Key messages
• Peoplewithatrialfibrillationonaspirin,clopidogrelornoantithromboticmedicationshouldbereviewedtoassesssuitabilityofanticoagulation.
• Warfarinorneworalanticoagulantsmaybesuitableafteraninformeddiscussionwiththepatient.
• Aspirindoesnotsignificantlyreducestrokeinatrialfibrillation.Atolderagesbleedingmayresultinnetharm.
SUMMARY GUIDELINES
ISBN 978-0-902238-96-1
Atrial fibrillation Improving anticoagulation: update
Aim of the guideline
Onlyhalfthepeoplewithatrialfibrillationareonanticoagulantswhichreducestrokesby64%.
Thisguidanceaimstoincreasetheuseofanticoagulantsandreducetheinapproriateuseofantiplateletagents.
What this guidance covers
Theguidanceconcernsantithromboticagentsforthetreatmentofnon-valvularatrialfibrillation.ItisconsistentwithNICEGuidance.
OCTOBER 2014
See 2014 NICE AF guideline 180guidance.nice.org.uk/cg180
2 IMPROVING ANTICOAGULATION
IMPROVING ANTICOAGULATION 3
Contents
p3 Aims and issues
p3 What you can do
p4 Aspirin in AF
p5 Flowchart
p6 APeL and GRASP tools
p7 AF investigation
P8 CHADS2 and CHA2DS2-VASc
p9 Bleeding and HAS-BLED
p10 New oral anticoagulants
p11 Atrial devices
p13 Switching to NOACs
Authors
JRobson,SAntoniou,PMacCallum,RSchilling,PGompertz,IStaveley.
Wearegratefulforadvicefrom:prescribingadvisors(EastLondonConsortium)BBrese,REnti,YHossenbaccus(NHSOuterNorthEastLondon)OChesa,BKrishek.
Haematologists:WMills,ATso,MEvans,LGreen,LBowles,NAkhtarCardiologists:AWragg,GLip.Generalpractitioners:SSen,SSelvaseelan,JJagens,PCockman,SHull,KBoomla,BHart,
CEGstaff:KPrescott,IDostalfortheAPeLtool
CEG Website
ThisguidelineisavailableontheCEGwebsiteblizard.qmul.ac.uk/ceg-resource-library.html
Contact Us
AnyqueriesregardingthisdocumentshouldbeaddressedtoCEGatihse-ceg-admin@qmul.ac.uk58TurnerSt,LondonE12AB
Tel:02078822553
Guidance
Thisdocumentisaguidetodecisionmakingandnotareplacementforclinicaljudgement.WehavebasedthisguidancelargelyontheEuropeanSocietyofCardiology2012atrialfibrillationguideline.
4 IMPROVING ANTICOAGULATION
Aim
Thisguidanceisintendedforuseinpatientswhohavealreadybeendiagnosedandclinicallyevaluatedwithnon-valvularatrialfibrillation.
•ThisguidanceaimstoincreaseanticoagulationinpeoplewithAF.Warfarinisthedrugoffirstchoiceunlesscontraindicated.
•Italsoidentifiestheroleofneworalanticoagulants(NOAC)suchasdabigatran,rivaroxaban,andapixabanandtheiradvantagesanddisadvantages.
•ItaimstoreducetheuseofantiplateletagentsinAFasthereislittleevidencetheyreducestroke.
The issues
•AFcauses20%ofstrokes=12,500pa1.
•Strokeriskis5-6timesgreaterinAFpatientsthaninsinusrhythm1.
•40%ofpatientsareonaspirinalthoughanticoagulantsreducestrokemoreeffectively2.
•Warfarinreducesstrokeriskby64%comparedtoplacebo3.NOACsaresimilarlyeffective.
•Aspirinonlyreducesthisriskby19%(nonsignificant)4.
•Neworalanticoagulantsshouldbeconsideredinpeopleunsuitableforwarfarin5.
References
1.www.medman.nhs.uk/ebt/merec/cardio/atrial/resources/merec_bulletin_vol12_no5.pdf
2. Mathur et al. Ethnicity and stroke risk in AF . Heart. 2013;99:1087-92.
3. NHS Improvement. Commissioning for Stroke Prevention in Primary Care – the role of atrial fibrillation 06/09
4. Mant et al Warfarin versus aspirin for stroke prevention. Lancet 2007;370: 493-503.
5. NICE HTA guidance 2012
6. European Society of Cardiology. Atrial fibrillation 2012
What you can do
Use APL or GRASP tools to review all
patients with AF and their stroke risk
with the CHADS2 or CHA2DS2-VASc and
HAS-BLED scores to consider whether
anticoagulation will reduce stroke without
excessive risk of bleeding.
