Evaluation and Prevention of Cardioembolic Stroke.10

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Evaluation and Prevention

of Cardioembolic StrokeAnthony S. Kim, MD, MASABSTRACT

Purpose of Review: The potential for cardioembolic stroke has importantimplications for clinical management. This review describes the diagnostic workupand management options for this key stroke subtype.Recent Findings: The suspicion for a cardioembolic source for stroke is raised with alarge vessel occlusion or when strokes occur in multiple vascular territories. Diagnosticworkup includes ECG, echocardiography, and cardiac monitoring. Atrial fibrillation isthe most common cause of cardioembolic stroke and typically justifies anticoagulationtherapy. New data on other mechanisms of cardioembolic strokeVsuch as congestiveheart failure, prosthetic valves, and aortic arch diseaseVas well as the availability ofnovel oral anticoagulants have implications for optimizing stroke prevention.Summary:Cardiogenic embolization is an important cause of stroke with importantimplications for diagnosis, treatment, and prevention.

Continuum (Minneap Minn) 2014;20(2):309322.

INTRODUCTION

Cardioembolic stroke accounts for a

substantial proportion of the overallburden of disease from stroke. Thisdisproportionate burden reflects theoverall prevalence of cardioembolicstroke combined with the greater sever-ity, less favorable prognosis, and highrecurrence risk of this stroke subtype.1

The potential for cardioembolism di-rectly affects primary prevention, acutemanagement, and secondary preventionof stroke. Recent advances in diagnosis,

risk stratification, and management devel-oped from clinical research, as well as theavailability of new therapeutic options,have had an impact on current clinicaldecision making.

Initial Clinical Evaluation

Cardioembolic stroke typically occurssuddenly, with neurologic symptoms thatare maximal at onset. A stroke syndromethat localizes to a large artery territory,

particularly when there is clinical evidence

of cortical involvement, also suggests acardioembolic source. Evidence of multi-

ple foci of concurrent or sequentialischemia, particularly in multiple cerebro-vascular or systemic vascular beds, is alsostrongly suggestive of a cardioembolicsource, although cardioembolism caninitially present with a single ischemiclesion. Certain examination and labo-ratory findings can be informative in thediagnosis of cardioembolic stroke, asoutlined inTable 3-1.

Neuroimaging StudiesNeuroimaging studies can help toconfirm or establish the vascular dis-tribution of both clinically evident andsubclinical ischemic lesions. Occlusionof a large- to medium-sized artery withan otherwise normal appearance ofthe parent vessel may suggest cardio-embolic stroke rather than strokedue to intrinsic atherosclerotic disease.Carotid studies may help to define an

alternative artery-to-artery mechanism.

Address correspondence toDr Anthony S. Kim, UCSFDepartment of Neurology,Sandler Neurosciences Center,675 Nelson Rising Lane, Room

411B, San Francisco, CA 94158,[email protected].

Relationship Disclosure:Dr Kim has received researchgrants from the AmericanHeart Association, the NIH,and SanBio, Inc; has servedas an expert witness providingrecord review in a courtcase; and has received anhonorarium and travelexpenses for speaking atan American NeurologicalAssociation training course.

Unlabeled Use ofProducts/Investigational

Use Disclosure:Dr Kim reports no disclosure.

* 2014, American Academyof Neurology.

309Continuum (Minneap Minn) 2014;20(2):309322 www.ContinuumJournal.com

Review Article

Copyright American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
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Echocardiography

Transthoracic echocardiography (TTE)provides a noninvasive assessment ofthe structure and function of the heartthat is essential to the cardioembolicstroke evaluation. Transesophageal echo-cardiography (TEE) has higher proceduralrisks but is more sensitive than TTE forevaluating the aortic arch, the aortic valve,the atrial septum, and left atrial append-

age.2

Bubble-contrast echocardiography,

which involves the injection of agitatedsaline as a contrast agent, can identify anintracardiac (eg, septal defect or patent

foramen ovale) or extracardiac shunt.

ATRIAL FIBRILLATION

An estimated 2.7 million Americans, in-cluding approximately 8% of the popu-lation more than 80 years of age, haveatrial fibrillation (AF).3 Given the in-creased risk of AF with age and theaging of the US population, the overallburden of AF and consequently strokefrom AF is expected to surge in the

coming decades.3,4

Because AF is res-ponsible for nearly half of all cardio-embolic strokes, and because strokesfrom AF are more severe and result ingreater disability and mortality thanother stroke subtypes, preventingstroke in patients with AF has a consid-erable impact on both individual patientoutcomes and population health.

