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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 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. Cer-

tain clinical syndromes such as Wernickes aphasia or

global aphasia without hemiparesis are common in

cardioembolic stroke. In the posterior circulation,

cardioembolism can produce Wallenbergs syndrome,

cerebellar infarcts, basilar syndrome, multilevel in-

farcts, 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 conscious-

ness at onset,1,2 rapid regression of symptoms,1,2 sudden

onset to maximal deficit < 5 min,1,2 and visual field de-

fects, neglect, or aphasia.1,2 Simultaneous or sequential

strokes in different arterial territories (combined anterior

and posterior, or bilateral, or multilevel posterior circula-

tion) 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, oc-

clusion 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

1 Acta Cardiol Sin 2005;21:112

Review Article Acta Cardiol Sin 2005;21:112

Received: April 28, 2004 Accepted: August 11, 20041Graduate 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,3Department 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: [email protected] or [email protected]

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 Uni-

versity Hospital Stroke Registry in 1995 described 676

patients with cerebral infarction, 20% of which were

cardioembolic stroke.7 Lacunar stroke was the most com-

mon 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 noncardioembolic pa-

tients, which might account for a higher case-fatality rate

than other cerebral infarction patients. Interestingly, only

3% of cardioembolic patients had carotid stenosis 50%.

HOW TO IDENTIFY A CARDIOEMBOLIC

STROKE?

Brain

MRI is more sensitive for the detection of car-

dioembolic 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 embo-

lism.1,6 There are two types of hemorrhagic trans-

formation: multifocal, which is less symptomatic, and

hematoma, which has mass effect and clinical deteriora-

tion. The mechanism of hemorrhagic transformation is

reperfusion of ischemic zones, which occurs with spon-

taneous resolution of the emboli. Arterial wall trauma

and dissection at the site of the thrombus are alternative

explanations.8 Decreased conscious level, total circula-

tion infarcts, severe strokes (National Institute of Health

Stroke Scale score > 14), proximal occlusion, large

hypodensity in more than 1/3 of the middle cerebral ar-

tery 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 hem-

orrhagic transformation.10

Between brain and heart

A thrombus originating in the heart can occlude the

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 ar-

tery 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 in-

jected in an antecubital vein.1 Transcranial Doppler can

also detect microembolic signals (high-intensity tran-

sient sign) in the middle cerebral artery.1 However,

high-intensity transient signs are rarer in cardiac embo-

lism 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

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 myocar-

dial 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, hy-

pertrophic 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

Acta Cardiol Sin 2005;21:112 2

Mei-Shu Lin et al.

a vulnerability index (latent atrial vulnerability).15,16 Pro-

grammed 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 for-

mation. However, the prognostic significance of atrial

vulnerability is uncertain.15,16

Transthoracic echocardiogram (TTE) can detect mitral

stenosis, dilated cardiomyopathy and other structural ven-

tricular 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, physi-

cal 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, pulmo-

nary veins, and valve vegetations.1,6,13 The common

potential findings of echocardiography in patients with

cardioembolic stroke and negative cardiac disease his-

tory 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 con-

sensual indication for anticoagulation.13 A Markov

decision analysis of benefit and cost concluded that do-

ing TEE in all stroke patients in sinus rhythm was more

cost-effective than either a sequential strategy (TTE fol-

lowed by TEE) or TTE alone in patients with negative

cardiac disease history.13 This study also found the preva-

lence 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

IMPORTANT CARDIOEMBOLIC SOURCES

AND CONDITIONS

Atheroma on aortic arch

Autopsy and TEE studies both showed that protrud-

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 thick-

ness over 4 mm, ulcerated, non-calcified plaques and

those with mobile components are associated with an in-

creased 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, coro-

nary 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. Unfortu-

nately, no large randomized trials have been completed

to prove the beneficial results in patients with aortic

atheroma receiving these treatments. Anticoagulant ther-

apy has a theoretical risk of cholesterol embolism.