Re-discuss reasons for not using anticoagulant
•Peopleonaspirinaretwotothreetimesmorelikelytohaveastrokeaspeopleonwarfarin.
•Warfarin‘contraindications’areoftenoverestimated.
•Riskoffallsarerarelyareasonnottouseanticoagulants.
•Ifadherenceisanissue,willthisbebetterwithaNOACwhichmaybemonitoredlessfrequently?
•IfthereisatruecontraindicationtowarfarinconsideruseofaNOACorreferralifindoubt.
•Ifbloodtestsremaintheobstacleconsiderreferralforaneworalanticoagulant(NOAC).
•Wherethereisdoubt,referforreassessmentbyhaematologist.
If bleeding is a risk should this be reassessed?
•Bleedingriskandseveritywithaspirinisasgreat,ifnotgreater,thanwithwarfarinatolderages.
•UsetheHAS-BLEDscore.Useanticoagulantswithcautionifthescoreis3ormore-discusswithhaematologist;morefrequentreviewmayberequired.
•Ifpreviousbleedingbutnomajorbleedwithin3years,discusstreatmentoptionswithhaematologist.
•Ifbleedingisanissueistherearoleforatrialablation?Seep11.
IMPROVING ANTICOAGULATION 5
AF without other CVDFor people with AF but who do not have IHD, stroke or TIA, aspirin can no longer be recom-mended as there is no evidence that benefits outweigh risks7.
When anticoagulants cannot be used
Aspirin and/or clopidogrel should only be considered where warfarin and NOACs cannot be used due to allergy or contraindications.
PrimaryPrevention
Noantithrombotic
Stroke/TIA ClopidogrelStableangina LowdoseaspirinOldMI LowdoseaspirinNewMI/ACS Dualantiplatelet:aspirin
pluseitherclopidogrel,ticagrelororprasugrelfor1yr
Aspirin in AF AspirinisnoteffectiveinstrokereductioninAF7.
WarfarinorNOACscombinedwithaspirinorclopidogrelisnotadvisableinmostcircumstancesandpatientsonthiscombinationshouldbereviewedwithaviewtostoppingantiplateletagents.Theincreasedriskofbleedingusuallyoutweighsthereductionofstroke8.ApatientwithAFafteruncomplicatedMIorstrokewillusuallybetreatedwithwarfarinaloneSeep.8forpatientswhomaybeonwarfarinandanantiplateletagentafterrecurrent MI,coronarystentsorothercoronarycomplexitywhoshouldbediscussedwiththecardiologist.
Risk of major bleedOverage80yearsbleedingriskwithaspirinisashigh,ifnotgreaterthanwithwarfarin4.
The BAFTA AF Trial4
RCTofwarfarinvs.aspirin75mginatrialfibrillation
•973patientswithAF;meanage=82yrs
•Strokeriskwashalvedinthewarfaringroupincomparisontothoseonaspirin
•50peoplewouldneedtobetreatedfor1yearwithwarfarinratherthanaspirintopreventonestroke(approx10peoplein5yrs)
•Therewasnoincreasedbleedingriskwithwarfarinincomparisonwithaspirin
Thereisnosubstantiveevidencethataspiriniseffectiveinpreventingstrokeinpeoplewithatrialfibrillationandtherisksofmajorbleedingoutweighthepossiblebenefitsatolderages.
Wherepatientshaveco-morbidCVDbuttheyareunable totakewarfarinorneworalanticoagulants,thenaspirinwithorwithoutclopidogreloranotherantiplateletagentiswillreducetheriskofrecurrentCVDevents.Seenextcolumn.
7. www.rcpe.ac.uk/sites/default/files/files/supplement-18.pdf
Age yrs Warfarin Aspirin Rel. Risk
75-79 1.1% 0.8% 1.44
80-84 2.3% 2.4% 0.9685+ 2.9% 3.7 0.77
Whiletheriskofstrokeisreducedwiththecombina-tionofaspirin/clopidogreloveraspirinalone,theriskofmajorbleedingisalsosignificantlyincreased.PPIstoreducegastrointestinalbleedingriskwithantiplateletagentsshouldbeusedwhereappropriate.
Ifanticoagulantscannotbeused,cliniciansrecommendthatforstroke/TIA:clopidogrelisthepreferredchoice*.
