Ischemic strokes caused by atrial fibrillation are a major health concern in the United States. They account for approximately 69,000 strokes annually. Compared to other causes of ischemic stroke, atrial fibrillation-related strokes tend to be more severe, disabling, and fatal. They are associated with longer hospital stays, higher rates of in-hospital complications, and poorer long-term outcomes. Patients often experience significant physical, emotional, and psychological impacts even years after their stroke. The burden on caregivers is also high. Timely management and treatment are critical to minimize damage from these strokes.

1. Defining Moments in
Non-Valvular Atrial Fibrillation
Pathophysiology and Consequences of
Ischemic Stroke

2. Disclaimer
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THE DISTRIBUTION OF THIS PRESENTATION.

3. Approximately 8 Ischemic Strokes Due to
Atrial Fibrillation Occur Every Hour in the
United States
~ 795,000 strokes annually1
~ 87%
~ 691,650 ischemic strokes1
~ 20%
~ 138,330 cardioembolic2
~ 50%
~ 69,165 cardioembolic
ischemic strokes due to AFib
annually2,3
1. Go AS et al. Circulation. 2013;127:e6-e245.
2. Sacco RL et al. Stroke. 2006;37:577-617.
3. Freeman WD et al. Neurotherapeutics. 2011;8:488-502.
4. Steger C et al. Eur Heart J. 2004;25:1734-1740..
5. Gattellari M et al. Cerebrovasc Dis. 2011;32:370-382.
Approximately 8 ischemic
strokes/hr due to AFib in the US
More likely to be bedridden, disabling,
and fatal than non-AFib-related
ischemic strokes4,5

4. Overview and
Pathophysiology

5. Atrial Fibrillation Is the Most Common Cause
of Cardioembolic Ischemic Stroke
Cardiac Diseases Leading to Cardioembolic Events
15%
Atrial fibrillation
Ventricular thrombus
15%
50%
Valvular heart disease
20%
Structural heart defects or tumors
1. Freeman WD, Aguilar MI. Neurol Clin. 2008;26:1129-1160.

6. Ischemic Stroke Risk Factors Are Common
in Patients With Atrial Fibrillation
6
70
5
60
N=1084
50
44.2
40
30
20
10
0
5.49
67.3
23.5
28.5
17.3
9.1
40.8
HR for event
Percentage of patients
Prevalence of risk factors for ischemic
80
Hazard ratio for ischemic stroke without
anticoagulation2
stroke1*
N=90,490
4
2.96
3
2
1
0.98
0
HR=hazard ratio; TIA=transient ischemic attack; TE=thromboembolic event.
*Patients with NVAF not on anticoagulation.
1. Lip GYH, et al. Chest. 2010;137:263-272.
2. Friberg L et al. Eur Heart J. 2012;33:1500-1510.
1.19
1.19
1.07
1.21

7. Atrial Fibrillation Predisposes to the Formation of
Clots in the Left Atrium and Appendage
Blood stasis
To carotid artery
Abnormal
blood
constituents
Left atrium
thrombus
Anatomical
and structural
defects
Watson T et al. Lancet. 2009;373:155-166.

8. Smaller Vessels Make the Brain Vulnerable
to Cardioembolic Ischemia
MCA1
ACA
ACA/PCA2
Cardioembolic clot3
LAD artery
(proximal)4
Femoral
artery5
ACA=anterior cerebral artery; LAD=left anterior descending;
MCA=middle cerebral artery; PCA=posterior cerebral artery.
1. Zurada A et al. Clin Anat. 2011;24:34-46.
2. Ashwini CA et al. Neuroanatomy. 2008;7:54-65.
3. Marder VJ et al. Stroke. 2006;37:2086-2093.
4. Dodge JT et al. Circulation. 1992;86:232-246.
5. Sandgren T et al. J Vasc Surg. 1999;29:503-510
MCA
PCA

9. Ischemia From Cardioembolic Thrombi Cause
Neurologic Damage to Vast Areas of Brain Territory
ACA territory
MCA territory
PCA territory
ACA=anterior cerebral artery; MCA=middle cerebral artery; PCA=posterior cerebral artery.
1. Maas MB, Safdieh JE. Neurology. 2009;13:1-16.