Patients with aortic plaque who were treated with warfa-

rin 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 ef-

fect 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 thick-

ness 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-


Cardioembolic Stroke

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 as-

sociated 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 complica-

tion. The editorial comment from Bittl and Caplan26

suggested it is self-evident and well known that

thrombolytics and heparin increase the risk of hemor-

rhagic stroke, and commented these two agents might

contribute directly or indirectly to the risk of brain em-

bolism 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, pri-

mary PCI should be favored over thrombolytics to avoid

stroke for acute myocardial infarction. The use of hepa-

rin has also been associated with an increased risk of the

cholesterol embolization syndrome, providing one hypo-

thetical connection between heparin use and adverse

outcomes among patients with stroke. Heparin is not rec-

ommended 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 dis-

lodge atheromatous material that embolizes to the

cerebral circulation. They indicated back bleeding

should be allowed whenever guide catheters are ad-

vanced around the aortic arch over a guide wire. If the

catheter is connected to a Y-adapter during advance-

ment, 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 po-

tential of some types of contrast agents. Bittl and

Caplan26 suggested more refined identification of risk

factors for embolization might come from the preprocedural

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, re-

gions 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 pro-

spective 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 Caplan26 concluded that further efforts should be

made to move beyond such traditional broad clinical cat-

egories 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 popu-

lation; 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 stud-

ies have cast doubt on the role of uncomplicated MVP in

stroke, even in youth.

Endocarditis

Two types of endocarditis, infective and non-infec-

tive, cause cardioembolic stroke. TEE can confirm valve

vegetations more reliably than TTE, and should be the

initial diagnostic procedure for all patients with moder-

ate 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 anti-

coagulants.

Infective endocarditis complicated with stroke oc-

curs in about 10% of cases.30,32 Most stroke in infective


Mei-Shu Lin et al.

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 in-

fective 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 fa-

vor surgery to prevent embolism include persistent large

vegetation 10 mm, embolic event during the first 2

weeks of antimicrobial treatment, or more than one em-

bolic event later in treatment.30 If urgent valve replacement

is necessary, stroke is not necessarily a contraindica-

tion.34 Cardiac surgery may preferably be performed

within 72 hours of stroke if CT/MRI excludes hemor-

rhagic transformation.34

Mycotic aneurysms complicate 1-5% of infective

endocarditis. Screening for mycotic aneurysms with con-

trast 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 rup-

ture, 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 rup-

tured 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. Paradoxi-

cal 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

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 min-

imum of 10 mm interatrial septal phasic movement and a

diameter of the ASA of at least 15 mm.1,6 Paradoxical em-

bolism, supraventricular arrhythmia, and thrombus from a

coexistent ASA are the more likely causes of stroke in pa-

tients 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 abnor-

malities. 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 pa-

tients with ischemic stroke and ASA or PFO alone

(regardless of its size). More aggressive preventive strat-

egies 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 pa-

tients with PFO were randomly assigned to receive

either aspirin or warfarin. There was no significant dif-

ference 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 al-

ternatives to aspirin. Device closure of PFO is safe and

results in substantial hospital-related cost savings when

compared with surgical closure.38 However, device clo-

sure 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

Non-valvular AF

Non-valvular AF is the commonest cause of cardio-

embolic stroke. The disorder is associated with thyroid

disorders, hypertension and heavy drinking.40,41 The risk of



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 associ-

ated 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 preven-

tion 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 in-

creased 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 car-

dioversion. 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 radio-

frequency/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 sev-

eral 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 proxi-

mal 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 un-

dergo open heart surgery49 and is associated with a

three-fold increase in the risk of stroke or transient

ischemic attack.49 Oral amiodarone and beta-blockers

significantly reduce the risk of postoperative stroke.50

How to prevent stroke and recurrent stroke in

patients with AF?

