Atrial Fibrillation and Cryptogenic Stroke: Is There a Link?

Rhea C. Pimentel, MDAssociate Professor of Medicine

Fellowship Program Director, Clinical Cardiac Electrophysiology Program

Disclosures

• Speakers Bureau: Medtronic

• Speakers Bureau: St. Jude Medical

• Speakers Bureau: Janssen Pharmaceuticals

• Speakers Bureau: Boston Scientific

Talk Outline

• Epidemiology of atrial fibrillation and stroke

• Management of thromboembolic risk

• Outpatient monitoring considerations

• Stroke risk based on atrial fibrillation burden

Epidemiology of Atrial Fibrillation and Stroke

Epidemiology of Atrial Fibrillation in the US: Rising Prevalence of the Disease

• As of 2010, 2.66 million Americans are estimated to have AF1

• Lifetime risk for developing AF is high2

– 1 in 4 for men and women aged 40 years

• Prevalence increases rapidly with age3

– 3.8% for persons 60 years old– 9% for persons 80 years old

• AF prevalence is predicted to increase by 2.5 fold by 2050

AF affects 1 in 25 adults aged >60 years and 1 in 10 adults >80 years3

Predicted Prevalence of AF1

2000

Year

16

14

0

5.1 5.6 6.16.8

7.58.4

9.410.3

11.111.7 12.1

5.15.9

6.77.7

8.9

10.2

11.7

13.1

14.3

15.215.9

Lloyd-Jones DM et al. Circulation. 2010;121:e1-e170. 2. Lloyd-Jones DM et al. Circulation. 2004;110:1042-1046.3. Go AS et al. JAMA. 2001;285:2370-2375.

0

1

2

3

4

5

6

7

1990 1995 2000 2005 2010 2015 2020 2025 2030 2035 2040 2045 2050

Year

Adul

ts w

ith A

F (m

illio

ns)

2.08

2.44

2.26

2.66

2.94

3.33

3.80

4.34

4.78

5.16

5.42

5.61

Go AS. et al. JAMA 2001;285:2370-2375.

Independent Risk Factors for Atrial Fibrillation* Framingham Heart Study

95% CI

Men 1.8-2.5 1.0-2.0 1.2-2.0 1.0-2.0 3.1-6.6 1.2-2.5

Women 1.9-2.6 1.1-1.2 1.1-1.8 0.8-1.8 4.2-8.4 2.5-4.5

*2-Year pooled logistic regression; †AF was diagnosed in 226 men in 16,529 follow-up person-examinations; ‡AF was diagnosed in 244 women in 23,763 follow-up person-examinations; §Valvular heart disease was a significantly more potent risk factor for the development of atrial fibrillation in women than in men.DM = diabetes mellitus; HTN = hypertension; MI = myocardial infarction; CHF = congestive heart failure.Benjamin EJ et al. JAMA. 1994;271:840-844.

Men† (N=2090)

Women‡ (N=2641)

P0.0001

P0.05

P0.0001

P0.0001

P0.0001

P0.01 P0.01P0.05

P0.01P0.05

P0.0001

§

Economic Impact and Public Health Burden of Hospitalizations in Those With Atrial Fibrillation

• Significant public health burden; total AF-attributable costs estimated at 6.65 billion1-5

• Annual cost per patient ~$47005

• Associated with more hospitalizations than any other arrhythmia6

– Approximately one third for cardiac rhythm disturbances1

– Increased hospitalizations impact quality of life and health care costs2,7

1. Fuster V et al. Circulation. 2006;114:e257-e354. 2. Le Heuzey J-Y et al. Am Heart J. 2004;147:121-126. 3. Coyne KS et al. Value Health. 2006;9:348-356. 4. Kim MH et al. Adv Ther. 2009;26:847-857. 5. Reynolds MR et al. J Cardiovasc Electrophysiol. 2007;18:628-633. 6. Singh SN et al. J Am Coll Cardiol. 2006;48:721-730. 7. Wattigney WA et al. Circulation. 2003;108:711-716.

