DR ABUL AZIM CONSULTANT IN ELDERLY MEDICINE & STROKE STROKE AND ATRIAL FIBRILLATION AND THE ROLE OF THE NOAC

Stroke and AF ,000 Strokes per year >20,000 TIA per year 15-20% of all ischaemic strokes have underlying AF AF related strokes tend to be severe and disabling with high mortality.

Stroke and AF High prevalence of AF – 1.2% - possible underestimate 1:4 individuals aged 40 years have a life time risk for developing AF In 2007, 6.3 million people in US, Japan and Europe were living with diagnosed AF. With an aging population now likely to double in 30 years. Prevalence of AF increases with age: 0.5% at years Almost 9% at years

Stroke and AF AF associated with 5 fold increase in stroke risk Risk of stroke same for all variants of AF Cardioembolic stroke has a 30 day mortality of 25% 15% reduction in hospital admission due to AF related strokes in the UK would save an estimated £30 million/year

Meta analysis of 29 trials show Warfarin reduced stroke by 64-70% Also showed decreased mortality

Warfarin reduces the risk of stroke in AF 8 Error bars = 95% CI; *Relative risk reduction for all strokes (ischaemic and haemorrhagic) Relative risk reduction (%)* 100–100500–50 AFASAK SPAF BAATAF CAFA SPINAF EAFT All trials Warfarin betterPlacebo better RRR = 64% ARR = 2.7% 95% CI: 49 to 74% Hart RG et al. Ann Intern Med 2007;146:857–67

9 Limited efficacy of aspirin in reducing the risk of stroke in patients with AF Relative risk reduction (%)* 100–100500–50 AFASAK SPAF EAFT ESPS II Aspirin betterPlacebo better RRR = 19% ARR = 0.8% 95% CI: –1 to 35% LASAF 125 mg/d 125 mg QOD UK-TIA 300 mg/d 1200 mg/d JAST All trials Hart RG et al. Ann Intern Med 2007;146:857–67 Error bars = 95% CI; *Relative risk reduction for all strokes (ischaemic and haemorrhagic)

AF in Elderly Percentage of stroke attributable to AF: 1.5% for patients in their fifties 2.8% for patients in their sixties 18.8% for patients in their seventies 23.9% for patients in their eighties BAFTA Trial: Patients >75 with AF Stroke risk halved No increased bleeding risk compared with Aspirin

Royal College of Physicians, Edinburgh UK Consensus (March 2012) Key recommendations: Detection of AF must be improved; a national screening programme should be introduced Uptake of OAC must be increased and methods of engaging patients in their AF management should be improved Aspirin should not be used for stroke prevention in AF Stott DJ, Dewar RI et al. RCPE UK Consensus Conference, March 2012.

Stroke risk assessment for patients with AF CHADS-2 Score CCongestive cardiac failure1 HHypertension > or on treatment1 AAge > 75 years1 DDiabetes mellitus1 SStroke/TIA2

Annual stroke risk – CHADS-2 CHADS SCORESTROKE RISK %

Anticoagulation therapy ScoreRiskAnticoagulation therapy Considerations 0LowNone or AspirinAspirin daily 1ModerateAspirin or WarfarinAspirin daily or raise INR to , depending on patient preference 2 or greaterModerate or highWarfarinRaise INR to , unless contraindicated

CHA 2 DS 2 -VASc ConditionPoints CCongestive heart failure (or Left ventricular systolic dysfunction) 1 HHypertension: blood pressure consistently above 140/90 mm/Hg (or treated hypertension on medication) 1 A2A2 Age>75 years2 DDiabetes mellitus1 S2S2 Prior stroke or TIA or thromboembolism2 VVascular disease (e.g., peripheral artery disease, myocardial infarction, aortic plaque) 1 AAge years1 ScSex category (i.e., female gender)1

CHA 2 DS 2 -VASc – STROKE RISK % CHA2DS2-VAS ScoreStroke Risk %

Anticoagulation ScoreRiskAnticoagulation Therapy Considerations 0LowNo antithrombotic therapy (or Aspirin) No antithrombotic therapy (or Aspirin mg daily) 1ModerateOral anticoagulant (or Aspirin) Oral anticoagulant, either new oral anticoagulant drug e.g., Dabigatran or well controlled Warfarin at INR 2.0 – 3.0 (or Aspirin mg daily, depending on factors such as patient preference) 2 or greater HighOral anticoagulantOral anticoagulant, using either a new oral anticoagulant drug (e.e., Rivaroxaban or Dabigatran) or well controlled Warfarin at INR

HAS-BLED Score for bleeding risk on oral anticoagulation in AF Hypertension systolic >1601 Abnormal renal function1 Abnormal LFT1 Age >65 years1 Stroke in past1 Bleeding history1 Labile INR1 Alcohol1 Other drug1 Score of 3 or more indicates increased 1 years bleed risks on anticoagulation (risk for intracranial bleed, bleed requiring hospitalisation on a Hg drop > 2g/L or that needs transfusion.

