Review Article

Acta Cardiol Sin 2005;21:1-12

New Advances in the Diagnosis and

Management of Cardioembolic Stroke
Mei-Shu Lin,1 Nen-Chung Chang2 and Tsung-Ming Lee3

Cardioembolic stroke accounts for one-fifth of ischemic stroke and is severe and prone to early recurrence.
Magnetic resonance imaging, transcranial Doppler, echocardiography, 24-hour electrocardiographic monitoring
and electrophysiological study are tools for detecting cardioembolic sources. Non-valvular atrial fibrillation (AF) is
the most common cause of cardioembolic stroke and long-term anticoagulation is proved to prevent stroke. Despite
knowledge of guidelines, doctors recommend anticoagulant for less than half of patients with AF who have risk
factors for cardioembolic stroke and no contraindication for its usage. Direct thrombin inhibitor offers the advantage
of not needing prothrombin time controls and dose adjustments, but it needs large clinical trial for confirmation. Any
type of anticoagulant by any route should not be used in acute cardioembolic stroke. Stroke after percutaneous
coronary intervention (PCI), although rare, is associated with high mortality. Cardiologist must flush catheters
thoroughly, minimize catheter manipulation and use minimal contrast medium during PCI.

Key Words:

Stroke Heart Embolism Percutaneous coronary intervention

INTRODUCTION

cardioembolic stroke. In the posterior circulation,

cardioembolism can produce Wallenbergs syndrome,
cerebellar infarcts, basilar syndrome, multilevel infarcts, or posterior cerebral artery infarct. Hemiparesis
and lacunar infarct, especially multiple lacunar infarcts,
are not likely cardioembolism- related.4-6
Cardioembolism can be reliably predicted clinically
but is hard to document.1,2 The features suggestive of
cardioembolic stroke are clinically decreased consciousness at onset,1,2 rapid regression of symptoms,1,2 sudden
onset to maximal deficit < 5 min,1,2 and visual field defects, neglect, or aphasia.1,2 Simultaneous or sequential
strokes in different arterial territories (combined anterior
and posterior, or bilateral, or multilevel posterior circulation) and hemorrhagic transformation of an ischemic
infarct found on computed tomography (CT) or magnetic
resonance imaging (MRI) are all characteristic findings.6
Early recanalization of occluded intracranial vessel, occlusion of the carotid artery by mobile thrombus, and
microembolism in both middle cerebral arteries noted on
ultrasound or angiography indicate cardioiembolic
stroke.1,6 The clinical and imaging features suggestive of

Cardioembolic stroke accounts for about 20% of

ischemic strokes. 1,2 Cardioembolic strokes are severe
and prone to early recurrence. 1-3 Cardiac emboli may
cause massive, superficial, single large striatocapsular
or multiple infarcts in the middle cerebral artery. Certain clinical syndromes such as Wernickes aphasia or
global aphasia without hemiparesis are common in

Received: April 28, 2004

Accepted: August 11, 2004
1
Graduate Institute of Epidemiology, School of Public Health,
National Taiwan University and Department of Pharmacy, National
Taiwan University Hospital, Taipei, 2Division of Cardiology, Department
of Internal Medicine, Taipei Medical University Hospital, Taipei,
3
Department of Internal Medicine, College of Medicine, Taipei
Medical University and Division of Cardiology, Department of
Internal Medicine, Chi-Mei Medical Center, Tainan, Taiwan.
Address correspondence and reprint requests to: Nen-Chung Chang,
MD, PhD, Division of Cardiology, Department of Internal Medicine,
Taipei Medical University Hospital, Taipei, or Tsung-Ming Lee, MD,
Division of Cardiology, Department of Internal Medicine, Chi-Mei
Medical Center, Tainan, Taiwan. Tel: 886-2-2737-2181 ext. 3101;
Fax: 886-2-2391-1200 or 886-2-2736-4222;
E-mail: ncchang@tmu.edu.tw or tsungm.lee@msa.hinet.net

Acta Cardiol Sin 2005;21:1-12

Mei-Shu Lin et al.

