Atrial Fibrillation Treatment

1
Atrial Fibrillation Treatment Anticoagulation and
Stroke
Dr Matthew Fay Westcliffe Medical
Practice National Clinical Lead NHS
Improvement-Stroke
2
Life is short, and Art long the crisis fleeting
experience perilous, and decision difficult
Hippocrates 4000BC
3
AF is a common disorder

• AF is the most common heart arrhythmia, with a
  prevalence of approximately 1.2 in primary care
  in the UK1
• Estimated numbers affected by AF
• England 600,0001
• Europe 4.5 million2
• USA 5.1 million3
• Nearly one in four people at age 55 years will go
  on to develop AF (24 of men and 22 of women)4

1. NHS Improvement. June 2009. Available at
http//www.improvement.nhs.uk/heart/Portals/0/ doc
uments2009/AF_Commissioning_Guide_v2.pdf
accessed April 2010 2. ACC/AHA/ESC guidelines
Fuster V et al. Circulation 2006114e257354 and
Eur Heart J 20062719792030 3. Miyasaka Y et
al. Circulation 200611411925 4. Heeringa J et
al. Eur Heart J 20062794953
4
Prevalence of AF predicted to more than double by
2050
Miyasaki Y et al. Circulation 200611411925
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Prevalence of AF increases with age
1. Heeringa J et al. Eur Heart J 20062794953
2. Go AS et al. JAMA 200128523705
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Prevalence AF by practice
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Direct Comparison
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SAFE Study
Fitzmaurice, D. A et al. BMJ 2007335383
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Opportunistic computer prompted screening 5/08
5/09
1883 patients aged 65 years and older
1569 patients pulse palpations
207 patients found with irregular pulse
130 patients with irregular pulse and no known AF
99 patients had ECGs
36 patients diagnosed with previously unknown
AF ( 19 )
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Key Facts

• 83.3 screened opportunistically
• 13 with irregular pulse
• 6.3 had ECGs
• 36 had AF on ECG
• Number needed to screen 43
• Change in prevalence 1.32 -gt 1.82
• Prevalence of 65ys and older 10.9

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THINK CAN I LOOK AFTER THEM?
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Think about the cause

• Ischaemic heart disease
• Can be the presenting feature of AMI
• Hypertension
• Valvular Heart Disease
• Thyrotoxicosis
• Cardiomyopathy
• Infection
• Alcohol
• Idiopathic

15
Think about the investigations

• 12 Lead ECG
• Full Blood Count
• Electrolytes
• Liver Function including the Gamma GT
• Thyroid Function

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Are they one of the below?

• Where an other cause is identified
• Thyrotoxicosis
• Cardiomyopathy
• Recent onset where cardioversion is appropriate
• Unresponsive to normal medication
• Associated with syncope
• Associated with valvular disease
• If diagnosis is in doubt

REFER THEM TO A SPECIALIST
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THINK RATE?
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How Are They?

• Acutely Unwell
• Breathless
• Suffering Palpitations
• Asymptomatic
• Tachycardic

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If the Heart Rate is Fast
Slow it down

• Beta-blockers
• Rate Limiting Calcium Channel Blockers
• Digoxin
• New medications on the way

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If the Heart Rate is Slow
Speed it up

• Stop rate limiting drugs
• Ask about symptoms
• No symptoms-Monitor them
• Otherwise

Refer them to a cardiologist
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THINK RHYTHM?
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How Are They?
Westcliffe Medical Practice Shipley Westcliffe
Cardiology Service

• Controlled heart rate-Yes
• But
• Breathless
• Suffering Palpitations
• Tired

Refer them to a cardiologist
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Anticoagulation and Stroke Prevention
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Stroke is a frequent complication of AF

• Stroke is the leading complication of AF
• Patients with AF have a five-fold higher stroke
  risk than those without AF1
• AF doubles the risk of stroke when adjusted for
  other risk factors2
• Without preventive treatment, each year
  approximately 1 in 20 patients (5) with AF will
  have a stroke3
• When transient ischaemic attacks and clinically
  silent strokes are considered, the rate of
  brain ischaemia associated with non-valvular AF
  exceeds 7 per year4
• It is estimated that 15 of all strokes are
  caused by AF5 and that 12,500 strokes per year in
  England are directly attributable to AF6

1. NICE clinical guideline 36.June 2006.
Available at http//www.nice.org.uk/guidance/CG36/
?c91497 accessed April 2010 2. ACC/AHA/ESC
guidelines Fuster V et al. Circulation
2006114e257354 Eur Heart J
20062719792030 3. Atrial Fibrillation
Investigators. Arch Intern Med 1994154144957
4. Carlson M. Medscape Cardiology. 20048
available at http//cme.medscape.com accessed
Feb 2010 5. Lip GYH, Lim HS. Lancet Neurol
20076981-93 6. NHS Improvement. June 2009.
Available at http//www.improvement.nhs.uk/heart/P
ortals/0/documents2009/AF_Commissioning_Guide_v2.p
df accessed April 2010
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Burden of AF in Wales

