Review Article
Evaluation and Prevention of Cardioembolic Stroke Anthony S. Kim, MD, MAS ABSTRACT Purpose of Review: The potential for cardioembolic stroke has important implications for clinical management. This review describes the diagnostic workup and management options for this key stroke subtype. Recent Findings: The suspicion for a cardioembolic source for stroke is raised with a large vessel occlusion or when strokes occur in multiple vascular territories. Diagnostic workup includes ECG, echocardiography, and cardiac monitoring. Atrial fibrillation is the most common cause of cardioembolic stroke and typically justifies anticoagulation therapy. New data on other mechanisms of cardioembolic strokeVsuch as congestive heart failure, prosthetic valves, and aortic arch diseaseVas well as the availability of novel oral anticoagulants have implications for optimizing stroke prevention. Summary: Cardiogenic embolization is an important cause of stroke with important implications for diagnosis, treatment, and prevention.
Address correspondence to Dr Anthony S. Kim, UCSF Department of Neurology, Sandler Neurosciences Center, 675 Nelson Rising Lane, Room 411B, San Francisco, CA 94158, [email protected]. Relationship Disclosure: Dr Kim has received research grants from the American Heart Association, the NIH, and SanBio, Inc; has served as an expert witness providing record review in a court case; and has received an honorarium and travel expenses for speaking at an American Neurological Association training course. Unlabeled Use of Products/Investigational Use Disclosure: Dr Kim reports no disclosure. * 2014, American Academy of Neurology.
Continuum (Minneap Minn) 2014;20(2):309–322.
INTRODUCTION Cardioembolic stroke accounts for a substantial proportion of the overall burden of disease from stroke. This disproportionate burden reflects the overall prevalence of cardioembolic stroke combined with the greater severity, less favorable prognosis, and high recurrence risk of this stroke subtype.1 The potential for cardioembolism directly affects primary prevention, acute management, and secondary prevention of stroke. Recent advances in diagnosis, risk stratification, and management developed from clinical research, as well as the availability of new therapeutic options, have had an impact on current clinical decision making. Initial Clinical Evaluation Cardioembolic stroke typically occurs suddenly, with neurologic symptoms that are maximal at onset. A stroke syndrome that localizes to a large artery territory, particularly when there is clinical evidence Continuum (Minneap Minn) 2014;20(2):309–322
of cortical involvement, also suggests a cardioembolic source. Evidence of multiple foci of concurrent or sequential ischemia, particularly in multiple cerebrovascular or systemic vascular beds, is also strongly suggestive of a cardioembolic source, although cardioembolism can initially present with a single ischemic lesion. Certain examination and laboratory findings can be informative in the diagnosis of cardioembolic stroke, as outlined in Table 3-1. Neuroimaging Studies Neuroimaging studies can help to confirm or establish the vascular distribution of both clinically evident and subclinical ischemic lesions. Occlusion of a large- to medium-sized artery with an otherwise normal appearance of the parent vessel may suggest cardioembolic stroke rather than stroke due to intrinsic atherosclerotic disease. Carotid studies may help to define an alternative artery-to-artery mechanism. www.ContinuumJournal.com
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Cardioembolic Stroke KEY POINTS
h Cardioembolic strokes are often more severe than other stroke subtypes and have a high recurrence risk.
TABLE 3-1
Clinical Evaluation for Cardioembolic Stroke
b Physical Examination
h The suspicion for
Temperature
cardioembolic stroke is raised with large artery occlusions or strokes in multiple vascular territories.
Cardiac auscultation Assessment of jugular venous pressure or peripheral edema Lung auscultation Retinal examination
h Transesophageal
Skin examination
echocardiography is helpful for evaluating the aortic arch, aortic valve, atrial septum, and left atrial appendage.
b Imaging Studies CT/MRI of brain Vascular imaging Chest x-ray
h The incidence of stroke
b Electrocardiography
from atrial fibrillation is expected to surge in the coming decades as the US population ages.
Serial ECG Cardiac telemetry Extended cardiac monitoring b Echocardiography
h Relatively short and asymptomatic periods of atrial fibrillation may be sufficient to form thrombus and cause stroke.
Transthoracic Transesophageal b Laboratory Studies White blood cell count Erythrocyte sedimentation rate C-reactive protein Blood cultures Thyroid function tests Troponin Antiphospholipid antibodies CT = computed tomography; MRI = magnetic resonance imaging; ECG = electrocardiogram.
Echocardiography Transthoracic echocardiography (TTE) provides a noninvasive assessment of the structure and function of the heart that is essential to the cardioembolic stroke evaluation. Transesophageal echocardiography (TEE) has higher procedural risks but is more sensitive than TTE for evaluating the aortic arch, the aortic valve, the atrial septum, and left atrial appendage.2 Bubble-contrast echocardiography,
310
which involves the injection of agitated saline as a contrast agent, can identify an intracardiac (eg, septal defect or patent foramen ovale) or extracardiac shunt. ATRIAL FIBRILLATION An estimated 2.7 million Americans, including approximately 8% of the population more than 80 years of age, have atrial fibrillation (AF).3 Given the increased risk of AF with age and the aging of the US population, the overall burden of AF and consequently stroke from AF is expected to surge in the coming decades.3,4 Because AF is responsible for nearly half of all cardioembolic strokes, and because strokes from AF are more severe and result in greater disability and mortality than other stroke subtypes, preventing stroke in patients with AF has a considerable impact on both individual patient outcomes and population health. Most AF-related strokes are caused by embolization from the left atrium and atrial appendage, which have direct access to the cerebral arteries. AF is also associated with enlargement of the left atrium, which contributes to relative stasis, clot formation, and subsequent embolization. Relatively short periods of AF may be sufficient to form thrombus because paroxysmal AF appears to present a similar risk for stroke as permanent or persistent AF, but whether there is a threshold burden of paroxysmal AF that confers this risk is uncertain. Risk Stratification in Atrial Fibrillation AF confers a 5% annual risk of stroke overall. However, the estimated risk of stroke for a particular patient may vary substantially depending on other risk factors. Risk stratification scores have been developed to estimate this risk and to inform the choice of antithrombotic therapy. As illustrated in Case 3-1, CHADS2 (congestive heart failure,
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KEY POINTS
Case 3-1
h Patients with atrial
An 80-year-old man with a history of hypertension suddenly developed left face and arm weakness and neglect. Head CT showed no hemorrhage, a neck CT angiogram showed no carotid stenosis, and an MRI demonstrated a small infarct in the distal right middle cerebral artery territory. His initial ECG showed sinus rhythm, but he had a 2-minute episode of atrial fibrillation (AF) captured on telemetry on the first hospital day. A transthoracic echocardiogram showed moderate left atrial enlargement. His primary care provider expressed some concern about initiating anticoagulation given this patient’s age and risk of falls. The patient’s wife was concerned about his taking ‘‘rat poison’’ because a family friend had sustained a warfarin-associated intracranial hemorrhage. After an extensive discussion, warfarin was initiated during the initial hospitalization given that a large infarct was not present, with a plan for close outpatient follow-up. Bridging aspirin therapy was stopped once an international normalized ratio (INR) of 2 was achieved several days later. Comment. This case illustrates the clear indication for anticoagulation conferred by atrial fibrillation and stroke. Simple risk scores can provide recommendations based on estimated stroke risk, but a history of stroke and AF is typically sufficient to justify anticoagulation on its own. This patient’s CHADS2 (congestive heart failure, hypertension, age Q 75 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 about falls, advanced age, and bleeding risks, while relevant, are likely to be outweighed by the benefits of anticoagulation. (This patient’s 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 threshold at which caution is warranted.)
