
CrCL 30<50ml/min,startwarfarin2daysbeforediscontinuingdabigatran.

BecausedabigatrancancontributetoanelevatedINR,theINRwillbetterreflectwarfarinseffectafterdabigatranhasbeen
stoppedforatleast2days.

Rivaroxabantowarfarin
Whenconvertingfromrivaroxabantowarfarin,warfarinshouldbegivenconcurrentlyuntiltheINRis 2.0.Forthefirsttwo
daysoftheconversionperiod,standardinitialdosingofwarfarinshouldbeusedfollowedbywarfarindosingguidedbyINR
testing.Whilepatientsareonbothrivaroxabanandwarfarin,theINRshouldnotbetestedearlierthan24hoursafterthe
previousdosebutpriortothenextdoseofrivaroxaban.

OncerivaroxabanisdiscontinuedINRtestingmaybedonereliablyatleast24hoursafterthelastdose.

PatientswhohavediscontinuedwarfarinandmovedontoNOACtreatmentwhothenneedtorevertbacktowarfarin
treatmentwillneedtogobackintotheanticoagulantserviceasanewstartastheywillhavebeendischargedfromthis
service.

Figure1:GM&CCardiacNetworkalgorithmfollowingCHA2DS2VASC

Appendix1:PatientflowchartforswitchingfromwarfarintoaNOAC

Patientreviewedinprimarycare.Patient Patientreviewedinanticoagulantclinic
unabletoachieveINRcontrolandisunder (ACC).Patientinadequatelycontrolledon
coagulatedINR<2onwarfarin/sinthromeat warfarin/Sinthromeatpresent.
present.

PatientmeetsGreaterManchestercriteriafor
neworalanticoagulants
(NOAC)(seeGMCCNguidance)

Yes Patientsuitable No
forNOACs

ACC:ReferbacktoGPto
GPActions discussoptionswith
Checksrenalfunction patient
ChecksCHADs2scoreandthatpatientfitslicence
criteriaorGMCCNguidanceforNOAC
Seespatientanddiscussespros&conson
treatment,sideeffects,importanceofcompliance
Dabigatran:IfINR>2IssueACUTEprescriptionfor
1/12NOACDabigatrantobetakenwhenINR<2
managedbyACC
Rivaroxaban:IfINR>3IssueACUTEprescriptionfor
1/12NOACRivaroxabantobetakenwhenINR<3
managedbyACC
IfINR<2NOACcanbecommencedbyGPandpatient
dischargedfromACC
Checksnointeractingdrugs
BookF/Uappointmentfor1/12

Anticoagulationclinic
MonitorINRuntil<2or3andpatientcancommence
NOAC
ReinforcecounsellingaroundNOAC
DischargefromA/Cclinic

PatientcommencesNOAC

GP
Seenagainat1/12
Compliance,sideeffectsreviewed
NOACissuedmonthlyonrepeat

GPannualreviewtomonitorrenal
functionandconcordance
PatientunabletotolerateNOAC
ConsideranalternativeNOAC
Ifgoesbackonwarfarinmanageas
intextrerefertoanticoagulation
clinicasnewstart
Appendix2:GuidelineforswitchingfromvitaminKantagonists(VKA)e.g.warfarintoaneworal
anticoagulanttherapy(NOAC)
(Inadditionseepatientflowchart)

GPistodiscusspossiblechangewithpatientandexplainreasonrisks/benefits
Consultwithanticoagulantclinicsiforalanticoagulantswitchingisrequired

Ifpatientconsentstochange:

Checkrenalfunction/LFTrequired

Considerdosetobeprescribedbasedonpatientage/renalfunctionseeSPC/appendix4

Reviewmedicationsforpotentialdruginteractions

Contactanticoagulantclinicandinformthemofimpendingconversationandbeadvisedtostopwarfarinwhen
patientattendsandwhentheclinicwillcheckINR

Givepatientanacuteprescriptionsothatpharmacistcanarrangesupply

VitaminKantagonisttobediscontinuedfor2days

PatientsINRmonitoredatclinic

INRtobetakenafter2daysomission

FordabigatranifINR<2NOACcancommence

ForrivaroxabanifINR<3NOACcancommence

GivethepatientanalertcardandpatientinformationleafletfortheNOAC

Ensurepatient/carersareawaretosendredundantwarfarinsupplybacktothepharmacyforsafe
destruction

EnsurerecallforannualU&Eisontheclinicalsystem.