• Stroke is the third most common cause of death in
  Wales and has a greater disability impact than
  other chronic diseases1
• Tackling stroke and improving stroke services has
  been identified as a top priority in Wales, to be
  brought about by such things as
• improved lifestyles, effective management of
  cardiac arrhythmias and rapid medical
  intervention post-TIA2
• Around 10,000 to 11,000 people in Wales suffer a
  stroke each year3
• Wales is the only part of the UK without a
  dedicated stroke strategy4

• Stroke Association www.stroke.org.uk/media_centre/
  facts_and_figures/index.html (accessed May 2010
  2. Improving Stroke Services. Welsh Health
  Circular 2007 www.wales.nhs.uk/documents/WHC(2007)
  082-new.pdf (accessed May 2010) 3. Report of
  Inquiry into Stroke Services in Wales March 2010
  www.assemblywales.org/cr-ld8032-e.pdf (accessed
  May 2010) 4. BBC www.news.bbc.co.uk/1/hi/wales/862
  6915.stm (accessed May 2010)

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Stroke is a serious complication of AF

• Stroke in AF is associated with a heavy burden of
  morbidity and mortality
• AF stroke is usually more severe than stroke due
  to other causes1
• Compared with other stroke patients, those with
  AF are more likely to
• Have cortical deficit (e.g. aphasia), severe limb
  weakness and diminished alertness, and be
  bedridden on admission2
• Have longer in-hospital stay with a lower rate of
  discharge to their own home3
• The mortality rate for patients with AF is double
  that in people with normal heart rhythm4

1. Savelieva I et al. Ann Med 20073937191 2.
Dulli DA et al. Neuroepidemiology 20032211823
3. NICE clinical guideline 36.June 2006.
Available at http//www.nice.org.uk/guidance/CG36/
?c91497 accessed April 2010 4. Benjamin EJ et
al. Circulation 19989894652
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Incidence of stroke in AF patients increases with
age
Incidence of stroke after diagnosis of AF (men)
45
40
35
30
Incidence of stroke per 1000 person-years
25
20
15
10
5
0
4044
8589
4549
5054
5559
6064
6569
7074
7579
8084
Age (yrs)
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22-year follow-up of 75 126 men in the Danish
National Registry of Patients
Frost L et al. Neuroepidemiology 20072810915
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Stroke risk persists even in asymptomatic/paroxysm
al AF

• The risk of stroke with asymptomatic or
  paroxysmal AF is comparable to that with
  permanent AF1,2

1. Hart RG et al. J Am Coll Cardiol
2000351837 2. Flaker GC et al. Am Heart J
200514965763
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Large artery stroke cardioembolic or
atherothrombotic
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CBF
CBV
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As to diseases, make a habit of two things to
help, or at least, to do no harm
Hippocrates 4000BC
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The Role Of Aspirin
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SPAF I Aspirin Eligible AF Patients
Anticoagulation Eligible Group I
Anticoagulation Ineligible Group II
Warfarin
Placebo (n 211) 18 events
Aspirin (n 206) 1 event
Aspirin (n 346) 25 events
Placebo (n 357) 26 events
SPAF Investigators. A differential effect of
aspirin on prevention of stroke in atrial
fibrillation.
Group II
Group I
Risk reduction 8p .75
Risk reduction 94p lt .001
Risk reduction 42 p .02
J Stroke Cerebrovasc Dis. 19933181-188
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The Role Of Aspirin
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Low-Dose Aspirin for Prevention of Stroke in
Low-Risk Patients With AFJapan AF Stroke Trial
Sato et al Stroke. 200637447-451
Primary end points included cardiovascular death,
symptomatic brain infarction, or TIA, whereas the
secondary end points included noncardiovascular
death, intracranial hemorrhage, major
bleeding, and peripheral embolization.
KaplanMeier survival curves for primary end
points (a) and for primary plus secondary end
points (b). Treatment with aspirin 150-200mg/day
was not superior to treatment without aspirin for
primary end points (log-rank P0.310) and
secondary end points (log-rank P0.109)
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Aspirin Has Little Role to Play
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Meta-analysis of ischaemic stroke or systemic
embolism
Category
W vs. placebo W vs. W low dose W vs. ASA W vs.
ASA clopidogrel W vs. ximelagatran W vs.
dabigatran 150
0
0.3
0.6
0.9
1.2
1.5
1.8
2.0
Favours warfarin
Favours other treatment
Dabigatran etexilate is in clinical development
and not licensed for clinical use in stroke
prevention for patients with atrial fibrillation
Camm J. Oral presentation at ESC on Aug 30th
2009.
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Risk reduction with warfarin

