ATRIAL FIBRILLATION: A London approach

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1 ATRIAL FIBRILLATION: A London approach So:ris Antoniou, Consultant Pharmacist, Cardiovascular Why is change necessary? What will change achieve? How will change be delivered? On behalf of Pan London Primary Care AF Improvement Programme 12 th Dec 2017 Aims Describe the key priori<es of Pan London AF programme Relate the performance of City & Hackney to Pan London AF programme List the key performance indicators set Describe and differen<ate the pharmacological ac<ons of available oral an<coagulants List the opportuni<es for you to improve the management of people with atrial fibrilla<on as part of DETECT, PROTECT and PERFECTadherence to improve outcomes 1

2 Atrial Fibrilla<on A brief introduc<on 2

23% 8% 30-day post stroke mortality 30% 17% 1-year post stroke mortality 63% 34% AF=atrial fibrillation; OR=odds ratio;

3 Survival is poorer and stroke recurrence rates are higher following AF-related stroke Framingham (10-year follow up from 1981) The Impact of AF on Stroke Outcomes 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% AF=atrial fibrillation; OR=odds ratio; CI=confidence interval 1. Lin HJ, et al. Stroke 1996; 27: ; 2. Dulli DA, et al. Neuroepidemiology 2003; 22:

4 Efficacy of Aspirin Compared With Placebo Antiplatelet agents cf placebo/control 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) Relative Risk Reduction (95% CI) 100% 50% 0-50% -100% Favors Antiplatelet Favors Placebo or Control Hart RG et al. Ann Intern Med. 2007;146: Efficacy of Warfarin for Stroke Reduc<on Compared With Placebo or Control in Six Studies Warfarin be]er Placebo be]er AFASAK SPAF BAATAF CAFA SPINAF EAFT All trials RRR 64% *, ARR 2.7% (95% CI: 49 74%) RRR (%) Aspirin RRR 19% 0.7% ARR Hart RG et al. Ann Intern Med 2007;146: Random effects model; Error bars = 95% CI; *p>0.2 for homogeneity; RelaFve risk reducfon (RRR) for all strokes (ischaemic and haemorrhagic) 4

5 So why the poor prescribing rates of anticoagulation? 5

6 Physician Concerns About Warfarin for Stroke Prevention in AF Risk vs benefit of warfarin 47% benefit greatly outweigh risk 34% risk slightly outweigh benefit 19% risk outweigh benefit Percent Risk of Fall History of GI Bleed History of Non-CNS Bleed History of CV Hemorrhage MoneSe et al. J Am Geriatr Soc. 1997;45: Pa:ent Concerns About AF % Percent % % 9% 2% 5% Stroke Death Major Bleeding Minor Side Effects Cost Inconvenience Man-Son-Hing et al. Arch Intern Med. 1996;156:

7 Older AF patients less likely to get warfarin Cowan C, et al Heart 2013;0:1-7 Falls what is the risk? 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-Hing et al Arch Intern Med. 1999;159:

From: Risk of Thromboembolism, Recurrent Hemorrhage, and Death After Warfarin Therapy Interruption for Gastrointestinal Tract Bleeding Arch Intern Med. 2012;172(19):1484-1491. doi:10.

8 From: Risk of Thromboembolism, Recurrent Hemorrhage, and Death After Warfarin Therapy Interruption for Gastrointestinal Tract Bleeding Arch Intern Med. 2012;172(19): doi: /archinternmed 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). BAFTA: Birmingham Atrial Fibrillation Treatment of the Aged ; 260 GPs in England and Wales 973 pts 75 years (81.5 ± 4.2) 72% CHADS % on warfarin, 42% on aspirin Warfarin (target INR 2 3) or aspirin (75 mg per day) 1 0 endpoint - fatal or disabling stroke (ischaemic or haemo-rrhagic), other intracranial haemorrhage, or clinically significant arterial embolism INR > % of the time Mant J, et al. Lancet 2007;370: Event free survival Aspirin Warfarin RR = 0.48 ( ) p = (1.8%) 48 (3.8%) Stroke: 0.8% vs 1.8% RR = 0.30 ( ) p = Years after randomization Intra-cranial haemorrhage on W vs A: 0.5% vs 0.4% (RR 1.15, , n.s.) Extra-cranial haemorrhage: 1.4% vs 1.6% (RR 0.87, , n.s.) 8