Most AF-related strokes are caused byembolization from the left atrium andatrial appendage, which have directaccess to the cerebral arteries. AF is alsoassociated with enlargement of the leftatrium, which contributes to relativestasis, clot formation, and subsequentembolization. Relatively short periods ofAF may be sufficient to form thrombusbecause paroxysmal AF appears to pres-ent a similar risk for stroke as permanentor persistent AF, but whether there is athreshold burden of paroxysmal AF thatconfers this risk is uncertain.

Risk Stratification in AtrialFibrillation

AF confers a 5% annual risk of strokeoverall. However, the estimated risk ofstroke for a particular patient may varysubstantially depending on other riskfactors. Risk stratification scores havebeen developed to estimate this risk andto inform the choice of antithrombotictherapy. As illustrated in Case 3-1,

CHADS2 (congestive heart failure,

KEY POINTS

h Cardioembolic strokes

are often more severe

than other stroke

subtypes and have ahigh recurrence risk.

hThe suspicion for

cardioembolic stroke is

raised with large artery

occlusions or strokes in

multiple vascular

territories.

hTransesophageal

echocardiography is

helpful for evaluating

the aortic arch, aortic

valve, atrial septum, and

left atrial appendage.

hThe incidence of stroke

from atrial fibrillation is

expected to surge in the

coming decades as the

US population ages.

h Relatively short and

asymptomatic periods

of atrial fibrillation may

be sufficient to form

thrombus and causestroke.

TABLE 3-1 Clinical Evaluationfor CardioembolicStroke

bPhysical Examination

Temperature

Cardiac auscultation

Assessment of jugular venouspressure or peripheral edema

Lung auscultation

Retinal examination

Skin examination

bImaging Studies

CT/MRI of brain

Vascular imaging

Chest x-ray

bElectrocardiography

Serial ECG

Cardiac telemetry

Extended cardiac monitoring

bEchocardiography

Transthoracic

Transesophageal

bLaboratory Studies

White blood cell count

Erythrocyte sedimentation rate

C-reactive protein

Blood cultures

Thyroid function tests

Troponin

Antiphospholipid antibodies

CT = computed tomography; MRI = magneticresonance imaging; ECG = electrocardiogram.

310 www.ContinuumJournal.com April 2014

Cardioembolic Stroke



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hypertension, age Q 75 years, diabetesmellitus,stroke/TIA symptoms previously)and CHA2DS2VASc (congestive heartfailure, hypertension, age Q 75 years,diabetes mellitus, stroke, vascular dis-ease,age 65Y74 years,sex category)Varefinement of CHADS2Vcombine read-

ily available clinical factors into simplescores that provide estimates of annualstroke risk (Table 3-2,Table 3-3).5,6

For each of these scores, a historyof stroke or TIA is typically sufficientto justify anticoagulation therapy inisolation. Nonetheless, neurologistsmay find utility by applying these scoresin more complex cases, particularlywhen the estimated stroke risk isweighed against other risks such as the

risk of bleeding.

Electrocardiogram and CardiacMonitoring

Detecting an irregularly irregular heart-beat on examination or by ECG mayestablish the diagnosis of AF. However,since paroxysmal AF is often asymp-tomatic, at least 24 hours of cardiac

monitoring after an ischemic stroke isrecommended. An initial ECG demon-strating sinus rhythm does not excludethe possibility of a transient episode ofnew-onset paroxysmal AF that mayhave preceded the onset of stroke.7

AF is likely to be systematicallyunderdiagnosed in patients with crypto-genic stroke. Extended cardiac monitor-ing with ambulatory electrocardiograms(Holter monitors), real-time continuous

heart monitors, external loop recorders,

KEY POINTS

h Patients with atrial

fibrillation and a history

of stroke or TIA are in a

high-risk category thattypically justifies

anticoagulation.

h The absence of

symptoms of atrial

fibrillation such as

reduced exercise

tolerance, shortness of

breath, or palpitations,

or an initial ECG

showing sinus rhythm is

not sufficient to exclude

the possibility ofparoxysmal atrial

fibrillation as a cause

of stroke.

Case 3-1An 80-year-old man with a history of hypertension suddenly developedleft face and arm weakness and neglect. Head CT showed no hemorrhage,a neck CT angiogram showed no carotid stenosis, and an MRI demonstrated asmall infarct in the distal right middle cerebral artery territory. His initial ECGshowed sinus rhythm, but he had a 2-minute episode of atrial fibrillation (AF)captured on telemetry on the first hospital day. A transthoracic echocardiogramshowed moderate left atrial enlargement.