Adverseeventsshouldbereported.Reportingformsandinformationcanbefoundatwww.yellowcard.gov.uk.Adverse
eventsshouldalsobereportedtoBoehringerIngelheimDrugsafetyon08003281627(freephone)fordabigatranorBayer
plcon01635563500forrivaroxaban.

Appendix3TemplatelettersentfromanticoagulationclinictoGP

Communityanticoagulationservice

DrBThinner
ThePractice
Salford
M56FW
Date

DearDrBThinner

Re:MrIRBeat24ACleveleysAvenue,Swinton,SalfordM27OLL

HospNo: 1000000
NHSNo: 6000000000
DateofBirth: 2/7/1945

Thispatientiscurrentlyunderourcareformonitoringofwarfarintherapy.Forthereasonshighlightedbelow,weare
requestingaGPreviewofthispatientsanticoagulationtherapyneedsinordertodecidedwhichdrugisbestforoptimal
strokepreventioninthisindividual.

TheINR%oftimeinthetherapeuticrangeof23lessthan65% Y/N
(TTRshouldbemeasuredforindividualpatientsusingtheRosendaalMethod)
UnexplainedINR>5morethan2times(in12months) Y/N

Otherclinicalconsiderations Y/N
Intolerancetowarfarin
Newlydiagnosedpatientforadvice
Newreferralpoststroke/TIA
Otherpleasestate

ReviewofanticoagulationtherapyshouldbeundertakeninlinewithGreaterManchestertreatmentalgorithms,includinga
reviewoftheindividualsCHADS2/VASCscorewhichwilldetermineifaneworalanticoagulantdruge.g.dabigatran/
rivaroxabanisindicatedasareplacementforwarfarin.

AdetailedguideonhowtomangethetransitionofthesepatientsisavailableonthePCTintranetat
http://nww.salfordpct.nhs.uk/MedicinesManagement/documents/NOAC.pdf

Wewouldbegratefulifyouwouldinformusassoonaspossibleofyourdecision.Pleasefeelfreetocontactmeon(insert
contactnumber)ifyouwishtodiscussthismatter.FurtherinformationcanalsobeobtainedfromtheCCGmedicines
managementteam.

Yourssincerely

AnticoagulantClinic

Appendix4:Prescribingchecklistfordabigatranandrivaroxaban

Patientname:DOB:

NHSNumber:Address:

(A)NICECriteria(2)forDABIGATRANuse(allmustbemettickallapplicable) Yes No

1. NonValvularAtrialFibrillation(AF)

Routineechocardiographyisnotrequiredpriortoinitiationofdabigatran.Itisnotrecommended
inpatientswithknownhaemodynamicallysignificantvalvularheartdiseaseorinpatientswith
prostheticheartvalves

2. eGRF>30mL/min

(N.B.IfeGFRisnotavailablee.g.inpatienttheCreatinineClearanceshouldbecalculated
instead(usingCockcroftformula).

3.DoesthepatienthaveaCHAD2SVAS2Cscoreof1?

4. Nocontraindicatedconcomitantmedications:

Ketoconazole,cyclosporineA,itraconazoleandtacrolimus,dronedarone

CautionshouldbeexercisedwithotherPgpinhibitors/inducers
(e.g.amiodarone,quinidineorverapamil,clarithromycin,rifampicin,
carbamazepine,phenytoin).ThislistisnotexhaustiverefertoBNF/manufacturersdatasheet
forfurtherdetails.