10. Acute and Long-term
Effects of Ischemic Strokes
Due to Atrial Fibrillation
• Severity of acute presentation
• Hospital course complications
• Short- and long-term disability
• Short- and long-term mortality

12. Clinical Outcome Measures for Ischemic
Stroke
Modified Rankin Scale1
Barthel Index2
• Measures degree of disability or
dependence in daily activities
• Score of 0-6
• Measure of the ability to perform
self-care and activities of daily
living
• Rates 10 performance items on a
point scale
– 0: No symptoms
– 1: No significant disability despite
symptoms
– 2: Slight disability
– 3: Moderate disability
– 4: Moderately severe disability
– 5: Severe disability
– 6: Dead
– Feeding, bathing, dressing, bowel
s, stairs, bladder, toilet
use, transfers (bed to chair and
back), grooming, and mobility
• Score 0-100
– A higher score is associated with
a greater likelihood of living at
home with a degree of
independence
1. Strokecenter.org. http://www.strokecenter.org/wp-content/uploads/2011/08/modified_rankin.pdf. Accessed March 1, 2013.
2. Strokecenter.org. http://www.strokecenter.org/wp content/uploads/2011/08/barthel_index.pdf. Accessed March 1, 2013.

13. Majority of Ischemic Strokes Due to Atrial
Fibrillation Present With Hemiplegia and Aphasia
Proportion of patients (%)
• 15% of patients with AFib-related stroke will present comatose1
Select stroke symptoms at presentation (p < 0.0001)2
80
60
67.9
AFib (n=6842)
59.9
50
No AFib (n=20,118)
40.4
40
14.3
20
11.8
17.3
12.3
0
Hemiplegia
•
Speech disturbances
Visual disturbances
Dysphagia
1 in 3 patients with AFib-related ischemic stroke at admission present1,3:
• Unable to feed, bathe, or groom themselves
• Bowel and bladder incontinent, unable to self-toilet
• Immobile, unable to use stairs, unable to sit
1. Steger C et al. Eur Heart J. 2004;25:1734-1740.
2. Gattellari M et al. Cerebrovasc Dis. 2011;32:370-382.
3. Strokecenter.org. http://www.strokecenter.org/wp content/uploads/2011/08/barthel_index.pdf. Accessed March 1, 2013.

14. Time Is Brain in Acute Ischemic Stroke
• Once an ischemic stroke has happened, timely management is
critical for ensuring the best possible outcome1-3
Potential Estimated Rate of Loss in Untreated Acute Ischemic Stroke4
Per Second
Per Hour
Per Stroke (~10 hr)
~32,000 neurons
lost
1.9 million
neurons lost
120 million
neurons lost
1.2 billion
neurons lost
~233 million
synapses lost
14 billion
synapses lost
830 billion
synapses lost
8.3 trillion
synapses lost
~218 yards of
fibers lost
7.5 miles of
fibers lost
447 miles of
fibers lost
4470 miles of
fibers lost
Accelerated
aging: 8.7 hours
1.
2.
3.
4.
Per Minute
Accelerated
aging: 3.1 weeks
Accelerated
aging: 3.6 years
Accelerated
aging: 36 y
Jauch EC et al. Stroke. 2013;44:870-947.
Fonarow GC et al. Circulation. 2011;123:750-758.
Hacke W et al. Lancet. 2004;363:768-774.
Saver JL. Stroke. 2006;37:263-266.

15. Patients With Atrial Fibrillation-Related Ischemic
Strokes Are More Likely to Have Complications in
the Hospital
Complications During Hospital Stay for Acute Ischemic Stroke
50
43.1
Proportion of patients (%)
45
40
35
30.8
AFib (n=6842)
30
No AFib (n=20,118)
25
20
15
10
14.7
14.6
11.6
5.9
8.4
11.4
10.5
7.5
5
0
Mechanical
vent/ICU/coma
(p<0.0001)
Pneumonia
(p<0.0001)
Gattellari M et al. Cerebrovasc Dis. 2011;32:370-382.
Urinary
incontinence
(p<0.0001)
Urinary tract
infection
(p<0.0001)
Any complication
(p<0.0001)

16. Patients With Ischemic Strokes Due to Atrial Fibrillation
Are More Likely to Be Disabled at Discharge and Less
Likely to Be Discharged to Home
• At discharge, patients with AFib-related ischemic stroke are more disabled
than patients without AFib1-3*
– Less able to perform self-care or activities of daily living
– More likely to be dependent
Percent of patients (%)
Percentage of patients discharged home1,4
70
60
50
40
30
20
10
0
27%
fewer
32%
fewer
60
44
AFib
66.4
45.1
No
AFib
Steger et al (n=992)*
†
Kimura et al (n=15,831)
*Patients with AFib were older, more likely to be female, have a history of stroke, CAD, and heart disease. 1
†Patients with AFib were older, more likely to be female, and have a history of stroke. 4
1. Steger C et al. Eur Heart J. 2004;25:1734-1740. 2. Strokecenter.org. http://www.strokecenter.org/wp-content/uploads/2011/08/modified_rankin.pdf.
Accessed March 1, 2013. 3. Strokecenter.org. http://www.strokecenter.org/wp content/uploads/2011/08/barthel_index.pdf. Accessed March 1, 2013.
4. Kimura K et al. J Neurol Neurosurg Psychiatry. 2005;76:679-683.