• Reduces relative risk of stroke by approx 70
• Absolute risk reduction
• Primary stroke 2.7
• Secondary stroke 8.4
• Numbers needed to treat for 1 year to prevent 1
  stroke
• Primary stroke 37
• Secondary stroke 12
• Overall 25 (approx)

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ACTIVE W Study
NEJM 20081182029
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BAFTA - primary endpoints

• Primary endpoints
• Fatal or non-fatal disabling stroke
• Other intracranial haemorrhage
• Arterial embolism
• Warfarin 1.8 / year Aspirin 3.8
  / year
• Relative risk 0.48
• (95 CI 0.28 0.8)

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RE-LY
RR 0.91 (95 CI 0.741.11) plt0.001 (NI) p0.34
(Sup)
0.05
0.04
RRR 34
Warfarin Dabigatran etexilate 110 mg Dabigatran
etexilate 150 mg
0.03
Cumulative hazard rates
RR 0.66 (95 CI 0.530.82) plt0.001 (NI) plt0.001
(Sup)
0.02
0.01
0.0
0
0.5
1.0
1.5
2.0
2.5
Years
RR, relative risk CI, confidence interval NI,
non-inferior Sup, superior
Connolly SJ., et al. NEJM published online on Aug
30th 2009. DOI 10.1056/NEJMoa0905561
Dabigatran etexilate is in clinical development
and not licensed for clinical use in stroke
prevention for patients with atrial fibrillation
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Kenneth W. Mahaffey, MD and Keith AA Fox, MB
ChBon behalf of the ROCKET AF Investigators
Rivaroxaban Once-daily oral direct factor Xa
inhibition Compared with vitamin K antagonism for
prevention of stroke and Embolism Trial in Atrial
Fibrillation
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Study Design

• Risk Factors
• CHF
• Hypertension
• Age ? 75
• Diabetes
• OR
• Stroke, TIA or Systemic embolus

At least 2 or 3 required
Atrial Fibrillation
Rivaroxaban
Warfarin
Randomize Double Blind / Double Dummy (n
14,000)
INR target - 2.5 (2.0-3.0 inclusive)
20 mg daily 15 mg for Cr Cl 30-49 ml/min
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
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Study Conduct
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Primary Efficacy OutcomeStroke and non-CNS
Embolism
Warfarin
Rivaroxaban
Cumulative event rate ()
HR (95 CI) 0.79 (0.66, 0.96) P-value
Non-Inferiority lt0.001
Days from Randomization
No. at risk Rivaroxaban 6958 6211 5786
5468 4406 3407 2472 1496
634 Warfarin 7004 6327 5911
5542 4461 3478 2539 1538 655
Event Rates are per 100 patient-years Based on
Protocol Compliant on Treatment Population
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Adverse Events and Liver Enzyme Data
Values are N () Based on Safety Population
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Summary

• Efficacy
• Rivaroxaban was non-inferior to warfarin for
  prevention of stroke and non-CNS embolism.
• Rivaroxaban was superior to warfarin while
  patients were taking study drug.
• By intention-to-treat, rivaroxaban was
  non-inferior to warfarin but did not achieve
  superiority.
• Safety
• Similar rates of bleeding and adverse events.
• Less ICH and fatal bleeding with rivaroxaban.
• Conclusion
• Rivaroxaban is a proven alternative to warfarin
  for moderate or high risk patients with AF.

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Costs and Concerns from the Exchequer
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RE-LY Study Stroke or Systemic embolism
NEJM, Sept 2009
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RELY - Mean time in therapeutic range by country
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RELY - Mean time in therapeutic range by country
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3895
3615
Overall cost / QALY 12640
56810
245910
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Risk factors for stroke in patients with AF
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Wolf P et al. Stroke 199122983-988
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• Stroke risk assessment
• Absolute risk (AR) of stroke increases with age
• and co-morbid conditions