Distribution of $6.65 Billion (US) in Annual Atrial Fibrillation Treatment Costs for 2005

Adapted from Coyne KS et al. Value Health. 2006;9:348-356.

$1.95 billion(29%)

$1.53 billion(23%)

$2.93 billion(44%)

$235 million(4%)

Outpatient

Drugs

Indirect inpatient

Direct Inpatient

Atrial Fibrillation Adversely Affects Quality of Life*

SF-36 = 36-question Short-Form health survey.*Across all scales, both the disease specific and generic QoL was significantly worse in the AF patients compared with the controls (P<0.05 compared with AF patients); †Values represent raw mean scores ± SD; ‡P<0.001 compared with AF patients.Dorian P et al. J Am Coll Cardiol. 2000;36:1303-1309.

‡‡

†‡

‡‡ ‡

SF

-36

Sco

re

*P<0.05.

Atrial Fibrillation Is Associated With Increased Mortality

Wolf PA et al. Arch Intern Med. 1998;158:229-234.

Cumulative Mortality by Age and Sex

65-74 75-84 85-89

*

*

*

*

*

*

Age, y

• 795,000 strokes occur annually in the US (from all causes)1

• ~185,000 strokes occur in people who have already had a previous stroke1

• Patients with AF have a 5-fold higher risk of stroke

• Over 87% of strokes are thromboembolic

Strokes in Atrial Fibrillation (AF)

1. Lloyd-Jones D et al. Circulation. 2010;121:e46-e215.

Strokes in Atrial Fibrillation (AF)• Stroke is the number one cause of long-term disability

and the third leading cause of death in patients with AF

• Annual stroke risk is equal for paroxysmal and permanent AF

• Greater than 90% of thrombus accumulation originates in the Left Atrial Appendage (LAA)

Atrial Fibrillation and Cryptogenic StrokeWhy AF Matters

• After standard neurologic evaluation, 36% of stroke survivors are classified as cryptogenic– AF and Atrial Flutter (AFL) are intermittent in 30% of stroke

patients2

• AF detection in cryptogenic stroke changes patient treatment– Only indication for stroke patients to receive anticoagulation– Prevent future strokes by treatment of underlying cause– Interrupt natural history progression of atrial fibrillation

2Jabaudon D et al. Stroke. 2004;35:1647-51.3Tayal AH et al. Neurology. 2008;71:1696-701

Clinical Presentation of Atrial Fibrillation

• AF presents with a wide range of symptoms1

– May also be asymptomatic

• Impact of asymptomatic AF2

– Potential for underlying electrical and structural damage to atrial myocardium

• While AF symptoms alone may not always be severe, untreated disease can result in significant morbidity and mortality3

PALPITATIONSLIGHT-HEADEDNESS

FATIGUE

DYSPNEASYNCOPE

CHEST PAIN

THROMBO-EMBOLISM

DEATH

1. Fuster V et al. Circulation. 2006;114:e257-e354. 2. Page RL et al. Circulation. 2003;107:1141-1145. 3. Stewart S et al. Am J Med. 2002;113:359-364.

Occurrence of Asymptomatic AF and Reliability of Symptoms

1 Strickberger SA, et al. Heart Rhythm. 2005;2:125-131.

Methods:

• “Almost 95% of documented AT episodes were asymptomatic, and symptoms attributed to atrial fibrillation were associated with AT only approximately 15% of the time.”

• “No significant differences in the specific symptoms that correlated with or without a documented atrial tachyarrhythmia were observed.”

• Multicenter trial following 48 patients for 12 months to correlate pacemaker-detected atrial tachyarrhythmia (AT) events with symptoms

Results/Conclusions:

Strickberger1

Management of Thromboembolic Risk

Copyright © The American College of Cardiology. All rights reserved.

