Cardio-embolic strokes

Risk & Prevention

Dr. Naeem Dean FRCP (UK)
Clinical Associate Professor,
Director Stroke Program,
Royal Alexandra Hospital,
Edmonton,
Canada
 Mr. Atherosclerosis

Large vessel injury

 Stroke Subtypes

Hemorrhagic
Ischemic 80%
20%
Diagnosis of Cardioembolic Stroke

“The presence of a potential cardioembolic

source in the absence of cerebrovascular
disease in a patient with a non-lacunar
stroke”

Cerebral Embolism Task Force, 1989

 How Often are Lacunes
Cardioembolic?

• About 20% have potential cardiac sources

• About 5 - 10% attributed to cardioembolism

• Cardioembolic lacunes often large(>1.5cm)

 Clinical Features of
Cardioembolic Stroke

• Abrupt non-progressive onset

• Decreased consciousness at onset
• Embolism to other organs
• Palpitations at onset
• Hemianopia without hemiparesis
 Multiple Acute Ischemic Lesions in
Different Vascular Territories on DWI

T2

DWI

ADC
“Embolic Pattern” on DWI
 Frequency of Cardioembolic Stroke*
Presumed
Study N Patient Age (Mean)
Cardioembolic, %

Oxfordshire, UK
224 73 20 †
(1989)
Melbourne,
353 -- 19
Australia (1989)

Lausanne,
1311 65 18
Switzerland (1991)

Klosterneuburg,
365 68 19
Austria (1992)

Umea, Sweden
953 72 31
(1992)
Barcelona, Spain
736 71 17
(1993)
Guayaquil,
313 61 14
Ecuador (1993)
Giessen, Germany
250 †† -- 17
(1994)
Lund, Sweden
166 73 28
(1994)
 Frequency of Cardioembolic Stroke*
Maastricht,
813 71 22
Holland (1994)
Paris, France
250 -- 29
(1995)
Warsaw, Poland
297 69 22
(1995)
Barcelona, Spain
1267 -- 18
(1997)
Taipei, Taiwan
676 65 20
(1997)
Riyadh, Saudi
756 -- 19
Arabia (1999)
Athens, Greece
885 70 38
(2000)
Bensaçon,
1776 69 31
France (2000)
Aggregate 11391 69 22
 Etiological work up for
cardioembolic strokes
• ECG and 24- hour Holter monitoring

• Echocardiography ( TTE, TEE)

• Cardiac MRI ( under investigation)

 Utility of Holter
• AF and flutter account for 50% of
cardioembolic strokes and 10% of all
strokes
• 30% of AF patients are unaware
• 25% of AF associated stroke have no prior
diagnosis
• Intermittent AF may be detected in 30% of
patients with stroke
 Utility of Holter
• Poor sensitivity of 12 lead ECG to detect
PAF
• 24-hour recording may detect previously
unrecognized AF in 2% of stroke patients
• Extending monitoring from 24H – 72 H
increases prevalence of AF after stroke from
1.2% - 6.1%
 Utility of Holter
( stroke2004;35:1647-51)
• AF detected in 22 out of 149 patients with
IS and TIA
• ECG detected 6.7% of AF
• 24-Holter detected AF in an additional 5%
• ELR ( 7 days monitoring) detected AF in an
additional 5.7%
 Echocardiography
• Low yield in patients with no history of cardiac
disease, normal exam, ECG and CXR. ( 2% VS
19% )
• TTE vs TEE:
TTE: LV thrombus, LVH , VHD
TEE: PFO , ASA, AAA, LA thrombus
• CV MR perhaps better than Echo in detecting
heart conditions contributing to thrombus
formation
 Cardioembolic Sources

High Risk Medium Risk Low / Unclear Risk

Atrial fibrillation LV hypokinesia / Patent foramen

aneurysm ovale
Recent anterior MI
Bioprostetic valve Atrial septal
Mechanical valve
Congestive failure aneurysm
Rheumatic mitral
stenosis Cardiomyopathy Spontaneous
echo contrast
Thrombus / tumor Myxomatous MVP

