Defining Moments in Non-Valvular Atrial FibrillationPathophysiology and Consequences of Ischemic Stroke

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Approximately 8 Ischemic Strokes Due to Atrial Fibrillation Occur Every Hour in the United States

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.

~ 795,000 strokes annually1

~ 691,650 ischemic strokes1

~ 138,330 cardioembolic2

~ 69,165 cardioembolic ischemic strokes due to AFib

annually2,3

~ 87%

~ 20%

~ 50%

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

Overview and Pathophysiology

Atrial Fibrillation Is the Most Common Cause of Cardioembolic Ischemic Stroke

1. Freeman WD, Aguilar MI. Neurol Clin. 2008;26:1129-1160.

50%

20%

15%

15%Atrial fibrillation

Ventricular thrombus

Valvular heart disease

Structural heart defects or tumors

Cardiac Diseases Leading to Cardioembolic Events

Ischemic Stroke Risk Factors Are Common in Patients With Atrial Fibrillation

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.

Prevalence of risk factors for ischemic stroke1*

HR

for

eve

nt

Hazard ratio for ischemic stroke without anticoagulation2

CHF

Hyper

tens

ion

Age ≥

75

Diabet

es m

ellitu

s

Stroke

/TIA

/TE

Vascu

lar d

iseas

e

Female

sex

0

10

20

30

40

50

60

70

80

23.5

67.3

28.5

17.3

9.1

44.240.8

Per

cen

tag

e o

f pa

tient

s

CHF

Hyper

tens

ion

Age ≥

75

Diabet

es m

ellitu

s

Stroke

/TIA

/TE

Vascu

lar d

iseas

e

Female

sex

0

1

2

3

4

5

6

0.98 1.19

5.49

1.19

2.96

1.07 1.21

N=1084 N=90,490

Atrial Fibrillation Predisposes to the Formation of Clots in the Left Atrium and Appendage

Blood stasis

Abnormal blood

constituents

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

Left atriumthrombus

To carotid artery

Anatomical and structural

defects

Smaller Vessels Make the Brain Vulnerable to Cardioembolic Ischemia

ACA/PCA2

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

ACA

MCA

PCALAD artery (proximal)4

Femoral artery5

MCA1

Cardioembolic clot3

Ischemia From Cardioembolic Thrombi Cause Neurologic Damage to Vast Areas of Brain Territory

ACA=anterior cerebral artery; MCA=middle cerebral artery; PCA=posterior cerebral artery.1. Maas MB, Safdieh JE. Neurology. 2009;13:1-16.

PCA territory

ACA territory

MCA territory

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

• Measures degree of disability or dependence in daily activities

• Score of 0-6– 0: No symptoms– 1: No significant disability despite

symptoms– 2: Slight disability– 3: Moderate disability– 4: Moderately severe disability– 5: Severe disability– 6: Dead

Barthel Index2

• Measure of the ability to perform self-care and activities of daily living

• Rates 10 performance items on a point scale

– Feeding, bathing, dressing, bowels, 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.

Majority of Ischemic Strokes Due to Atrial Fibrillation Present With Hemiplegia and Aphasia

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

Hemiplegia Speech disturbances Visual disturbances Dysphagia0

1020304050607080

67.9

50

14.3 17.3

59.9

40.4

11.8 12.3

AFib (n=6842)

No AFib (n=20,118)

Pro

por

tion

of p

atie

nts

(%) Select stroke symptoms at presentation (p < 0.0001)2

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.

• 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

Time Is Brain in Acute Ischemic Stroke

• Once an ischemic stroke has happened, timely management is critical for ensuring the best possible outcome1-3

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.