17. Atrial Fibrillation-Related Ischemic Stroke Is
Associated With Higher Short- and Long-Term
Mortality
Adjusted mortality in patients
post-ischemic stroke1
Annual mortality rate
post-ischemic stroke2
60
30
25
AFib (n=6842)
20.9
20
15
No AFib
(n=20,118)
14.7
14.1
50
23.1
Annualized rate (%/yr)
Proportion of patients (%)
26.7
10.9
10
AFib (n=869)
40
No AFib (n=2661)
30
20
5
10
0
0
30 day
90 day
1 year
1. Gattellari M et al. Cerebrovasc Dis. 2011;32:370-382.
2. Marini C et al. Stroke. 2005;36:1115-1119.
1
2
3
4
5
Years
6
7
8

18. Patients With Atrial Fibrillation-Related Ischemic
Stroke Are More Likely to Remain Disabled
Disability post-ischemic stroke
90
79.5
Mean Barthel Index score
80
79
70
80.3
64.3
58.6
60
49.7
50
46.1
40
29.6
30
AFib (n=30)
20
No AFib (n=120)
10
0
Acute
3 months 6 months 12 months
Lin H-J et al. Stroke. 1996;27:1760-1764.

19. Patient Emotional and Psychological Phases
Through Their Stroke* Evolution
Acute Care
Inpatient Rehabilitation
Discharge Home
• Focus on “getting
better” & returning to
pre-stroke life
• Intensive therapy
• Marked improvement
• Present focused
• Increased risk of injury
• Loss of control/independence
• Drastic decrease in treatment
intensity
• Reach a plateau in functional
recovery
• Increased “self” focus
• Comparison between pre- &
post-stroke life
• Begin to realize long-term impact
on functional status
Stroke Survivors
• Limited memory
of this phase
Phase 1 – Stroke
Crisis
Phase 2 – Expectations for Recovery
Phase 3 – Crisis of Discharge
*Not specific to AFib-related ischemic stroke.
Used with permission. Lutz BJ, Young ME, Cox KJ, et al. The Crisis of Stroke: Experiences of Patients and Their Family
Caregivers, Topics in Stroke Rehabilitation, 2011;18(6):189. www.strokejournal.com.

20. Transitioning Out of the Hospital After a Stroke*
May Have Significant Emotional and Psychological
Impact on Caregivers
Phase 1 – Stroke
Crisis
• Crisis mode
• No preparation
• Focus on patient
survival
• Uncertain
prognosis/future
• Family support
• Decision about
rehabilitation
Phase 2 – Expectations for Recovery
Focus on recovery
Expecting return to
pre-stroke life
• Begin to plan for &
to try to anticipate
post-discharge
needs
• Become
overwhelmed
with discharge
preparation
• Multiple competing
demands
Phase 3 – Crisis of Discharge
• Realize the enormity
of the caregiver role
& need for help
• 24/7 responsibility
• Assume new roles/
responsibilities
• Feel
alone/abandoned/
isolated/overwhelmed
• Become exhausted
• Concern about
survivor’s mental
& physical health
• Increased risk for
injury & poor health
• Increased concerns
about financial
impact
• Loss/change in
future plans
Family Caregivers
Increasing focus on & responsibility for patient’s needs
Decreasing focus on self/own self-care
*Not specific to AFib-related ischemic stroke.
Used with permission. Lutz BJ, Young ME, Cox KJ, et al. The Crisis of Stroke: Experiences of Patients and Their Family
Caregivers, Topics in Stroke Rehabilitation, 2011;18(6):189. www.strokejournal.com

21. Stroke Not Only Impacts Physical Symptoms, but
Emotional as Well
Meta-analysis of depression frequency post-stroke
Phase/study
Acute
Population
Hospital
Rehabilitation
Subtotal
Proportional Frequency (95% CI)
33% (29% to 37%)
36% (0% to 73%)
30% (16% to 44%)
32% (19% to 44%)
Medium-term
Population
Hospital
Rehabilitation
Subtotal
33% (0% to 72%)
32% (23% to 41%)
36% (20% to 39%)
34% (20% to 39%)
Long-term
Population
Hospital
Rehabilitation
Subtotal
34% (24% to 43%)
34% (24% to 45%)
34% (26% to 42%)
34% (29% to 39%)
Overall
33% (29% to 36%)
0
20
40
60
Percent
80
100
• As many as 1 in 3 stroke patients will report symptoms of depression, regardless of stroke etiology
Used with permission from Hackett ML et al. Stroke. 2005;36:1330-1340.