Endocarditis
 Causes of cardioembolic strokes

• Atrial Fibrillation 45 %
• LV dysfunction 25%
• Valvular heart disease 10%
• Prosthetic valves 10%
• Misc. ( tumors, IE, etc.) 10%
 Embolic Sources for
Cryptogenic Strokes
• Patent foramen ovale
• Atrial septal aneurysms
• Spontaneous echo contrast
• Occult atrial fibrillation
• Aortic atheromas
 Cardioembolic strokes
• Atrial Fibrillation
• Patent Foramen Ovale
• LV dysfunction
• Aortic Arch Atheroma
Atrial Fibrillation
 Pathophysiology of AF-associated ischemic stroke

Hart, R. G. et al. Stroke 2001;32:803-808

Copyright ©2001 American Heart Association

 Atrial Fibrillation
• Persistent and PAF predictors of first and
recurrent strokes
• Overall RR with warfarin is 68%
• Estimated RR with ASA compared to
placebo is 21%
 Risk factors for thrombo-embilisim in AF
Less Validated or Weaker
Risk Factors Moderate-Risk Factors High-Risk Factors

Female gender Age greater than or equal to 75 y Previous stroke, TIA or

embolism

Age 65 to 74 y Hypertension Mitral stenosis

Coronary artery disease Heart failure Prosthetic heart valve*

Thyrotoxicosis LV ejection fraction 35% or less

Diabetes mellitus

*If mechanical valve, target international normalized ratio (INR) greater than 2.5.
INR indicates international normalized ratio; LV, left ventricular; and TIA, transient ischemic
attack.
 Stroke Risk in Patients with Nonvalvular AF Not
Treated With Anticoagulation According to the
CHADS2 Index

CHADS2 Risk Criteria Score

Prior stroke or TIA 2

Age >75 y 1

Hypertension 1

Diabetes mellitus 1

Heart failure 1
 Stroke Risk in Patients With Nonvalvular AF
Not Treated With Anticoagulation According
to the CHADS2 Index
Adjusted Stroke
Patients Rate (%/y)
(N = 1733) (95% Cl) CHADS2 Score

120 1.9 (1.2 to 3.0) 0

463 2.8 (2.0 to 3.8) 1
523 4.0 (3.1 to 5.1) 2
337 5.9 (4.6 to 7.3) 3
220 8.5 (6.3 to 11.1) 4
65 12.5 (8.2 to 17.5) 5
5 18.2 (10.5 to 27.4) 6
Anticoagulation Patients with Atrial Fibrillation:
The ACCP Guidelines
High stroke risk
(e.g. age > 75, prior ischemic stroke or TIA, LV dysfunction,
hypertension, diabetes):
• Oral Vitamin K antagonist. (e.g. warfarin)

Intermediate stroke risk (age 65-75, no other risk factors):

• Oral VKA or ASA 325 mg daily

Lower stroke risk (age <65, no other risk factors):

• ASA 325 mg daily
Singer DE, et al. Chest 2004;126:429-256
Gage BF, et al. JAMA 2001;285:2864-70
Antithrombotic Therapy for Patients
With Atrial Fibrillation
Risk Category Recommended Therapy

No risk factors ( ASR 1%) Aspirin, 81 to 325 mg daily

One moderate-risk factor (ASR 4%) Aspirin, or warfarin

Any high-risk factor or more than 1 Warfarin

moderate-risk factor (ASR 8-12%)