(B)GeneralAssessment Yes No

5. Abilitytocomplywithmedicationdosing

N.B.Duetotheshorthalflifeofdabigatrancomparedtowarfarinerraticcompliancecouldresult
inworseanticoagulation.Dosingistwicedaily.

6. Noothercontradictionstoanticoagulation(notlistedabove)
Majorbleedingpotentialortendencye.g.severehaemophilia
Activepepticulcer,oesophagealvarices,aneurysm,proliferativeretinopathy
Recentorganbiopsy
Recenttraumaorsurgerytothehead,orbitorspine
Recentstroke(usually<2weeks)
Confirmedintracranialorintraspinalbleed(usuallywithinlast4weeksalthoughrequires
individualassessment)
Uncontrolledhypertension
InfectiveEndocarditis

7. Baselinebloodssatisfactory:
Notrecommendedif
FBC:Platelet<70x109/L
eGFR:seeabove
LFT:Liverenzymeselevated>2xnormal
 CoagulationScreen:APTT>1.5xnormal;INR>1.4

8. Explainpurposeofanticoagulation/dabigatran
Avoidanceofembolicstroke/peripheralemolisationsecondarytoatrialfibrillation

9. ExplainSeriousSideEffects:Bleeding
Seekurgentmedicalattentionifdevelopsnew:

Bloodinurine,faeces,vomitorsputum,vaginalbleeding(otherthanregularperiod)
Severeunusualheadache(particularlyiffollowingheadtrauma)

10. Explain
Needtoinformanyoneprescribingmedicationsthattheyareondabigatranandto
confirmthatitdoesnotinteract

Explainneedforannualreview/bloodtesttoassessrenalfunctionorifchange

DyspepsiaandGIbleedingweretheonlyadverseeventsnotedtobestatisticallymore
commonwithdabigatranthanwarfarin.Dyspepsiamaybeamelioratedbytaking
medicationwithfood.Cautionshouldbeexercisedifsymptomspersit/recenthistoryof
pepticulcerdisease

Thereisnoknownantidotetodabigatran(unlikewarfarin).Intheeventoflife
threateningbleedingorneedforemergencysurgerystopdabigatrananticoagulant
effectwillwearoffafterapproximately2436hourspostlastdose

Althoughtherearenoanticipatedlongtermadverseeffectsfromthelargemultinational
studythereisnolongdatacurrentlyavailable.Dabigatranhasblacktrianglestatus
prescribersarerequiredtocompleteayellowcardforanysuspectedadversedrug
reactions

Renalfunctionshouldbeassessedatleastonceayearinpatientstreatedwith
dabigatranormorefrequentlyasneededincertainclinicalsituationswhenitis
suspectedthattherenalfunctioncoulddeclineordeteriorate(suchashypovolemia,
dehydration,andwithcertaincomedications,etc)

Dabigatranisnotsuitableformonitoreddosesystems(e.g.dosetteboxes)andmustbe
storedinoriginalpackaging.Onceabottleisopenedthetabletsmustbefinishedwithin
4months(SPC)

Standardcoagulationtestse.g.INRandAPTTmaybeprolongedbydabigatranbutare
notpredictableandshouldnotberoutinelymonitored

 DosingRecommendation:

(1) 150mgbdPOStandarddose
(2) 110mgbdPOSuitablepatients:

Allpatientsaged>80y
Selectedpatientsaged>75yifbleedingrisk
Otherhighriskbleedingpatients,especiallyifborderlinerenalfunction
Concomitantverapamil

IfpatientsareswitchingfromwarfarincommencedabigatranwhenINR<2.

Misseddoses:Aforgottendosemaystillbetakenupto6hourspriortothenextscheduleddose.From
6hourspriortothenextscheduleddoseon,themisseddoseshouldbeomitted.Nodoubledoseshould
betakentomakeupformissedindividualdoses.

