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ATRIALFIBRILLATION:ALondonapproach

•  Whyischangenecessary?•  Whatwillchangeachieve?•  Howwillchangebedelivered?

So:risAntoniou,ConsultantPharmacist,CardiovascularOnbehalfofPanLondonPrimaryCareAFImprovementProgramme12thDec2017

Aims

•  Describethekeypriori<esofPanLondonAFprogramme•  RelatetheperformanceofCity&HackneytoPanLondonAFprogramme

•  Listthekeyperformanceindicatorsset•  Describeanddifferen<atethepharmacologicalac<onsof

availableoralan<coagulants•  Listtheopportuni<esforyoutoimprovethemanagementofpeoplewithatrialfibrilla<onaspartofDETECT,PROTECTandPERFECTadherencetoimproveoutcomes

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AtrialFibrilla<on

Abriefintroduc<on

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TheImpactofAFonStrokeOutcomes

�  SurvivalispoorerandstrokerecurrenceratesarehigherfollowingAF-relatedstroke

AF=atrialfibrillation;OR=oddsratio;CI=confidenceinterval1.LinHJ,etal.Stroke1996;27:1760–4;2.DulliDA,etal.Neuroepidemiology2003;22:118–23

AF patients (n=30)

Non-AF patients (n=120)

1-year post stroke recurrence 23% 8%

30-day post stroke mortality 30% 17%

1-year post stroke mortality 63% 34%

Framingham(10-yearfollowupfrom1981)

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HartRGetal.AnnInternMed.2007;146:857-867

Study Year AFASAK I 1989; 1990 SPAF I 1991 EAFT 1993 ESPS II 1997 LASAF 1997

Daily Alternate day

UK-TIA 300 mg daily 1200 mg daily

1999

JAST 2006

Aspirin trials (n=7)

Antiplatelet agents cf placebo/control Relative Risk Reduction (95% CI)

Favors Antiplatelet Favors Placebo or Control

100% 50% 0 -50% -100%

EfficacyofAspirinComparedWithPlacebo

Randomeffectsmodel;Errorbars=95%CI;*p>0.2forhomogeneity; †RelaFveriskreducFon(RRR)forallstrokes(ischaemicandhaemorrhagic)HartRGetal.AnnInternMed2007;146:857–67.

Warfarinbe]er Placebobe]er

RRR(%)†100 –100 50 0 –50

AFASAK

SPAF

BAATAF

CAFA

SPINAF

EAFT

All trials RRR64%*,ARR2.7%(95%CI:49–74%)

AspirinRRR19%0.7%ARR

EfficacyofWarfarinforStrokeReduc<onComparedWithPlaceboorControlinSixStudies

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So why the poor prescribing rates of anticoagulation?

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Physician Concerns About Warfarin for Stroke Prevention in AF

0

20

40

60

80

Risk of Fall History of GI Bleed

History of Non-CNS Bleed

History of CV Hemorrhage

Risk vs benefit of warfarin §  47% benefit greatly outweigh risk §  34% risk slightly outweigh benefit §  19% risk outweigh benefit

Perc

ent

MoneSeetal.JAmGeriatrSoc.1997;45:1060-1065.

Pa:entConcernsAboutAF

0

25

50

75

100

Stroke Death Major Bleeding

Inconvenience Minor Side Effects Cost

Man-Son-Hing et al. Arch Intern Med. 1996;156:1841-1848.

Perce

nt

91%

38%

13% 9% 2% 5%

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CowanC,etalHeart2013;0:1-7

Older AF patients less likely to get warfarin

Falls–whatistherisk?

