Aims. AF and Stroke risk Guidance re anticoagulation Novel oral anticoagulants (NOACs) in non-valvular AF (NVAF) Practical Issues Patient Case Studies

Aims AF and Stroke risk Guidance re anticoagulation Novel oral anticoagulants (NOACs) in non-valvular AF (NVAF) Practical Issues Patient Case Studies

AF and Stroke AF prevalence approx doubles with each decade (9% at 80-89 years) 1 Stroke prevalence increases nearly 5 fold when AF is present 2 In patients with AF, blood clots tend to form in the atria, particularly within the left atrial appendage These clots may travel to the brain, causing an ischaemic stroke Around 20% of ischaemic strokes are caused by blood clots originating in the heart (cardioembolic); of these, AF is the most common cause 3 1. NICE CG36 Atrial fibrillation 2006 2. Wolf PA et al. Stroke 1991;22:983 988; 3. Paciaroni M et al. Stroke 2007;38:423 430

2-year age-adjusted incidence of stroke/1,000 Patients with AF have approx fivefold increased ischaemic stroke risk 60 50 Framingham Heart Study (N=5,070) Risk ratio=4.8 p<0.001 40 30 20 10 0 Individuals Individuals *Patients were seldom treated with antithrombotic therapy when this study was performed in line with clinical practice at the time without AF with AF* 1. Adapted from Wolf PA et al. Stroke 1991;22:983 988

Risk factors for stroke and thrombo-embolism in non-valvular AF AF= atrial fibrillation; EF = ejection fraction (as documented by echocardiography, radionuclide ventriculography, cardiac catheterization, cardiac magnetic resonance imaging, etc.); LV = left ventricular; TIA = transient ischaemic attack.

CHADS 2 score and stroke rate *The adjusted stroke rate was derived from the multivariable analysis assuming no aspirin usage; these stroke rates are based on data from a cohort of hospitalised AF patients, published in 2001, with low numbers in those with a CHADS 2 score of 5 and 6 to allow an accurate judgement of the risk in these patients. Given that stroke rates are declining overall, actual stroke rates in contemporary non-hospitalised cohorts may also vary from these estimates. Adapted from Gage BF et al. AF = atrial fibrillation; CHADS 2 = cardiac failure, hypertension, age, diabetes, stroke (doubled).

Risk factor-based point-based scoring system - CHA 2 DS 2 -VASc *Prior myocardial infarction, peripheral artery disease, aortic plaque. Actual rates of stroke in contemporary cohorts may vary from these estimates.

Adjusted stroke rate according to CHA 2 DS 2 -VASc score

CHADS 2 score Why use CHA 2 DS 2 -VASc? CHA 2 DS 2 VaSc score % of n Stroke risk per 100pt yrs 0-1 n=47,576 0 15.8% 0.84 (0.65-1.08) 1 21.2% 1.79 (1.53-2.09) 2 30.1% 3.67 (3.34-4) 3 29.8% 5.75 (5.33-6.21) 4 3.1% 8.18 (6.68-1.02) Olesen et al, Thrombosis and haemostasis June 2012

CHADS 2 score Why use CHA 2 DS 2 -VASc? CHA 2 DS 2 VaSc score % of n Stroke risk per 100pt yrs 0-1 n=47,576 0 15.8% 0.84 (0.65-1.08) 1 21.2% 1.79 (1.53-2.09) 2 30.1% 3.67 (3.34-4) 3 29.8% 5.75 (5.33-6.21) 4 3.1% 8.18 (6.68-1.02) 0 n=7536 0 0.84 3 3.2 Olesen et al, Thrombosis and haemostasis June 2012

The HAS-BLED bleeding risk score *Hypertension is defined as systolic blood pressure > 160 mmhg. INR = international normalized ratio.

Choice of anticoagulant in AF: ESC Guidelines 2012 Atrial fibrillation Valvular AF Yes Best option Alternative Adapted from: Camm et al. Eu Heart J August 2012 NOAC VKA

Choice of anticoagulant in AF: ESC Guidelines 2012 Atrial fibrillation Yes Valvular AF <65 years and lone AF (including female) No Assess risk of stroke (CHA 2 DS 2 -VASc score) Yes No (i.e. non-valvular AF) Best option Alternative 0 No antithrombotic therapy Adapted from: Camm et al. Eu Heart J August 2012 NOAC VKA

Choice of anticoagulant in AF: ESC Guidelines 2012 Atrial fibrillation Yes Valvular AF <65 years and lone AF (including female) No Assess risk of stroke (CHA 2 DS 2 -VASc score) Yes No (i.e. non-valvular AF) Best option Alternative 0 1 >2 No antithrombotic therapy Adapted from: Camm et al. Eu Heart J August 2012 Oral anticoagulant therapy Assess bleeding risk (HAS-BLED score) Consider patient values and preferences NOAC* VKA *NOACs are broadly preferable to VKA in the vast majority of patients with NVAF For full recommendations please refer to the ESC Guidelines for the management of atrial fibrillation (2012 update).