22. Long-term Burden on Caregivers of Stroke
Patients Can Be Significant
• Study of 115 caregivers of stroke
patients at least 3 years post-stroke.
Caregivers were assessed for burden
of caregiving (using Sense of
Competence Questionnaire) and
potential explanatory factors
Items associated with high level of caregiver burden
“I feel that my social life has suffered because of my involvement with
my partner”
“I worry all the time about my partner”
“The responsibility for my partner weighs heavily on me over and
above the responsibilities for my family, my job, etc”
“It is unclear to me how much care my partner needs”
“I feel that my partner seems to expect me to take care of him/her as
if I were the only one he/she could depend on”
Scholte op Reimer WJM et al. Stroke. 1998;29:1605-1611.

23. Management of Patients
With Atrial Fibrillation

24. Atrial Fibrillation Management Is
Multifactorial, Involving Rate/ Rhythm Control and
Thromboprophylaxis
Paroxysmal AFib
Persistent AFib
• No rate or rhythm
• Anticoagulation as
control unless needed
indicated
for significant
• Rate control as needed
symptoms
if minimal or no
• Anticoagulation as
symptoms
indicated
• If disabling symptoms,
• Consider ablation if
consider pharmacologic
antiarrhythmics fail
therapy first, then direct
current cardioversion if
needed
• Consider ablation if
antiarrhythmics fail
Fuster V et al. Circulation. 2011;123:e269-e367.
Permanent AFib
• Anticoagulation and
rate control as
needed

25. Ischemic Stroke Risk Is Similar Regardless of
Rate/Rhythm Control or Pattern of Atrial Fibrillation
Observed Rate of Ischemic Stroke
by Rate or Rhythm Control1
Observed Rate of Ischemic Stroke by
Risk Group and Type of AFib2
8
14
7.1
Annualized stroke rate, (%/yr)
7
Percent of patients, (%)
(p= 0.79)
6
5.5
5
4
3
2
1
0
(p= NS)
12
Paroxysmal (n= 460)
Sustained (n= 1552)
10
8
(p= NS)
6
4
(p= NS)
2
0
Rate
Rhythm
Low-Risk*
Moderate-Risk†
High-Risk‡
*No moderate or high-risk features.
†Hypertension (systolic BP > 160 mm Hg or diastolic BP > 90 mm Hg) and age ≤ 75 years; diabetes (definition not indicated),
and no high-risk features.
‡Age > 75 years and hypertension or female, prior stroke or TIA.
1. Wyse DG et al. N Engl J Med. 2002;347:1825-1833.
2. Adapted with permission from Hart RG et al. J Am Coll Cardiol. 2000;35:183-187.

26. CHADS2 and CHA2DS2-VASc Are Risk Stratification
Schemes That Can Help Assess the Risk of Ischemic
Stroke in Non-valvular Atrial Fibrillation
Stroke risk stratification
CHADS2
score1
Criteria
CHA2DS2-VASc
Score2
1
C
CHF/LV dysfunction
1
1
H
Hypertension
1
1
A
Age ≥75 years
2
1
D
Diabetes mellitus
1
2
S
Stroke/TIA/TE
2
N/A
V
Vascular disease*
1
N/A
A
Age 65-74 years
1
N/A
Sc
Sex category
(female gender)
1
Assessment of risk based on score2
0: Low risk
1: Intermediate risk
≥ 2: High risk
*Includes prior myocardial infarction, peripheral artery disease, or aortic plaque. 2
1. Gage BF et al. JAMA. 2001;285:2864-2870.
2. Lip GYH et al. Chest. 2010;137:263-272.

27. HAS-BLED Is a Risk Stratification Scheme That Can Help
Assess the Risk of Bleeding in Atrial Fibrillation
HAS-BLED Scoring System1
Score
Annualized rate of major bleeding in
anticoagulated* patients with AFib2
18
Criteria
15.5
1
H
Hypertension
1 or 2
A
Abnormal renal and liver
function (1 pt each)
1
S
Stroke
1
B
Bleeding
1
L
Labile INRs
Annualized rate (%/yr)
16
14
12
10
8
E
Elderly
1 or 2
D
Drugs or alcohol (1 pt each)
3.4
4
2
1
5.7
6
1.9
2.4
2
3
0.7
0
1
4
HAS-BLED score
*48,599 patients with AFib on anticoagulation, does not include patients on anticoagulation + aspirin
1. Pisters R et al. CHEST. 2010;138:1093-1100.
2. Friberg L et al. Eur Heart J. 2012;33:1500-1510.
5
6