1.2 billion neurons lost

8.3 trillion synapses lost

4470 miles of fibers lost

Accelerated aging: 36 y

Per Second

~32,000 neurons lost

Potential Estimated Rate of Loss in Untreated Acute Ischemic Stroke4

Per Minute Per Hour Per Stroke (~10 hr)

~233 million synapses lost

~218 yards of fibers lost

Accelerated aging: 8.7 hours

1.9 million neurons lost

14 billion synapses lost

7.5 miles of fibers lost

Accelerated aging: 3.1 weeks

120 million neurons lost

830 billion synapses lost

447 miles of fibers lost

Accelerated aging: 3.6 years

Patients With Atrial Fibrillation-Related Ischemic Strokes Are More Likely to Have Complications in the Hospital

Mechanical vent/ICU/coma Pneumonia Urinary incontinence Urinary tractinfection

Any complication0

5

10

15

20

25

30

35

40

45

50

11.614.6

10.5

14.7

43.1

5.98.4 7.5

11.4

30.8AFib (n=6842)

No AFib (n=20,118)

Complications During Hospital Stay for Acute Ischemic Stroke

Pro

port

ion

of p

atie

nts

(%)

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

(p<0.0001) (p<0.0001) (p<0.0001) (p<0.0001) (p<0.0001)

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

Steger et al (n=992)* Kimura et al (n=15,831)0

10

20

30

40

50

60

70

44 45.1

60 66.4

AFib

No AFib

Percentage of patients discharged home1,4

*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.

Per

cen

t of

pat

ient

s (%

)

27% fewer

32% fewer

†

Atrial Fibrillation-Related Ischemic Stroke Is Associated With Higher Short- and Long-Term Mortality

30 day 90 day 1 year0

5

10

15

20

25

30

14.1

20.9

26.7

10.9

14.7

23.1AFib (n=6842)

No AFib (n=20,118)

Adjusted mortality in patientspost-ischemic stroke1

1 2 3 4 5 6 7 80

10

20

30

40

50

60

AFib (n=869)

No AFib (n=2661)

Annual mortality ratepost-ischemic stroke2

Years

Pro

por

tion

of p

atie

nts

(%)

Ann

ualiz

ed r

ate

(%/y

r)

1. Gattellari M et al. Cerebrovasc Dis. 2011;32:370-382.2. Marini C et al. Stroke. 2005;36:1115-1119.

Acute 3 months 6 months 12 months

0

10

20

30

40

50

60

70

80

90

29.6

49.746.1

64.358.6

79.5 79 80.3

AFib (n=30)

No AFib (n=120)

Patients With Atrial Fibrillation-Related Ischemic Stroke Are More Likely to Remain Disabled

Mea

n B

arth

el In

dex

scor

e

Lin H-J et al. Stroke. 1996;27:1760-1764.

Disability post-ischemic stroke

Patient Emotional and Psychological Phases Through Their Stroke* Evolution

*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.

Phase 3 – Crisis of DischargePhase 2 – Expectations for Recovery

• 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

• Focus on “getting better” & returning to pre-stroke life

• Intensive therapy• Marked improvement• Present focused

• Limited memory of this phase

Acute Care Inpatient Rehabilitation Discharge Home

Phase 1 – Stroke Crisis

Stroke Survivors

Transitioning Out of the Hospital After a Stroke* May Have Significant Emotional and Psychological Impact on Caregivers

*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

• Crisis mode• No preparation• Focus on patient

survival• Uncertain

prognosis/future• Family support• Decision about

rehabilitation

Focus on recoveryExpecting return to

pre-stroke life

• Begin to plan for &to try to anticipatepost-discharge needs

• Become overwhelmedwith dischargepreparation

• Multiple competingdemands

• 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 aboutsurvivor’s mental& physical health

• Increased risk forinjury & poor health

• Increased concernsabout financialimpact

• Loss/change infuture plans

Family Caregivers

Increasing focus on & responsibility for patient’s needs

Decreasing focus on self/own self-care

Phase 3 – Crisis of DischargePhase 2 – Expectations for RecoveryPhase 1 – Stroke

Crisis

Stroke Not Only Impacts Physical Symptoms, but Emotional as Well

• 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.