• Markov decision analytic model was used to determine the preferred treatment strategy in patients > 65 yrs/old

•  Patients need to fall >295 times per year for risk to outweigh benefit

• Mean number of falls / year of elderly people who fall: 1.8

Man-Son-HingetalArchInternMed.1999;159:677-685

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From: Risk of Thromboembolism, Recurrent Hemorrhage, and Death After Warfarin Therapy Interruption for Gastrointestinal Tract BleedingArch Intern Med. 2012;172(19):1484-1491. doi:10.1001/archinternmed.2012.4261

Figure. Time-to-outcome analysis according to resuming warfarin therapy status. A, Thrombosis (P = .002, log-rank test); B, recurrent gastrointestinal tract bleeding (GIB) (P = .10, log-rank test); C, death (P < .001, log-rank test); and D, death including only patients who died at least 7 days after the index GIB (P < .001, log-rank test).

Birmingham Atrial Fibrillation Treatment of the Aged

•  2001-2004;260GPsinEnglandandWales•  973pts≥75years(81.5±4.2)•  72%CHADS2≤2•  40%onwarfarin,42%onaspirin•  Warfarin(targetINR2–3)oraspirin(75mgper

day)•  10endpoint-fatalordisablingstroke(ischaemic

orhaemo-rrhagic),otherintracranialhaemorrhage,orclinicallysignificantarterialembolism

BAFTA:

RR=0.48(0.28–0.80)p=0.0027

0 1 2 3 4 5 6

Aspirin Warfarin

Years after randomization

Even

t fre

e su

rviv

al

100

75

50

25

0

Mant J, et al. Lancet 2007;370:493-503

24 (1.8%)

48 (3.8%)

Intra-cranial haemorrhage on W vs A: 0.5% vs 0.4% (RR 1.15, 0.29 – 4.77, n.s.)

Extra-cranial haemorrhage: 1.4% vs 1.6% (RR 0.87, 043 – 1.73, n.s.)

INR > 3.0 14% of the time

Stroke: 0.8% vs 1.8% RR = 0.30 (0.13-0.63) p = 0.0004

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Riskstra<fica<on

Think of a patient……. (1)

� 87yearoldmale� Irregularpulse AFconfirmed

onECG� RelevantPMH

� Hypertension

� Howdoweknowifheisatrisk....?

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CHADS2 criteria Score

Congestive heart failure 1

Hypertension 1

Age >75 yrs 1

Diabetes mellitus 1

Stroke / transient ischaemic attack

2

1 Gage BF et al. JAMA 2001;285:2864–70. 2 Based on data from Gage BF et al. JAMA 2001;285:2864–70.

0

4

8

12

16

20

0 1 2 3 4 5 6

CHADS2 score

Adjusted stroke risk

NRA

F a

dju

ste

d s

tro

ke ra

te

pe

r 100

pa

tient

ye

ars

, with

out

asp

irin

Score 0-1 low risk - use aspirin Score ≥2 moderate risk – consider warfarin

HowdoIrisk-assessAFpa<entssimply?StrokeriskassessmentwithCHADS2

StrokeriskassessmentwithCHA2DS2-VAScCHA2DS2-VASc criteria Score Congestive heart failure/ left ventricular dysfunction

1

Hypertension 1 Age ≥75 yrs 2 Diabetes mellitus 1 Stroke/transient ischaemic attack/TE 2

Vascular disease (prior myocardial infarction, peripheral artery disease or aortic plaque)

1

Age 65–74 yrs 1 Sex category (i.e. female gender)

1

CHA2DS2-VASc total score

Rate of stroke/other TE (%/year)*

0 0.0

1 1.3

2 2.2

3 3.2

4 4.0

5 6.7

6 9.8

7 9.6

8 6.7

9 15.2

*Theore:calrateswithouttherapy:assumingthatwarfarinprovidesa64%rela:vereduc:onin TErisk(2.7%ARR),basedonHartetal.

1LipGYHetal.Stroke2010;41:2731–2738.2HartRGetal.AnnInternMed2007;146:857–67.

TE=thromboembolism

PeoplewithCHADS2risk0or1canhaveaCHA2DS2-VASc=3

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For our patient……

87yearoldmanwithhypertension

An<coagulate!