His primary care provider expressed some concern about initiatinganticoagulation given this patients age and risk of falls. The patients wife wasconcerned about his taking rat poison because a family friend had sustained awarfarin-associated intracranial hemorrhage. After an extensive discussion,warfarin was initiated during the initial hospitalization given that a large infarctwas not present, with a plan for close outpatient follow-up. Bridging aspirintherapy was stopped once an international normalized ratio (INR) of 2 wasachieved several days later.

Comment.This case illustrates the clear indication for anticoagulationconferred by atrial fibrillation and stroke. Simple risk scores can providerecommendations based on estimated stroke risk, but a history of strokeand AF is typically sufficient to justify anticoagulation on its own. Thispatients CHADS2 (congestive heart failure, hypertension,age Q75 years,diabetes mellitus, stroke/TIA symptoms previously) score was 4 (8.5%annual stroke risk), and his CHA2D2-Vasc (congestive heart failure,hypertension,age Q 75 years, diabetes mellitus, stroke, vascular disease,age 65Y74 years, sex category) score was 5 (9.3% risk). Concerns aboutfalls, advanced age, and bleeding risks, while relevant, are likely to beoutweighed by the benefits of anticoagulation. (This patients HAS-BLED

[hypertension,abnormal liver or renal function, stroke,bleeding,labile INR,elderly age,drug or alcohol use] score was 3 [5.8% annual risk]Va thresholdat which caution is warranted.)




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TABLE 3-2 The CHADS2Risk Score to Estimate Risk of Stroke in PatientsWith Atrial Fibrillationa,b

CHADS2 ScoreAnnual StrokeRisk %

95% ConfidenceInterval Recommendation

0 1.9 1.2Y3.0 No antithrombotic

1 2.8 2.0Y3.8 Antiplatelet oranticoagulation

2 4.0 3.1Y5.1 Anticoagulation




6 18.2 10.5Y27.4 Anticoagulationa Data from Gage BF, et al, JAMA.5 jama.jamanetwork.com/article.aspx?articleid=193912.b

CHADS2Congestive heart failure 1 pointHypertension 1 pointAge Q75 years 1 pointDiabetes mellitus 1 pointStroke/TIA symptoms previously 2 points

TABLE 3-3 The CHA2DS2-VASc Risk Score to Estimate Risk of Stroke inPatients With Atrial Fibrillationa,b

CHA2DS2-VAScScore

AnnualStroke Risk %


0 0.8 0.6Y1.0 No antithrombotic

1 2.0 1.7Y2.4 Antiplatelet oranticoagulation








9 23.6 10.6Y52.6 Anticoagulationa Data from Olesen JB, et al, BMJ.6 www.bmj.com/content/342/bmj.d124.b CHA2DS2-VASc

Congestive heart failure 1 pointHypertension 1 pointAge Q75 years 2 pointsDiabetes mellitus 1 pointStroke/TIA/thromboembolism 2 pointsVascular disease history (previous myocardial infarction, peripheral arterial disease, or aortic plaque) 1 pointAge 65Y74 years 1 pointSex category (female) 1 point



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or implantable loop recorders all allowfor a longer sampling period to detecttransient episodes of AF after stroke.

The 30-Day Cardiac Event Monitor Beltfor Recording Atrial Fibrillation After aCerebral Ischemic Event (EMBRACE)study evaluated 572 patients with cryp-togenic ischemic stroke or TIA who wererandomized to either 30 days of home-based cardiac monitoring or repeatHolter monitoring.8 Significantly morepatients were diagnosed with newAF in the 30-day monitoring groupcompared with the repeat Holter mon-

itoring group (16% versus 3%, PG

.001).However, the appropriate candidatesfor monitoring, the optimal durationand mode of monitoring, and theclinical significance of fleeting episodesof AF that can now be detected withprolonged monitoring have not beenestablished.

Antithrombotic Therapy

The mainstay of stroke prevention in AFhas been oral anticoagulation with war-farin to an international normalized ratio(INR) goal of 2.0 to 3.0 (Figure 3-19).Warfarin can effectively reduce the riskof stroke by up to 68% (95% CI 50% to79%), which corresponds to an absolutereduction in the annual risk of strokefrom 4.5% to 1.4%.10 In contrast, aspirinis substantially less effective (21% rela-tive risk reduction; 95% CI 0% to 38%)and is reserved for patients who areunable to take oral anticoagulants.

Adding aspirin to warfarin increasesbleeding risk and does not provideclear additional benefits, and thereforeis generally discouraged.11 The use ofmedications for rate control or rhythmcontrol for AF does not obviate theneed for appropriate antithrombotictherapy to prevent stroke.