Clopidogrelafter/strokeTIAisrecommendedasintrials,dipyridamolewasmorelikelytobediscontinuedbecauseofheadacheandclopidogrelwascheaperandatleast,ifnotmoreeffective.
ForACS/STEMIandNSTEMI*dualantiplateletherapy-acombinationofaspirinplusclopidogrelorticagrelororprasugrelshouldbecontinuedforthefirstyear.
*NICEwasunabletorecommendclopidogrelforTIA/STEMIbecauseclopidogrelisnotlicensedforthisuse.TheselocalvariationsareacceptedbyCCGprescribingadvisorsassatisfactoryalternatives.
8. Oldgren J, Wallentin L, Alexander JH. New oral antico-agulants in addition to single or dual antiplatelet therapy after an acute coronary syndrome: a systematic review and meta-analysis. Eur Heart J. 2013;34:1670-80.
6 IMPROVING ANTICOAGULATION
Bleeding risk?
Major bleed or HAS-BLED ≥ 3 ? Do benefits of anticoagulation outweigh risks of bleed?
Consider NOACs if ... warfarin allergy/contraindications unable to adhere to monitoring unable to achieve INR in range patient preference after informed discussion
GFR >50 ml/min
Age <75 yrs Weight >60 kg
Age >75-80 years; weight <50-60kg or GFR 30-50 ml/min or less See BNF. Indications for reduced dose differ.
Dabigatran GFR<30 ml/min Apixaban/rivaroxaban GFR <15 ml/min
Apixaban, dabigatran or rivaroxaban dose based on age, weight & GFR (Note*: use Cockcroft Gault for GFR rather than eGFR)
Dabigatran 150mg BD Apixaban 5mg BD Rivaroxaban 20mg OD
Dabigatran not advised previous MI Reduce dose if additional bleeding risk
Dabigatran 110mg BD <75yrs <50kg Apixaban 2.5mg BD <80 yrs <60kg Rivaroxaban 15mg OD Consult haematologist for advice. If GFR< 50ml/min use Cockcroft Gault to calculate GFR.
NOT suitable
CHA2DS2VASC Score
Score = 0 No antithrombotic or antiplatelet necessary
Warfarin or NOAC after an informed discussion with patient
Men score ≥ 1 Women ≥ 2 or age ≥ 65 yrs
Anticoagulation not suitable: only use aspirin +/-clopidogrel or other antiplatelet agent if previous CVD. See text for detail.
Anticoagulation in atrial fibrillation
IMPROVING ANTICOAGULATION 7
APeL tool
CEGdevisedtheAPeLtool:APeLAtrialfibrillationProgrammeeLondon.ThisworksinasimilarwaytoGRASPasanaidinclinicaldecisionmaking,andcalculatesthemorerecentCHA2DS2-VAScscorewhichpredictstheriskofstrokeinpeoplewithatrialfibrillationandtheHAS-BLEDscoreswhichpredictsriskofbleeding.
CHADS2andCHA2DS2-VAScarenowcalculatedautomaticallywithinEMISandalsobytheAPeLtoolwhichdisplaysbothpreviouslycalculatedandthelatestscoretoshowwherethesearemissingorrequireupdating.Datashowsfurtherrelevantclinicaldetailsincludingdementia,palliativecare,alcoholconsumption,fallsandco-morbiditiesforindividualpatients.
ThescreenshotbelowshowsanexampleoftheAPeLmaindisplayshowingpeopleonaspirinorclopidogrel.
APeLcanbeadaptedforanycomputersystemandisavialablefromtheClinicalEffectivenessGroupQMUL.
GRASP-AF
NationallytherehavebeenmajorattemptstoimproveanticoagulationusingtheGRASP-AFtoolthatextractsdatafromGPrecords.ItisdescribedontheNHSImprovementwebsite.
Nationallythishasimprovedwarfarinanticoagulationbyamodestamount(52%to54%).
GRASP-AFissupportedbyPRIMIS.Downloadfrom:
www.primis.nottingham.ac.uk/AF_CHADS/NHS_Improvement_files/PRIMIS_GRASPAF_Register.htm
Health Analytics
InouterNorthEastLondonHealthAnalyticalsoprovidesimilardisplaysofpatientsatrisk.ForfurtherdetailscontactCliveSutherlandatClive.Sutherland@onel.nhs.uk
QOF 2013
FromApril2012QOFrequiresCHADS2calculationinallpatientswithAF.WerecommendGPsusebothCHADS2andCHA2DS2-VAScscorestofitwithQOF.