Think of a patient….. (2)

� 66yearoldBri<shwoman,newlyregisteredpa<entü  AF(2009)onwarfarinü  Hypertension

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Refining risk assessment

So,whattodohere?

An<coagulate!

•  AF is a major risk factor for stroke (five-fold increased risk).

•  AF is a contributing factor in 1 in 5 strokes. o  More severe o  Higher mortality o  More likely to require long-term nursing care

•  Treatment with anticoagulation reduces the risk of AF-related stroke by approximately two-thirds.

BUT

Only 69% of high risk AF patients are anticoagulated (QOF 2013/14).

Only 41% of patients known to have AF presenting with a new stroke are anticoagulated (SSNAP 2014/15).

Atrialfibrilla:onandstrokeNa:onalperspec:ve

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TopreventAF-relatedstrokeandassociatedmortalitythroughbe]eriden<fica<onandmanagementofpeoplewithatrialfibrilla<on

VisionforLondon

Increasingan<coagula<onofuntreatedhighriskAFpa<ents

Improvingthequalityofan<coagula<on

Increasingthedetec<onofundiagnosedAFinhighriskpa<ents

MeasurableOutcomes

AGREEDAFQUALITYSTANDARDS•  Propor<onofpa<entswithaCHA2DS2VAScscore≥2onan<coagula<ontreatment:aim>80%(noexcep<ons)•  Propor<onofpa<entswithaCHA2DS2VAScscore≥2onan<-platelettreatment:aim<10%(noexcep<ons)•  Propor<onofpa<entstakingwarfarinwithaTTR<65%whohavetheiran<coagula<onqualityreassessedatleast

onceeverysixmonths–aim=100%

•  Propor<onofpa<entsover65whohaveapulsecheck(manualorothertechnology)over5years–aim>90%

SYSTEMLEVELIMPACTMEASUREMENT•  Numbersofpa<entswhodiedasaconsequenceofastroke

•  NumberofAF-relatedstrokeepisodes

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•  Detecto  Awarenesscampaignso  PulseCheckso  Detec<ondevices

•  Protecto  Increasean<coagula<on(decreaseaspirin)o  Ini<atean<coagula<oninprimarycareo  (heartrateandrhythmcontrol)

•  Perfecto  An<coagula<onqualityo  Self-monitoringandmanagemento  OACsadherence

WhatdoesthismeanforCity&HackneyCCG?

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366

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Protect%Ratesofan:coagula:oninhighriskAFpa:ents(CHADSVASc>1)andnumberofuntreatedhighriskpa:entswithinCity&HackneyCCG(QoF2016/17)

Howcanweimprovean<coagula<on?

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Na<onalIns<tuteofHealthCareExcellence(NICE)ClinicalGuideline180.Atrialfibrilla<on:themanagementofatrialfibrilla<on.June2014;Na<onalIns<tuteofHealthCareExcellence(NICE)ClinicalGuideline180.Atrialfibrilla<on:themanagementofatrialfibrilla<on–methods,evidenceandrecommenda<ons.June2014

Poorcontrol

Lowrisk

Assessbleedingriskstra<fica<onusingHAS-BLED

Discussrisksandbenefitsofan<coagula<on

Iden<fylowriskpa<entsi.e.CHA2DS2-VASc=0(men)or1(women)

CHA2DS2-VASc=1(inmen)Consideroralan<coagulant

CHA2DS2-VASc≥2Offeroralan<coagulant

Discusstheop<onsforan<coagula<onwiththepersonandbasethechoiceontheirclinicalfeaturesandpreferences

VitaminKantagonist(VKA) Non-VKAoralan<coagulant(NOAC)(dabigatran,apixaban,rivaroxaban)

Peoplewhochoosenottohavetreatment

Noan<-thrombo<ctherapy

Lesatrialappendageocclusion

Assessan<coagula<oncontrolNon-VKAoralan<coagulant(NOAC)(dabigatran,apixaban,rivaroxaban)

Annualreviewforallpa<ents

Non-VKAcontraindicatedor

nottolerated

An<coagula<oncontraindicated

Assessstrokeriskstra<fica<onusingCHA2DS2-VASc

2014NICEAFguidelineforstrokepreven<on:firstupdatesince2006

Warfarin § Most commonly used anticoagulant

worldwide § Highly effective oral anticoagulant §  But it has its limitations….