For patients deemed unsuitable fororal anticoagulation because of a spe-cific bleeding risk or patient prefer-

ence, adding clopidogrel to aspirin

provides additional efficacy for strokeprevention in AF (2.4% annual risk)over aspirin alone (3.3% annual risk;relative risk of stroke for aspirin com-pared with aspirin and clopidogrel is1.6; 95% CI 1.3 to 1.9), but this benefitappears to be offset by a higher risk ofmajor bleeding (2.0% versus 1.3% an-nual risk) that is similar to warfarin.12

Therefore, national guidelines recom-mend aspirin alone rather than thecombination of aspirin and clopidogrelfor patients with AF and clear contra-indications to oral anticoagulation ther-apy, particularly in patients withhemorrhagic risks.11 Apixaban 5 mg

twice daily may be a potential alterativefor high-risk patients (see the sectionon novel oral anticoagulants).13

For patients with AF and ischemicstroke despite therapeutic anticoagulation,the optimal management strategy is notdefined. Most patients with ischemicstroke while on warfarin therapy arefound to have a subtherapeutic INR. Therisk of ischemic stroke rapidly rises as theINR drops below 2 (Figure 3-19),14 and

the percentage of time that patients

KEY POINTS

h Extended cardiac

monitoring increases

the sampling period for

detecting paroxysmal

atrial fibrillation, but theappropriate candidates

for monitoring, the

optimal duration and

mode of monitoring,

and the clinical

significance of fleeting

episodes of atrial

fibrillation have not

been established.

h Anticoagulation is

preferred over

antiplatelet agents forsecondary stroke

prevention in most

patients with atrial

fibrillation.

h Medications for rate or

rhythm control for atrial

fibrillation do not

obviate the need for

antithrombotic therapy

in patients with atrial

fibrillation.

FIGURE 3-1 Adjusted odds ratios for ischemic stroke andintracranial bleeding in relation to intensity of

anticoagulation. The dashed vertical lines delimitthe typical therapeutic range for warfarin therapy.

Reprinted with permission from European Heart RhythmAssociation, et al, J Am Coll Cardiol.9 B2006 AmericanCollege of Cardiology Foundation. content.onlinejacc.org/article.aspx?articleID=1137853.


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spend in the therapeutic range may be60% to 70% at most. For selectedpatients, an increased INR goal could

be considered, but bleeding risks areincreased and direct evidence of ben-efit is lacking.

Timing of InitiatingAnticoagulation AfterAcute Stroke

During the first few weeks after a newischemic stroke, the risks of hemor-rhagic transformation, particularly forpatients with large-territory infarcts or

with evidence of associated hemor-rhage, likely outweigh the potentialbenefits of anticoagulation to preventearly recurrent cardioembolic eventsfor most patients. For high-risk patientswith smaller strokes, well-controlledblood pressure, and no evidence ofbleeding, earlier initiation of anticoagu-lation can be considered, particularlywith warfarin since the achieving a fulltherapeutic effect typically takes severaldays anyway.

Novel Oral Anticoagulants

The intensive laboratory monitoring,narrow therapeutic range, and numer-ous drug interactions associated withwarfarin have prompted the develop-ment of alternative oral anticoagu-lants. As of December 2013, the US

Food and Drug Administration (FDA)has approved the direct thrombininhibitor dabigatran15,16 and two fac-

tor Xa inhibitors (rivaroxaban17,18

andapixaban19,20) for prevention of strokein nonvalvular AF (Table 3-4).

These agents have fixed dosing, donot require frequent laboratory moni-toring, have a rapid onset of anticoag-ulant effect, and have fewer druginteractions than warfarin. All werefound to be noninferior to warfarinfor stroke and systemic embolism(Rivaroxaban Versus Warfarin in Non-

valvular Atrial Fibrillation [ROCKET-AF],

18

Randomized Evaluation of Long-Term Anticoagulant Therapy [RE-LY],15

and Apixaban for the Prevention ofStroke in Subjects With Atrial Fibril-lation [ARISTOTLE]20). Dabigatran(150 mg dose) and apixaban also metsuperiority end points. Apixaban showeda mortality benefit over warfarin. Intra-cranial hemorrhage rates were lower forall three agents compared with warfarin,but major gastrointestinal bleeding washigher with dabigatran and rivaroxabancompared with warfarin.

As illustrated in Case 3-2, theseagents can be considered as an alter-native to warfarin in most patientswith AF and stroke, particularly giventhe lower intracranial hemorrhagerates seen in these initial studies. But

KEY POINT

hPotential benefits of

novel oral anticoagulants

compared to warfarin

include noninferior(rivaroxaban) or superior

efficacy (dabigatran and

apixaban), lower

intracranial bleeding,

fixed dosing, fewer

drug-drug interactions,

rapid onset of

anticoagulant effect,

and a mortality benefit

(apixaban).