The Aspirin Story Weak evidence for aspirin efficacy OAC 39% risk reduction compared antiplatelet Risk of major bleeding or ICH similar to OAC Warfarin risk/year Aspirin risk/year HR (95% CI) Major extracranial haemorrhage 1.4 1.6 0.87 (0.43-1.73) All major haemorrhage 1.9 2 0.96 (0.53-1.75) BAFTA study 2007 in patients >75yrs Aspirin and clopidogrel is more effective than single therapy and less effective than OAC but with higher bleeding risk

Oral anti-coagulation is shown to be effective for stroke prevention in AF Study, year Reduction of risk of thromboembolism in AF 1 Relative risk reduction (95% CI) Absolute risk reduction AFASAK I, 1989; 1990 SPAF I, 1991 BAATAF, 1991 CAFA, 1991 SPINAF, 1992 EAFT, 1993 All trials (n=6) 2.6% 4.7% 2.4% 1.2% 3.3% 8.4% primary prevention 2.7, secondary prevention 8.4 100% 50% 0 50% 100% Favours VKA Favours placebo Hart RG et al. Ann Intern Med 2007;146:857 867

Age, years Oral anti-coagulation: benefit risk improves with increasing age Net clinical benefit: events prevented per 100 person-years 1 85 1.29 2.34 3.30 75 84 0.44 1.00 1.40 65 74 0.37 0.11 0.40 <65 0.65 0.25 0.08 1 0.5 0 0.5 1 1.5 2 2.5 3 3.5 Worse with warfarin Better with warfarin Singer DE et al. Ann Intern Med 2009;151:297 305

Odds ratio for event Oral Anticoagulant Therapy - Warfarin Warfarin reduces stroke risk by 64% and all cause mortality by 26% (metanalysis) But.. 20 15 10 Ischaemic stroke Intracranial bleeding 5 Target INR 1 1.0 2.0 3.0 4.0 5.0 6.0 7.0 8.0 International normalized ratio

Drug and food interactions with warfarin

% of patients without stroke Poor INR control increases the risk of stroke in real-world practice Stroke survival in 37,907 AF patients UK General Practice Research Database (27,458 warfarin users and 10,449 not treated with an antithrombotic) 100 95 90 85 80 75 No warfarin %TTR > 70 61 70 51 60 41 50 31 40 < 30 I I I I I I 0 20 40 60 80 100 Months Adapted from Gallagher et al. Thromb Haemost 2011;106:968 77. 20

Anticoagulant Drugs Rivaroxaban and Apixaban Dabigatran

Contraindications to Warfarin Poor medication compliance Liver disease or severe hepatic impairment Bleeding diathesis Alcohol abuse High falls risk High bleeding risk All Oral Anticoagulants See SPC for each medicine for specific information

Dabigatran Rivaroxaban Apixaban Edoxaban Direct Thrombin Inhibitor Xa inhibitor

Dabigatran Rivaroxaban Apixaban Edoxaban Direct Thrombin Inhibitor Xa inhibitor No monitoring or food interactions Take with food

Dabigatran Rivaroxaban Apixaban Edoxaban Direct Thrombin Inhibitor 80% renal excretion Xa inhibitor No monitoring or food interactions Take with food 35% renal excretion 27% renal excretion 50% renal excretion

Dabigatran Rivaroxaban Apixaban Edoxaban Direct Thrombin Inhibitor Xa inhibitor No monitoring or food interactions Take with food 80% renal excretion 35% renal excretion 27% renal excretion 50% renal excretion Dyspepsia 5-10% Poss increase MI No GI problems

Dabigatran Rivaroxaban Apixaban Edoxaban Direct Thrombin Inhibitor Xa inhibitor No monitoring or food interactions Take with food 80% renal excretion 35% renal excretion 27% renal excretion 50% renal excretion Dyspepsia 5-10% No GI problems 150mg bd 20mg od 5mg bd 15-60mg od 110mg bd if >80, frail, verapamil 15mg od if GFR 15-49 ml/min 2.5mg bd if GFR15-30 2.5 mg bd if 2+ of: >80 yrs, <60 kg, cr >133μmol/l