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Warfarinanditschallengingtherapeu:cwindow

ACC/AHA/ESCguidelines:FusterVetal.CirculaFon2006;114:e257–e354.

1Interna:onalnormalizedra:o(INR)

Odd

sra:

o

2

15

8

10

5

01

3 4 5 6 7

Intracranialbleed

Therapeu:crange

20Requiresdoseadjustmentandregularmonitoring

Ischaemicstroke

Why<meintherapeu<crange(TTR)ma]ers

0 500 1000 1500

Survivaltostroke(days)

0.6

0.7

0.8

0.9

1.0

Cumula:

vesu

rvival 71–100%

Warfaringroup

61–70%51–60%41–50%31–40%<30%Nonwarfarin

MorganCLetal.ThrombosisResearch2009;124:37–41.

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NICE Guideline for AF (June 2014)

•  ReviewTTRateachvisit(exclude1st6weeksandmustbeoveraperiodof≥6/12):–  Reassessifoverthepast6months

•  x2INRs>5orx1INR>8orx2INRs<1.5•  TTR<65%

•  Trytocorrectandtakeintoaccountreasonsforpoorcontrol:–  Cogni<vefunc<on–  Adherence–  Illness–  Interac<ngdrugRx–  LifestyleincdietandEtOH

•  Ifcannotbeimprovedconsiderotherstrategies

Featuresofnoveloralan<coagulants

*Ofabsorbedsubstance;#OfgivensubstanceBCRP=breastcancerresistanceprotein;CYP=cytochromeP450;P-gp=P-glycoprotein1.Erikssonetal.ClinPharmacokinet2009;48:1–22;2.Xarelto[packageinsert].Titusville,NJ:JanssenPharmaceu<cals,Inc.;2011;3.ELIQUISSummaryofProductCharacteris<cs.BristolMyersSquibb/PfizerEEIG,UK;4.Ruffetal.HotTopicsinCardiology2009;18:1–32;5.Matsushimaetal.ClinPharmacolDrugDev2013;2:358–366;6.Matsushimaetal.AmAssocPharmSci2011;abstract;7.Ogataetal.JClinPharmacol2010;50:743–753;8.EdoxabanSummaryofProductCharacteris<cs(SmPC)2015;9.Gonzalez-Quesada&Giugliano.AmJCardiovascDrugs2014;14:111–127

Dabigatran1 Rivaroxaban1,2 Apixaban1,3 Edoxaban4-9

Target IIa(thrombin) Xa Xa Xa

HourstoCmax 1.25–3 2–4 3–4 1–2

CYPmetabolism None 32% ~25% <10%

Bioavailability 6% 80% 60% 62%

Transporters P-gp P-gp/BCRP P-gp/BCRP P-gp

Proteinbinding 35% 93% 87% 50%

Half-life 14–17h 7–11h 8–15h 10–14h

Renalelimina<on 80%* 33%# 27%# 50%*

Administra<on BD OD BD OD

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PhaseIIIAFtrials:Baselinecharacteris<cs

1.Connollyetal.NEnglJMed2009;361:1139–1151;2.Pateletal.NEnglJMed2011;365:883–891;3.Grangeretal.NEnglJMed2011;365:981–992;4.Giuglianoetal.NEnglJMed2013;369:2093–2104

RE-LY1 ROCKET-AF2 ARISTOTLE3 ENGAGEAF4

Drug Dabigatran Rivaroxaban Apixaban Edoxaban

Enrolled 18,113 14,264 18,201 21,105

Age (yrs) 72 ± 9 73 [65-78] 70 [63-76] 72 [64-77]