APeL Tool example: those on aspirin in a practice patient and GP details removed in this
TheEMISandAPELCHADSscoresmaydifferbecausethetabledisplaysthelastscoreenteredinthepatientsrecordintheEMIScolumnandthenewlycalculatedscoreintheAPELcolumn.
8 IMPROVING ANTICOAGULATION
AF causes and investigation
Valvular heart disease Lung cancer
IHD, heart failure Obesity
Cardiomyopathy Alcohol
Thyroid disease Sleep apnoea
Diabetes Family history: AFor premature CVD
Renal disease Hypertension
ThediagnosisofAFshouldalwaysincludea12leadECGandasearchforconditionsthatpredisposetoAF.
FBC,U&E/GFR,proteinuria,ALT,thyroidfunctiontests,fastingglucose/HbA1c,CXR,12leadECG.
AnechocardiogramtoshowcardiacabnormalitiesoratrialthrombusisadvisedinallnewcasesofAF.
NotetheneedforCockcroftGaultGFRratherthaneGFRinpeopleover80yearsorthosewithpoorrenalfunction.(seedetailslater).
Decision to treat
Thedecisiontoanticoagulateshouldconsider
•Riskofstroke;CHA2DS2-VAScscore.
•Riskofbleeding;HAS-BLEDscore.
•Inabilitytomanagemedicines/monitoring.eg.mentalimpairment,alcoholism,etc.
•Theriskoffalls–bleedingriskisgenerallylessthantheriskofastrokeandfallsarerarelyareasonfornotusinganticoagulants.
•Co-morbidities:Riskincreaseswithco-morbidconditions-seeCHADSscores.
Referral
Considerreferralforfurtherassessmentorobtainconsultantadvice,
• wherethereisdoubtabouttheratioofbenefitstorisksofanticoagulation.
• inthoseunder65yearsorthosewithcomplexco-morbidityordruginteraction.
• Patientsunsuitableforwarfarinshouldbeconsideredforneworalanticoagulants.
• Consideratrialablationwherebleedingprecludesanticoagulant.
Paroxysmal AF and atrial flutter
Strokeandthrombo-embolicriskinparoxysmalAFandatrialflutterissimilartopersistentAFandantithrombotictherapyisrecommendedforthesepatients.Reversiontosinusrhythmmaybeintermittentandisnotareasontostoptherapy.
Warfarin plus aspirin/clopidogrelAddingeitheraspirinand/orclopidogreltowarfarinorNOACs,usuallyincreasesbleedingrisktoamuchgreaterextentthananyreductioninCVDandtheadditionofanantiplateletagenttowarfarinorNOACsisnotgenerallyrecommended.
However,somepatientsatveryhighriskwhohaveeitherhadanMIwhilstonwarfarinorafterstentingorothercomplexcardiacinterventionsmayrequirebothwarfarinandantiplateletagentsforadefinedperiod;usuallyayear.
Peopleonbothantiplateletagentsandwarfarinshouldbereviewedandconsiderationgiventostoppingantiplateletagentsunlessthereisaclearindicationfortheiruseagreedwithcardiologistsorotherspecialities.
IMPROVING ANTICOAGULATION 9
CHA2DS2-VASc and CHADS2 scores
TheCHA2DS2-VAScscoreisamoreaccurateindicatorofriskthantheearlierCHADS2score9.
Patients at low risk:Patientsaged<65years(bothwomenandmen)withloneAFandnoothermajorriskfactors:No antithrombotic therapy is usually the preferred option.
One or more risk factors:anticoagulation with warfarin is the preferred first option in men and in women aged ≥ 65 years or women score ≥ 2
Neworalanticoagulantsareanoptionifwarfarinisunabletobeused.
AspirinorclopidogrelareonlyrecommendedifthepatientisathighCVDriskandanticoagulantscannotbeused.
CHADS2 Risk Factor CHA2DS2-VASc
1
Congestive heart failure/LV dysfunction
1
1 Hypertension 1
1 Age ≥75 y 2
1 Diabetes mellitus
1
2 Stroke/TIA/embolism
2
IHD, peripheral artery disease
1
Age 65–74 y 1Female* 1
*Female = 0 if under 65 yrs no other risks
Calculating CHA2DS2-VASc
ForpatientswithAF,tocalculatethescoresimplysumeachpoint.Forexample,a67-year-oldwomanwithdiabetesandhypertensionhasascoreof:Age=1,Female=1,Diabetes=1,Hypertension=1TotalScore=4.EMIScalculatesthisautomaticallyNB. Women under 65 no risks = 0, F ≥ 65 yrs = 2
Risk of stroke and CHA2DS2-VASc 9,10
CHA2DS2-VASc re
Stroke 1 yr
/100
Stroke 5 yrs
/100 0 0.9 4.5 1 2.2 5.5 2 2.2 12.0 3 6.3 17.0 4 7.8 21.0 5 8.4 19.0
Review of AF
ThereviewofpatientswithAFnotonanticoagulantsshouldincludethebenefits,risks,andcontinuingneedforantithrombotictherapy.