hypertension, age Q 75 years, diabetes mellitus, stroke/TIA symptoms previously) and CHA2DS2VASc (congestive heart failure, hypertension, age Q 75 years, diabetes mellitus, stroke, vascular disease, age 65Y74 years, sex category)Va refinement of CHADS2Vcombine readily available clinical factors into simple scores that provide estimates of annual stroke risk (Table 3-2, Table 3-3).5,6 For each of these scores, a history of stroke or TIA is typically sufficient to justify anticoagulation therapy in isolation. Nonetheless, neurologists may find utility by applying these scores in more complex cases, particularly when the estimated stroke risk is weighed against other risks such as the risk of bleeding. Continuum (Minneap Minn) 2014;20(2):309–322
fibrillation and a history of stroke or TIA are in a high-risk category that typically 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 of paroxysmal atrial fibrillation as a cause of stroke.
Electrocardiogram and Cardiac Monitoring Detecting an irregularly irregular heartbeat on examination or by ECG may establish the diagnosis of AF. However, since paroxysmal AF is often asymptomatic, at least 24 hours of cardiac monitoring after an ischemic stroke is recommended. An initial ECG demonstrating sinus rhythm does not exclude the possibility of a transient episode of new-onset paroxysmal AF that may have preceded the onset of stroke.7 AF is likely to be systematically underdiagnosed in patients with cryptogenic stroke. Extended cardiac monitoring with ambulatory electrocardiograms (Holter monitors), real-time continuous heart monitors, external loop recorders, www.ContinuumJournal.com
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Cardioembolic Stroke
to Estimate Risk of Stroke in Patients TABLE 3-2 The CHADS2 Risk Score a,b With Atrial Fibrillation Annual Stroke CHADS2 Score Risk %
95% Confidence Interval
Recommendation
0
1.9
1.2Y3.0
No antithrombotic
1
2.8
2.0Y3.8
Antiplatelet or anticoagulation
2
4.0
3.1Y5.1
Anticoagulation
3
5.9
4.6Y7.3
Anticoagulation
4
8.5
6.3Y11.1
Anticoagulation
5
12.5
8.2Y17.5
Anticoagulation
6
18.2
10.5Y27.4
Anticoagulation
a
Data from Gage BF, et al, JAMA.5 jama.jamanetwork.com/article.aspx?articleid=193912. b CHADS2 Congestive heart failure 1 point Hypertension 1 point Age Q75 years 1 point Diabetes mellitus 1 point Stroke/TIA symptoms previously 2 points
Estimate Risk of Stroke in TABLE 3-3 The CHA2DS2-VASc Risk Score toa,b Patients With Atrial Fibrillation CHA2DS2-VASc Score
95% Confidence Interval
Recommendation
0
0.8
0.6Y1.0
No antithrombotic
1
2.0
1.7Y2.4
Antiplatelet or anticoagulation
2
3.7
3.4Y4.1
Anticoagulation
3
5.9
5.5Y6.3
Anticoagulation
4
9.3
8.7Y9.9
Anticoagulation
5
15.3
14.3Y16.2
Anticoagulation
6
19.7
18.2Y21.4
Anticoagulation
7
21.5
18.8Y24.6
Anticoagulation
8
22.4
16.3Y30.8
Anticoagulation
9
23.6
10.6Y52.6
Anticoagulation
a b
312
Annual Stroke Risk %
6
Data from Olesen JB, et al, BMJ. www.bmj.com/content/342/bmj.d124. CHA2DS2-VASc Congestive heart failure 1 point Hypertension 1 point Age Q75 years 2 points Diabetes mellitus 1 point Stroke/TIA/thromboembolism 2 points Vascular disease history (previous myocardial infarction, peripheral arterial disease, or aortic plaque) 1 point Age 65Y74 years 1 point Sex category (female) 1 point
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or implantable loop recorders all allow for a longer sampling period to detect transient episodes of AF after stroke. The 30-Day Cardiac Event Monitor Belt for Recording Atrial Fibrillation After a Cerebral Ischemic Event (EMBRACE) study evaluated 572 patients with cryptogenic ischemic stroke or TIA who were randomized to either 30 days of homebased cardiac monitoring or repeat Holter monitoring.8 Significantly more patients were diagnosed with new AF in the 30-day monitoring group compared with the repeat Holter monitoring group (16% versus 3%, PG.001). However, the appropriate candidates for monitoring, the optimal duration and mode of monitoring, and the clinical significance of fleeting episodes of AF that can now be detected with prolonged monitoring have not been established. Antithrombotic Therapy The mainstay of stroke prevention in AF has been oral anticoagulation with warfarin to an international normalized ratio (INR) goal of 2.0 to 3.0 (Figure 3-19). Warfarin can effectively reduce the risk of stroke by up to 68% (95% CI 50% to 79%), which corresponds to an absolute reduction in the annual risk of stroke from 4.5% to 1.4%.10 In contrast, aspirin is substantially less effective (21% relative risk reduction; 95% CI 0% to 38%) and is reserved for patients who are unable to take oral anticoagulants. Adding aspirin to warfarin increases bleeding risk and does not provide clear additional benefits, and therefore is generally discouraged.11 The use of medications for rate control or rhythm control for AF does not obviate the need for appropriate antithrombotic therapy to prevent stroke. For patients deemed unsuitable for oral anticoagulation because of a specific bleeding risk or patient preference, adding clopidogrel to aspirin Continuum (Minneap Minn) 2014;20(2):309–322
FIGURE 3-1
Adjusted odds ratios for ischemic stroke and intracranial bleeding in relation to intensity of anticoagulation. The dashed vertical lines delimit the typical therapeutic range for warfarin therapy. Reprinted with permission from European Heart Rhythm Association, et al, J Am Coll Cardiol.9 B 2006 American College of Cardiology Foundation. content.onlinejacc.org/ article.aspx?articleID=1137853.
provides additional efficacy for stroke prevention in AF (2.4% annual risk) over aspirin alone (3.3% annual risk; relative risk of stroke for aspirin compared with aspirin and clopidogrel is 1.6; 95% CI 1.3 to 1.9), but this benefit appears to be offset by a higher risk of major bleeding (2.0% versus 1.3% annual risk) that is similar to warfarin.12 Therefore, national guidelines recommend aspirin alone rather than the combination of aspirin and clopidogrel for patients with AF and clear contraindications to oral anticoagulation therapy, particularly in patients with hemorrhagic risks.11 Apixaban 5 mg twice daily may be a potential alterative for high-risk patients (see the section on novel oral anticoagulants).13 For patients with AF and ischemic stroke despite therapeutic anticoagulation, the optimal management strategy is not defined. Most patients with ischemic stroke while on warfarin therapy are found to have a subtherapeutic INR. The risk of ischemic stroke rapidly rises as the INR 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 the appropriate 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 for secondary 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.