cardioembolism are highly specific but less sensitive

with a positive predictive value below 50%.1,6
Only a few papers regarding cardioembolic stroke in
Taiwan have been published. The National Taiwan University Hospital Stroke Registry in 1995 described 676
patients with cerebral infarction, 20% of which were
cardioembolic stroke.7 Lacunar stroke was the most common type (29%). The percentage and characteristic features
of cardioembolic stroke in Taiwan were similar to those in
western countries.1,6,7 Cardioembolic patients had a higher
percentage of atrial fibrillation (AF) (69%), cardiomegaly,
and ischemic heart disease than non- cardioembolic patients, which might account for a higher case-fatality rate
than other cerebral infarction patients. Interestingly, only
3% of cardioembolic patients had carotid stenosis 50%.

internal carotid artery. Ultrasonography can detect such

emboli as oscillating, homogeneous, elastic-mass
echos.11 The suspicion of cardioembolism increases if
angiography or transcranial Doppler shows that the artery in the territory of the infarct is patent, or if there is
early recanalization of a previously occluded vessel.
Transcranial Doppler is helpful for the diagnosis of
right-to-left shunting by detecting bubble signals
(high-signal bubble sign) passing the middle cerebral
artery less than 20 seconds after agitated saline is injected in an antecubital vein.1 Transcranial Doppler can
also detect microembolic signals (high-intensity transient sign) in the middle cerebral artery. 1 However,
high-intensity transient signs are rarer in cardiac embolism than in carotid embolism. They disappear a few
days after the embolic event, and their relationship with
the cardioembolic risk or with the type of antithrombotic
treatment is controversial.12

HOW TO IDENTIFY A CARDIOEMBOLIC

STROKE?

Heart
There are three high-risk cardiac origins1,6,13 for
cardioembolic strokes: atrium, valve and ventricle. Atrial
fibrillation (AF), atrial flutter, sick sinus syndrome, left
atrial thrombus, left atrial appendage thrombus and left
atrial myxoma are atrial origins. Mitral stenosis, prosthetic
valve and endocarditis are valvular origins. Left ventricular
thrombus, left ventricular myxoma, recent anterior myocardial infarct and dilated cardiomyopathy are ventricular
origins. However, patent foramen ovale (PFO), atrial septal
aneurysm (ASA), atrial spontaneous echo contrast, mitral
annulus calcification, mitral valve prolapse, calcified aortic
stenosis, akinetic/dyskinetic ventricular wall segment, hypertrophic obstructive cardiomyopathy and congestive
heart failure are low or uncertain risks. In many patients
such as those with AF, sick sinus syndrome, rheumatic
valve and prosthetic valve disease, it is sufficient to make
the diagnosis of a cardioembolic condition by history,
physical examination, and electrocardiogram (ECG).1,6,13
Paroxysmal AF is an important cause of brain embolism
that is difficult to document. It might be detected by
48-hour ECG monitoring immediately after stroke, by
events recorder, or by electrophysiological studies.14 The
ability of ambulatory ECG monitoring to detect emboligenic
arrhythmias such as AF or sick sinus syndrome in patients
with stroke is low.1,6,13 Electrophysiological studies can
measure atrial refractoriness and conduction time to define

Brain
MRI is more sensitive for the detection of cardioembolic stroke than CT.1,6 The sensitivity of MRI to
hemorrhagic transformation is higher than that of CT.1,6
Hemorrhagic transformation develops in up to 70% of
cardioembolic strokes. 1,6 About 90% of hemorrhagic
transformations are caused by cardiogenic brain embolism. 1,6 There are two types of hemorrhagic transformation: multifocal, which is less symptomatic, and
hematoma, which has mass effect and clinical deterioration. The mechanism of hemorrhagic transformation is
reperfusion of ischemic zones, which occurs with spontaneous resolution of the emboli. Arterial wall trauma
and dissection at the site of the thrombus are alternative
explanations.8 Decreased conscious level, total circulation infarcts, severe strokes (National Institute of Health
Stroke Scale score > 14), proximal occlusion, large
hypodensity in more than 1/3 of the middle cerebral artery territory, and delayed recanalization > 6 hours after
onset predict hemorrhagic transformation in acute
cardioembolic stroke. 1,6,9 Gradient-echo T2-weighted
brain MRI-shown old microbleeds are predictors of hemorrhagic transformation.10
Between brain and heart
A thrombus originating in the heart can occlude the
Acta Cardiol Sin 2005;21:1-12