•Assessstrokeriskandbleedingriskbeforestartinganticoagulation.
•DespiteanticoagulationofmoreelderlypatientswithAF,ratesofintracerebralhaemorrhageareconsiderablylowerthaninthepast,typically1to5/1000pa.IntracranialbleedingincreaseswithINRvalues3.5–4.0ormore.ThereisnoincreaseinriskwithINRvalues2.0-3.0comparedwithlowerINRlevels.
•Aspirinhasasimilarmajorbleedingrisktowarfarininelderlypeople.
•Concernaboutfallsmaybeoverestimated,asapatientmayneedtofall300timesperyearfortheriskofintracranialhaemorrhagetooutweighthebenefitoforalanticoagulantsinstrokeprevention6.
9. Lip GYH. J of Thrombosis and Haemostasis 2011; 9 (Suppl.1):344-351
10. Larsen et al. Added predictive ability of CHA2DS2-VASc risk score for stroke and death in patients with atrial fibrillation. Circulation 2012;5.Doi:10.11.61
10 IMPROVING ANTICOAGULATION
Bleeding and HAS-BLED
Anewbleedingriskscore,HAS-BLED(hypertension,abnormalrenal/liverfunction,stroke,bleedinghistory,labileINR,elderly(>65),drugs/alcoholconcomitantly),hasbeenvalidated.
Ascoreof≥3indicates‘highrisk’,andregularreviewadvisedwhetheronanticoagulantoraspirin.
Risk Factor Score
H Hypertension(≥160mmHg)
1
A Abnormalrenalandliverfunction1pointeach
1 or 2
S Stroke(haemorrhagicorischaemic)
1
B Bleeding 1 L LabileINRs 1 E Elderlyage≥65years 1 D Drugsoralcohol
1pointeach1 or 2
Max 9 pts
•Hypertension’isdefinedassystolicbloodpressure160mmHgormore.
•‘Abnormalkidneyfunction’=renaldialysis,renaltransplantationorserumcreatinine≥200mmol/L.
•‘Abnormalliverfunction’=chronichepaticdisease(e.g.cirrhosis)orbiochemicalevidence(e.g.bilirubin2xupperlimitofnormal,inassociationwithAST/ALT3xupperlimitnormal)
•‘Bleeding’referstopreviousbleedinghistoryand/orpredispositiontobleeding,e.g.bleedingdiathesis,anaemia,
•‘LabileINRs’referstounstable/highINRsorpoortimeintherapeuticrange(e.g.<60%)
•Drugs/alcoholusereferstoconcomitantuseofdrugs,suchasantiplateletagents,non-steroidalanti-inflammatorydrugs,oralcoholexcess,etc.
Perioperative anticoagulation
Localpoliciesshouldbefollowed.PatientswithAFwhoareanticoagulatedrequiretemporaryinterruptionoftreatmentbeforemostbutnotalltypesofsurgery.ManysurgeonsrequireanINR≤1.5beforeundertakingsurgery.Ifwarfarinisused,(half-lifeof36–42hrs),treatmentshouldbeinterrupted3-5daysbeforesurgerytoallowtheINRtofallappropriately.Warfarinshouldberesumedatthe‘usual’maintenancedose(withoutaloadingdose)ontheeveningof(orthemorningafter)surgerydependingonbleedingrisk.Subcutaneouslowmolecularweightheparinisoftenusedasabridgingtherapyinpeopleundergoingoperativecareorawaitingoralanticoagulation.
ForpatientsonNOAC’swhorequiresurgery,experienceislimitedatpresentandspecialistadviceshouldbesoughtinadvance
Community anticoagulant monitoring
ProgrammesforpracticebasednearpatienttestingforINRhavebeensuccessfullyestablishedinmanyCCGs,coveringupto60%ofthosewithAFrequiringwarfarinmonitoring.TheseclinicsarelargelyGPpracticebasedinsomeCCGs,andamixtureofpharmacyandGPbasedinothers.Intrialstheseprogrammeswereassociatedwithsimilarlevelsoftimeintherapeuticrangeandhadhigherlevelsofpatientsatisfaction,betteraccessibilityandsubstantiallylowerpatientcoststhancentrallyrunhospitalbasedschemes.