Authorisation:

Signatureofmedicalpractitionerundertakingassessment:

PrintName:

OptionalCHAD2SVAS2cScoreScore(circle)

Congestiveheartfailure/LVdysfunction 1
Hypertension 1
Age75y 2
Diabetesmellitus 1
Stroke/TIA/TE 2
VascularDisease(MI/PVD/AorticPlaque) 1
Age6575 1
SexCategoryi.e.female 1

TOTAL..

Reference:

1 MHRADrugsafetyupdateVol5Issue5,Dec2011:A2

2 NICETA249(15thMarch2012)dabigatranetexilateforthepreventionofstrokeandsystemicembolismin
atrialfibrillation

Patientname:DOB:

NHSNumber:Address:

(A)NICECriteria(2)forRIVAROXABANuse(allmustbemettickallapplicable) Yes No

1. NonValvularAtrialFibrillation(AF)

Routineechocardiographyisnotrequiredpriortoinitiationofrivaroxaban.Itisnot
recommendedinpatientswithknownhaemodynamicallysignificantvalvularheartdiseaseorin
patientswithprostheticheartvalves

2. eGFR>15mL/min

IfeGFR<50and15doseshouldbereducedto15mgOD.
Rivaroxaban istobeusedwithcautioninpatientswithcreatinineclearance1529ml/min.
Useisnotrecommendedinpatientswithcreatinineclearance<15ml/min

3.DoesthepatienthaveaCHAD2SVAS2Cscoreof1?

4.Nocontraindicatedconcomitantmedications:

TheuseofRivaroxabanisnotrecommendedinpatientsreceivingconcomitantsystemic
treatmentwithazoleantimycotics(suchasketoconazole,itraconazole,voriconazoleand
posaconazole)orHIVproteaseinhibitors(e.g.ritonavir).ThislistisnotexhaustiverefertoBNF
/manufacturersdatasheetforfurtherdetails.

(B)GeneralAssessment Yes No

5.Abilitytocomplywithmedicationdosing

N.B.DuetotheshorthalflifeofRivaroxabancomparedtowarfarinerraticcompliancecould
resultinworseanticoagulation.Dosingisoncedaily.

6.Othercontradictionstoanticoagulation(notlistedabove)

congenitaloracquiredbleedingdisorders
uncontrolledseverearterialhypertension
activeulcerativegastrointestinaldisease
recentgastrointestinalulcerations
vascularretinopathy
recentintracranialorintracerebralhaemorrhage
intraspinalorintracerebralvascularabnormalities
recentbrain,spinalorophthalmologicalsurgery
bronchiectasisorhistoryofpulmonarybleeding.







7. Baselinebloodssatisfactory:
Notrecommendedif
Creatinineclearance<15ml/min(eGFR<15ml/min/1.73m2)

8. Explainpurposeofanticoagulation/rivaroxaban
Avoidanceofembolicstroke/peripheralembolisationsecondarytoatrialfibrillation

9. ExplainSeriousSideEffects:Bleeding
Seekurgentmedicalattentionifdevelopsnew:

Bloodinurine,faeces,vomitorsputum,vaginalbleeding(otherthanregularperiod)
Severeunusualheadache(particularlyiffollowingheadtrauma)

10. Explain
Needtoinformanyoneprescribingmedicationsthattheyareonrivaroxabanandto
confirmthatitdoesnotinteract

Explainneedforannualreview/bloodtesttoassessrenalfunctionorifchange

Thereisnoknownantidotetorivaroxaban(unlikewarfarin).Intheeventoflife
threateningbleedingorneedforemergencysurgerystoprivaroxabananticoagulant
effectwillwearoffafterapproximately2436hourspostlastdose

Althoughtherearenoanticipatedlongtermadverseeffectsfromthelargemultinational
studythereisnolongdatacurrentlyavailable.Rivaroxabanhasblacktrianglestatus
prescribersarerequiredtocompleteayellowcardforanysuspectedadversedrug
reactions