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Cardioembolic Stroke KEY POINT
spend in the therapeutic range may be 60% to 70% at most. For selected patients, an increased INR goal could be considered, but bleeding risks are increased and direct evidence of benefit is lacking.
h Potential 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).
Timing of Initiating Anticoagulation After Acute Stroke During the first few weeks after a new ischemic stroke, the risks of hemorrhagic transformation, particularly for patients with large-territory infarcts or with evidence of associated hemorrhage, likely outweigh the potential benefits of anticoagulation to prevent early recurrent cardioembolic events for most patients. For high-risk patients with smaller strokes, well-controlled blood pressure, and no evidence of bleeding, earlier initiation of anticoagulation can be considered, particularly with warfarin since the achieving a full therapeutic effect typically takes several days anyway. Novel Oral Anticoagulants The intensive laboratory monitoring, narrow therapeutic range, and numerous drug interactions associated with warfarin have prompted the development of alternative oral anticoagulants. As of December 2013, the US
Food and Drug Administration (FDA) has approved the direct thrombin inhibitor dabigatran15,16 and two factor Xa inhibitors (rivaroxaban17,18 and apixaban19,20) for prevention of stroke in nonvalvular AF (Table 3-4). These agents have fixed dosing, do not require frequent laboratory monitoring, have a rapid onset of anticoagulant effect, and have fewer drug interactions than warfarin. All were found to be noninferior to warfarin for stroke and systemic embolism (Rivaroxaban Versus Warfarin in Nonvalvular Atrial Fibrillation [ROCKET-AF],18 Randomized Evaluation of LongTerm Anticoagulant Therapy [RE-LY],15 and Apixaban for the Prevention of Stroke in Subjects With Atrial Fibrillation [ARISTOTLE] 20). Dabigatran (150 mg dose) and apixaban also met superiority end points. Apixaban showed a mortality benefit over warfarin. Intracranial hemorrhage rates were lower for all three agents compared with warfarin, but major gastrointestinal bleeding was higher with dabigatran and rivaroxaban compared with warfarin. As illustrated in Case 3-2, these agents can be considered as an alternative to warfarin in most patients with AF and stroke, particularly given the lower intracranial hemorrhage rates seen in these initial studies. But
TABLE 3-4 Properties of Oral Anticoagulant Therapies
314
Warfarin
Rivaroxaban
Mechanism
Vitamin K antagonist
Factor Xa inhibitor
Typical Dose for Atrial Fibrillation
Variable
Renal Dose Adjustment
Dabigatran Etexilate
Apixaban
20 mg daily
Direct thrombin inhibitor 150 mg twice daily
Factor Xa inhibitor 5 mg twice daily
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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KEY POINTS
Case 3-2
h Potential drawbacks
A 65-year-old man with a history of paroxysmal atrial fibrillation and a right middle cerebral artery stroke 1 year ago had been maintained on warfarin therapy. He reported good medication adherence, and his international normalized ratio was usually between 2 and 3 at his follow-up visits to the anticoagulation clinic. Renal function was normal. He would like to discuss whether he is a candidate for a novel oral anticoagulant. Comment. For patients who are already well managed on warfarin, continuing warfarin therapy may be reasonable. However, the lower risks of intracranial hemorrhage that have been reported with the novel oral anticoagulants could justify making the transition from warfarin to a novel oral anticoagulant in carefully selected patients. Renal disease, liver disease, medication interactions, medication adherence, availability of reversal agents, and cost are all considerations when choosing an oral anticoagulant.
patients with renal impairment, liver disease, mechanical valves or other valvular disease, or an anticipated need for reversal of anticoagulant effect for gastrointestinal bleeding (for dabigatran and rivaroxaban) may be well served to remain on warfarin. A validated reversal strategy and a laboratory test of anticoagulant effect are not yet available for these novel anticoagulants. Poor adherence to a twice-daily dosing schedule could result in a subtherapeutic anticoagulant effect more quickly compared with warfarin. Higher drug costs and controversy regarding whether patients on these agents could be candidates for acute thrombolytic therapy are also relevant considerations. Underutilization of Anticoagulation Up to two-thirds of patients with AF, particularly those at highest risk of stroke, are not on appropriate anticoagulation therapy.21 The underuse of anticoagulation for AF is based, in part, on the challenges of warfarin therapy; however, other significant barriers remain. The bleeding risks associated with frequent falls or advanced age are often outweighed by the stroke-prevention Continuum (Minneap Minn) 2014;20(2):309–322
benefits of anticoagulation. Patients at risk for falls with a CHADS2 score of 2 or higher generally benefit from anticoagulation therapy, even when there is an increased risk of hemorrhage from falls.22 Although elderly patients have higher risks for both ischemic and hemorrhagic stroke, a meta-analysis of 12 clinical trials found that the benefits of anticoagulation appear to extend to elderly patients. This benefit was driven by hemorrhage rates that were similar with aspirin and with warfarin therapy.23 Ultimately though, the decision to initiate anticoagulation is often complex and should incorporate patient preferences. The HAS-BLED (Hypertension, Abnormal liver or renal function, Stroke, Bleeding, Labile INR, Elderly age, Drug or alcohol use) scale was developed to estimate the risk of hemorrhage with anticoagulation and to highlight modifiable factors that are associated with increased risk such as concomitant antiplatelet therapy or alcohol intake (Table 3-5 24,25 ). 24 HAS-BLED can provide additional information for clinical decision making, but should not be used as the sole reason to withhold anticoagulation
of novel oral anticoagulants compared to warfarin include 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 from anticoagulation 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.