Dabigatran Rivaroxaban Apixaban Edoxaban Direct Thrombin Inhibitor Xa inhibitor No monitoring or food interactions Take with food 80% renal excretion 35% renal excretion 27% renal excretion 50% renal excretion Dyspepsia 5-10% No GI problems 150mg bd 20mg od 5mg bd 15-60mg od 110mg bd if >80, frail, verapamil 15mg od if GFR 15-49 ml/min 2.5mg bd if GFR15-30 2.5 mg bd if 2+ of: >80 yrs, <60 kg, cr >133μmol/l No antidote or easy monitoring test

Dosage according to renal function 1,2,3 Creatinine clearance 50 + ml/min 20mg Once daily 5 mg bd 150mg BD or 110mg BD Creatinine clearance 50 + ml/min Creatinine clearance 30-49 ml/min 15mg Once daily 5mg bd 150mg BD with caution. Consider using 110mg BD if high bleeding risk. Dose adjust based on age, weight and medications Creatinine clearance 30 50 ml/min Creatinine clearance 15-29 ml/min Creatinine clearance <15 ml/min 15mg Once daily with caution Not recommended 2.5 mg bd* Not recommended Contraindicated Creatinine clearance <30 ml/min Rivaroxaban Apixaban Dabigatran 1. Xarelto SmPC 2. Pradaxa SmPC 3. Eliquis SmPC * * Patients with 2 of the following: age 80 years, body weight 60 kg, or a serum creatinine level 1.5 mg/dl (133 μmol/l).

Verapamil: Use Rivaroxaban Diltiazem: Use Dabigatran, Apixaban or Rivaroxaban (with caution) Amiodarone: Use Rivaroxaban with caution Dronedarone: Stick to warfarin http://europace.o xfordjournals.org/ Please refer to the relevant SPCs for further information.

RE-LY: Study Design Non-Valvular Atrial fibrillation 1 Risk Factor Absence of contra-indications 951 centers in 44 countries NVAF with: 1.Previous stroke or TIA 2.a left ventricular ejection fraction < 40% 3.NYHA class II or higher heart-failure symptoms within 6 months 4.> 75 years or an age of 65 to 74 years plus diabetes mellitus, hypertension, or coronary artery disease. Blinded Event Adjudication Open Blinded Warfarin adjusted (INR 2.0-3.0) N=6000 Dabigatran Etexilate 110 mg BID N=6000 Dabigatran Etexilate 150 mg BID N=6000 Primary Endpoint: Stroke or non-cns Systemic Embolism Connolly SJ, et al. N Engl J Med. 2009;361:1139-1151

Rocket AF Design Non-Valvular Atrial Fibrillation Risk Factors CHF Hypertension At least 2 or Age 75 3 required* Diabetes OR Stroke, TIA or Systemic embolus Rivaroxaban 20 mg daily 15 mg for Cr Cl 30-49 ml/min Randomize Double Blind / Double Dummy (n ~ 14,000) Warfarin INR target - 2.5 (2.0-3.0 inclusive) Monthly Monitoring Adherence to standard of care guidelines Primary Endpoint: Stroke or non-cns Systemic Embolism * Enrollment of patients without prior Stroke, TIA or systemic embolism and only 2 factors capped at 10% Rocket AF Investigators, AHA 2010

Aristotle Design Non-Valvular Atrial Fibrillation 1 Risk Factors CHF Hypertension Age 75 Diabetes Stroke, TIA or Systemic embolus Apixaban 5 mg twice daily 2.5 mg bd if 2 or age>80, weight<60kg or Cr>133umol/l Randomize Double Blind / Double Dummy (n ~18201) Warfarin INR target - 2.5 (2.0-3.0 inclusive) Monthly Monitoring Adherence to standard of care guidelines Primary Endpoint: Stroke or non-cns Systemic Embolism Granger et al, Aristotle NEJM Sept 2011

Drug/trial (vs warfarin) Stroke/ thromboembolism Haemorrhagic stroke Ischaemic stroke Major bleeding Dabigatran 150/RELY 34% RRR 0.58% ARR P<0.001 Dabigatran 110/RELY Non inferior Rivaroxaban /ROCKET-AF Non inferior Apixaban/ 21% RRR ARISTOTLE 0.33% ARR P = 0.01 Results are from a comparison of individual NOACs with warfarin. These data are not based on direct comparisons between NOACs and should therefore be interpreted with caution.