Renalfunctionshouldbeassessedatleastonceayearinpatientstreatedwith
rivaroxabanormorefrequentlyasneededincertainclinicalsituationswhenitis
suspectedthattherenalfunctioncoulddeclineordeteriorate(suchashypovolemia,
dehydration,andwithcertaincomedications,etc)

Standardcoagulationtestse.g.INRandAPTTmaybeprolongedbyrivaroxabanbutare
notpredictableandshouldnotberoutinelymonitored

 DosingRecommendation:

(3) 20mgoncedailyPOStandarddose
(4) 15mgoncedailyPOSuitablepatients:

Patientswithmoderate(creatinineclearance3049ml/min)orsevere(creatinineclearance15
29ml/min)renalimpairment

IfpatientsareswitchingfromwarfarincommencerivaroxabanwhenINR<3.

Misseddoses:Rivaroxabanistakenoncedailyandpatientsareadvisediftheyhavemissedadose,take
itassoonastheyremember.Donottakemorethanonetabletinasingledaytomakeupforaforgotten
dose.Takethenexttabletonthefollowingdayandthencarryontakingonetabletonceaday.

Authorisation:

Signatureofmedicalpractitionerundertakingassessment:

PrintName:

OptionalCHAD2SVAS2CScoreScore(circle)

Congestiveheartfailure/LVdysfunction 1
Hypertension 1
Age75y 2
Diabetesmellitus 1
Stroke/TIA/TE 2
VascularDisease(MI/PVD/AorticPlaque) 1
Age6575 1
SexCategoryi.e.female 1

TOTAL..

Reference:

(1) NICETA256(May2012)Rivaroxabanforthepreventionofstrokeandsystemicembolism
inpeoplewithatrialfibrillation
Appendix5Choiceoforalanticoagulante.g.warfarin,dabigatran,rivaroxaban

Thissummaryprovidedanoverviewofthevariousoralanticoagulantsnowavailable.TheindividualSummaryofProduct
characteristicsshouldbeaccessedforfullprescribinginformationwhenaspecificdrugisselectedforprescribing.

Indication

Drug Warfarin Dabigatran(Pradaxa) Rivaroxaban(Xarelto)

Indication(in Prophylaxisof Preventionofstrokeandsystemicembolismin Preventionofstrokeand
relationto systemicembolism adultpatientswithnonvalularatrialfibrillation systemicembolisminadult
stroke inpatientswith withoneormoreofthefollowingriskfactors: patientswithnonvalvular
prevention) rheumaticheart atrialfibrillationwithoneor
diseaseandatrial Hypersensitivitytotheactivesubstanceorto moreriskfactors:
fibrillation anyoftherecipients Congestiveheartfailure
Previousstroke,transientischemicattack,or Hypertension
systemicembolism(SEE) Age>75years
Leftventricularejectionfraction<40% Diabetesmellitus
Symptomaticheartfailure,NewYorkHeart Priorstrokeortransient
Association(NYHA)Class2 ischaemicattack
Age75years
Age65yearsassociatedwithoneofthe
following:diabetesmellitus,coronaryartery
diseaseorhypertension

Dose,monitoringandformulation

Drug Warfarin Dabigatran(Pradaxa) Rivaroxaban

Dose Variabledose(ONCEADAY) 150mgTWICEADAY 20mgONCEADAY(takenwith
generallyatteatime.Dose food)
dependentonINRandtarget 150mgTWICEADAY7580yearsif
range bleedingriskishighand
thromboembolicrisklowphysician
canconsider110mgBD

110mgTWICEADAY(aged80and
over
Monitoring INRmonitoring Visiblemonitoringofthepatientfor Visiblemonitoringofthe
signsofbleedingandanaemia.(No patientsforsignsofbleeding
clinicalmonitoringavailableINR andanaemia(Noclinical
notabletobeusedasdifferent monitoringavailable;INRnot
pathwayaction.) abletobeusedasdifferent
pathwayofaction).
Formulation 0.5mg,1mg,3mgand5mg 110mgand150mgtablet 15mgand20mgtablet
tablet