Cardioembolic Stroke

a vulnerability index (latent atrial vulnerability).15,16 Programmed atrial stimulation assesses the inducibility of
sustained AF. In patients with cryptogenic stroke, there
is a significant association between atrial vulnerability
and atrial septal abnormalities, which raises the question
of atrial transient arrhythmias resulting in thrombus formation. However, the prognostic significance of atrial
vulnerability is uncertain.15,16
Transthoracic echocardiogram (TTE) can detect mitral
stenosis, dilated cardiomyopathy and other structural ventricular diseases, ventricular thrombus, vegetations, or
tumors. This method also enables the measurement of left
atrial size and left ventricular systolic function. However,
TTE provides little information additional to history, physical examination, and ECG; thus, its cost-effectiveness is
doubtful.13 Transesophageal echocardiogram (TEE) is used
to study the aortic arch and ascending aorta, left atrium
and left atrial appendages, inter-atrial septum, pulmonary veins, and valve vegetations. 1,6,13 The common
potential findings of echocardiography in patients with
cardioembolic stroke and negative cardiac disease history and in sinus rhythm are left atrial or left atrial
appendage thrombus, atrial spontaneous echo contrast,
PFO, ASA, and aortic plaques.13 Left atrial thrombus and
left atrial appendage thrombus are conditions with a consensual indication for anticoagulation. 13 A Markov
decision analysis of benefit and cost concluded that doing TEE in all stroke patients in sinus rhythm was more
cost-effective than either a sequential strategy (TTE followed by TEE) or TTE alone in patients with negative
cardiac disease history.13 This study also found the prevalence of left atrial or left trial appendage thrombus to be
8%. 13 However, in another study, TEE detected atrial
thrombus in no more than 1% of patients in sinus rhythm,
leading the researchers to conclude that TEE is not
cost-effective if used routinely.17 A plausible implication
of such conflicting evidence is that TEE is more likely to
be helpful in young patients with stroke, all-age stroke of
unknown cause, and patients with non-lacunar stroke.17

ing aortic atheroma (> 4-5 mm) is 3-9 times more

common in stroke patients than in healthy controls. 1,6
The relative risk of recurrent stroke and other ischemic
events in stroke patients with atheroma in the aorta
thicker than 4 mm ranges from 1.5 to 4.18 Besides thickness over 4 mm, ulcerated, non-calcified plaques and
those with mobile components are associated with an increased risk of stroke recurrence. 19 Thick or complex
aortic arch atheroma is more common in elderly patients
with stroke and is associated with carotid stenosis, coronary artery disease, AF, hypertension, diabetes, and
smoking. 20,21 Antiplatelet treatment, anticoagulants,
statins, and surgery have been advocated to reduce the
risk of stroke in patients with aortic atheroma. Unfortunately, no large randomized trials have been completed
to prove the beneficial results in patients with aortic
atheroma receiving these treatments. Anticoagulant therapy has a theoretical risk of cholesterol embolism.
Patients with aortic plaque who were treated with warfarin had a low (1%) rate of cholesterol embolism. The
rate of embolism was significantly lower in patients
treated with conventional warfarin than in patients
treated with low-dose warfarin and aspirin. 22 The
ongoing ARCH (Aortic arch-Related Cerebral Hazard)
trial,23 a randomized controlled trial, is comparing the effect of warfarin with target international normalized ratio
(INR) 2.0-3.0 and those of clopidogrel (75 mg/day) plus
aspirin (75-325 mg/day) in the secondary prevention of
stroke and other serious vascular events in patients with
prior ischemic stroke or peripheral embolism associated
with proximal aortic plaque with complex ( 4 mm thickness and/or mobile) features. At the present time, a
reasonable strategy is to use antiplatelet drugs and statins
in all patients with symptomatic aortic atheroma greater
than 4 mm and to reserve anticoagulants for those with
mobile thrombus.24 Surgery is an option for patients with
recurrent embolism and permanent thrombus despite
anticoagulation.