Meta-analysis of depression frequency post-stroke

Acute

PopulationHospitalRehabilitationSubtotal

Medium-term

PopulationHospitalRehabilitationSubtotal

Long-term

PopulationHospitalRehabilitationSubtotal

Overall

Phase/study Proportional Frequency (95% CI)

33% (29% to 37%)36% (0% to 73%)30% (16% to 44%)32% (19% to 44%)

33% (0% to 72%)32% (23% to 41%)36% (20% to 39%)34% (20% to 39%)

34% (24% to 43%)34% (24% to 45%)34% (26% to 42%)34% (29% to 39%)

33% (29% to 36%)

0 20 40 60 80 100Percent

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

“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.

“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 social life has suffered because of my involvement with my partner”

“I worry all the time about my partner”

Items associated with high level of caregiver burden

Management of Patients With Atrial Fibrillation

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

Fuster V et al. Circulation. 2011;123:e269-e367.

Paroxysmal AFib Persistent AFib Permanent AFib

• No rate or rhythm control unless needed for significant symptoms

• Anticoagulation as indicated

• Consider ablation if antiarrhythmics fail

• Anticoagulation as indicated

• Rate control as needed if minimal or no symptoms

• If disabling symptoms, consider pharmacologic therapy first, then direct current cardioversion if needed

• Consider ablation if antiarrhythmics fail

• Anticoagulation and rate control as needed

Ischemic Stroke Risk Is Similar Regardless of Rate/Rhythm Control or Pattern of Atrial Fibrillation

*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.

Rate Rhythm0

1

2

3

4

5

6

7

8

5.5

7.1

(p= 0.79)

Per

cen

t of

pat

ient

s, (

%)

Observed Rate of Ischemic Stroke by Rate or Rhythm

Control1

Paroxysmal (n= 460)

Sustained (n= 1552)

0

2

4

6

8

10

12

14

High-Risk‡

(p= NS)

Low-Risk*

(p= NS)

Moderate-Risk†

(p= NS)

Observed Rate of Ischemic Stroke by Risk Group and Type of AFib2

Ann

ualiz

ed s

tro

ke r

ate,

(%

/yr)

CHADS2 and CHA2DS2-VASc Are Risk Stratification Schemes That Can Help Assess the Risk of Ischemic Stroke in Non-valvular Atrial Fibrillation

CHADS2 score1 Criteria

CHA2DS2-VASc Score2

1 CCHF/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 ScSex category (female gender)

1

*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.

Stroke risk stratification

Assessment of risk based on score2

0: Low risk 1: Intermediate risk≥ 2: High risk

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

1 2 3 4 5 60

2

4

6

8

10

12

14

16

18

0.71.9 2.4

3.4

5.7

15.5Score Criteria

1 H Hypertension

1 or 2 AAbnormal renal and liver function (1 pt each)

1 S Stroke

1 B Bleeding

1 L Labile INRs

1 E Elderly

1 or 2 D Drugs or alcohol (1 pt each)

*48,599 patients with AFib on anticoagulation, does not include patients on anticoagulation + aspirin1. Pisters R et al. CHEST. 2010;138:1093-1100.2. Friberg L et al. Eur Heart J. 2012;33:1500-1510.

Annualized rate of major bleeding in anticoagulated* patients with AFib2

Ann

ualiz

ed r

ate

(%/y

r)

HAS-BLED score

HAS-BLED Scoring System1

Anticoagulation Is Recommended to Reduce the Risk of Ischemic Stroke and Systemic Thromboembolism

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.

• 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

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†

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%

*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 AnticoagulationOral Anticoagulation Is Prescribed for Only 41% to 65% of Eligible

Patients With AFib1-7

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.

55 54 51

65

52

41

64

0

50

100

Pat

ient

s T

reat

ed W

ith O

ral

Ant

icoa

gula

tion,

(%

)

ATRIA1

N= 11,082NABOR2

N= 945Hylek3

N= 405Medicare4

N= 17,272Walker5

N= 116,969Williams6

N= 50,071Euro

Heart Study7

N= 2706

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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