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Cardioembolic Stroke
TABLE 3-5 HAS-BLEDa,bScore to Estimate the Risk of Hemorrhage With Warfarin HAS-BLED Score
Bleeding Risk %
95% Confidence Interval
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
4
8.9
5.2Y14.0
Caution warranted
5
9.1
1.1Y29.2
Caution warranted
Insufficient data
Insufficient data
Caution warranted
Q6 a b
Data from Pisters R, et al, Chest,24 journal.publications.chestnet.org/article.aspx?articleid=1045174. and Lip GY, et al, J Am Coll Cardiol.25 www.sciencedirect.com/science/article/pii/S0735109710043378. HAS-BLED Hypertension 1 point Systolic blood pressure 9160 mm Hg Abnormal renal and/or liver function 1 or 2 points Renal: dialysis, kidney transplant, or creatinine Q2.6 mg/dL (1 point) Liver: cirrhosis or bilirubin 92 normal; or AST, ALT, or AlkPhos 93 normal (1 point) Stroke 1 point Bleeding predisposition or history 1 point Labile international normalized ratio (INR) 1 point Time spent in therapeutic range G60% Elderly 1 point Age 965 years Drugs and/or excess alcohol use 1 or 2 points Antiplatelet agents or nonsteroidal anti-inflammatory drugs Maximum HAS-BLED Score is 9 points AST = aspartate aminotransferase; ALT = alanine aminotransferase; AlkPhos = alkaline phosphatase.
therapy for patients who have other indications for anticoagulation for stroke secondary prevention. Surgical Procedures for Atrial Fibrillation Left atrial appendage closure devices and left atrial appendage excision or exclusion procedures as well as Cox maze procedures (a series of surgical incisions to the atria to interrupt atrial reentry) and radioablation have been developed to treat AF. For most patients, these procedures do not obviate the need for long-term anticoagulation therapy because a continued risk for recurrent AF remains even after treatment, and the risk of recurrent stroke for patients with AF who have already had a stroke or TIA is high. Therefore, the precise role for these procedural approaches to
316
Recommendation
prevent stroke with AF has not been established. VALVULAR DISEASE Infective Endocarditis Stroke is often the primary presenting symptom of infective endocarditis. Although direct infection of normal valves can occur, the risk of endocarditis is much higher when the native valve is compromised. Although rheumatic heart disease is uncommon in developed counties, it is still the most common cause of valvular disease globally. Bicuspid aortic valve and prosthetic valve implantation confer higher risks for infection as well. IV drug use is more commonly associated with right-sided valvular disease (eg, tricuspid valve) and typically results in septic embolization to the lungs rather
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April 2014
than ischemic stroke, but IV drug use still confers a higher risk for left-sided endocarditis. Staphylococcus aureus, Streptococcus viridans, and Enterococcus are the most common organisms.26 Endocarditis is suggested by fever, weight loss, a history of IV drug use or other source of bacteremia, a new murmur on physical examination, or evidence of systemic embolization to other vascular territories. Multiple blood cultures, serial ECG (to evaluate for myocardial infarction, heart block, or conduction delay), and TEE are critical elements of the diagnostic workup. TTE is not adequate to exclude the possibility of valvular vegetations when endocarditis is suspected.27 An elevated erythrocyte sedimentation rate or C-reactive protein, and a leukocytosis, which is not always present, support this diagnosis but are relatively nonspecific. Brain MRI is better suited than head CT for demonstrating the multiple foci of ischemia and cerebral microbleeds that are typical for endocarditis. The lesions in endocarditis are classically of differing ages and in multiple vascular distributions or in a watershed distribution; subclinical brain lesions are common. Antibiotic therapy may reduce the risk of continued embolization. Antithrombotic therapy in the acute setting is associated with an increased risk of hemorrhage. For patients with AF or mechanical heart valve prostheses who present with endocarditis and stroke, short-term interruption of anticoagulation therapy may be necessary in some cases, despite the high risks of thrombosis and recurrent stroke during the period that anticoagulation is withheld. Nonbacterial Thrombotic Endocarditis Nonbacterial thrombotic endocarditis (marantic endocarditis) involves the aggregation of sterile vegetations along the Continuum (Minneap Minn) 2014;20(2):309–322
edge of heart valves and is primarily associated with systemic malignancy. Heparin or low-molecular-weight heparin rather than warfarin is generally recommended.28 Libman-Sacks endocarditis, which is associated with systemic lupus erythematosus and the antiphospholipid antibody syndrome, involves a similar deposition of immune complexes that result in small inflammatory vegetations. Direct evidence is lacking, but antiplatelet therapy for primary prevention or anticoagulation for secondary prevention is reasonable. Rheumatic Heart Disease Rheumatic heart disease, a complication of Group A streptococcal infection, most commonly affects the mitral valve. Concurrent AF is common.11 The risk of stroke remains even after successful valvuloplasty, so continued anticoagulation to a goal INR of 2.0 to 3.0 is recommended.
KEY POINTS
h A transthoracic echocardiogram is not adequate to exclude the possibility of valvular vegetations 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 heart valves.
Prosthetic Mechanical Valves and Bioprosthetic Valves Prosthetic mechanical valves present a high risk for thromboembolization, especially for devices with caged-ball or tilting-disc mechanisms and for devices in the mitral position. Anticoagulation is indicated for all patients with mechanical valves; the intensity of anticoagulation therapy and the specific indications for concomitant antiplatelet therapy are based on the type and position of the prosthetic valve. For patients with prosthetic valves that present with embolic events such as stroke despite adequate antithrombotic therapy, national guidelines provide comprehensive suggestions on intensifying antithrombotic therapy for various clinical scenarios, although definitive data to support these recommendations are admittedly sparse (Table 3-629). Bioprosthetic valves do not present the same degree of embolic www.ContinuumJournal.com
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Cardioembolic Stroke
TABLE 3-6 Suggested Intensification of Antithrombotic Therapy for Stroke With Prosthetic Valve Replacementa Therapy on Presentation With New Stroke Warfarin, international normalized 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
Data from Bonow RO, et al, J Am Coll Cardiol.29 www.sciencedirect.com/science/article/pii/S0735109708018330.