Percutaneous Coronary Intervention (PCI)

Stroke after PCI, although rare, is associated with
high rates of mortality and morbidity. Recently,
Dukkipati et al. 25 identified the incidence, predictors,
and outcomes of stroke in patients undergoing PCI.
Stroke occurred in hospital in 0.3% after PCI. On
multivariate analysis, patients with stroke more fre-

IMPORTANT CARDIOEMBOLIC SOURCES

AND CONDITIONS
Atheroma on aortic arch
Autopsy and TEE studies both showed that protrud3

Acta Cardiol Sin 2005;21:1-12

Mei-Shu Lin et al.

quently had diabetes, hypertension, previous stroke and

creatinine clearance 40 mL/min. Strokes also were
noted more often when PCI were urgent or emergent and
when intra-aortic balloons were used. Thrombolytics or
heparin use before PCI was independently associated
with periprocedural stroke. Stroke was independently associated with in-hospital death, renal failure, and the
new need for hemodialysis. Also, the amount of contrast
agent used in those with stroke was significantly higher
and was independently associated with this complication. The editorial comment from Bittl and Caplan 26
suggested it is self-evident and well known that
thrombolytics and heparin increase the risk of hemorrhagic stroke, and commented these two agents might
contribute directly or indirectly to the risk of brain embolism as the most common cause of ischemic stroke
after PCI. Thrombolytics on occasion may break up
intracavitary thrombi, and their use has been associated
with the cholesterol embolization syndrome. Thus, primary PCI should be favored over thrombolytics to avoid
stroke for acute myocardial infarction. The use of heparin has also been associated with an increased risk of the
cholesterol embolization syndrome, providing one hypothetical connection between heparin use and adverse
outcomes among patients with stroke. Heparin is not recommended for the treatment of cholesterol embolization
syndrome. Dukkipati et al.25 and Bittl and Caplan26 also
suggested coronary interventional procedures must be
performed with meticulous attention to technical detail.
Large-bore catheters or intra-aortic balloons may dislodge atheromatous material that embolizes to the
cerebral circulation. They indicated back bleeding
should be allowed whenever guide catheters are advanced around the aortic arch over a guide wire. If the
catheter is connected to a Y-adapter during advancement, the valve should be left open. This should always
be followed by strict double flushing, to discard any
atherosclerotic debris that may be entrained by the guide
catheter. Cholesterol embolization to the kidneys is
probably responsible for the occurrence of renal failure
and the new need for dialysis. They also suggested that
use of minimal contrast medium is important and stroke
may relate to the previously described thrombogenic potential of some types of contrast agents. Bittl and
Caplan26 suggested more refined identification of risk
factors for embolization might come from the preprocedural
Acta Cardiol Sin 2005;21:1-12

assessment of cardiac and aortic anatomy. Most plaques

are located in the curvature of the arch from the distal
ascending aorta to the proximal descending aorta, regions that can be shown by ultrasound. 27 Although it
may seem intuitive that a right brachial or radial approach
may reduce cholesterol embolization by decreasing the
linear contact between catheter and aorta, a recent prospective study showed an equal incidence of the
cholesterol embolization syndrome for both the brachial
and femoral approaches. 28 Patients with protruding
atheromas confined to the arch or descending aorta,
however, may have a lower risk of catheter-induced
embolization if a right forearm approach is used. Bittl
and Caplan 26 concluded that further efforts should be
made to move beyond such traditional broad clinical categories as diabetes and hypertension to define the
individual characteristics such as shaggy aortas that put
patients as high risk of stroke from embolization.