Contraindications

Drug Warfarin Dabigatran(Pradaxa) Rivaroxaban(Xarelto)

Contra Knownhypersensitivityto Hypersensitivitytoactive Hypersensitivitytothe
indications warfarinortoanyofthe substanceortoanyofthe activesubstanceortoany
SeeSPCfor excipients excipients oftheexcipients
fulldetails Haemorrhagicstroke Patientswithsevererenal Clinicallysignificantactive
Clinicallysignificant impairments(CrCL<30ml/min) bleeding
bleeding Activeclinicallysignificant Hepaticdiseaseassociated
Within72hoursofmajor bleeding withcoagulopathyand
surgerywithriskofsevere Organiclesionatriskof clinicallyrelevantbleeding
bleeding bleeding riskincludingcirrhotic
Within48HOURSpostpartum Spontaneousor patientswithChildPughB
Pregnancy(firstandthird pharmacologicalimpairmentof andC
trimesters) haemostasis Pregnancyandbreast
Drugswhereinteractions Hepaticimpairmentorliver feeding
mayleadtoasignificantly diseaseexpectedtohaveany
increasedriskofbleeding impactonsurvival
Concomitanttreatmentwith
systemicketoconazole,
cyclosporine,itraconzole,
tacrolimus,dronedarone.

Cautions

Drug Warfarin Dabigatran(Pradaxa) Rivaroxaban

Cautions/ Therapyshouldbereviewedon
Special aregularbasis(mostADRsare
warningfor duetooveranticoagulation).All
use patientsshouldhaveayellow
anticoagulationbooklet.
Thrombophiliapatientswith
proteinCorSdeficiency.
Thyroiddisordersclosely
monitorpatients.
Thefollowingmayincrease
bleedingrisk;lossofweight,
acuteillness,cessationof
smoking(dosesmayneedtobe
reduced)
Thefollowingmayreduce
efficacy;weightgain,diarrhoea,
vomiting(dosesmayneedtobe
increased)
Geneticconditionsinrelationto
CYP2C9andVKORC1closer
monitoringrequired
Patientwithelevatedliverenzymes
>2ULNshouldnotbeprescribed
dabigatran.Usewithcautionin
conditionswithanincreasedriskof
bleeding
SeeSPCforinformationon
convertingfrom
warfarin/sinthrometo
rivaroxaban
Renalimpairment
Mild:(CrCI5080ml/min)no
doseadjustmentnecessary
Moderate:(CrCI3049ml/min)
15mgONCEADAY
Severe:(CrCI1529ml/min)
15mgONCEADay(usecaution
inthesepatients)
Verysevere:CrCI<15ml/min
notrecommendedinthisgroup
ofpatients
Limitedclinicaldataforpatients
withsevererenalimpairment
(creatinineclearance1529
ml/min)indicatethat
rivaroxabanplasma
concentrationsaresignificantly
increasedtherefore,
rivaroxabantobeusedwith
cautioninthesepatients.

DrugInteraction

Warfarin Dabigatran(Pradaxa) Rivaroxaban(Xarelton)