risk as mechanical valves and can generally be managed with antiplatelet therapy. However, warfarin is recommended for the first 3 months after implantation of a mitral bioprosthetic valve. Dabigatran is not recommended for use in patients with mechanical heart valves, and rivaroxaban and apixaban have not been evaluated for this indication. Therefore, warfarin remains the preferred treatment for this indication. Mitral Valve Prolapse Mitral valve prolapse is a largely echocardiographic diagnosis that is characterized by abnormal movement of one or more valve leaflets into the left atrium during systole. Data on the relationship between mitral valve prolapse and stroke are conflicting. Most patients with stroke and mitral valve prolapse can be managed with antiplatelet therapy.30 CARDIOMYOPATHY AND STRUCTURAL HEART LESIONS Heart Failure Heart failure is associated with an increased risk of stroke from altered flow within dilated heart chambers, relative stasis of blood, increased risk of concomitant AF, and an associated relative prothrombotic state. For pa-
318
Dose Adjustment Option
tients with associated AF or left ventricular thrombus, anticoagulation is generally preferred over antiplatelet therapy. As illustrated in Case 3-3, for patients with heart failure and sinus rhythm, the optimal choice of antiplatelet or anticoagulation therapy is uncertain. In the Warfarin and Antiplatelet Therapy in Chronic Heart Failure (WATCH) study, patients with symptomatic heart failure, sinus rhythm, and a left ventricular ejection fraction of 35% or less were randomized to aspirin (162 mg/d), clopidogrel (75 mg/d), or warfarin (INR 2.5 to 3.0).32 There were no significant differences between the three treatment arms for the risk of the composite primary end point of death, myocardial infarction, or stroke. Similarly, in the Warfarin and Aspirin in Patients With Heart Failure and Sinus Rhythm (WARCEF) study, patients with an ejection fraction below 35% with sinus rhythm were randomized to aspirin 325 mg/d or adjusted-dose warfarin (goal INR of 2.75; range 2.0 to 3.5).31 Anticoagulation did not provide an overall benefit: a reduction in ischemic stroke was offset by an increase in major hemorrhage. For secondary prevention, warfarin, aspirin, clopidogrel, or aspirin plus extended dipyridamole are all reasonable
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KEY POINTS
Case 3-3
h For patients with
A 64-year-old woman with a history of congestive heart failure presented with an acute right middle cerebral stroke. Her echocardiogram showed biatrial enlargement and a left ventricular ejection fraction of 30%; no thrombus or valvular disease was seen. ECG showed sinus rhythm. A brain MRI showed multiple foci of restricted diffusion in the right middle cerebral artery territory, as well as three small foci of restricted diffusion in the left hemisphere. The patient was discharged home on antiplatelet therapy, but, given the suspicion for a cardioembolic source, she was referred for extended cardiac monitoring. One week later, she had an asymptomatic 5-minute episode of atrial fibrillation noted on cardiac monitoring and returned to clinic to transition to anticoagulation therapy. Comment. This case illustrates the initial management of a stroke patient with a history of congestive heart failure with a reduced ejection fraction and sinus rhythm with antiplatelet therapy based on the Warfarin and Aspirin in Patients With Heart Failure and Sinus Rhythm (WARCEF) study.31 However, the distribution of the infarcts suggested a cardioembolic source, and the documented paroxysmal atrial fibrillation demonstrated in follow-up provided a clear justification for anticoagulation therapy.
options, but comparative data are lacking. Data on the use of novel oral anticoagulants in this setting are not available. Myocardial Infarction and Left Ventricular Thrombus Left ventricular thrombus, a complication of myocardial infarction, presents a high risk for embolization and subsequent stroke. Left ventricular thrombus is more common with anterior ST-segment elevation myocardial infarction because of the relative stasis of blood within the ventricle. Therefore, for patients at high risk of developing left ventricular thrombus, a screening TTE is recommended. For patients with documented left ventricular thrombus and myocardial infarction, at least 3 months of anticoagulation is recommended.11 Follow-up TTE to evaluate left ventricular ejection fraction and residual thrombus may help with individualized decisions on the optimal duration of anticoagulation therapy. Again, novel oral anticoagulants have not been evaluated in this setting and are not recommended. Continuum (Minneap Minn) 2014;20(2):309–322
congestive heart failure with sinus rhythm, the choice of anticoagulation 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.
Other Cardiac Lesions Atrial myxoma, a tumor of mesenchymal cells of the heart, is a rare cause of cardioembolic stroke that is seen most often in younger patients. An atrial mass is seen on echocardiography and can be present even without a mitral stenosis murmur or a tumor plop on auscultation. Papillary fibroelastoma is a rare cause of stroke that is also apparent on echocardiography. For both lesions, the ongoing risk of embolization typically warrants surgical resection. AORTIC ARCH ATHEROSCLEROSIS Aortic arch atherosclerosis confers a risk for both systemic and cerebrovascular embolization. This commonly occurs via thromboembolism of larger clots that lodge and fragment in medium and large vessels. However, cholesterol embolization from the plaque itself may also occur and typically showers much smaller emboli into the arterioles in multiple vascular territories. Cholesterol embolization from the plaque itself can shower much smaller emboli into arterioles in multiple vascular territories. www.ContinuumJournal.com
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TEE is generally preferred over TTE for assessing the aortic arch. Plaque thickness greater than 4 mm, ulceration, and actively mobile elements have been implicated as potential risk factors for embolization.33Y35 Increased plaque thickness suggests a complex plaque with overlying thrombus. Ulceration is thought to increase the risk of thrombus formation. Mobile elements suggest that a thrombus is superimposed on an unstable plaque. Aortic arch atherosclerosis shares risk factors in common with stroke more generally, so these patients often have clear indications for aggressive risk factor modification and antiplatelet therapy for secondary prevention irrespective of aortic arch disease. Statins may have the potential to stabilize or even regress plaques. The Aortic Arch Related Cerebral Hazard Trial (ARCH) trial compared the combination of aspirin and clopidogrel with adjusted-dose warfarin to prevent recurrent vascular events in patients with significant aortic arch disease and a recent TIA or minor stroke.36 The final results of this study are not yet available; however, the trial was recently and prematurely terminated for futility. SUMMARY Cardioembolism is an important cause of stroke that requires an initial clinical suspicion, a tailored diagnostic workup, particularly for atrial fibrillation, and a prevention strategy that draws upon current clinical evidence and therapeutic options. REFERENCES 1. Lin HJ, Wolf PA, Kelly-Hayes M, et al. Stroke severity in atrial fibrillation. The Framingham Study. Stroke 1996;27(10):1760Y1764. 2. Pearson AC, Labovitz AJ, Tatineni S, Gomez CR. Superiority of transesophageal echocardiography in detecting cardiac source of embolism in patients with cerebral