Thereareasmallnumberofpatientswhoeitherself-testtheirownINRsusingapurchasedpoint-of-caredeviceanddoseadjustwithadvicefromtheirlocalanticoagulantserviceorself-manage,ie.doboththeirownINRtestingandwarfarindoseadjustment.Thesepatientsshouldbelinkedtoalocalanticoagulantserviceforcontinuingclinicalreviewandforexternalqualitycontrolpurposes.
IMPROVING ANTICOAGULATION 11
New oral anticoagulants: apixaban, dabigatran and rivaroxaban
Incomparativetrialsthesenewdrugswereatleastaseffectiveaswarfarininreducingstroke.Theoverallriskofmajorbleedingdidnotdiffersignificantlybetweenwarfarin,dabigatranandrivaroxabanbutoverallbleedingwasreducedwithapixaban.NOACsreducedintracerebralhaemorrhageincomparisontowarfarin.
IntrialsNOACshavefewerdruginteractionsbutthereareneverthelesssomeimportantdruginteractionsandexperienceinwideruseislimited.NOACshavetheadvantagethattheydonotrequirebloodtestsformonitoring.However,fewervisitsmaymeanlessadherence–evenintrialsabout20%ofpatientsdiscontinuedeitherNOACorwarfarin.
NOAC indications
NICEguidanceconsidersthechoiceofwarfarinorNOACforanticoagulatiuonshouldbemadeafteraninformeddiscussionwiththepatintaboutrisksandbenefitsinrelationtothepatientsclinicalfeatures,patientpreferencesorfactorsthatmayinfluencetheirabilitytomonitortreatmentorsustainconcordancewithtreatment.
NOACsareappropriateforpatientswhoareunable:
•totakewarfarinduetocontraindications.
•toadheretothemonitoringrequirementsassociatedwithwarfarintherapy.
•toachieveanINRinthetargettherapeuticrangedespiteadherencetotreatment.TTR<65%.
(It is doubtful whether NOAC have advantages in people who are not adherent to treatment).
11.ConnollySJ,EzekowitzMD,YusufS,etal.Dabigatranversuswarfarininpatientswithatrialfibrillation.NEJM2009;361:1139-51.
12.PatelMR,MahaffeyKW,GargJ,etal.Rivaroxabanversuswarfarininnonvalvularatrialfibrillation.NEJM2011;365:883-91
NOAC evidence
TrialswithdabigatranandrivaroxabanselectedpeopleinAFathighriskofastroke(typicallyCHADS≥2).
WithallthreeNOACstherewerefewerintracranialhaemorrhages.
Forstrokereduction,rivaroxabananddabigatran110mgwereshowntobenon-inferiortowarfarin.Dabigatran150mgBDandapixaban5mgBDbothshowedasignificantreductionintheprimaryoutcome;strokeandsystemicembolism.
IntheRELY11trialwithdabigatran,therewasnodifferenceintherateofmajorbleedingwiththe150mgBDdose,whereasthe110mgBDdoseshowedsuperiorityoverwarfarinformajorbleeding.Bothdosesdemonstratedahigherincidenceofmajorgastrointestinalbleedingthanwarfarin.
Warfarinwasmoreeffectivethandabigatraninreducingmyocardialinfarctionanddabigatranisnotadvisedinpeoplewithischaemicheartdisease.RivaroxabanandapixabanshowednosignificantdifferenceinMIreduction.
IntheROCKET12trialwithrivaroxabantherewasnosignificantdifferenceinmajorbleeding,fewerfatalbleedsbutmoremajorgastrointestinalbleeding.
IntheARISTOTLE13trial,apixabanwasassociatedwithfewermajorbleeds,butmoregastrointestinalbleedsthanwarfarin.
Dyspepsia:wasmorecommonwithdabigatran150mgthanwarfarinbutwasnotlistedasanadverseeventwithrivaroxabanorapixaban.Drugswerediscontinuedin~20%ofpatientsat2yrs–similartothosestoppingwarfarin.PPIsmaybenecessaryfordyspepsia.
Totalmortalitywasreducedwithapixaban;3.52%peryearcomparedto3.94%peryearinthewarfaringroup(95%CI0.80–0.99,P=0.047).Non-significantreductionintotalmortalitywasfoundwithdabigatran150mgandrivaroxaban20mg.