Dabigatran etexilate for the prevention of stroke and systemic embolism in AF NICE TA Appraisal Guidance Dabigatran etexilate is recommended as an option for the prevention of stroke and systemic embolism within its licensed indication, that is, in people with nonvalvular atrial fibrillation with one or more of the following risk factors: Previous stroke, transient ischaemic attack or systemic embolism Left ventricular ejection fraction below 40% Symptomatic heart failure of New York Heart Association (NYHA) class 2 or above Age 75 years or older Age 65 years or older with one of the following: Diabetes mellitus, coronary artery disease or hypertension.

Guidance 1.2 The decision about whether to start treatment with Dabigatran etexilate should be made after an informed discussion between the clinician and the person about the risks and benefits of Dabigatran etexilate compared with Warfarin. For people who are taking Warfarin, the potential risks and benefits of switching to Dabigatran etexilate should be considered in light of their level of international normalised ratio (INR) control.

Rivaroxaban for the prevention of stroke and systemic embolism in people with AF NICE TA Appraisal Guidance Rivaroxaban is recommended as an option for the prevention of stroke and systemic embolism within its licensed indication, that is, in people with nonvalvular atrial fibrillation with one or more risk factors such as: Congestive heart failure Hypertension Age 75 years or older Diabetes mellitus Prior stroke or transient ischaemic attack.

Guidance 1.2 The decision about whether to start treatment with Rivaroxaban should be made after an informed discussion between the clinician and the person about the risks and benefits of Rivaroxaban compared with Warfarin. For people who are taking Warfarin, the potential risks and benefits of switching to Rivaroxaban should be considered in light of their level of international normalised ratio (INR) control.

Evidence with new oral anticoagulants RE-LY and Dabigatran ROCKET-AF and Rivaroxaban ARISTOTLE and APIXABAN

DABIGATRAN – RELY Study Compared Warfarin with Dabigatran in patients with AF 18,113 people randomised Two doses used i) 150 mg bd ii) 110 mg bd Dabigatran 110 mg bd – non inferior to Warfarin Dabigatran 150 mg bd – statistically significantly more effective than Warfarin at reducing stroke and systemic embolism Rates of major bleeding: 2.71%/yr low dose Dabigatran 3.11%/yr high dose Dabigatran 3.36%/yr for Warfarin A non statistically significant reduction all cause mortality. Both doses non statistically significant increased risk of myocardial infarction.

DABIGATRAN – RELY Study Both doses of Dabigatran shows statistically significant reduction in incidence of haemorrhagic stroke compared with Warfarin Both doses shows statistically significant fewer life threatening bleeds compared with Warfarin Both doses associate with significantly higher rate of gastro intestinal bleeding compared with Warfarin. Dabigatran 150 mg bd associated with significantly higher incidence of major gastrointestinal bleeding and also life threatening gastrointestinal bleeding.

RIVAROXABAN – ROCKET-AF Trial Compared Rivaroxaban with Warfarin in patients with AF 140,009 were enrolled Rivaroxaban was demonstrated to be non-inferior compared to Warfarin Significant reduction in rate of fatal bleed with intracranial haemorrhage with Rivaroxaban compared with Warfarin Higher rate of gastrointestinal bleed

Concerns with Warfarin Need for regular monitoring and have blood tests etc. Frequent dosage adjustment Slow onset of action Drug and food interactions Impact on people’s work, social and family life

Concerns with NOACs Lack of long term safety data Lack of specific antidote Renal failure or impaired renal function and also the risk of acute decline in renal function due to acute illness like dehydration, shock, initiation of nephrotoxin medication. Compliance and difficult to monitor compliance

Concerns with NOACs Some concern with increased risk of MI Higher risk of GI bleeding Rivaroxaban cannot be dialysed Expense and cost pressure

Advantage with NOAC No need for monitoring INR and hence more patient friendly In Warfarin intolerant patients In patients difficult to control INR - TTR <60% Useful for rapid anticoagulation following TIA in certain high risk groups.

Advantage with NOAC Patients suffering stroke/TIA despite being on Warfarin (Dabigatran 150 mg bd) Again, Dabigatran 150 mg bd more effective than Warfarin in preventing stroke Fewer drug and food interactions Reduced risk of intracranial haemorrhage in both

SUMMARY Patients with AF at high risk of disabling stroke Following risk satisfaction more patients should be anticoagulated as opposed to using Aspirin Warfarin – well established with proven efficacy Scope/role of the NOAC in certain patient groups. However, should be used with caution because of some concerns.