Risk factors for thromboembolism in AF include pre-

vious 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, hy-

pertension, heart failure and significant left ventricular

systolic dysfunction, diabetes, and coronary artery dis-

ease.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. As-

pirin 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 pros-

thetic valves) and 4.0 in patients with previous stroke or

transient ischemic attack.52 If the INR rises to over 6, low-

dose oral vitamin K should be prescribed.52

Despite the preventive potential of warfarin in pa-

tients 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 warfa-

rin 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 contrain-

dications for warfarin. In the ATRIA (AnTicoagulation

and Risk factors In Atrial fibrillation) study,55 the stron-

gest predictors of receiving warfarin were previous

stroke and heart failure. However, an age of 85 years or

older and previous intracranial or gastrointestinal hem-

orrhages 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


Mei-Shu Lin et al.



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

Warfarin (INR 2-3);

If age > 75: INR 1.5-2.0

Moderate risk: age 65-75, DM, CAD, thyrotoxicosis Warfarin or aspirin

Low risk: no risk factor, age < 65 Aspirin or none

Acute Heparin then warfarin

Cardioversion 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 (-) Aspirin and LMWH

Risk factors (+): anterior MI, CHF, AF,

systemic/pulmonary embolism, mural thrombus, severe LV

dysfunction

Heparin then warfarin

Previous MI

With CHF Aspirin or warfarin

With ventricular aneurysm Aspirin

With mobile or protuberant thrombus Warfarin

None of above Aspirin

Mechanical valve prosthesis Warfarin +/- aspirin

Bio-prosthesis

< 3 ms after valve insertion Warfarin

With AF, LA thrombus, systemic emboli Warfarin

None of above Aspirin

Rheumatic valve Warfarin

Atrial flutter Warfarin

Sick sinus syndrome Warfarin

Heart failure + sinus rhythm, for primary prevention None

DCM Warfarin

Atrial thrombus Warfarin

Ventricular Thrombus Aspirin or warfarin

Mobile or protuberant Warfarin

Calcified aortic stenosis Aspirin

HOCM Aspirin

MVP Aspirin or none

Mitral annular calcification Aspirin or warfarin

Infective endocarditis Antibiotics

native valve No anticoagulant

mechanical valve prosthesis Continue anticoagulant

mechanical valve prosthesis + large stroke Stop anticoagulant

Non-infective endocarditis Heparin then warfarin

Myxoma Surgery

ASA Aspirin or none

PFO+ASA Aspirin

Atrial echo contrast Aspirin

Aortic atheroma

< 4 mm None or aspirin

4 mm Aspirin + statin

4 mm + mobile or protuberant thrombus 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.

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

aspirin (325 mg/day) was insufficient for stroke preven-

tion. The rates of major bleeding were similar in both

treatment groups. In the AFASAK 2 (Second Copenha-

gen Atrial Fibrillation, Aspirin, and Anticoagulation)

Study,57 minidose warfarin (1.25 mg/day) plus aspirin

(300 mg/day) had no advantage over adjusted-dose war-

farin (target INR 2.0-3.0) for stroke prevention in AF.

Prevention of embolic events in patients with mechani-

cal valve prosthesis58 and prevention of serious vascular

events in acute myocardial infarction59 and probably in

congestive heart failure60 are the evidence-based indica-

tions 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 tri-

als,61 comparing a direct thrombin inhibitor (ximelagatran)

with warfarin for prevention of thromboembolism in pa-

tients with non-valvular AF, are underway. Ximelagatran

offers the advantage of not needing prothrombin time

controls and dose adjustments.

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 ben-

efit 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 eluci-

dated 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-hemor-

rhagic 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 evi-

dence.66 Observational data suggested that thrombolysis

might be more effective in patients with cardioembolic

stroke than in those with atherothrombotic stroke.66 A re-

cent 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 hem-

orrhagic stroke is a therapeutic dilemma. The data from

Mayo Clinic, including half of the patients with pros-

thetic 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

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 treat-

ment 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 al-

ternatives 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.

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