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ischemia of uncertain etiology. J Am Coll Cardiol 1991;17(1):66Y72. 3. Go AS, Mozaffarian D, Roger VL, et al. Heart disease and stroke statisticsV2013 update: a report from the American Heart Association. Circulation 2013;127(1):e6Ye245. 4. Go AS, Hylek EM, Phillips KA, et al. Prevalence of diagnosed atrial fibrillation in adults: national implications for rhythm management and stroke prevention: the AnTicoagulation and Risk Factors in Atrial Fibrillation (ATRIA) Study. JAMA 2001;285(18): 2370Y2375. 5. Gage BF, Waterman AD, Shannon W, et al. Validation of clinical classification schemes for predicting stroke: results from the National Registry of Atrial Fibrillation. JAMA 2001;285(22):2864Y2870. 6. Olesen JB, Lip GY, Hansen ML, et al. Validation of risk stratification schemes for predicting stroke and thromboembolism in patients with atrial fibrillation: nationwide cohort study. BMJ 2011;342:d124. 7. Jauch EC, Saver JL, Adams HP Jr, et al. Guidelines for the early management of patients with acute ischemic stroke: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2013;44(3):870Y947. 8. Gladstone D, Spring M, Dorian P, et al. Prolonged ambulatory cardiac monitoring improves the detection and treatment of atrial fibrillation in patients with cryptogenic stroke: primary results from the EMBRACE multicenter randomized trial. Honolulu, HI: International Stroke Conference, 2013. 9. European Heart Rhythm Association; Heart Rhythm Society; Fuster V, Ryde´n LE, Cannom DS, et al. ACC/AHA/ESC 2006 guidelines for the management of patients with atrial fibrillationVexecutive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Revise the 2001 Guidelines for the Management of Patients With Atrial Fibrillation). J Am Coll Cardiol 2006;48(4): 854Y906. 10. Risk factors for stroke and efficacy of antithrombotic therapy in atrial fibrillation. Analysis of pooled data from five randomized controlled trials. Arch Intern Med 1994;154(13): 1449Y1457. 11. Furie KL, Kasner SE, Adams RJ, et al. Guidelines for the prevention of stroke in patients with stroke or transient ischemic
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attack: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2011;42(1): 227Y276. 12. Connolly SJ, Pogue J, Hart RG, et al. Effect of clopidogrel added to aspirin in patients with atrial fibrillation. N Engl J Med 2009;360(20):2066Y2078. 13. Furie KL, Goldstein LB, Albers GW, et al. Oral antithrombotic agents for the prevention of stroke in nonvalvular atrial fibrillation: a science advisory for healthcare professionals from the American Heart Association/ American Stroke Association. Stroke 2012;43(12):3442Y3453. 14. American College of Cardiology Foundation; American Heart Association; European Society of Cardiology; Heart Rhythm Society, Wann LS, Curtis AB, Ellenbogen KA, et al. Management of patients with atrial fibrillation: a report of the American College of Cardiology/ American Heart Association Task Force on Practice Guidelines. Circulation 2013;127(18): 1916Y1926. 15. Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009;361(12): 1139Y1151. 16. Diener HC, Connolly SJ, Ezekowitz MD, et al. Dabigatran compared with warfarin in patients with atrial fibrillation and previous transient ischaemic attack or stroke: a subgroup analysis of the RE-LY trial. Lancet Neurol 2010;9(12):1157Y1163. 17. Hankey GJ, Patel MR, Stevens SR, et al. Rivaroxaban compared with warfarin in patients with atrial fibrillation and previous stroke or transient ischaemic attack: a subgroup analysis of ROCKET AF. Lancet Neurol 2012;11(4):315Y322. 18. Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011;365(10):883Y891. 19. Easton JD, Lopes RD, Bahit MC, et al. Apixaban compared with warfarin in patients with atrial fibrillation and previous stroke or transient ischaemic attack: a subgroup analysis of the ARISTOTLE trial. Lancet Neurol 2012;11(6):503Y511. 20. Granger CB, Alexander JH, McMurray JJ, et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2011;365(11):981Y992. 21. Birman-Deych E, Radford MJ, Nilasena DS, Gage BF. Use and effectiveness of warfarin in Medicare beneficiaries with atrial fibrillation. Stroke 2006;37(4):1070Y1074. Continuum (Minneap Minn) 2014;20(2):309–322
22. Gage BF, Birman-Deych E, Kerzner R, et al. Incidence of intracranial hemorrhage in patients with atrial fibrillation who are prone to fall. Am J Med 2005;118(6):612Y617. 23. van Walraven C, Hart RG, Connolly S, et al. Effect of age on stroke prevention therapy in patients with atrial fibrillation: the atrial fibrillation investigators. Stroke 2009;40(4):1410Y1416. 24. Pisters R, Lane DA, Nieuwlaat R, et al. A novel user-friendly score (HAS-BLED) to assess 1-year risk of major bleeding in patients with atrial fibrillation: the Euro Heart Survey. Chest 2010;138(5):1093Y1100. 25. Lip GY, Frison L, Halperin JL, Lane DA. Comparative validation of a novel risk score for predicting bleeding risk in anticoagulated patients with atrial fibrillation: the HAS-BLED (Hypertension, Abnormal Renal/Liver Function, Stroke, Bleeding History or Predisposition, Labile INR, Elderly, Drugs/Alcohol Concomitantly) score. J Am Coll Cardiol 2011;57(2):173Y180. 26. Selton-Suty C, Celard M, Le Moing V, et al. Preeminence of Staphylococcus aureus in infective endocarditis: a 1-year population-based survey. Clin Infect Dis 2012;54(9):1230Y1239. 27. Nishimura RA, Carabello BA, Faxon DP, et al. ACC/AHA 2008 guideline update on valvular heart disease: focused update on infective endocarditis: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines endorsed by the Society of Cardiovascular Anesthesiologists, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. Circulation 2008;118(8): 887Y896. 28. Whitlock RP, Sun JC, Fremes SE, et al. Antithrombotic and thrombolytic therapy for valvular disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012;141(2 suppl):e576SYe600S. 29. Bonow RO, Carabello BA, Chatterjee K, et al. 2008 focused update incorporated into the ACC/AHA 2006 guidelines for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to revise the 1998 guidelines for the management of patients with valvular heart disease). Endorsed by the Society of Cardiovascular Anesthesiologists, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. J Am Coll Cardiol 2008;52(13): e1Ye142. www.ContinuumJournal.com
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30. Lansberg MG, O’Donnell MJ, Khatri P, et al. Antithrombotic and thrombolytic therapy for ischemic stroke: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012;141(2 suppl):e601SYe636S. 31. Homma S, Thompson JL, Pullicino PM, et al. Warfarin and aspirin in patients with heart failure and sinus rhythm. N Engl J Med 2012;366(20):1859Y1869. 32. Massie BM, Collins JF, Ammon SE, et al. Randomized trial of warfarin, aspirin, and clopidogrel in patients with chronic heart failure: the Warfarin and Antiplatelet Therapy in Chronic Heart Failure (WATCH) trial. Circulation 2009;119(12):1616Y1624.
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33. The French Study of Aortic Plaques Group. Atherosclerotic disease of the aortic arch as a risk factor for recurrent ischemic stroke. N Eng J Med 1996;334(19):1216Y1221. 34. The Stroke Prevention in Atrial Fibrillation Investigators Committee on Echocardiography. Transesophageal echocardiographic correlates of thromboembolism in high-risk patients with nonvalvular atrial fibrillation. Ann Intern Med 1998;128(8):639Y647. 35. Amarenco P, Cohen A, Tzourio C, et al. Atherosclerotic disease of the aortic artch and the risk of ischemic stroke. N Engl J Med 1994;331(22):1474Y1479. 36. Aortic Arch Related Cerebral Hazard Trial (ARCH). www.clinicaltrials.gov/ct/show/ NCT00235248. Accessed August 26, 2013.