Female 36% 40% 35% 38%

CHADS2 score ≥3 32% 87% 30% 52%

VKA naive 50% 38% 43% 41%

Paroxysmal AF 33% 18% 15% 25%

Prior stroke/TIA 20% 55%** 19% 18% / 12%

Diabetes 23% 40% 25% 36%

Prior CHF 32% 62% 35% 56%

Hypertension 79% 91% 87% 90%

**includes prior systemic embolism !!!Directcomparisonsimpossibleduetoselec:onbiasanddifferencesindesign!!!

Rela<verisk(95%CI) NOACevents WarfarineventsStudyRela<verisk(95%CI)

RE-LY(dabigatran)* 0.66(0.53–0.82)P=0.0001 134/6,076 199/6,022

ROCKETAF(rivaroxaban)† 0.88(0.75–1.03)P=0.12 269/7,081 306/7,090

ARISTOTLE(apixaban)‡ 0.80(0.67–0.95)P=0.012 212/9,120 265/9,081

ENGAGEAF-TIMI48(edoxaban)§ 0.88(0.75–1.02)P=0.10 296/7,035 337/7,036

Combined# 0.81(0.73–0.91)P<0.0001 911/29,312 1107/29,229

Compara<veefficacyofNOACsandwarfarin:Strokeorsystemicembolicevents

Datafromtheintent-to-treatpopula<on*Dabigatran150mgtwice-daily;†rivaroxaban20mgonce-daily;‡apixaban5mgtwice-daily;§Edoxaban60mgonce-dailyregimen(includespa<ent-specificdosereduc<ontoedoxaban30mgonce-daily)CI=confidenceinterval;NOAC=non-vitaminKantagonistan<coagulantRuffCTetal.Lancet2014;383:955–962

0.5 1.0 1.5

FavoursNOAC Favourswarfarin

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Secondaryefficacyoutcomes:PooledNOACsversuspooledwarfarin

Treatmentarmsanalysed:Dabigatran150mgtwice-daily;rivaroxaban20mgonce-daily;apixaban5mgtwice-daily;edoxaban60mgonce-dailyregimen(includespa<ent-specificdosereduc<ontoedoxaban30mgonce-daily)CI=confidenceinterval;NOAC=non-vitaminKantagonistan<coagulantRuffCTetal.Lancet2014;383:955–962

Rela<verisk(95%CI) NOACevents WarfarineventsOutcomeRela<verisk(95%CI)

Ischaemicstroke 0.92(0.83–1.02)P=0.10 665/29,292 724/29,221

Haemorrhagicstroke

0.49(0.38–0.64)P<0.0001 130/29,292 263/29,221

Myocardialinfarc<on

0.97(0.78–1.20)P=0.77 413/29,292 432/29,221

All-causemortality 0.90(0.85–0.95)P=0.0003 2,022/29,292 2245/29,221

0.5 1.0 1.5

FavoursNOAC Favourswarfarin

Rela<verisk(95%CI)NOACevents WarfarineventsOutcome

Rela<verisk(95%CI)

Intracranialhaemorrhage

0.48(0.39–0.59)P<0.0001 204/29,287 425/29,211

Gastrointes<nalbleeding

1.25(1.01–1.55)P=0.043 751/29,287 591/29,211

Secondarysafetyoutcomes:PooledNOACsversuspooledwarfarin

Treatmentarmsanalysed:Dabigatran150mgtwice-daily;rivaroxaban20mgonce-daily;apixaban5mgtwice-daily;edoxaban60mgonce-dailyregimen(includespa<ent-specificdosereduc<ontoedoxaban30mgonce-daily)CI=confidenceinterval;NOAC=non-vitaminKantagonistan<coagulantRuffCTetal.Lancet2014;383:955–962