TABLE 3-4 Properties of Oral Anticoagulant Therapies

Warfarin RivaroxabanDabigatranEtexilate Apixaban

Mechanism Vitamin K antagonist Factor Xa inhibitor Direct thrombininhibitor

Factor Xa inhibitor

Typical Dose forAtrial Fibrillation

Variable 20 mg daily 150 mg twice daily 5 mg twice daily

Renal DoseAdjustment

No Yes Yes Yes

Half-Life 20Y60 hours 5Y9 hours 12Y17 hours about 12 hours

Onset of Action 24Y72 hours 3Y4 hours 0.5Y2 hours 3Y4 hours





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patients with renal impairment, liverdisease, mechanical valves or othervalvular disease, or an anticipatedneed for reversal of anticoagulanteffect for gastrointestinal bleeding(for dabigatran and rivaroxaban) maybe well served to remain on warfarin.

A validated reversal strategy and alaboratory test of anticoagulant effect

are not yet available for these novelanticoagulants. Poor adherence to atwice-daily dosing schedule could re-sult in a subtherapeutic anticoagulanteffect more quickly compared withwarfarin. Higher drug costs and con-troversy regarding whether patientson these agents could be candidatesfor acute thrombolytic therapy arealso relevant considerations.

Underutilization ofAnticoagulation

Up to two-thirds of patients with AF,particularly those at highest risk of stroke,are not on appropriate anticoagulationtherapy.21 The underuse of anticoagula-tion for AF is based, in part, on thechallenges of warfarin therapy; however,other significant barriers remain.

The bleeding risks associated withfrequent falls or advanced age are often

outweighed by the stroke-prevention

benefits of anticoagulation. Patientsat risk for falls with a CHADS2 scoreof 2 or higher generally benefitfrom anticoagulation therapy, evenwhen there is an increased risk ofhemorrhage from falls.22 Althoughelderly patients have higher risksfor both ischemic and hemorrhagicstroke, a meta-analysis of 12 clinical

trials found that the benefits of anticoagulation appear to extend toelderly patients. This benefit wasdriven by hemorrhage rates that weresimilar with aspirin and with warfarintherapy.23 Ultimately though, the deci-sion to initiate anticoagulation is oftencomplex and should incorporate patientpreferences.

The HAS-BLED (Hypertension, Ab-normal liver or renal function, Stroke,

Bleeding, Labile INR, Elderly age,Drug or alcohol use) scale was devel-oped to estimate the risk of hemor-rhage with anticoagulation and tohighlight modifiable factors that areassociated with increased risk such asconcomitant antiplatelet therapy oralcohol intake (Table 3-524,25).24

HAS-BLED can provide additional in-formation for clinical decision making,but should not be used as the sole

reason to withhold anticoagulation

KEY POINTS

h Potential drawbacks

of novel oral

anticoagulants

compared to warfarininclude the lack of a

validated reversal

strategy or laboratory

test of anticoagulant

effect, uncertainty

about candidacy for

acute thrombolytic

therapy, and cost.

h A significant proportion

of patients with atrial

fibrillation who would

benefit fromanticoagulation are not

on anticoagulation

therapy.

h Overestimating the

bleeding risk associated

with falls and advanced

age and

underappreciating

the benefits of

anticoagulation with

age contribute to the

underuse of

anticoagulation for

atrial fibrillation.

Case 3-2A 65-year-old man with a history of paroxysmal atrial fibrillation and aright middle cerebral artery stroke 1 year ago had been maintained onwarfarin therapy. He reported good medication adherence, and hisinternational normalized ratio was usually between 2 and 3 at hisfollow-up visits to the anticoagulation clinic. Renal function was normal.He would like to discuss whether he is a candidate for a novel oralanticoagulant.

Comment.For patients who are already well managed on warfarin,continuing warfarin therapy may be reasonable. However, the lower risksof intracranial hemorrhage that have been reported with the novel oralanticoagulants could justify making the transition from warfarin to a noveloral anticoagulant in carefully selected patients. Renal disease, liverdisease, medication interactions, medication adherence, availability ofreversal agents, and cost are all considerations when choosing an oralanticoagulant.




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therapy for patients who have otherindications for anticoagulation forstroke secondary prevention.