From: 2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society

J Am Coll Cardiol. 2014;64(21):e1-e76. doi:10.1016/j.jacc.2014.03.022

Summary of Recommendations for Risk-Based Antithrombotic Therapy

• The CHADS2 Scoring System

• A points based system for predicting risk of stroke in AF, based on key risk factors1,2

– Prior stroke or TIA 2 points– Age >75y 1 point– Hypertension 1 point– Diabetes mellitus 1 point – Heart failure 1 point

TIA = transient ischemic attack1. ACC/AHA/ESC 2006 guidelines J Am Coll Cardiol 2006;48:854-9062. Gage BF et al. JAMA 2001;285:2864–70.

CHA2DS2-VASc

Risk factor score

C Congestive heart failure/LV dysfunction 1

H Hypertension 1

A2 Age ≥75y 2

D Diabetes mellitus 1

S2 Stroke/TIA/TE 2

V Vascular disease (prior myocardial infarction, peripheral artery disease, or aortic plaque) 1

A Age 65-74y 1

Sc Sex category (ie female gender) 1

Maximum Score 9Lip GY, et al., Chest 137, 263-272, 2010

maximum score is 9 since age may contrubute 0, 1, or 2 points

Comparison of Stroke Risk

Friberg L: Eur Heart J 2012;33:1500-1510.

HAS-BLED scoreHypertension, Abnormal Liver or Renal Fxn, Stroke, Bleeding, Labile INR, Elderly, Drugs or Alcohol

Chest. 2010 Nov;138(5):1093-100

ACTIVE-W study• Patients with atrial fibrillation were randomized to standard

therapy with oral anticoagulation (warfarin) or clopidogrel plus aspirin and followed for approximately two years

• When halted in September 2005, ACTIVE-W had enrolled its target of 6600 patients.

• Data safety and monitoring board stopped the trial after a clear increase in efficacy was seen in the warfarin arm of the trial.

Connolly S. American Heart Association Scientific Sessions 2005; Nov 13-16, 2005; Dallas, TX.

Connolly S. American Heart Association Scientific Sessions 2005; Nov 13-16, 2005; Dallas, TX.

Vascular Events and Major Bleeding: ACTIVE-W

End point Clopidogrel+ASA Warfarin Relative risk

p

Vascular events (%/year)

5.64 3.63 1.45 0.0002

Major bleeding (%/year)

2.4 2.2 1.06 0.67

Outpatient Monitoring Considerations

• Recognition of AF may be difficult due to its often ‘silent’ nature

-- 1/3 of patients not aware of so-called ‘asymptomatic AF

• Much earlier detection of the arrhythmia might allow – Timely introduction of therapies to treat AF (rate/rhythm

control)– Interruption of the natural progression of AF

-- Assists in the decision to initiate or discontinue anticoagulation therapy

• Ability to document onset mechanism of AF to aide in treatment

Cardiac Monitoring for Diagnosing AF

Camm AJ et al. Eur Heart J. 2010;31:2369-429.Jabaudon D et al. Stroke. 2004;35:1647-51.

Cardiac Diagnostics Landscape

• 24-Hour Holter

2.5 Million

Event Recorder

1.5 Million

14-30 Day Mobile Cardiac Telemetry

Monitor

250,000

Insertable Cardiac Monitor

25,000

Source: Frost & Sullivan report: North American Cardiac Monitoring and Diagnostic Services Markets

Long term monitorUp to 14 days of monitoringWay for patient to report symptoms during this timeNo access to EKG’s during the monitoring period

Z100A4770.01 | Feb. 2013

-FDA approved for up to 14 days of continuous monitoring

-Patients may “mark” symptoms during this time -No access to rhythm strips during monitoring period

AliveCor• Fully secure, HIPAA-compliant online access• FDA approved December 2012• Sold to US licensed medical providers as a

prescription to record, transmit and store single channel EKG

Not covered by insurance

Currently only works with iPhones

As Cardiac Monitoring Evolves, Diagnostic Yield Improves

Event Monitor: Non-looping

CardioNet MCOT

(Mobile Cardiac

Outpatient Telemetry)