ACC/AHA/ESC guide lines for management of AF; Circulation

2 Aug 06
 AC in elderly with AF
• 12% > 75 have AF
• 56% of AF patients are >75
• AF increases risk of stroke by 5 fold
• AC increases the risk of bleeding by 1-
3%/Y
• Increase risk of serious hemorrhage in
elderly
 BAFTA study ( Lancet 2007;370: 490-
503)
• RCT of >75 years of age ; Warfarin ( INR
2-3) vs ASA 75 mg
• AC was twice as effective as ASA and no
difference in bleeding
• Close monitoring , lower INR, BP control
• >75 years of age with high risk of bleeding
but no absolute CI to AC a low target INR
of 2 ( 1.6-2.5) (ACC,AHA & ESC guidelines;
circulation Aug 2006)
 Alternatives to AC in AF
• ASA 81-325 mg
• Oral direct thrombin inhibitors vs warfarin
(Ximelegatran in SPORTIF-III and V )
• Combination of antiplatelets
ACTIVE-W : ASA + P VS Warfarin
ACTIVE-I : ASA + P VS ASA
• Occlusion of LAA ( WATCHMAN device
and PROTECT-AF trial)
Figure 1. WATCHMAN(r) Left Atrial Appendage System. The WATCHMAN device
is comprised of a self-expanding nitinol frame structure with fixation barbs and a
permeable polyester fabric that covers the atrial face of the device. The device is
constrained in a 12F delivery catheter and is available in 5 sizes: 21, 24, 27, 30,
and 33 mm.
Secondary prevention of stroke in AF
ASA guide lines: stroke 2006;37;577-617

• IS or TIA with persistent or PAF AC with

warfarin ( INR 2-3) is recommended ( class
1, Level of evidence A)
• Unable to take warfarin , ASA 325 mg / d
( Class1, Level of evidence A)
 Timing of
starting
Anticoagualtion

?
 Recent Trial Results
Trial Recurrent Stroke (%)

IST (AF subgroup) Heparin 2.8

(N = 3169) No heparin 4.9
TOAST (cardioembolism) Danaparoid 0
(N = 266) Placebo 1.6
HAEST (all with AF) Dalteparin 8.5
(N = 449) Aspirin 7.5
TAIST* HD Tinzaparin 3.3
(N = 1484) LD Tinzaparin 4.7
Aspirin 3.1

*no benefit in cardioembolism subgroup

 Current Recommendations
• In patients with IS and AF, AC can be safely
delayed for 7-10 days
• Reasonable to start ASA and prophylactic
dose of Heparin
 Patent foramen ovale

“Smoking gun guilty by association”

 PFO
• 20-25% of normal population has a PFO

• Yearly risk of cryptogenic stroke in healthy

persons with a PFO may be as low as 0.1%
 PFO
• 43% of strokes in young adults are
cryptogenic
• PFO detected in more than half of these
individuals
• Meta-analysis of studies looking at
cryptogenic strokes: Overell JR, Neurology
2000;55:1172-9
• Meta-analysis of case control studies in patients with cryptogenic
stroke
 Mechanism of stroke with PFO
• Paradoxical embolisim
• Valsalva inducing activities?
• Occult deep vein thrombosis?
• ASA and thrombus?
• Large PFO?
• Atrial arrythmias?
 Investigations for suspected PFO

• Younger patients with IS of unknown cause

• TCD bubble study /TEE

• Tests for DVT and thrombophilia

 Stroke Recurrence Following
Cryptogenic Stroke in Young Patients
Group 4 yr Stroke Risk

No atrial septal abnormality 4.2% (1.8 – 6.6)

(N = 304)

PFO alone (N = 216) 2.3% (0.3 – 4.3)

PFO and ASA (N = 51) 15.2% (1.8 – 28.6)*

NEJM 2001; 345:740-746

*p = 0.007 (compared with no atrial septal abnormality)
All patients received ASA 300 mg/day; ages 18 – 55 years
 PFO in cryptogenic strokes
(PICCS)
Circulation 2002;105:2625-31
• WARSS ( warfarin-Aspirin Recurrent
Stroke Study) NEJM 2001;345:1444-51

• PICCS substudy of WARRS, 630 patients

underwent TEE
Table 2. Two-Year Rates of Recurrent Stroke or Death in Patients
With Different PFO Size From: Homma: Circulation, Volume
105(22).June 4, 2002.2625-2631
 Antithrombotic Therapy for
PFO-Associated Stroke
The PICSS Sub-study of WARSS
Group Stroke or Death (2 yrs)