Surgical Procedures for AtrialFibrillation

Left atrial appendage closure devices andleft atrial appendage excision or exclu-sion procedures as well as Cox maze

procedures (a series of surgical incisionsto the atria to interrupt atrial reentry) andradioablation have been developed totreat AF. For most patients, these pro-cedures do not obviate the need forlong-term anticoagulation therapy be-cause a continued risk for recurrent AFremains even after treatment, and therisk of recurrent stroke for patientswith AF who have already had a strokeor TIA is high. Therefore, the precise

role for these procedural approaches to

prevent stroke with AF has not beenestablished.

VALVULAR DISEASEInfective Endocarditis

Stroke is often the primary presentingsymptom of infective endocarditis.Although direct infection of normalvalves can occur, the risk of endocar-

ditis is much higher when the nativevalve is compromised. Although rheu-matic heart disease is uncommon indeveloped counties, it is still the mostcommon cause of valvular diseaseglobally. Bicuspid aortic valve andprosthetic valve implantation conferhigher risks for infection as well. IVdrug use is more commonly associatedwith right-sided valvular disease (eg,tricuspid valve) and typically results in

septic embolization to the lungs rather

TABLE 3-5 HAS-BLED Score to Estimate the Risk of Hemorrhage WithWarfarina,b

HAS-BLEDScore

BleedingRisk %


0 0.9 0.4Y1.9 None

1 3.4 2.5Y4.6 None

2 4.1 2.9Y5.6 None

3 5.8 3.9Y8.3 Caution warranted



Q6 Insufficient data Insufficient data Caution warranteda Data from Pisters R, et al, Chest,24 journal.publications.chestnet.org/article.aspx?articleid=1045174.

and Lip GY, et al, J AmColl Cardiol.25 www.sciencedirect.com/science/article/pii/S0735109710043378.b

HAS-BLEDHypertension 1 pointSystolic blood pressure 9160 mm Hg

Abnormal renal and/or liver function 1 or 2 pointsRenal: dialysis, kidney transplant, or creatinine Q2.6 mg/dL (1 point)Liver: cirrhosis or bilirubin 92normal; or AST, ALT, or AlkPhos 93 normal (1 point)

Stroke 1 pointBleeding predisposition or history 1 pointLabile international normalized ratio (INR) 1 point

Time spent in therapeutic range G60%Elderly 1 point

Age 965 yearsDrugs and/or excess alcohol use 1 or 2 points

Antiplatelet agents or nonsteroidal anti-inflammatory drugsMaximum HAS-BLED Score is 9 pointsAST = aspartate aminotransferase; ALT = alanine aminotransferase; AlkPhos = alkaline phosphatase.



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than ischemic stroke, but IV drug usestill confers a higher risk for left-sidedendocarditis. Staphylococcus aureus,

Streptococcus viridans,and Enterococ-cusare the most common organisms.26

Endocarditis is suggested by fever,weight loss, a history of IV drug use orother source of bacteremia, a newmurmur on physical examination, orevidence of systemic embolization toother vascular territories. Multiple bloodcultures, serial ECG (to evaluate formyocardial infarction, heart block, orconduction delay), and TEE are critical

elements of the diagnostic workup. TTEis not adequate to exclude the possibilityof valvular vegetations when endocardi-tis is suspected.27 An elevated erythro-cyte sedimentation rate or C-reactiveprotein, and a leukocytosis, which isnot always present, support this diag-nosis but are relatively nonspecific.

Brain MRI is better suited thanhead CT for demonstrating the multi-ple foci of ischemia and cerebralmicrobleeds that are typical for endo-carditis. The lesions in endocarditisare classically of differing ages and inmultiple vascular distributions or in awatershed distribution; subclinicalbrain lesions are common.

Antibiotic therapy may reduce the riskof continued embolization. Anti-thrombotic therapy in the acute settingis associated with an increased risk ofhemorrhage. For patients with AF ormechanical heart valve prostheses who

present with endocarditis and stroke,short-term interruption of anticoagula-tion therapy may be necessary in somecases, despite the high risks of throm-bosis and recurrent stroke during theperiod that anticoagulation is withheld.

Nonbacterial ThromboticEndocarditis

Nonbacterial thrombotic endocarditis(marantic endocarditis) involves the ag-

gregation of sterile vegetations along the

edge of heart valves and is primarilyassociated with systemic malignancy.Heparin or low-molecular-weight hepa-

rin rather than warfarin is generallyrecommended.28 Libman-Sacks endo-carditis, which is associated with sys-temic lupus erythematosus and theantiphospholipid antibody syndrome,involves a similar deposition of immunecomplexes that result in small inflamma-tory vegetations. Direct evidence islacking, but antiplatelet therapy forprimary prevention or anticoagulationfor secondary prevention is reasonable.