Holter Monitor

AF Auto-

trigger Monitor

Invasive Implantable

Loop Recorder5% – 13%

15%

Event Monitor:Looping Memory

Syncope6% – 25%

Palpitations39% – 68%

36%

ECG symptom

correlation

45% – 88%

88%

Assar MD et al. Am J Cardiol. 2003; Fechter P. Schweiz Med Wochenschr. 1991; Fogel RI et al. Am J Cardiol. 1997; Gibson TC et al. Am J Cardiol. 1984; Kinlay S et al. Ann Intern Med. 1996; Krahn AD et al. Circulation. 2001; Krahn AD et al. PACE. 2004; Linzer M et al. Am J Cardiol. 1990; Reiffel JA et al. Am J Cardiol. 2005; Rothman SA et al. J Cardiovasc Electrophysiol. 2007; Zeldis SM et al. Chest. 1980; Zimetbaum P et al. Am J

Cardiol. 1997.

Relative diagnostic yield

Stroke Risk Based on Atrial Fibrillation Burden

From: 2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society

J Am Coll Cardiol. 2014;64(21):e1-e76. doi:10.1016/j.jacc.2014.03.022

Summary of Recommendations for Electrical and Pharmacological Cardioversion of AF and Atrial Flutter

Relationship Between Atrial Arrhythmia Burden and Stroke Risk (TRENDS Study)

4 Glotzer T, et al. Circ Arrhythm Electrophysiol. 2009;2:474-480.

Methods:

• /AF burden ≥ 5.5 hours on any of 30 prior days appeared to double TE risk

•Prospective, observational study analyzing 2,486 patients with ≥ 1 stroke risk receiving pacemakers or defibrillators that monitor atrial tachycardia (AT)/AF burden

•Annualized TE rates were determined according to AT/AF burden subsets: zero, low (< 5.5 hours [median duration of subsets with nonzero burden]), and high (≥ 5.5 hours)

Results/Conclusions:

AT/AF Burden Subset Annualized TE Rate

(95% Confidence Interval)

Zero AT/AF burden 1.1 [0.8, 1.6] %

Low AT/AF burden (< 5.5 hours)

1.1 [0.4, 2.8] %

High AT/AF burden (≥ 5.5 hours)

2.4 [1.2, 4.5] %

How Much AF For a Stroke: 5.5 Hrs?

TRENDS Study Subgroup AnalysisNewly Detected AF (“NDAF”) in Patients with Thromboembolic Events

Ziegler P. et al. Stroke. 2010;41

• 163 patients with previous ischemic stroke/TIA, no known AF, were continuous monitored via pacemaker or ICD

• NDAF > 5 minute duration were found in 28% patients.

• 73% of patients had newly detected AT/AF on <10% of follow-up days Time from Device Implant (months)

0 3 mo. 6 mo. 9 mo. 12 mo.

Free

dom

from

AT/

AF

0.5

0.6

0.7

0.8

0.9

1.0

Number at Risk: 163 127 111 106 67

89% of NDAF patients identified beyond 1 day

78% of NDAF patients identified beyond 7 days

60% of NDAF patients identified beyond 30 days

How Much AF for a Stroke: 6 min?Assert Study

Results:• 2580 pts with mean CHADS2 score

of 2.29 followed prospectively for 2.5 yrs

• 10.1% pts with >1 Subclinical AF episode (>190 bpm for >6 min) within first 3 months– Associated with increased risk of

Clinical AF (HR 5.56 [3.78-8.17]; p<0.001)

– Associated with increased risk of Ischemic Stroke or Systemic Embolism (HR 2.49 [1.28-4.85]; p=0.007)

Cum

ulati

ve H

azar

d

Healey, JS et al. Subclinical Atrial Fibrillation and the Risk of Stroke. N Engl J Med 2012;366:120-129.

Among patients with AT/AF episodes >17.72 hours, annual rate of stroke or systemic embolism was 4.89 (95% CI, 1.96 to 10.07)

Conclusions• Atrial fibrillation (AF) is a common disorder with

significant morbidity, mortality, economic and social considerations

• Appropriate therapy for AF is dependent on a patient’s risk factors for thromboembolism

• Long term cardiac monitoring can help diagnose AF and guide appropriate treatment

• Prior observational studies have demonstrated a link between AF burden and stroke risk

Thank You