Drug/trial (vs warfarin) Stroke/ thromboembolism Haemorrhagic stroke Ischaemic stroke Major bleeding Dabigatran 150/RELY 34% RRR 0.58% ARR P<0.001 74% RRR 0.28% ARR P<0.001 Dabigatran 110/RELY Non inferior 69% RRR 0.26% ARR P<0.001 Rivaroxaban /ROCKET-AF Non inferior 41% RRR 0.18% ARR P = 0.024 Apixaban/ ARISTOTLE 21% RRR 0.33% ARR P = 0.01 49% RRR 0.23% ARR P <0.001 Results are from a comparison of individual NOACs with warfarin. These data are not based on direct comparisons between NOACs and should therefore be interpreted with caution.

Drug/trial (vs warfarin) Stroke/ thromboembolism Haemorrhagic stroke Ischaemic stroke Major bleeding Dabigatran 150/RELY 34% RRR 0.58% ARR P<0.001 74% RRR 0.28% ARR P<0.001 24% RRR 0.28% ARR P=0.03 Dabigatran 110/RELY Non inferior 69% RRR 0.26% ARR P<0.001 11% RRI 0.14% ARI P=0.35 Rivaroxaban /ROCKET-AF Non inferior 41% RRR 0.18% ARR 6% RRR 0.08% ARR P = 0.024 P = 0.58 Apixaban/ ARISTOTLE 21% RRR 0.33% ARR P = 0.01 49% RRR 0.23% ARR P <0.001 8% RRR 0.06% ARR P=0.42 Results are from a comparison of individual NOACs with warfarin. These data are not based on direct comparisons between NOACs and should therefore be interpreted with caution.

Drug/trial (vs warfarin) Stroke/ thromboembolism Haemorrhagic stroke Ischaemic stroke Major bleeding Dabigatran 150/RELY 34% RRR 0.58% ARR P<0.001 74% RRR 0.28% ARR P<0.001 24% RRR 0.28% ARR P=0.03 Similar Dabigatran 110/RELY Non inferior 69% RRR 0.26% ARR P<0.001 11% RRI 0.14% ARI P=0.35 20% RRR 0.65% ARR P=0.003 Rivaroxaban /ROCKET-AF Non inferior 41% RRR 0.18% ARR 6% RRR 0.08% ARR Similar P = 0.024 P = 0.58 Apixaban/ ARISTOTLE 21% RRR 0.33% ARR P = 0.01 49% RRR 0.23% ARR P <0.001 8% RRR 0.06% ARR P=0.42 31% RRR 0.96% ARR P<0.001 Results are from a comparison of individual NOACs with warfarin. These data are not based on direct comparisons between NOACs and should therefore be interpreted with caution.

Averroes: Apixaban v Aspirin 5599 patients unsuitable/unwilling warfarin 55% RRR in stroke/embolism. (2.1% ARR) No difference major bleeding 1000 NVAF patients Rx Apixaban versus ASA would prevent: 21 patients Strokes/systemic emboli 1 33 CV Hospitalisations 2 1 Connolly SJ et al. N Engl J Med 2011;364:806-817 2 Hohnloser et al. Europ H J 2013 Sep;34(35):2752-9

Summary? Warfarin and NOACs are all effective drugs for stroke and systemic embolus prevention in patients with NVAF NOACs all reduce risk of haemorrhagic stroke cf warfarin Predictable anticoagulation for NOACs No antidotes for NOACs Effect of NOACs can t be easily monitored NOACs excretion depends on renal function NOACs more expensive but other savings to NHS and meets cost effectiveness

Cost Implications NOACs approx 760-800/year Warfarin costs 11-12/year Warfarin clinic costs very variable 115-415 Difficult to control patients cost more Reduced strokes/complications with NOACs vs warfarin, saves money

Which one to choose? Dabigatran Rivaroxaban Apixaban Pros 150mg better stroke reduction than warfarin 150mg best ischaemic stroke reduction 110mg bd less major bleeding than warfarin Cons Higher GI side effects Twice daily Most susceptible to renal impairment These data are not based on direct comparisons between NOACs and should therefore be interpreted with caution.

Which one to choose? Dabigatran Rivaroxaban Apixaban Pros Cons 150mg better stroke reduction than warfarin 150mg best ischaemic stroke reduction 110mg bd less major bleeding than warfarin Higher GI side effects Twice daily Most susceptible to renal impairment Once daily Use down to CrCl 15 Can go in dosette Well tolerated Fewer drug interactions Not clearly superior to warfarin Higher GI bleeding Take with food These data are not based on direct comparisons between NOACs and should therefore be interpreted with caution.