Rheumatic Heart Disease

Rheumaticheart disease, a complication ofGroup A streptococcal infection, mostcommonly affects the mitral valve. Con-current AF is common.11 The risk ofstroke remains even after successfulvalvulopla sty, so continued anti -coagulation to a goal INR of 2.0 to 3.0 isrecommended.

Prosthetic Mechanical Valves

and Bioprosthetic ValvesProsthetic mechanical valves present ahigh risk for thromboembolization, es-pecially for devices with caged-ball ortilting-disc mechanisms and for devicesin the mitral position. Anticoagulationis indicated for all patients with me-chanical valves; the intensity of anti-coagulation therapy and the specificindications for concomitant antiplatelettherapy are based on the type and

position of the prosthetic valve.For patients with prosthetic valves

that present with embolic events suchas stroke despite adequate anti-thrombotic therapy, national guidelinesprovide comprehensive suggestions onintensifying antithrombotic therapy forvarious clinical scenarios, although de-finitive data to support these recom-mendations are admittedly sparse(Table 3-629). Bioprosthetic valves do

not present the same degree of embolic

KEY POINTS

h A transthoracic

echocardiogram is not

adequate to exclude the

possibility of valvularvegetations when

endocarditis is

suspected. Rather, a

transesophageal

echocardiogram is

critical to the diagnostic

workup of possible

endocarditis.

h Anticoagulation with

warfarin is strongly

indicated for all patients

with mechanical heartvalves.




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risk as mechanical valves and cangenerally be managed with anti-platelet therapy. However, warfarin isrecommended for the first 3 monthsafter implantation of a mitral bio-prosthetic valve.

Dabigatran is not recommended foruse in patients with mechanical heartvalves, and rivaroxaban and apixabanhave not been evaluated for this indi-

cation. Therefore, warfarin remains thepreferred treatment for this indication.

Mitral Valve Prolapse

Mitral valve prolapse is a largely echo-cardiographic diagnosis that is charac-terized by abnormal movement of oneor more valve leaflets into the left atriumduring systole. Data on the relationshipbetween mitral valve prolapse andstroke are conflicting. Most patients with

stroke and mitral valve prolapse can bemanaged with antiplatelet therapy.30

CARDIOMYOPATHY ANDSTRUCTURAL HEART LESIONSHeart Failure

Heart failure is associated with anincreased risk of stroke from alteredflow within dilated heart chambers,relative stasis of blood, increased riskof concomitant AF, and an associated

relative prothrombotic state. For pa-

tients with associated AF or left ven-tricular thrombus, anticoagulation isgenerally preferred over antiplatelettherapy.

As illustrated in Case 3-3, for patientswith heart failure and sinus rhythm, theoptimal choice of antiplatelet oranticoagulation therapy is uncertain. Inthe Warfarin and Antiplatelet Therapy inChronic Heart Failure (WATCH) study,

patients with symptomatic heart failure,sinus rhythm, and a left ventricularejection fraction of 35% or less wererandomized to aspirin (162 mg/d),clopidogrel (75 mg/d), or warfarin (INR2.5 to 3.0).32 There were no significantdifferences between the three treat-ment arms for the risk of the compositeprimary end point of death, myocardialinfarction, or stroke. Similarly, in theWarfarin and Aspirin in Patients With

Heart Failure and Sinus Rhythm(WARCEF)study, patients with an ejectionfraction below 35% with sinus rhythmwere randomized to aspirin 325 mg/dor adjusted-dose warfarin (goal INR of2.75; range 2.0 to 3.5).31 Anticoagulationdid not provide an overall benefit: a re-duction in ischemic stroke was offset byan increase in major hemorrhage.For secondary prevention, warfarin,aspirin, clopidogrel, or aspirin plus

extended dipyridamole are all reasonable

TABLE 3-6 Suggested Intensification of Antithrombotic Therapyfor Stroke With Prosthetic Valve Replacementa

Therapy on PresentationWith New Stroke Dose Adjustment Option

Warfarin, internationalnormalized ratio (INR) 2.0Y3.0

Increase INR goal to 2.5Y3.5

Warfarin, INR 2.5Y3.5 Increase INR goal to 3.5Y4.5

No aspirin Initiate aspirin 75Y100 mg/d

Warfarin + aspirin 75Y100 mg/d Increase aspirin dose to 325 mg/d

Aspirin 75Y100 mg/d Increase aspirin dose to 325 mg/d,and/or add clopidogrel 75 mg/d,and/or add warfarin

a DatafromBonow RO, etal, J AmColl Cardiol.29www.sciencedirect.com/science/article/pii/S0735109708018330.



http://www.sciencedirect.com/science/article/pii/S0735109708018330http://www.sciencedirect.com/science/article/pii/S0735109708018330


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options, but comparative data are lacking.Data on the use of novel oral anticoagu-lants in this setting are not available.