Mitral valve prolapse (MVP) 6,29

MVP is found in about 3-6% of asymptomatic population; it is most common in young women. The early
studies using M-mode echocardiographic criteria found
up to 30% of patients under age 45 years with cerebral
ischemia had MVP. The recurrent stroke event rate was
reported to be as high as 15%. Subsequent investigations
identified myxomatous degeneration, redundant valve,
and supraventricular arrhythmias as risk factors for
stroke in MVP. The recent cohort and case control studies have cast doubt on the role of uncomplicated MVP in
stroke, even in youth.
Endocarditis
Two types of endocarditis, infective and non-infective, cause cardioembolic stroke. TEE can confirm valve
vegetations more reliably than TTE, and should be the
initial diagnostic procedure for all patients with moderate to high clinical suspicion of endocarditis.30
Non-infective endocarditis can complicate systemic
cancer, lupus, and the antiphospholipid syndrome. Valvular
lesions are common in patients with high anticardiolipin
antibodies. 31 Patients with stroke and non-infective
endocarditis should receive heparin followed by oral anticoagulants.
Infective endocarditis complicated with stroke occurs in about 10% of cases.30,32 Most stroke in infective
4

Cardioembolic Stroke

maneuver immediately preceding the onset of stroke.1,6

ASA is detected in 0.2-4.0% of patients examined with
TEE. Criteria for the diagnosis of ASA by TEE are a minimum of 10 mm interatrial septal phasic movement and a
diameter of the ASA of at least 15 mm.1,6 Paradoxical embolism, supraventricular arrhythmia, and thrombus from a
coexistent ASA are the more likely causes of stroke in patients with PFO.1,6,36
A recently completed study36 recruited patients with
an ischemic stroke of unknown origin to clarify the risks
of recurrent stroke associated with PFO and/or ASA. All
patients had undergone TEE and received aspirin (300
mg/day) and were followed up for 4 years. Patients with
PFO were younger and less likely to have traditional risk
factors for stroke. The risk of recurrent stroke was 15%
among those with PFO and ASA, 2% among the patients
with PFO alone, 0% among the patients with ASA alone,
and 4% among those with neither of these cardiac abnormalities. Only the subgroup of patients with PFO and
ASA had an increased risk ratio of 4 for recurrent stroke.
Aspirin is an appropriate preventive medication for patients with ischemic stroke and ASA or PFO alone
(regardless of its size). More aggressive preventive strategies other than aspirin should be considered for patients
who have both PFO and ASA. In the PICSS (the Patent
foramen ovale In the Cryptogenic Stroke Study),37 patients with PFO were randomly assigned to receive
either aspirin or warfarin. There was no significant difference in recurrent stroke or death rate between the two
treatment groups. The implication is that warfarin offers
no advantage over aspirin for the secondary prevention
of stroke in patients with PFO.
Surgical or interventional closures of the PFO are alternatives to aspirin. Device closure of PFO is safe and
results in substantial hospital-related cost savings when
compared with surgical closure.38 However, device closure must be assessed against antithrombotic regimen
(aspirin, clopidogrel, or a combination of antiplatelet
drugs) in randomized clinical trials, such as the ongoing
PC (Patent foramen ovale and Cryptogenic embolism)
trial.39

endocarditis happens early in the course of the disease

and before or during the first 2 weeks of antimicrobial
therapy. Emboli can be multiple, especially in the case
of infection of prosthetic valves and in infections due to
aggressive organism, such as Staphylococcus aureus.
Most emboli are fragments of vegetations, and therefore,
the best antiembolic regimen is appropriate antibiotic
treatment. The use of anticoagulants in native valve infective endocarditis is associated with increased
mortality.33 In most patients with mechanical prosthetic
valves who were given anticoagulants, treatment was
maintained lifelong. Echocardiographic features that favor surgery to prevent embolism include persistent large
vegetation > 10 mm, embolic event during the first 2
weeks of antimicrobial treatment, or more than one embolic event later in treatment.30 If urgent valve replacement
is necessary, stroke is not necessarily a contraindication. 34 Cardiac surgery may preferably be performed
within 72 hours of stroke if CT/MRI excludes hemorrhagic transformation.34
Mycotic aneurysms complicate 1-5% of infective
endocarditis. Screening for mycotic aneurysms with contrast CT or MR angiography is only warranted in patients
with neurological symptoms. Mycotic aneurysms can heal
with medical therapy, but they may also enlarge and rupture, which is fatal in many cases. Decisions concerning
medical versus surgical treatment of mycotic aneurysms
must be individualized.31 An enlarging or a ruptured distal
aneurysm should be treated surgically. Endovascular stent
treatment is an alternative to surgery for growing or ruptured aneurysms.35