Which one to choose? Dabigatran Rivaroxaban Apixaban Pros 150mg better stroke reduction than warfarin Once daily More effective than aspirin with no bleeds 150mg best ischaemic stroke reduction 110mg bd less major bleeding than warfarin Use down to CrCl 15 Can go in dosette Well tolerated Fewer drug interactions Better stroke reduction than warfarin (& major bleeding) Small Mortality benefit Can go in dosette Well tolerated Best data in renal failure Cons Higher GI side effects Not clearly superior to warfarin Twice daily Twice daily Higher GI bleeding Most susceptible to renal impairment Take with food These data are not based on direct comparisons between NOACs and should therefore be interpreted with caution.

NICE is Naughty NICE AF 2014 Anticoagulation may be with apixaban, dabigatran etexilate, rivaroxaban or a vitamin K antagonist. Discuss the options for anticoagulation with the person and base the choice on their clinical features and preferences. [new 2014] NICE CKD 2014 Consider apixaban in preference to warfarin in people with a confirmed egfr of 30 50 ml/min/1.73 m2 and nonvalvular atrial fibrillation who have 1 or more of the following risk factors: prior stroke or transient ischaemic attack age 75 years or older hypertension diabetes mellitus symptomatic heart failure. [new 2014]

Practical considerations Who to switch Switching patients Warfarin to NOAC NOAC to warfarin Between NOACs Long term follow up Bleeding Operations

Practical considerations (see SPCs) Switching patients Stop warfarin and start NOAC when INR<2-3 Start warfarin 2-3 days before stopping NOAC & stop when INR>2

Follow Up

Standardised NOAC card

Bleeding Patients on NOAC presenting with bleeding Check haemodynamic status, basic coagulation tests to assess anticoagulation effect (e.g. aptt for dabigatran, PT or anti Xa activity for rivaroxaban), renal function, etc. Minor Delay next dose or discontinue treatment Moderate-severe Symptomatic/supportive treatment Mechanical compression Fluid replacement Blood transfusion Oral charcoal if recently ingested a Very severe Consider rfviia or PCC Charcoal filtration a / haemodialysis *a * haemodialysis unlikely to be an effective means of managing apixaban overdose - a With dabigatran Adapted from Camm et al. Eur Heart J 2012;e-published August 2012, doi:10.1093/eurheartj/ehs253. 49

Invasive procedures and surgery Stop NOAC at least 24 hours before intervention (depends on type surgery and GFR) If this is not possible, assess relative risk of bleeding compared to urgency of intervention Restart as soon as possible after the intervention if situation allows and haemostasis established Please refer to individual product SPC for further information

Case 1 58 male Bus driver in Hexham Asymptomatic NVAF at work medical egfr 60 CHA 2 DS 2 -VASc = 2, (diabetes and hypertension) 2.2% risk stroke/yr Warfarin commenced by GP Struggles due to work to get to clinic

Case 2 45 man with first episode of NVAF after chest infection (>48hrs) Symptomatic Normal heart on echo egfr normal Works away Planning cardioversion

Case 3 76 female Persistent NVAF CHA 2 DS 2 -VASc = 4 (age, gender, BP) Estimated stroke risk 4% per year Mild cognitive impairment Supportive family but can t manage warfarin Dosette box for meds

Case 4 85 female Frail (58kg) but cognitively aware Previous IDA investigated appropriately Cr 135 egfr 27 Persistent NVAF CHA 2 DS 2 -VASc = 7 (age, gender, BP, stroke & vasc disease) Estimated stroke risk 9.6% per year

Case 5 67 man Impaired LV function, IHD, BP, diabetes Paroxysmal NVAF CHA 2 DS 2 -VASc = 5 Estimated stroke risk 6.7% per year Subtherapeutic INR despite 13mg warfarin

Case 6 78 female Persistent NVAF CHA 2 DS 2 -VASc = 3 Estimated stroke risk 3.2% per year Hair loss with warfarin

Case 7 35 man Paroxysmal NVAF, pill in pocket Otherwise fit What if female

Case 8 69 woman Persistent NVAF Asthma, Hypertension CHA 2 DS 2 -VASc = 3 Rx digoxin and diltiazem for rate control Hates taking warfarin as likes to cruise.. What if on Verapamil Verapamil: Use Rivaroxaban Diltiazem: Use Dabigatran or Rivaroxaban (with caution) Amiodarone: Use Rivaroxaban with caution Dronedarone: Stick to warfarin

Case 9 75 male Longstanding AF on warfarin Presents with ischaemic stroke Good recovery

Case 10 75 man Persistent AF CKD secondary to BP and DM, egfr 25 CHA 2 DS 2 -VASc = 4 Estimated stroke risk 4% per year What if egfr 15