Myocardial Infarction and LeftVentricular Thrombus

Left ventricular thrombus, a complica-tion of myocardial infarction, presentsa high risk for embolization andsubsequent stroke. Left ventricularthrombus is more common with ante-rior ST-segment elevation myocardialinfarction because of the relative stasisof blood within the ventricle. There-fore, for patients at high risk ofdeveloping left ventricular thrombus,a screening TTE is recommended.

For patients with documented leftventricular thrombus and myocardialinfarct ion, at least 3 months of anticoagulation is recommended.11

Follow-up TTE to evaluate left ventric-ular ejection fraction and residualthrombus may help with individual-ized decisions on the optimal dura-tion of anticoagulation therapy. Again,novel oral anticoagulants have notbeen evaluated in this setting and are

not recommended.

Other Cardiac Lesions

Atrial myxoma, a tumor of mesenchy-mal cells of the heart, is a rare cause ofcardioembolic stroke that is seen mostoften in younger patients. An atrial massis seen on echocardiography and can bepresent even without a mitral stenosismurmur or a tumor plop on ausculta-tion. Papillary fibroelastoma is a rarecause of stroke that is also apparent onechocardiography. For both lesions, theongoing risk of embolization typicallywarrants surgical resection.

AORTIC ARCH ATHEROSCLEROSIS

Aortic arch atherosclerosis confers arisk for both systemic and cerebrovas-

cular embolization. This commonly oc-curs via thromboembolism of largerclots that lodge and fragment in medi-um and large vessels. However, choles-terol embolization from the plaqueitself may also occur and typicallyshowers much smaller emboli into thearterioles in multiple vascular terri-tories. Cholesterol embolization fromthe plaque itself can shower muchsmaller emboli into arterioles in multi-

ple vascular territories.

KEY POINTS

h For patients with

congestive heart failure

with sinus rhythm, the

choice ofanticoagulation or

antiplatelet agent for

secondary stroke

prevention is uncertain.

h Patients with left

ventricular thrombus

should generally be

treated with

anticoagulation for at

least 3 months.

Case 3-3A 64-year-old woman with a history of congestive heart failure presentedwith an acute right middle cerebral stroke. Her echocardiogram showedbiatrial enlargement and a left ventricular ejection fraction of 30%; nothrombus or valvular disease was seen. ECG showed sinus rhythm. A brainMRI showed multiple foci of restricted diffusion in the right middlecerebral artery territory, as well as three small foci of restricted diffusion inthe left hemisphere. The patient was discharged home on antiplatelettherapy, but, given the suspicion for a cardioembolic source, she wasreferred for extended cardiac monitoring. One week later, she had anasymptomatic 5-minute episode of atrial fibrillation noted on cardiacmonitoring and returned to clinic to transition to anticoagulation therapy.

Comment.This case illustrates the initial management of a strokepatient with a history of congestive heart failure with a reduced ejectionfraction and sinus rhythm with antiplatelet therapy based on the Warfarinand Aspirin in Patients With Heart Failure and Sinus Rhythm (WARCEF)study.31 However, the distribution of the infarcts suggested a cardioembolicsource, and the documented paroxysmal atrial fibrillation demonstrated infollow-up provided a clear justification for anticoagulation therapy.




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TEE is generally preferred over TTEfor assessing the aortic arch. Plaquethickness greater than 4 mm, ulcera-

tion, and actively mobile elementshave been implicated as potential riskfactors for embolization.33Y35

Increased plaque thickness suggestsa complex plaque with overlying throm-bus. Ulceration is thought to increasethe risk of thrombus formation. Mobileelements suggest that a thrombus issuperimposed on an unstable plaque.

Aortic arch atherosclerosis sharesrisk factors in common with stroke

more generally, so these patients oftenhave clear indications for aggressive riskfactor modification and antiplatelettherapy for secondary preventionirrespective of aortic arch disease.Statins may have the potential to stabi-lize or even regress plaques. The AorticArch Related Cerebral Hazard Trial(ARCH) trial compared the combina-tion of aspirin and clopidogrel withadjusted-dose warfarin to prevent re-current vascular events in patients withsignificant aortic arch disease and arecent TIA or minor stroke.36 The finalresults of this study are not yet avail-able; however, the trial was recentlyand prematurely terminated for futility.

SUMMARY

Cardioembolism is an important causeof stroke that requires an initial clini-cal suspicion, a tailored diagnosticworkup, particularly for atrial fibrilla-tion, and a prevention strategy thatdraws upon current clinical evidenceand therapeutic options.

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