13.Apixabanversuswarfarininpatientswithatrialfibrillation.GrangerCB,AlexanderJH,McMurrayJJ,etal.NEJM2011;365:981-92.
12 IMPROVING ANTICOAGULATION
NOAC evidence contd.
167peoplewouldneedtobetreatedwithapixabanand86withdabigatranratherthanwarfarinfor2yearstoavertonestroke.
Thecostofayear’streatmentwithanyofthethreenewagentsissimilarat£730-£780peryear.Thecostofwarfarinplusmonitoringis~£400.
Comparedtonotreatment,NOACarecost-effectivebutinpeopleonwarfarinwithgoodINRcontroltheyarenotcosteffectiveatcurrentprices14.However,inpeoplewithpoorINRcontroldespiteadherence,whoareathighriskofstroke(CHADS2≥3)NOACarelikelytobecost-effective.
Meta-analysisofallmajorNOACtrialsincomparisonwithwarfarinconfirmssignificantreductionsinstroke,intracranialhaemorrhage,andmortality,butincreasedgastrointestinalbleeding15.
Reversing anticoagulation
ThemajorconcernwithNOACsistheinabilitytorapidlyreverseamajorbleed.Theeffectsofwarfarincanberapidlyandeasilyreversed.However,thisisnotthecasewithNOACswhichhaveahalf-lifeof13-17hrsinolderpatients.
Thisisofconcerntohaematologistswhoregularlymanagebleedsinanticoagulatedpatientsandexperienceinacutesituationsislimited.Warfarinisthecommonestreasonforhospitaladmissionforadversedrugevents–almostentirelybleeding.
Thatbloodmonitoringisnotneededisanadvantage.However,inrealworldsettingstheabsenceofconstantremindersmayresultinlesssatisfactoryadherenceunlessregularreviewsareundertaken.Inwellcontrolledindividuals,monitoringwarfarin3monthlyisasgoodasmorefrequenttestingwhichfurtherreducestheadvantageofNOACinthisgroup.
14. MHRA guidance, dabigatran October 2011.15. Ruff CT, Giugliano RP, Braunwald E. Compar ison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation:a meta-analysis of randomised trials.Lancet 2014;383:955-62.
Renal function
SomeuncertaintyremainsoverdosageofNOACsinrenaldisease,thefrailelderlyorwithdrugssuchasamiodarone.PeoplewithpoorrenalfunctionshouldbeassessedusingtheCockcroft-Gaultestimateofrenalfunction.TheeGFRtendstogivehighervalues(atlowlevelsoffunction)andthusmayunderestimatetheextentofimpairedrenalfunction.IfeGFRisusedthenpatientswithpoorrenalfunctionmayreceiveaninapproriatelyhighdose.NOACsarenotrecommendedinpatientswithsevererenalorliverdiseaseandusewithamiodarone,azolessuchasketoconazole,quinidine,verapamilandrifampicinshouldbeavoided.
CumbriaNHShaveanexcellentwebsiteonNOACswww.cumbria.nhs.uk/ProfessionalZone/MedicinesManagement/Guidelines/Prescribing-Guidance-for-NOACs.pdf
MHRAguidanceadvisesassessmentofrenalfunctioninallpatientsstartingNOACswhenpoorrenalfunctionissuspectedandatleastannuallyinpatientsolderthan75orthosewithrenalimpairment.
TheCockcroftGaultcalculatorisavailableonthewebathttp://www.nuh.nhs.uk/nch/antibiotics/Renal%20impairment/clcrcalc.asp
New atrial devices
InembolusassociatedwithAF,theoriginin90%istheleftatrialappendage.Newdevicestoclosetheappendageareimplantedpercutaneouslyundergeneralanaesthetic.Inlargerandomisedtrialstheyhavebeenshowntoprovidesimilarefficacytowarfarinforstrokeprevention16.Theproceduredoeshaveanoperativeriskandthetechnologyhasonlybeenproveninonestudy.ThesedevicesarethereforerecommendedforpatientsathighriskofstrokeandwhoareunabletotakewarfarinorNOACs,specificallybecauseofhighriskofbleeding.
16. Holmes DR, et al. Lancet. 2009 374:534-42
IMPROVING ANTICOAGULATION 13
Warfarin start or switchCCGsandprescribingadvisorshavedetailedguidanceonstartingorswitchingtowarfarinandavarietyofwaysofmonitoringINRandclinicallyreviewingthepatient.