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Evaluation and Prevention of Cardioembolic Stroke Anthony S. Kim, MD, MAS ABSTRACT Purpose of Review: The potential for cardioembolic stroke has important implications for clinical management. This review describes the diagnostic workup and management options for this key stroke subtype. Recent Findings: The suspicion for a cardioembolic source for stroke is raised with a large vessel occlusion or when strokes occur in multiple vascular territories. Diagnostic workup includes ECG, echocardiography, and cardiac monitoring. Atrial fibrillation is the most common cause of cardioembolic stroke and typically justifies anticoagulation therapy. New data on other mechanisms of cardioembolic strokeVsuch as congestive heart failure, prosthetic valves, and aortic arch diseaseVas well as the availability of novel oral anticoagulants have implications for optimizing stroke prevention. Summary: Cardiogenic embolization is an important cause of stroke with important implications for diagnosis, treatment, and prevention.
Address correspondence to Dr Anthony S. Kim, UCSF Department of Neurology, Sandler Neurosciences Center, 675 Nelson Rising Lane, Room 411B, San Francisco, CA 94158, [email protected]. Relationship Disclosure: Dr Kim has received research grants from the American Heart Association, the NIH, and SanBio, Inc; has served as an expert witness providing record review in a court case; and has received an honorarium and travel expenses for speaking at an American Neurological Association training course. Unlabeled Use of Products/Investigational Use Disclosure: Dr Kim reports no disclosure. * 2014, American Academy of Neurology.
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INTRODUCTION Cardioembolic stroke accounts for a substantial proportion of the overall burden of disease from stroke. This disproportionate burden reflects the overall prevalence of cardioembolic stroke combined with the greater severity, less favorable prognosis, and high recurrence risk of this stroke subtype.1 The potential for cardioembolism directly affects primary prevention, acute management, and secondary prevention of stroke. Recent advances in diagnosis, risk stratification, and management developed from clinical research, as well as the availability of new therapeutic options, have had an impact on current clinical decision making. Initial Clinical Evaluation Cardioembolic stroke typically occurs suddenly, with neurologic symptoms that are maximal at onset. A stroke syndrome that localizes to a large artery territory, particularly when there is clinical evidence Continuum (Minneap Minn) 2014;20(2):309–322
of cortical involvement, also suggests a cardioembolic source. Evidence of multiple foci of concurrent or sequential ischemia, particularly in multiple cerebrovascular or systemic vascular beds, is also strongly suggestive of a cardioembolic source, although cardioembolism can initially present with a single ischemic lesion. Certain examination and laboratory findings can be informative in the diagnosis of cardioembolic stroke, as outlined in Table 3-1. Neuroimaging Studies Neuroimaging studies can help to confirm or establish the vascular distribution of both clinically evident and subclinical ischemic lesions. Occlusion of a large- to medium-sized artery with an otherwise normal appearance of the parent vessel may suggest cardioembolic stroke rather than stroke due to intrinsic atherosclerotic disease. Carotid studies may help to define an alternative artery-to-artery mechanism. www.ContinuumJournal.com
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Cardioembolic Stroke KEY POINTS
h Cardioembolic strokes are often more severe than other stroke subtypes and have a high recurrence risk.
TABLE 3-1
Clinical Evaluation for Cardioembolic Stroke
b Physical Examination
h The suspicion for
Temperature
cardioembolic stroke is raised with large artery occlusions or strokes in multiple vascular territories.
Cardiac auscultation Assessment of jugular venous pressure or peripheral edema Lung auscultation Retinal examination
h Transesophageal
Skin examination
echocardiography is helpful for evaluating the aortic arch, aortic valve, atrial septum, and left atrial appendage.
b Imaging Studies CT/MRI of brain Vascular imaging Chest x-ray
h The incidence of stroke
b Electrocardiography
from atrial fibrillation is expected to surge in the coming decades as the US population ages.
Serial ECG Cardiac telemetry Extended cardiac monitoring b Echocardiography
h Relatively short and asymptomatic periods of atrial fibrillation may be sufficient to form thrombus and cause stroke.
Transthoracic Transesophageal b Laboratory Studies White blood cell count Erythrocyte sedimentation rate C-reactive protein Blood cultures Thyroid function tests Troponin Antiphospholipid antibodies CT = computed tomography; MRI = magnetic resonance imaging; ECG = electrocardiogram.
Echocardiography Transthoracic echocardiography (TTE) provides a noninvasive assessment of the structure and function of the heart that is essential to the cardioembolic stroke evaluation. Transesophageal echocardiography (TEE) has higher procedural risks but is more sensitive than TTE for evaluating the aortic arch, the aortic valve, the atrial septum, and left atrial appendage.2 Bubble-contrast echocardiography,
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which involves the injection of agitated saline as a contrast agent, can identify an intracardiac (eg, septal defect or patent foramen ovale) or extracardiac shunt. ATRIAL FIBRILLATION An estimated 2.7 million Americans, including approximately 8% of the population more than 80 years of age, have atrial fibrillation (AF).3 Given the increased risk of AF with age and the aging of the US population, the overall burden of AF and consequently stroke from AF is expected to surge in the coming decades.3,4 Because AF is responsible for nearly half of all cardioembolic strokes, and because strokes from AF are more severe and result in greater disability and mortality than other stroke subtypes, preventing stroke in patients with AF has a considerable impact on both individual patient outcomes and population health. Most AF-related strokes are caused by embolization from the left atrium and atrial appendage, which have direct access to the cerebral arteries. AF is also associated with enlargement of the left atrium, which contributes to relative stasis, clot formation, and subsequent embolization. Relatively short periods of AF may be sufficient to form thrombus because paroxysmal AF appears to present a similar risk for stroke as permanent or persistent AF, but whether there is a threshold burden of paroxysmal AF that confers this risk is uncertain. Risk Stratification in Atrial Fibrillation AF confers a 5% annual risk of stroke overall. However, the estimated risk of stroke for a particular patient may vary substantially depending on other risk factors. Risk stratification scores have been developed to estimate this risk and to inform the choice of antithrombotic therapy. As illustrated in Case 3-1, CHADS2 (congestive heart failure,
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KEY POINTS
Case 3-1
h Patients with atrial
An 80-year-old man with a history of hypertension suddenly developed left face and arm weakness and neglect. Head CT showed no hemorrhage, a neck CT angiogram showed no carotid stenosis, and an MRI demonstrated a small infarct in the distal right middle cerebral artery territory. His initial ECG showed sinus rhythm, but he had a 2-minute episode of atrial fibrillation (AF) captured on telemetry on the first hospital day. A transthoracic echocardiogram showed moderate left atrial enlargement. His primary care provider expressed some concern about initiating anticoagulation given this patient’s age and risk of falls. The patient’s wife was concerned about his taking ‘‘rat poison’’ because a family friend had sustained a warfarin-associated intracranial hemorrhage. After an extensive discussion, warfarin was initiated during the initial hospitalization given that a large infarct was not present, with a plan for close outpatient follow-up. Bridging aspirin therapy was stopped once an international normalized ratio (INR) of 2 was achieved several days later. Comment. This case illustrates the clear indication for anticoagulation conferred by atrial fibrillation and stroke. Simple risk scores can provide recommendations based on estimated stroke risk, but a history of stroke and AF is typically sufficient to justify anticoagulation on its own. This patient’s CHADS2 (congestive heart failure, hypertension, age Q 75 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 about falls, advanced age, and bleeding risks, while relevant, are likely to be outweighed by the benefits of anticoagulation. (This patient’s 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 threshold at which caution is warranted.)
