Defining Moments in

Non-Valvular Atrial Fibrillation

Pathophysiology and Consequences of
Ischemic Stroke
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 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 Approximately 8 ischemic

ischemic strokes due to AFib strokes/hr due to AFib in the US
annually2,3

More likely to be bedridden, disabling,

1. Go AS et al. Circulation. 2013;127:e6-e245. and fatal than non-AFib-related
2. Sacco RL et al. Stroke. 2006;37:577-617.
3. Freeman WD et al. Neurotherapeutics. 2011;8:488-502. ischemic strokes4,5
4. Steger C et al. Eur Heart J. 2004;25:1734-1740..
5. Gattellari M et al. Cerebrovasc Dis. 2011;32:370-382.
Overview and
Pathophysiology
 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.

 Ischemic Stroke Risk Factors Are Common
in Patients With Atrial Fibrillation
Hazard ratio for ischemic stroke without
Prevalence of risk factors for ischemic stroke1* anticoagulation2
80 6 5.49
Percentage of patients

70 67.3
5
60

HR for event
50 N=1084 4 N=90,490
44.2
40.8
40 2.96
3
28.5
30 23.5
17.3 2
20 1.19 1.19 1.21
9.1 0.98 1.07
10 1
0
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.
 Atrial Fibrillation Predisposes to the Formation of
Clots in the Left Atrium and Appendage

Blood stasis
To carotid artery

Abnormal Left atrium

blood thrombus
constituents
Anatomical
and structural
defects

Watson T et al. Lancet. 2009;373:155-166.

 Smaller Vessels Make the Brain Vulnerable
to Cardioembolic Ischemia
MCA1
ACA
ACA/PCA2

Cardioembolic clot3
MCA

PCA
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
 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.
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

 Clinical Outcome Measures for Ischemic
Stroke
Modified Rankin Scale1 Barthel Index2
• Measures degree of disability or • Measure of the ability to perform
dependence in daily activities self-care and activities of daily
• Score of 0-6 living
– 0: No symptoms • Rates 10 performance items on a
– 1: No significant disability despite point scale
symptoms – Feeding, bathing, dressing, bowel
– 2: Slight disability s, stairs, bladder, toilet
– 3: Moderate disability use, transfers (bed to chair and
– 4: Moderately severe disability back), grooming, and mobility
– 5: Severe disability • Score 0-100
– 6: Dead – 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.
 Majority of Ischemic Strokes Due to Atrial
Fibrillation Present With Hemiplegia and Aphasia

• 15% of patients with AFib-related stroke will present comatose1

Select stroke symptoms at presentation (p < 0.0001)2

Proportion of patients (%)

80
67.9
59.9 AFib (n=6842)
60 50 No AFib (n=20,118)
40.4
40

14.3 17.3
20 11.8 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.
 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 Minute Per Hour Per Stroke (~10 hr)

~32,000 neurons 1.9 million 120 million 1.2 billion

lost neurons lost neurons lost neurons lost

~233 million 14 billion 830 billion 8.3 trillion

synapses lost synapses lost synapses lost synapses lost

~218 yards of 7.5 miles of 447 miles of 4470 miles of

fibers lost fibers lost fibers lost fibers lost

Accelerated Accelerated Accelerated Accelerated

aging: 8.7 hours aging: 3.1 weeks aging: 3.6 years aging: 36 y

1. Jauch EC et al. Stroke. 2013;44:870-947.

2. Fonarow GC et al. Circulation. 2011;123:750-758.
3. Hacke W et al. Lancet. 2004;363:768-774.
4. Saver JL. Stroke. 2006;37:263-266.
 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
45 43.1
Proportion of patients (%)

40
35
AFib (n=6842) 30.8
30
25 No AFib (n=20,118)
20
14.6 14.7
15 11.6 11.4
10.5
10 8.4 7.5
5.9
5
0
Mechanical Pneumonia Urinary Urinary tract Any complication
vent/ICU/coma incontinence infection
(p<0.0001) (p<0.0001) (p<0.0001) (p<0.0001) (p<0.0001)

Gattellari M et al. Cerebrovasc Dis. 2011;32:370-382.

 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

Percentage of patients discharged home1,4

27% 32%
70 fewer 60 fewer 66.4
Percent of patients (%)

60
50 44 AFib 45.1
40
No
30 AFib
20
10
0
†
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.
 Atrial Fibrillation-Related Ischemic Stroke Is
Associated With Higher Short- and Long-Term
Mortality
Adjusted mortality in patients Annual mortality rate
post-ischemic stroke1 post-ischemic stroke2
30 60
26.7

25 AFib (n=6842) 23.1

50
Proportion of patients (%)

Annualized rate (%/yr)

20.9 AFib (n=869)
20 No AFib 40
(n=20,118) No AFib (n=2661)

14.1 14.7
15 30
10.9
10 20

5 10

0 0
30 day 90 day 1 year 1 2 3 4 5 6 7 8
Years
1. Gattellari M et al. Cerebrovasc Dis. 2011;32:370-382.
2. Marini C et al. Stroke. 2005;36:1115-1119.
 Patients With Atrial Fibrillation-Related Ischemic
Stroke Are More Likely to Remain Disabled

Disability post-ischemic stroke

90
79.5 79 80.3
80
Mean Barthel Index score

70 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.