Warfarin (N = 97) 16.5%

Aspirin (N = 106) 13.2%

No increase in stroke rate with large PFOs; 51 patients

with ASA +PFO had similar event rates and no
differential response to warfarin vs. aspirin
 Treatment of PFO
(ASA. Stroke 2006;37;577-617)
• Aspirin first line
• Warfarin for high risk e.g. venous
thrombosis, hypercoagulable state
• Closure may be considered for recurrent
cryptogenic strokes despite optimal medical
therapy
• CLOSURE study
Left ventricular dysfunction
&
stroke risk
 LV dysfunction
• RR of stroke associated with CHF is about
4.1 among 50-59 years of age
• RR about 1.5 by age 80-89 years
• SAVE: Neurology, Volume 54(2).January 25, 2000.288
 LV dysfunction and recurrent
stroke
• 5 year recurrent stroke risk in patients with
cardiac failure reported to be as high as
45%
• Uncertainity around use of antiplatelets vs
warfarin ( WATCH & WARCEF trials)
 ASA recommendation
Stroke 2006;37;577-617
• Patients with IS or TIA with dilated
cardiomyopathy either warfarin ( INR 2.0-
3.0) or antiplatelet therapy may be
considered for prevention of recurrent
events ( class II b, Level of evidence C)
Aortic Arch Atheroma
 Amarenco, NEJM 1992

Aortic Plaque Autopsy Study

• Aortic plaques not associated with
extracranial carotid stenosis

• Frequency of plaques increase with age

(rarely seen in patients <60 years)

• 3-fold increase in aortic plaques among

cryptogenic stroke cases after adjusting
for stroke risk factors
 Amarenco, NEJM 1992
Pathologic Evaluation of the Aortic Arch
in 500 Patients with Neurologic Diseases
Patient Group N Ulcerated Aortic
Plaques

Other neurologic disease 261 5%

Ischemic stroke 183 28%*

identified cause 155 22%

unexplained stroke 28 61%*

*p <0.001
 Amarenco, NEJM 1994

TEE Case-Control Study

• Enrolled 250 consecutive stroke patients and
250 controls > 60 years of age. Proximal
plaques separated from distal plaques.

• After adjustment for stroke risk factors stroke

patients were 9 times more likely to have large
plaques (≥ 4mm) proximal to the left
subclavian artery (large mobile plaques 14x).
 Amarenco, NEJM 1994

TEE Case-Control Study

Ascending or Transverse
Patient Group N Plaques (≥4mm)

Elderly Controls 250 2%

Stroke Patients 250 14%*

Stroke Subtypes
Another likely cause 74 5%
Presumed lacunar infarct 44 9%
Another possible cause 54 11%
No other apparent cause 22 28%*

*p <0.001
 French Study Group, NEJM 1996

Risk of Stroke Recurrence in

Patients with Aortic Plaques
• Prospective follow-up study of 331
consecutive stroke patients ≥ 60 years of age

• All underwent TEE; size and thickness of

proximal aortic plaques assessed

• 2.4 year mean follow-up to determine the

incidence of recurrent stroke and other
vascular events
Atherosclerosis of the Aortic Arch
and Recurrent Ischemic Stroke
Atherosclerosis of the Aortic Arch
and Recurrent Vascular Events
 French Study Group, NEJM 1996

Results – Stroke Recurrence

Stroke Vascular
Patient Group N Recurrence Events
(% / yr) (% / yr)

No plaques 2.8 5.9

Small plaques (1-3.9mm) 3.5 9.1
Large plaques (≥ 4mm) 11.9* 26.0*

* p< 0.001
 Possible therapies for AAA
• No therapy has been adequately
evaluated

• Options: antiplatelet agents, Statins,

anti-hypertensives, anticoagulants,
surgery
 The Aortic arch-related cerebral
hazard trial ( ARCH)
• ASA + Plavix vs warfarin in patients with
an embolic event and complex atheroma

• Start date Feb 2002

• Expected completion date Oct 2008

Thank you