9 Risk stra<fica<on Think of a patient. (1) 87 year old male Irregular pulse Relevant PMH Hypertension AF confirmed on ECG How do we know if he is at risk...? 9

10 How do I risk-assess AF pa<ents simply? Stroke risk assessment with CHADS 2 CHADS 2 criteria Score 20 Adjusted stroke risk Congestive heart failure 1 Hypertension 1 Age >75 yrs 1 Diabetes mellitus 1 Stroke / transient ischaemic attack 2 NRAF adjusted stroke rate per 100 patient years, without aspirin Score 0-1 low risk - use aspirin Score 2 moderate risk consider warfarin CHADS 2 score 1 Gage BF et al. JAMA 2001;285: Based on data from Gage BF et al. JAMA 2001;285: Stroke risk assessment with CHA 2 DS 2 -VASc CHA 2 DS 2 -VASc criteria Congestive heart failure/ left ventricular dysfunction Score 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) Age yrs 1 Sex category (i.e. female gender) CHA 2 DS 2 -VASc total score Rate of stroke/other TE (%/year)* People with CHADS2 risk 0 or 1 can have a CHA 2 DS 2 -VASc = * Theore:cal rates without therapy: assuming that warfarin provides a 64% rela:ve reduc:on in TE risk (2.7% ARR), based on Hart et al. TE = thromboembolism 1 Lip GYH et al. Stroke 2010;41: Hart RG et al. Ann Intern Med 2007;146:

11 For our patient An<coagulate! 87 year old man with hypertension Think of a patient.. (2) 66 year old Bri<sh woman, newly registered pa<ent ü AF (2009) on warfarin ü Hypertension 11

Refining risk assessment An<coagulate! So, what to do here?

increased risk). AF is a contributing factor in 1 in 5 strokes.

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

12 Refining risk assessment An<coagulate! So, what to do here? Atrial fibrilla:on and stroke Na:onal perspec:ve 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). 12

13 Vision for London To prevent AF-related stroke and associated mortality through be]er iden<fica<on and management of people with atrial fibrilla<on Increasing an<coagula<on of untreated high risk AF pa<ents Improving the quality of an<coagula<on Increasing the detec<on of undiagnosed AF in high risk pa<ents Measurable Outcomes AGREED AF QUALITY STANDARDS Propor<on of pa<ents with a CHA 2 DS 2 VASc score 2 on an<coagula<on treatment: aim > 80% (no excep<ons) Propor<on of pa<ents with a CHA 2 DS 2 VASc score 2 on an<-platelet treatment: aim < 10% (no excep<ons) Propor<on of pa<ents taking warfarin with a TTR < 65% who have their an<coagula<on quality reassessed at least once every six months aim = 100% Propor<on of pa<ents over 65 who have a pulse check (manual or other technology) over 5 years aim > 90% SYSTEM LEVEL IMPACT MEASUREMENT Numbers of pa<ents who died as a consequence of a stroke Number of AF-related stroke episodes 13

14 What does this mean for City & Hackney CCG? Detect o Awareness campaigns o Pulse Checks o Detec<on devices Protect o Increase an<coagula<on (decrease aspirin) o Ini<ate an<coagula<on in primary care o (heart rate and rhythm control) Perfect o An<coagula<on quality o Self-monitoring and management o OACs adherence

15 Protect % Rates of an:coagula:on in high risk AF pa:ents (CHADSVASc>1) and number of untreated high risk pa:ents within City & Hackney CCG (QoF 2016/17) How can we improve an<coagula<on? 15

2014 NICE AF guideline for stroke preven<on: first update since 2006 Assess stroke risk stra<fica<on using CHA 2 DS 2 -VASc Discuss risks and benefits of an<coagula<on Assess bleeding risk

ple who choose not to have treatment Iden<fy low risk pa<ents i.e. CHA 2 DS 2 -VASc = 0 (men) or 1 (women) Low risk No an<-thrombo<c therapy CHA 2 DS 2 -VASc = 1 (in men) Consider oral an<coagulant