 Patient Emotional and Psychological Phases
Through Their Stroke* Evolution
Acute Care Inpatient Rehabilitation Discharge Home

• Increased risk of injury

• Loss of control/independence
Stroke Survivors
• Drastic decrease in treatment
• Focus on “getting
intensity
better” & returning to
• Reach a plateau in functional
• Limited memory pre-stroke life
recovery
of this phase • Intensive therapy
• Increased “self” focus
• Marked improvement
• Comparison between pre- &
• Present focused
post-stroke life
• Begin to realize long-term impact
on functional status

Phase 1 – Stroke
Phase 2 – Expectations for Recovery Phase 3 – Crisis of Discharge
Crisis

*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.
 Transitioning Out of the Hospital After a Stroke*
May Have Significant Emotional and Psychological
Impact on Caregivers
Phase 1 – Stroke
Phase 2 – Expectations for Recovery Phase 3 – Crisis of Discharge
Crisis

• Begin to plan for & • Realize the enormity • Concern about

• Crisis mode to try to anticipate of the caregiver role survivor’s mental
• No preparation post-discharge & need for help & physical health
• Focus on patient needs • 24/7 responsibility • Increased risk for
survival Focus on recovery
• Become • Assume new roles/ injury & poor health
• Uncertain Expecting return to
overwhelmed responsibilities • Increased concerns
prognosis/future pre-stroke life
with discharge • Feel about financial
• Family support preparation alone/abandoned/ impact
• Decision about • Multiple competing isolated/overwhelmed • Loss/change in
rehabilitation demands • Become exhausted 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
 Stroke Not Only Impacts Physical Symptoms, but
Emotional as Well
Meta-analysis of depression frequency post-stroke
Phase/study Proportional Frequency (95% CI)
Acute
Population 33% (29% to 37%)
Hospital 36% (0% to 73%)
Rehabilitation 30% (16% to 44%)
Subtotal 32% (19% to 44%)

Medium-term
Population 33% (0% to 72%)
Hospital 32% (23% to 41%)
Rehabilitation 36% (20% to 39%)
Subtotal 34% (20% to 39%)

Long-term
Population 34% (24% to 43%)
Hospital 34% (24% to 45%)
Rehabilitation 34% (26% to 42%)
Subtotal 34% (29% to 39%)

Overall 33% (29% to 36%)

0 20 40 60 80 100
Percent

• 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.

 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.

Management of Patients
With Atrial Fibrillation
 Atrial Fibrillation Management Is
Multifactorial, Involving Rate/ Rhythm Control and
Thromboprophylaxis

Paroxysmal AFib Persistent AFib Permanent AFib

• No rate or rhythm • Anticoagulation as • Anticoagulation and
control unless needed indicated rate control as
for significant needed
• 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.

 Ischemic Stroke Risk Is Similar Regardless of
Rate/Rhythm Control or Pattern of Atrial Fibrillation
Observed Rate of Ischemic Stroke Observed Rate of Ischemic Stroke by
by Rate or Rhythm Control1 Risk Group and Type of AFib2
8
7.1 14
7 (p= NS)

Annualized stroke rate, (%/yr)

(p= 0.79) 12 Paroxysmal (n= 460)
6 5.5 Sustained (n= 1552)
Percent of patients, (%)

10
5
8 (p= NS)
4

3 6

2 4
(p= NS)
1 2
0 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.
 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 CHA2DS2-VASc
score1 Criteria 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
Sex category
N/A Sc 1
(female gender)

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.
 HAS-BLED Is a Risk Stratification Scheme That Can Help
Assess the Risk of Bleeding in Atrial Fibrillation

HAS-BLED Scoring System1 Annualized rate of major bleeding in

anticoagulated* patients with AFib2
18
Score Criteria
16 15.5
1 H Hypertension

Annualized rate (%/yr)

14
Abnormal renal and liver 12
1 or 2 A
function (1 pt each)
10
1 S Stroke 8
5.7
1 B Bleeding 6
4 3.4
1 L Labile INRs 1.9 2.4
2 0.7
1 E Elderly
0
1 or 2 D Drugs or alcohol (1 pt each) 1 2 3 4 5 6
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.
 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. Fuster V et al. Circulation. 2011;123:e269-e367.

2. Hart RJ. Neurology. 2000;55:907-908.
3. Fang MC et al. Stroke. 2012;43:1-5.
4. Hart RJ et al. Ann Intern Med. 2007;146:857-867.
 In Anticoagulation Risk-Benefit Assessment, the
Risk of Events Must Be Weighed Against Their
Relative Frequency and Severity
Event Annual Event Rate1,2 Mortality at 30 Days2,3
Ischemic Stroke* CHADS2 score† 27.7%
0: 0.6%
1: 3.4%
2: 4.7%
3: 8.0%
4: 12.6%
5: 14.1%
6: 14.6%
Intracranial Bleed 0.47% 48.6%

Major Extracranial Bleed‡ 0.64% 5.1%

*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.
 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
100
Patients Treated With Oral
Anticoagulation, (%)

65 64
55 54 52
51
50
41

0
ATRIA1 NABOR2 Hylek3 Medicare4 Walker5 Williams6 Euro
N= 11,082 N= 945 N= 405 N= 17,272 N= 116,969 N= 50,071 Heart Study7
N= 2706
ATRIA= Anticoagulation and Risk Factors in Atrial Fibrillation.
NABOR= National Anticoagulation Benchmark and Outcomes Report.
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.
 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 AFib-
related ischemic strokes and yet it is underutilized
• Use of anticoagulation should be weighed against the
increased risk of bleeding

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