PFO/ASA
PFO is present in 1/3 of all patients with stroke and is
found in up to 40% of patients with ischemic stroke who
are younger than 55 years of age.1,6 PFO can cause stroke
through paradoxical embolism, an event that is difficult to
prove because it requires the thrombus to be shown at the
PFO by echocardiography, particularly by TEE. Paradoxical embolism is a possible diagnosis if there is an arterial
embolism without source found in the left cardiac cavities
and valves, ascending aorta and aortic arch, pulmonary
veins, cervical extracranial arteries, or in the large basal
intracranial arteries.1,6 Paradoxical embolism may occur
in case of right-to-left shunt coexisting with deep venous
thrombosis or pulmonary embolism, or cough or Valsalva

Non-valvular AF
Non-valvular AF is the commonest cause of cardioembolic stroke. The disorder is associated with thyroid
disorders, hypertension and heavy drinking.40,41 The risk of
5

Acta Cardiol Sin 2005;21:1-12

Mei-Shu Lin et al.

ischemic attack. 49 Oral amiodarone and beta-blockers

significantly reduce the risk of postoperative stroke.50

stroke is at least six times higher in patients with AF than

in healthy controls. AF is an increasingly important risk
factor for stroke, both symptomatic and asymptomatic, in
older people.1,6 The attributable risk of stroke due to AF
rises from 1.5% at the age of 50 years to 25% at the age of
80. Loss of atrial contraction in AF leads to stasis that is
most marked in the left atrial appendage. Stasis is associated with increased concentrations of fibrinogen, D-dimer,
and von Willebrand factor, which are indicative of a
prothrombotic state.42
Treatment of AF aims to restore sinus rhythm, control
of ventricular rate, and prevention of thromboembolism.43
A strategy for the control of rhythm is not inferior to a
strategy for the restoration of sinus rhythm for the prevention of embolism and death.43 Restoration of sinus rhythm
in AF can be achieved pharmacologically or by electrical
cardioversion.43 Cardioversion is associated with an increased risk of stroke, which may occur if left atrial
thrombi are dislodged when sinus rhythm is restored. The
strategy used to decrease such risk is to keep the patient
anticoagulated for 3 weeks before and 4 weeks after cardioversion. An alternative is established if cardioversion
is urgent.44 Such an alternative requires TEE to detect
atrial thrombi. If no thrombus is found, cardioversion is
done immediately under heparin protection. If a thrombus
is identified, the patient should be treated with warfarin
for 3 weeks and repeat TEE thereafter. In some patients,
maintenance of sinus rhythm is not possible with
antiarrhythmic therapy. Such patients are candidates for
atrial pacing, implantation of atrial defibrillator, or radiofrequency/surgical ablation of foci that cause AF.40,45 On
the basis that in AF there are multiple re-entrant wavelets
in both atria, the maze operation aims to restore sinus
rhythm.46 In maze surgery, the atria are dissected into several segments and rejoined by suturing. However, this
procedure does not improve atrial function. An alternative
intervention that was recently introduced is the surgical or
catheter radiofrequency isolation of the four pulmonary
veins.47 This intervention is based on the finding that AF
can originate in muscular sleeves that extend to the proximal pulmonary veins.47 The left atrial appendage, where
thrombi are most commonly situated, can also be
transcatheter-occluded.48
Postoperative AF occurs in 30% of patients who undergo open heart surgery 49 and is associated with a
three-fold increase in the risk of stroke or transient
Acta Cardiol Sin 2005;21:1-12