Drug Pharmacodynamicandotherinteractions(avoid Generallyinteractions Interactionsbelowleadto
interactions orusewithcautions): leadtoanbleeding anbleedingrisk
(seeindividual riskpatientsshouldbe patientsshouldbe
SPCsforfull Carewithconcomitant Dipyridamole monitoredcloselyfor monitoredcloselyfor
detailsand includingNSAIDs Sulfinpyrazone signsofbleedingand signsofbleedingand
action) (includingaspirinand Fondaparinux, anaemia anaemia
COX2s)andplatelet rivaroxaban
aggregationinhibitors GlycoproteinIIb/ Cautionwith Concomitantuseof
(e.g.clopidogrel) IIIareceptor concomitant;systemic systemicazole
Heparins(unless antagonists azoleantimycotics antimycoticse.g
clinicallyindicateddue SSRI/SNRI e.g.ketoconazole, Ketoconazole
tolowINR) antidepressants circlosporin, Itraconazole
Thrombininhibitorse.g. Concomitant itraconazole Voriconazole
bivalirundin,dabigatran glucosamine tacrolimusarecontra HIVproteaseinhibitors
Drugsinhibiting isnot indicated,also Concomitantuseof
haemostasis,clottingor recommended posaconazole(dueto dronedaroneshouldbe
plateletactions lackofsafetydatafor avoided
thiscombination) Cautionwith
Generallyinteractionsleadtoanbleedingrisk Cautionwith concomitantother
patientsshouldbemonitoredcloselyforsigns concomitantstrongP anticoagulants
ofbruising,bleedingandanaemia(howeverwill gpinhibitorse.g. Cautionwith
beguidedbyINRandanticoagulationclinicfor amiodarone,quinidine, concomitantNSAIDs
dosevariations) verapamil andplateletaggregation
inhib itors(e.g.
Azoleantifungals(e.g Methylphenidate Cautionconcomitant clopidogrel)
ketoconazole Zafirlukast useofamiodarone(nb:
fluconazole) Fibrates amiodaronehasalong Interactionsbelo wleadto
Paracetamol(prolonged Statins(not halflifeandinteraction ain anticoagulant
use) mayexistforweeks concentratio ntherefore
pravastatin)
Allopurinol afterdiscontinuation, treatmentmaybe
Erythromycin
especiallyinpatient suboptimal
Capecitabine Sulfamethoxazole
withmidrenal
Erlotinib Metronidazole
impairment) Cautionconcomitant
Disulfiram Excessivealcohol
useofstrongCYP3A
Omeprazole consumption
Cautionwith inducerse.g.
Propafenone Cranberryjuice concomitantuseof Phenytoin
Amiodarone shouldbeavoided quinidineespeciallyin Carbamezepine
Tamoxifen patientswithmild Phenobarbital
moderateimpairment St JohnsWort
Interactionsbelowleadtoanin Cautionwith
anticoagulantconcentrationthereforetreatment concomitantuseof
maybesuboptimal(howeverwillbeguidedby verapamildose
INRandanticoagulationclinicfordoseregulations reductionadvisedfrom
150mgBDto110mgBD
inpatientstaking
Barbiturates StJohnsWort concomitantverapamil
Primidone combinationnot interactionmorelikely
Carbamazepine supported inpatientswithmild
Griseofulvin Largeamountsof moderateimpairment)
Oralcontraception foodcontainingvitamink Cautionwith
concomitantuseof
Rifampicin i.e.suddenchangesin
dietoftheseproducts clarithromycin,
Azathioprine
mayaffectanticoagulant especiallyinpatients
Pheytoin
control withmildmoderate

renalimpairment
Proteaseinhibitors(e.g.
ritonavircontaining
products)shouldnotbe
 prescribed
concomitantly(dueto
lackofavailablesafety
dataforthis
combination
Interactionsbelowlead
toainanticoagulant
concentration
thereforetreatment
maybesuboptimal
Cautionwith
concomitantuseof
strongCYP344inducers
e.g.rifampicin,St
JohnsWort,
Carbamazepine,
Phenytoin

RelevantResources

Drug Warfarin Dabigatran(Pradaxa) Rivaroxaban(Xarelto)

Relevantresources WarfarinSPCs SPC150mgtablets SPC20mgtablets
(e.gSPC) SPC110mgtablets SPC15mgtablets


Appendix6:SRFTGuideline:Emergencyreversalofanticoagulationinpatientstakingnoveloral
anticoagulants(eg.Dabigatran,Rivaroxabanetc)