28. Anticoagulation Is Recommended to Reduce
the Risk of Ischemic Stroke and Systemic
Thromboembolism
•
ACCF/AHA/HRS Guidelines for Antithrombotic Therapy for Patients With AFib1*
• For primary prevention of thromboembolism in patients with NVAF
• Antithrombotic therapy with either aspirin or an anticoagulant is reasonable in
patients with one moderate risk factor
• Antithrombotic therapy is recommended for patients with more than 1
moderate risk factor
•
Anticoagulation is associated with an increased risk of bleeding, including hemorrhagic
stroke. This risk must be weighed against the benefit of stroke risk reduction2,3
•
Anticoagulation therapy has been shown to reduce the risk of ischemic stroke up to 2/3
(67%) vs control/placebo4
ACCF=American College of Cardiology Foundation; AHA=American Heart Association; HRS=Heart Rhythm Society
*The American Heart Association is a voluntary national health agency to help reduce disability and death from cardiovascular
disease and stroke. The full guidelines can be located online at: http://circ.ahajournals.org/content/123/10/e269.
High-risk factors: prior thromboembolism (stroke, TIA, or systemic embolism) and mitral stenosis, prosthetic heart valve.1
Moderate-risk factors: age ≥75 years, hypertension, heart failure, LVEF ≤ 35%, and diabetes mellitus.1
Less validated risk factors: female gender, age 65-74 years, coronary artery disease, thyrotoxicosis.1
1.
2.
3.
4.
Fuster V et al. Circulation. 2011;123:e269-e367.
Hart RJ. Neurology. 2000;55:907-908.
Fang MC et al. Stroke. 2012;43:1-5.
Hart RJ et al. Ann Intern Med. 2007;146:857-867.

29. In Anticoagulation Risk-Benefit Assessment, the
Risk of Events Must Be Weighed Against Their
Relative Frequency and Severity
Annual Event Rate1,2
Mortality at 30 Days2,3
Ischemic Stroke*
CHADS2 score†
0: 0.6%
1: 3.4%
2: 4.7%
3: 8.0%
4: 12.6%
5: 14.1%
6: 14.6%
27.7%
Intracranial Bleed
0.47%
48.6%
Major Extracranial Bleed‡
0.64%
5.1%
Event
*In patients not on anticoagulation.
†Adjusted for aspirin use.
‡Major extracranial bleeding was defined as fatal, requiring transfusion of ≥2 units of packed red blood cells, or hemorrhage
into a critical anatomic site.
1. Friberg L et al. Eur Heart J. 2012;33:1500-1510.
2. Fang MC et al. Am J Med. 2007;120:700-705.
3. Fang MC et al. Stroke. 2012;43:1793-1799.

30. Approximately 50% of Patients With Atrial
Fibrillation Do Not Receive Anticoagulation
Oral Anticoagulation Is Prescribed for Only 41% to 65% of Eligible
Patients With AFib1-7
Patients Treated With Oral
Anticoagulation, (%)
100
65
55
54
50
0
64
52
51
41
ATRIA1
N= 11,082
NABOR2
N= 945
Hylek3
N= 405
Medicare4
N= 17,272
Walker5
N= 116,969
ATRIA= Anticoagulation and Risk Factors in Atrial Fibrillation.
NABOR= National Anticoagulation Benchmark and Outcomes Report.
Williams6
Euro
N= 50,071 Heart Study7
N= 2706
1. Go AS et al. Ann Intern Med. 1999;131:927-934. 2. Waldo AL et al. J Am Coll Cardiol. 2005;46:1729-1736. 3. Hylek EM et al. Stroke. 2006;37:1075-1080.
4. Birman-Deych E et al. Stroke. 2006;37:1070-1074. 5. Walker AM, Bennett D. Heart Rhythm. 2008;5:1365-1372. 6. Williams CJ et al. American College of
Cardiology 58th Annual Scientific Session; March 29-31, 2009; Orlando, FL. 7. Nieuwlaat R et al. Eur Heart J. 2006;27:3018-3026.

31. Conclusions
• AFib is a common cause of ischemic stroke that has
devastating consequences for patients and families
• AFib-related ischemic strokes can result in worse patient
outcomes than those caused by other underlying
etiologies
• The risk of ischemic stroke remains regardless of the
pattern of AFib or rate/rhythm intervention
• Anticoagulating is critical to reducing the risk of AFibrelated ischemic strokes and yet it is underutilized
• Use of anticoagulation should be weighed against the
increased risk of bleeding
AFIB574903PROF