AsNOACsarerecentintroductionswehavesummarisedbelowthestepsfortheirinitiationandmonitoring
Starting NOAC or switching from antiplatelet or warfarin to NOAC Whenstartingorswitchingdiscussreasonsforthenewdrugwiththepatientandtherisksandbenefits.
•CheckALT&renalfunction•NOACdosebasedonage,weightandrenalfunction•Reviewmedicationsforpotentialinteractions•Wherepatienthasheartvalve,stentorothercardiacprocedureseekcardiologistadviceGivepatientprescriptionsopharmacistcanarrangesupply.
If switching from aspirin/clopidogrel, discontinue for 24 hours, then start the NOAC.
If switching from warfarin discontinue for 2 days, then start NOAC.
•ContactanticoagulantclinicandgetthemreadytocheckINRpriortochangeand2daysafterstoppingwarfarin.•ForapixabananddabigatrancommenceNOACifINR<2;forrivaroxabancommenceifINR<3•Give the patient an alert card and patient informa- tion leaflet for the NOAC. •Ensurepatient/carerssendremainingwarfarintopharmacy.•Ensurerecallfornextandannualreviewisontheclinicalsystem.CCGsmaydifferinwaysofmonitor-ingandsupportforadherencetoNOACs.
Patient advice on new anticoagulant
• Indication and duration of treatment
• Changed circumstanceWhattodoifnewdiagnosis,majorsurgery,immobilityorbleedingrisk.
• Compliance.Askpatienttobringmedicationtocheckremainingdoses.Emphasiseneedtoavoidmissingdosesasshorterhalf-lifethanwarfarin.Dosettebox;Smartphonereminderaids.
• Missed doses - see below
• Bleeding. Thisisthecommonestadverseeffectofanticoagulants.‘Nuisance’bleedingpreventivemeasurespossible?(cf.haemorrhoidectomy).
• Doesbleedingimpactonqualityoflife–?revisedose.Considerbleedingversusstrokerisk(CHA2DS2-VASc).CheckHb.
• When to seek medical attention.SymptomsTIA,stroke,pulmonaryembolism.Bleeding.
• Other side effects.Nauseaandgastrointestinalsideeffectsarerelativelycommon.RelationtoNOAC/warfarin–alternativeanticoagulant?
• Interacting medications? OTCmedicationorNSAID?
• Dental treatment or surgery arrangements.
Annually checkHb,renalfunctionandALT.6 monthlyifCrCl<60ml/min,age75yrs+ormultipleco-morbidityand3 monthly ifCrCl<30ml/min.
Alert cardMakesurepatientstillhasandcarriesalertcard.
Missed doses Dabigatranandapixabanaretakentwiceaday.Ifmissed,takeitassoonasrememberedbutomitdoseiflessthan6hourstothenextdose.Donottakeadoubledosetomakeupformisseddoses.
Rivaroxabanisoncedaily.Ifmissedtakeitassoonasremembered.Donottakemorethanonetabletinasingledaytomakeupforamisseddose.Carryononcedailyasusualthefollowingday.
CCGs currently recommend initiating anticoagulation in specialist clinics
14 IMPROVING ANTICOAGULATION
Alert cards
PatientalertcardsfortheindividualNOACsareavail-abletoorderinthefollowingway:
Rivaroxaban(Xarelto®)(Bayerplc)ContacttheMedicinesInformationDepartmentTel:01895523740
Dabigatran(Pradaxa®)BoehringerIngelheimLtd)Orderdirectlyfromwebsite:http://www.pradaxa.co.uk/hcp/spaf/education-al-pack-uk.php
Apixaban(Eliquis®)(Bristol-MyersSquibb-Pfizer)ContacttheMedicinesInformationDepartmentTel:01895523740
NHS Medicines management guidance
Moredetailedguidnceonwafarinandnewanti-coagulantsisavaialablefromtheNHSmedicinesmanagementwebsitesinthelocalareas.
NorthCentralhttp://ncl-jfc.org.uk/noac-prescrib-ing-guides.html
SimilarguidanceisavailablefromtheNELondonMedicineManagamentsGroup.
blizard.qmul.ac.uk/ceg-resource-library.html
Centre for Primary Care and Public HealthBarts and The London School of Medicine and DentistryYvonne Carter Building58 Turner StreetLondon E1 2ABTel: 020 7882 2553 Fax: 020 7882 2522email: [email protected]: blizard.qmul.ac.uk/ceg-resource-library.html