How to prevent stroke and recurrent stroke in

patients with AF?
Risk factors for thromboembolism in AF include previous stroke (including previous transient ischemic attack
or ischemic stroke or embolic stroke), age > 65 years,
structural cardiac disease (particularly rheumatic or other
significant valvular heart disease), prosthetic valve, hypertension, heart failure and significant left ventricular
systolic dysfunction, diabetes, and coronary artery disease.51 Patients with AF associated with history of
transient ischemic attack or stroke have indication for
long-term anticoagulation with a target INR of between 2
and 4.51 Only those patients without risk factors or with
contraindications to warfarin should be given aspirin. Aspirin has a modest protective effect in patients with AF
and seems to primarily reduce non-cardioembolic
strokes.51 The risk of stroke rises largely at INR below
2.52 The risk of intracranial bleeding rises at INR over 4.52
The INR should not exceed 3.0 in primary prevention of
embolism in patients with AF (except those with prosthetic valves) and 4.0 in patients with previous stroke or
transient ischemic attack.52 If the INR rises to over 6, lowdose oral vitamin K should be prescribed.52
Despite the preventive potential of warfarin in patients with AF (70% reduction of the risk of ischemic
stroke and 30% reduction of the risk of death), several
studies done in western countries have shown that warfarin is underused.53,54 Despite knowledge of guidelines,
doctors recommend anticoagulation for less than half of
patients with AF who have risk factors and no contraindications for warfarin. In the ATRIA (AnTicoagulation
and Risk factors In Atrial fibrillation) study,55 the strongest predictors of receiving warfarin were previous
stroke and heart failure. However, an age of 85 years or
older and previous intracranial or gastrointestinal hemorrhages were predictors of not receiving warfarin.
Alternative to warfarin in patients with AF
The SPAF (Stroke Prevention in Atrial Fibrillation)
III study56 reported that adjusted-dose warfarin (target
INR 2.0-3.0) is highly efficacious for prevention of
stroke in patients with non-valvular AF at high risk for
thromboembolism. However, low-intensity, fixed-dose
6

Cardioembolic Stroke

Table 1. Antithrombotic treatment for the prevention of stroke in different cardioembolic sources
Sources

Managements

AF
High risk: previous stroke/TIA, systemic embolus, valve
disease, hypertension, LV dysfunction, age > 75, 2
moderate risk factors
Moderate risk: age 65-75, DM, CAD, thyrotoxicosis
Low risk: no risk factor, age < 65
Acute
Cardioversion

Warfarin (INR 2-3);

If age > 75: INR 1.5-2.0
Warfarin or aspirin
Aspirin or none
Heparin then warfarin
Warfarin for 3 wks before and 4 wks after, or if no thrombus
on TEE, heparin before and warfarin 4 wks after

AMI
Risk factor (-)
Risk factors (+): anterior MI, CHF, AF,
systemic/pulmonary embolism, mural thrombus, severe LV
dysfunction
Previous MI
With CHF
With ventricular aneurysm
With mobile or protuberant thrombus
None of above
Mechanical valve prosthesis
Bio-prosthesis
< 3 ms after valve insertion
With AF, LA thrombus, systemic emboli
None of above
Rheumatic valve
Atrial flutter
Sick sinus syndrome
Heart failure + sinus rhythm, for primary prevention
DCM
Atrial thrombus
Ventricular Thrombus
Mobile or protuberant
Calcified aortic stenosis
HOCM
MVP
Mitral annular calcification
Infective endocarditis
native valve
mechanical valve prosthesis
mechanical valve prosthesis + large stroke
Non-infective endocarditis
Myxoma
ASA
PFO+ASA
Atrial echo contrast
Aortic atheroma
< 4 mm
4 mm
4 mm + mobile or protuberant thrombus

Aspirin and LMWH

Heparin then warfarin

Aspirin or warfarin
Aspirin
Warfarin
Aspirin
Warfarin +/- aspirin
Warfarin
Warfarin
Aspirin
Warfarin
Warfarin
Warfarin
None
Warfarin
Warfarin
Aspirin or warfarin
Warfarin
Aspirin
Aspirin
Aspirin or none
Aspirin or warfarin
Antibiotics
No anticoagulant
Continue anticoagulant
Stop anticoagulant
Heparin then warfarin
Surgery
Aspirin or none
Aspirin
Aspirin
None or aspirin
Aspirin + statin
Warfarin

Abbreviations: INR = international normalized ratio; AF = atrial fibrillation; TIA = transient ischemic attack; LV = left ventricle; DM =
diabetes mellitus; CAD = coronary artery disease; TEE = transesophageal echocardiography; AMI = acute myocardial infarction; LMWH =
low molecular weight heparin; CHF = congestive heart failure; LA = left atrium; DCM = dilated cardiomyopathy; vent = ventricular; HOCM
= hypertrophic obstructive cardiomyopathy; MVP = mitral valve prolapse; ASA = atrial septal aneurysm; PFO = patent foramen ovale.
7