16 2014 NICE AF guideline for stroke preven<on: first update since 2006 Assess stroke risk stra<fica<on using CHA 2 DS 2 -VASc Discuss risks and benefits of an<coagula<on Assess bleeding risk stra<fica<on using HAS-BLED People who choose not to have treatment Iden<fy low risk pa<ents i.e. CHA 2 DS 2 -VASc = 0 (men) or 1 (women) Low risk No an<-thrombo<c therapy CHA 2 DS 2 -VASc = 1 (in men) Consider oral an<coagulant CHA 2 DS 2 -VASc 2 Offer oral an<coagulant An<coagula<on contraindicated Discuss the op<ons for an<coagula<on with the person and base the choice on their clinical features and preferences Vitamin K antagonist (VKA) Assess an<coagula<on control Poor control Non-VKA oral an<coagulant (NOAC) (dabigatran, apixaban, rivaroxaban) Non-VKA oral an<coagulant (NOAC) (dabigatran, apixaban, rivaroxaban) Annual review for all pa<ents Non-VKA contraindicated or not tolerated Les atrial appendage occlusion Na<onal Ins<tute of Health Care Excellence (NICE) Clinical Guideline 180. Atrial fibrilla<on: the management of atrial fibrilla<on. June 2014; Na<onal Ins<tute of Health Care Excellence (NICE) Clinical Guideline 180. Atrial fibrilla<on: the management of atrial fibrilla<on methods, evidence and recommenda<ons. June 2014 Warfarin Most commonly used anticoagulant worldwide Highly effective oral anticoagulant But it has its limitations. 16

17 Warfarin and its challenging therapeu:c window Ischaemic stroke Therapeu:c range Requires dose adjustment and regular monitoring Odds ra:o 10 5 Intracranial bleed ACC/AHA/ESC guidelines: Fuster V et al. CirculaFon 2006;114:e257 e Interna:onal normalized ra:o (INR) 8 Why <me in therapeu<c range (TTR) ma]ers Cumula:ve survival Warfarin group % 61 70% 51 60% 41 50% 31 40% <30% Non warfarin Survival to stroke (days) Morgan CL et al. Thrombosis Research 2009;124:

18 NICE Guideline for AF (June 2014) Review TTR at each visit (exclude 1 st 6 weeks and must be over a period of 6/12): Reassess if over the past 6 months x2 INRs > 5 or x1 INR > 8 or x2 INRs < 1.5 TTR < 65% Try to correct and take into account reasons for poor control: Cogni<ve func<on Adherence Illness Interac<ng drug Rx Lifestyle inc diet and EtOH If cannot be improved consider other strategies Features of novel oral an<coagulants Dabigatran 1 Rivaroxaban 1,2 Apixaban 1,3 Edoxaban 4-9 Target IIa (thrombin) Xa Xa Xa Hours to C max CYP metabolism None 32% ~25% <10% Bioavailability 6% 80% 60% 62% Transporters P-gp P-gp/BCRP P-gp/BCRP P-gp Protein binding 35% 93% 87% 50% Half-life h 7 11 h 8 15 h h Renal elimina<on 80%* 33%# 27%# 50%* Administra<on BD OD BD OD *Of absorbed substance; # Of given substance BCRP=breast cancer resistance protein; CYP=cytochrome P450; P-gp=P-glycoprotein 1. Eriksson et al. Clin Pharmacokinet 2009;48:1 22; 2. Xarelto [package insert]. Titusville, NJ: Janssen Pharmaceu<cals, Inc.; 2011; 3. ELIQUIS Summary of Product Characteris<cs. Bristol Myers Squibb/Pfizer EEIG, UK; 4. Ruff et al. Hot Topics in Cardiology 2009;18:1 32; 5. Matsushima et al. Clin Pharmacol Drug Dev 2013;2: ; 6. Matsushima et al. Am Assoc Pharm Sci 2011; abstract; 7. Ogata et al. J Clin Pharmacol 2010;50: ; 8. Edoxaban Summary of Product Characteris<cs (SmPC) 2015; 9. Gonzalez-Quesada & Giugliano. Am J Cardiovasc Drugs 2014;14:

19 Phase III AF trials: Baseline characteris<cs RE-LY 1 ROCKET-AF 2 ARISTOTLE 3 ENGAGE AF 4 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% CHADS 2 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%!!! Direct comparisons impossible due to selec:on bias and differences in design!!! **includes prior systemic embolism 1. Connolly et al. N Engl J Med 2009;361: ; 2. Patel et al. N Engl J Med 2011;365: ; 3. Granger et al. N Engl J Med 2011;365: ; 4. Giugliano et al. N Engl J Med 2013;369: Study RE-LY (dabigatran)* Compara<ve efficacy of NOACs and warfarin: Stroke or systemic embolic events Rela<ve risk Rela<ve risk (95% CI) (95% CI) NOAC events Warfarin events 0.66 ( ) P= /6, /6,022 ROCKET AF (rivaroxaban) 0.88 ( ) P=0.12 ARISTOTLE (apixaban) 0.80 ( ) P= /7, /7, /9, /9,081 ENGAGE AF-TIMI 48 (edoxaban) 0.88 ( ) P= /7, /7,036 Combined # 0.81 ( ) P< /29, /29, Favours NOAC Favours warfarin Data from the intent-to-treat popula<on *Dabigatran 150 mg twice-daily; rivaroxaban 20 mg once-daily; apixaban 5 mg twice-daily; Edoxaban 60 mg once-daily regimen (includes pa<ent-specific dose reduc<on to edoxaban 30 mg once-daily) CI=confidence interval; NOAC=non-vitamin K antagonist an<coagulant Ruff CT et al. Lancet 2014;383:

20 Secondary efficacy outcomes: Pooled NOACs versus pooled warfarin Outcome Rela<ve risk Rela<ve risk (95% CI) (95% CI) NOAC events Warfarin events Ischaemic stroke Haemorrhagic stroke Myocardial infarc<on All-cause mortality 0.92 ( ) P= ( ) P< ( ) P= ( ) P= /29, /29, /29, /29, /29, /29,221 2,022/29, /29, Favours NOAC Favours warfarin Treatment arms analysed: Dabigatran 150 mg twice-daily; rivaroxaban 20 mg once-daily; apixaban 5 mg twice-daily; edoxaban 60 mg once-daily regimen (includes pa<ent-specific dose reduc<on to edoxaban 30 mg once-daily) CI=confidence interval; NOAC=non-vitamin K antagonist an<coagulant Ruff CT et al. Lancet 2014;383: Secondary safety outcomes: Pooled NOACs versus pooled warfarin Outcome Rela<ve risk (95% CI) Rela<ve risk (95% CI) NOAC events Warfarin events Intracranial haemorrhage Gastrointes<nal bleeding 0.48 ( ) P< ( ) P= /29, /29, /29, /29, Favours NOAC Favours warfarin Treatment arms analysed: Dabigatran 150 mg twice-daily; rivaroxaban 20 mg once-daily; apixaban 5 mg twice-daily; edoxaban 60 mg once-daily regimen (includes pa<ent-specific dose reduc<on to edoxaban 30 mg once-daily) CI=confidence interval; NOAC=non-vitamin K antagonist an<coagulant Ruff CT et al. Lancet 2014;383:

21 Dose Adjustments in NVAF ABCD rule Rivaroxaban Apixaban Pa<ent has risk factor for stroke Pa<ent has risk factor for stroke Es<mate CrCl Es<mate CrCl <15 ml/min ml/min 30 ml/min Check age Check weight Check serum crea<nine <15 ml/min ml/min* 50 ml/min 80 years 60 kg 133 µmol/l If 2 features if 1 features Not recommended 15 mg od 20 mg od Not recommended 2.5 mg bid 2.5 mg bid 5 mg bid Dabigatran Pa<ent has risk factor for stroke Edoxaban Pa<ent has risk factor for stroke Es<mate CrCl <30 ml/min ml/min >50 ml/min Es<mate CrCl Age >80 years Age <75 years Age years Age >80 years <15 ml/min ml/min >50 ml/min Contraindicated Age 75 years or high risk of bleeding Low thromboembolic risk and high bleeding risk Not recommended 30 mg od 60 kg 60 mg od Potent P-gp inhibitors 110 mg bid 110 mg bid 150 mg bid 150 mg bid 110 mg bid 150 mg bid 110 mg bid 30 mg od 30 mg od 1. Rivaroxaban SmPC; 2. Apixaban SmPC; 3. Dabigatran SmPC; 4. Edoxaban SmPC Maximising adherence 21

22 New Medicine Service (NMS) Improve adherence 10% 22

23 pharmacist confidence and experience with vitamin K antagonists Hamedi N,.Antoniou S. Int J Clin Pharm 2017 Pharmacist confidence and experience with Non-vitamin K antagonist Oral An<coagulants (NOACs) Hamedi N,.Antoniou S. Int J Clin Pharm

Resources accessed when undertaking NMS Resource Number of pharmacists Na:onal Bri:sh

(SPC) and/or Pa:ent Informa:on Leaflet (PIL) 18% (23/131) An:coagulant resources 10%

7%(9/131) Na:onal Pharmacy Associa:on NMS resources 4% (5/131) Standard Opera:ng

24 Resources accessed when undertaking NMS Resource Number of pharmacists Na:onal Bri:sh Formulary (BNF) 66% (87/131) Internet 35% (44/131) Summary of Product Characteris:cs (SPC) and/or Pa:ent Informa:on Leaflet (PIL) 18% (23/131) An:coagulant resources 10% (13/131) New Medicine Service and or Medicine Use Review resources 7% (9/131) Ar:cles 7%(9/131) Na:onal Pharmacy Associa:on NMS resources 4% (5/131) Standard Opera:ng Procedure or guideline on NMS 2%(3/131) Other 8%(10/131) Hamedi N,.Antoniou S. Int J Clin Pharm

Atrial fibrilla:on in England 1,400,000 1,200,000 1,000,000 800,000 474,395 1.

4%) 600,000 400,000 200,000 888,926 1,363,321 Almost 900,000 recorded AF cases (prevalence 1.

25 Atrial fibrilla:on in England 1,400,000 1,200,000 1,000, , , million people in England are es<mated to have AF (prevalence 2.4%) 600, , , ,926 1,363,321 Almost 900,000 recorded AF cases (prevalence 1.6%) Over a third are undiagnosed 0 QOF 2013/14 NCVIN Undiagnosed AF Detect - London AF prevalence AF prevalence (%) QOF 2013/14 England = 1.57% London average = 0.92%

Detect London shorrall 3.0 2.5 2.0 City & H 1.2 vs 0.

9 % Expected Prevalence QOF Prevalence 2013/14 England 2.4 vs 1.

26 Detect London shorrall City & H 1.2 vs 0.6 % AF expected vs QOF prevalence 2013/14 London 1.7 vs 0.9 % Expected Prevalence QOF Prevalence 2013/14 England 2.4 vs 1.6% NCVIN AF prevalence, yhpho.org.uk What about the role for pharmacy? 26

27 DETECT: Finding more AF - Devices 13/12/17 Blood Pressure monitors J Non 12Lead ECG Smart phone applica<on J ALIVECOR (Kardia Mobile and Kardia App) 27

28 ATRIAL FIBRILLATION: A London approach So:ris Antoniou, Consultant Pharmacist, Cardiovascular Why is change necessary? What will change achieve? How will change be delivered? On behalf of Pan London Primary Care AF Improvement Programme 12 th Dec

Atrial Fibrilla5on. Aims. A brief introduc5on

Atrial Fibrilla5on. Aims. A brief introduc5on Aims Describe the key priori5es of Pan London AF programme Relate the performance of Barnet to Pan London AF programme List the key performance indicators set Describe and differen5ate the pharmacological