Gage B et al. JAMA 2001 285 (22) 28642870.
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Gage B et al. JAMA 2001 285 (22) 28642870.
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REACH Registry
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Comparison of Risk Stratification Schemes to
Predict Thromboembolism in People With
Nonvalvular Atrial Fibrillation
Fang FC et al. JACC 200851810-815
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Fang FC et al. JACC 200851810-815
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Rietbrock S et al. Am Heart J 200815657-64
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Prognostic risk of atrial fibrillation in
acute myocardial infarction complicated by
left ventricular dysfunction the OPTIMAAL
experience
Transient Atrial Fibrillation Complicating Acute
Inferior Myocardial Infarction Implications for
Future Risk of Ischemic Stroke
Siu CW et al. Chest 2007 1324449
Lehto M et al. EHJ 2005 26 350-356
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CHA2DS2VASc
Lip G et al. Chest 2010 137 (2) 263272
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CHA2DS2VASc
Validated The Euro Heart Survey on Atrial
Fibrillation
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CHA2DS2VASc

• Slightly better c-statistic than CHADS2
• Low risk is virtually no risk
• Score 2 is suggested to be high risk
• 1.9 annual stroke risk considered high
• 75 of AF population classed at high risk

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Considerations on implementation

• Is a traditional three tier system of low
  moderate high risk helpful?
• How big is the moderate risk category?
• How do we balance benefit against risk?
• Where to set the cut offs?
• Does cost come into it?
• How will new oral anticoagulants affect the
  equation?

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• Choice of intervention

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An Approach to Risk Assessment
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An Approach to Risk Assessment
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Balancing risk vs harm

• Whats the risk?
• 1.9 major haemorrhage risk with warfarin in
  BAFTA1
• Haemorrhage risk increases with age (2.9 gt 85)
• 25 of major haemorrhage are due to intracranial
  haemorrhage
• 15 mortality of major bleed ( Walraven et al2 )
• Whats the benefit of anticoagulation?
• 60-70 relative risk reduction of ischaemic
  stroke3 NNT of 25 at CHADS2 score of 2 ( 36 at
  1 )
• Wheres the balance? NNT 25 vs NNH 53
• Is NNT vs NNH too simplistic? NNH of death or
  lasting disability gt200

1 Mant J et al. Lancet 2007 370 2 Walraven C et
al. JAMA 2002 288 3 Hart RG et al. Ann Intern
Med 1999 131
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An Approach to Risk AssessmentHAS-BLED
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Is this a role for left atrial appendage
occluders?
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Figure 4 The Watchman occlusion device
Block PC (2006) Percutaneous left atrial
appendage closure in a patient with atrial
fibrillation Nat Clin Pract Cardiovasc Med 3
456459 doi10.1038/ncpcardio0610
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Is this a role for left atrial appendage
occluders?
Showing soon at a Conference Center local to this
venue LAA Closure Devices they Safe and
Effective Staring Dr Mark Earley
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Guidance on Risk Assessment and Stroke Prevention
for Atrial Fibrillation GRASP-AFTools to
support data collection and analysis for GRASP AF

• Acknowledgement
• Keith Tyndall, Leeds AF clinic
• James Barrett, Primis
• West-Yorkshire Cardiovascular Network

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The CHART GRASP-AF tool

• CHART is an Excel program (97-2003, 2007)
• The CHART GRASP-AF library is available from NHS
  Improvement http//www.improvement.nhs.uk/graspaf
  /
• Run locally within the practice
• Queries written for the MIQUEST interpreter
• Versions available for all the main GP systems
• Queries can be identifiable or pseudonymised
• Queries extract a set of information about
  patients with atrial fibrillation

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CHART GRASP-AF Tool

• Identifies patients with atrial fibrillation
• Looks for co-morbidities and works out CHADS2
  score for all
• Determines whether patients are currently on
  warfarin or aspirin (or both)
• Looks out for recorded reasons for NOT treating
  with warfarin
• Has a comprehensive Advice sheet

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CHART GRASP-AF Dashboard
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Summary

• Big variation in stroke risk amongst AF patients
  -gt importance of risk assessment
• Lots of risk assessment tools none is perfect
• Ongoing development to improve predictive value,
  ie CHA2DS2VASc
• Majority of AF patients can be classified easily
  as high or low risk
• Small intermediate risk group requires careful
  weighing up of risks vs benefits of SPAF
• The cut offs are being re-evaluated
• GRASP-AF makes life easy for the GP.

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Food for thought

• 150,000 strokes per year in the UK1
• 410 per day
• 17 per hour
• Within the next four hours, 10 patients with AF
  will have suffered a stroke
• 8 would have been known to be high risk of stroke
• 6 should have been on warfarin
• 3 will go home
• 5 will end up in residential care
• 2 will die....

The Stroke Association www.stroke.org.uk. Base
on Office of National Statistics Health
Statistics Quarterly (12) Winter 2001 "Stroke
incidence and risk factors in a population based
cohort study. Scottish Stroke Care Audit
2005/2006. The Stroke Association estimate that
5,000 people per year have a stroke in Northern
Ireland
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Thank you for your attention

• Question
• matthew.fay_at_bradford.nhs.uk