Acta Cardiol Sin 2005;21:1-12

Mei-Shu Lin et al.

stroke than in those with atherothrombotic stroke.66 A recent study indicated that embolic occlusions due to
cardiac thrombi had a lower likelihood of being resolved
by intra-arterial thrombolysis.67
Discontinuation of anticoagulant in patients with
high thromboembolic risk cardiac disorders and a hemorrhagic stroke is a therapeutic dilemma. The data from
Mayo Clinic, including half of the patients with prosthetic valve, showed that discontinuation of warfarin for
a median of 10 days was associated with a 30-day low
(3%) risk of embolic stroke.68

warfarin (INR 1.2-1.5 for initial dose adjustment) plus

aspirin (325 mg/day) was insufficient for stroke prevention. The rates of major bleeding were similar in both
treatment groups. In the AFASAK 2 (Second Copenhagen Atrial Fibrillation, Aspirin, and Anticoagulation)
Study,57 minidose warfarin (1.25 mg/day) plus aspirin
(300 mg/day) had no advantage over adjusted-dose warfarin (target INR 2.0-3.0) for stroke prevention in AF.
Prevention of embolic events in patients with mechanical valve prosthesis58 and prevention of serious vascular
events in acute myocardial infarction59 and probably in
congestive heart failure60 are the evidence-based indications for the use of combined warfarin and aspirin. The
SPORTIF (Stroke Prevention using an ORal Thrombin
Inhibitor in patients with atrial Fibrillation) III and V trials,61 comparing a direct thrombin inhibitor (ximelagatran)
with warfarin for prevention of thromboembolism in patients with non-valvular AF, are underway. Ximelagatran
offers the advantage of not needing prothrombin time
controls and dose adjustments.

CONCLUSIONS
During the past two decades, enormous progress has
been made in the diagnosis of cardioembolic disorders
and in establishing evidence-based recommendations for
the primary and secondary prevention of cardioembolic
stroke. Table 1 summarizes the updated antithrombotic
treatment for the prevention of stroke in different
cardioembolic sources and conditions. Because AF is by
far the commonest cause of cardioembolic stroke, the
mortality, disability, and costs related to cardioembolic
stroke will mainly be decreased by advances in the treatment of AF. The future task is to develop more sensitive
methods to identify paroxysmal AF, to achieve definitive
treatment of this disorder by the least invasive methods
and to introduce safer anticoagulants to obtain optimal
control of anticoagulation. For low- or uncertain-risk
cardioembolic disorders, the preventive therapeutic alternatives should be studied in large randomized
controlled trials.
What is to be learned from the pathogenesis of
stroke after PCI? Avoiding stroke continues to be good
reason to choose primary PCI over thrombolytics for
acute myocardial infarction. Cardiologists must flush
catheters thoroughly, minimize catheter manipulation,
and use minimal contrast medium during PCI.

ACUTE ANTITHROMBOTIC THERAPY

Several recent trials,62 reviews,63 and meta-analyses64
clearly showed that subcutaneous unfractionated heparin
and low molecular weight heparin do not have any effect
on stroke outcome or progression, and that their small benefit in reducing early recurrent stroke is outweighed by a
small increase in intracranial hemorrhages. The effect of
intravenous heparin in acute ischemic stroke will be elucidated in the ongoing RAPID (Rapid Anticoagulation
Preventing Ischemic Damage) trial.65 Until this trial is
completed, any type of heparin by any route should not
be used in acute cardioembolic stroke. The time to start
anticoagulation for secondary prevention is unclear. It
seems reasonable to start anticoagulant immediately in
transient ischemic attacks and minor strokes with a
high-risk source of cardioembolism and non-hemorrhagic infarcts and to delay it for 5-15 days in disabling
strokes and large or hemorrhagic infarcts.
Intravenous tissue plasminogen activator given
within 3 hours seems to be beneficial for patients with
AF and acute ischemic stroke based on limited evidence.66 Observational data suggested that thrombolysis
might be more effective in patients with cardioembolic
Acta Cardiol Sin 2005;21:1-12

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