0.0 1.0 2.01.50.5

FavoursNOAC Favourswarfarin

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<15ml/min

Notrecommended

Pa<enthasriskfactorforstroke

Es<mateCrCl

15–49ml/min*

15mgod

≥50ml/min

20mgod

Rivaroxaban

2.5mgbid 2.5mgbid 5mgbid

Apixaban

Pa<enthasriskfactorforstroke

Es<mateCrCl

<15ml/min 15–29ml/min ≥30ml/min

Checkage Checkweight Checkserumcrea<nine

≥80years ≤60kg ≥133µmol/l

If≥2features if≤1features

Notrecommended

EdoxabanPa<enthasriskfactorforstroke

Es<mateCrCl

<15ml/min 15–50ml/min >50ml/min

Notrecommended 30mgod

30mgod 30mgod

60mgod

≤60kg PotentP-gpinhibitors

1.RivaroxabanSmPC;2.ApixabanSmPC;3.DabigatranSmPC;4.EdoxabanSmPC

Pa<enthasriskfactorforstroke

Es<mateCrCl

<30ml/min 30–50ml/min >50ml/min

Age>80years

Age<75years

Age75–80years

Age>80years

Contraindicated

Lowthromboembolicriskandhighbleedingrisk

110mgbid

110mgbid

150mgbid

150mgbid

110mgbid

150mgbid

110mgbid

Dabigatran

Age≥75yearsorhighriskofbleeding

ABCDruleDoseAdjustmentsinNVAF

Maximisingadherence

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NewMedicineService(NMS)

Improveadherence10%

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pharmacist confidence and experience with vitamin K antagonists

HamediN,….AntoniouS.IntJClinPharm2017

PharmacistconfidenceandexperiencewithNon-vitaminKantagonistOralAn<coagulants(NOACs)

HamediN,….AntoniouS.IntJClinPharm2017

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ResourcesaccessedwhenundertakingNMS

Resource Numberofpharmacists

Na:onalBri:shFormulary(BNF) 66%(87/131)

Internet 35%(44/131)

SummaryofProductCharacteris:cs(SPC)and/orPa:entInforma:onLeaflet(PIL)18%(23/131)

An:coagulantresources 10%(13/131)

NewMedicineServiceandorMedicineUseReviewresources 7%(9/131)

Ar:cles 7%(9/131)

Na:onalPharmacyAssocia:onNMSresources 4%(5/131)

StandardOpera:ngProcedureorguidelineonNMS 2%(3/131)

Other 8%(10/131)

HamediN,….AntoniouS.IntJClinPharm2017

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Atrialfibrilla:oninEngland

•  1.4millionpeopleinEnglandarees<matedtohaveAF

(prevalence2.4%)

•  Almost900,000recordedAFcases(prevalence1.6%)

•  Overathirdareundiagnosed888,926

1,363,321

474,395

0

200,000

400,000

600,000

800,000

1,000,000

1,200,000

1,400,000

QOF2013/14 NCVIN UndiagnosedAF

Detect-LondonAFprevalence

0.00

0.20

0.40

0.60

0.80

1.00

1.20

1.40

1.60

1.80

AFprevalence(%)QOF2013/14

Londonaverage=0.92%

England=1.57%

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0.0

0.5

1.0

1.5

2.0

2.5

3.0

ExpectedPrevalence

QOFPrevalence2013/14

AFexpectedvsQOFprevalence2013/14 England2.4vs1.6%

London1.7vs0.9%City&H1.2vs0.6%

NCVIN–AFprevalence,yhpho.org.uk

Detect–Londonshorrall

Whatabouttheroleforpharmacy?

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J

J

DETECT

:Findingm

oreAF

-De

vices

Non12-LeadECG

Smartphoneapplica<on

BloodPressuremonitors

ALIVECOR(Kardia™MobileandKardiaApp)

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ATRIALFIBRILLATION:ALondonapproach

•  Whyischangenecessary?•  Whatwillchangeachieve?•  Howwillchangebedelivered?

So:risAntoniou,ConsultantPharmacist,CardiovascularOnbehalfofPanLondonPrimaryCareAFImprovementProgramme12thDec2017