DR ABUL AZIM

CONSULTANT IN ELDERLY MEDICINE & STROKE

STROKE AND ATRIAL FIBRILLATION AND

THE ROLE OF THE NOAC

Stroke and AF

• 110-120,000 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 50-59 years

Almost 9% at 80-89 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 –10050 0 –50

AFASAK

SPAF

BAATAF

CAFA

SPINAF

EAFT

All trials

Warfarin better Placebo 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 –10050 0 –50

AFASAKSPAFEAFT

ESPS II

Aspirin better Placebo better

RRR = 19%ARR = 0.8%

95% CI: –1 to 35%

LASAF125 mg/d

125 mg QOD

UK-TIA300 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

C Congestive cardiac failure1

H Hypertension >140-90 or on treatment1

A Age > 75 years1

D Diabetes mellitus1

S Stroke/TIA2

Annual stroke risk – CHADS-2

CHADS SCORE STROKE RISK %

0 1.9

1 2.8

2 4.0

3 5.9

4 8.5

5 12.5

6 18.2

Anticoagulation therapyScore Risk Anticoagulation

therapyConsiderations

0 Low None or Aspirin Aspirin daily

1 Moderate Aspirin or Warfarin Aspirin daily or raise INR to 2.0-3.0, depending on patient preference

2 or greater Moderate or high Warfarin Raise INR to 2.0-3.0, unless contraindicated

CHA2DS2-VASc

Condition Points

C Congestive heart failure (or Left ventricular systolic dysfunction)

1

H Hypertension: blood pressure consistently above 140/90 mm/Hg (or treated hypertension on medication)

1

A2 Age>75 years 2

D Diabetes mellitus 1

S2 Prior stroke or TIA or thromboembolism 2

V Vascular disease (e.g., peripheral artery disease, myocardial infarction, aortic plaque)

1

A Age 65-74 years 1

Sc Sex category (i.e., female gender) 1

CHA2DS2-VASc – STROKE RISK %

CHA2DS2-VAS Score Stroke Risk %

0 0

1 1.3

2 2.2

3 3.2

4 4.0

5 6.7

6 9.8

7 7.6

8 6.7

9 15.2

Anticoagulation

Score Risk Anticoagulation Therapy

Considerations

0 Low No antithrombotic therapy (or Aspirin)

No antithrombotic therapy (or Aspirin 75-325 mg daily)

1 Moderate Oral 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 75-325 mg daily, depending on factors such as patient preference)

2 or greater

High Oral anticoagulant Oral anticoagulant, using either a new oral anticoagulant drug (e.e., Rivaroxaban or Dabigatran) or well controlled Warfarin at INR 2.0 - 3.0

HAS-BLED Score for bleeding risk on oral anticoagulation in AF

Hypertension systolic >160 1

Abnormal renal function 1

Abnormal LFT 1

Age >65 years 1

Stroke in past 1

Bleeding history 1

Labile INR 1

Alcohol 1

Other drug 1

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 AFNICE TA Appraisal Guidance 249

1.1 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 256

1.1 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.