hypertension, age Q 75 years, diabetes mellitus, stroke/TIA symptoms previously) and CHA2DS2VASc (congestive heart failure, hypertension, age Q 75 years, diabetes mellitus, stroke, vascular disease, age 65Y74 years, sex category)Va refinement of CHADS2Vcombine readily available clinical factors into simple scores that provide estimates of annual stroke risk (Table 3-2, Table 3-3).5,6 For each of these scores, a history of stroke or TIA is typically sufficient to justify anticoagulation therapy in isolation. Nonetheless, neurologists may find utility by applying these scores in more complex cases, particularly when the estimated stroke risk is weighed against other risks such as the risk of bleeding. Continuum (Minneap Minn) 2014;20(2):309–322
fibrillation and a history of stroke or TIA are in a high-risk category that typically 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 of paroxysmal atrial fibrillation as a cause of stroke.
Electrocardiogram and Cardiac Monitoring Detecting an irregularly irregular heartbeat on examination or by ECG may establish the diagnosis of AF. However, since paroxysmal AF is often asymptomatic, at least 24 hours of cardiac monitoring after an ischemic stroke is recommended. An initial ECG demonstrating sinus rhythm does not exclude the possibility of a transient episode of new-onset paroxysmal AF that may have preceded the onset of stroke.7 AF is likely to be systematically underdiagnosed in patients with cryptogenic stroke. Extended cardiac monitoring with ambulatory electrocardiograms (Holter monitors), real-time continuous heart monitors, external loop recorders, www.ContinuumJournal.com
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Cardioembolic Stroke
to Estimate Risk of Stroke in Patients TABLE 3-2 The CHADS2 Risk Score a,b With Atrial Fibrillation Annual Stroke CHADS2 Score Risk %
95% Confidence Interval
Recommendation
0
1.9
1.2Y3.0
No antithrombotic
1
2.8
2.0Y3.8
Antiplatelet or anticoagulation
2
4.0
3.1Y5.1
Anticoagulation
3
5.9
4.6Y7.3
Anticoagulation
4
8.5
6.3Y11.1
Anticoagulation
5
12.5
8.2Y17.5
Anticoagulation
6
18.2
10.5Y27.4
Anticoagulation
a
Data from Gage BF, et al, JAMA.5 jama.jamanetwork.com/article.aspx?articleid=193912. b CHADS2 Congestive heart failure 1 point Hypertension 1 point Age Q75 years 1 point Diabetes mellitus 1 point Stroke/TIA symptoms previously 2 points
Estimate Risk of Stroke in TABLE 3-3 The CHA2DS2-VASc Risk Score toa,b Patients With Atrial Fibrillation CHA2DS2-VASc Score
95% Confidence Interval
Recommendation
0
0.8
0.6Y1.0
No antithrombotic
1
2.0
1.7Y2.4
Antiplatelet or anticoagulation
2
3.7
3.4Y4.1
Anticoagulation
3
5.9
5.5Y6.3
Anticoagulation
4
9.3
8.7Y9.9
Anticoagulation
5
15.3
14.3Y16.2
Anticoagulation
6
19.7
18.2Y21.4
Anticoagulation
7
21.5
18.8Y24.6
Anticoagulation
8
22.4
16.3Y30.8
Anticoagulation
9
23.6
10.6Y52.6
Anticoagulation
a b
312
Annual Stroke Risk %
6
Data from Olesen JB, et al, BMJ. www.bmj.com/content/342/bmj.d124. CHA2DS2-VASc Congestive heart failure 1 point Hypertension 1 point Age Q75 years 2 points Diabetes mellitus 1 point Stroke/TIA/thromboembolism 2 points Vascular disease history (previous myocardial infarction, peripheral arterial disease, or aortic plaque) 1 point Age 65Y74 years 1 point Sex category (female) 1 point
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or implantable loop recorders all allow for a longer sampling period to detect transient episodes of AF after stroke. The 30-Day Cardiac Event Monitor Belt for Recording Atrial Fibrillation After a Cerebral Ischemic Event (EMBRACE) study evaluated 572 patients with cryptogenic ischemic stroke or TIA who were randomized to either 30 days of homebased cardiac monitoring or repeat Holter monitoring.8 Significantly more patients were diagnosed with new AF in the 30-day monitoring group compared with the repeat Holter monitoring group (16% versus 3%, PG.001). However, the appropriate candidates for monitoring, the optimal duration and mode of monitoring, and the clinical significance of fleeting episodes of AF that can now be detected with prolonged monitoring have not been established. Antithrombotic Therapy The mainstay of stroke prevention in AF has been oral anticoagulation with warfarin to an international normalized ratio (INR) goal of 2.0 to 3.0 (Figure 3-19). Warfarin can effectively reduce the risk of stroke by up to 68% (95% CI 50% to 79%), which corresponds to an absolute reduction in the annual risk of stroke from 4.5% to 1.4%.10 In contrast, aspirin is substantially less effective (21% relative risk reduction; 95% CI 0% to 38%) and is reserved for patients who are unable to take oral anticoagulants. Adding aspirin to warfarin increases bleeding risk and does not provide clear additional benefits, and therefore is generally discouraged.11 The use of medications for rate control or rhythm control for AF does not obviate the need for appropriate antithrombotic therapy to prevent stroke. For patients deemed unsuitable for oral anticoagulation because of a specific bleeding risk or patient preference, adding clopidogrel to aspirin Continuum (Minneap Minn) 2014;20(2):309–322
FIGURE 3-1
Adjusted odds ratios for ischemic stroke and intracranial bleeding in relation to intensity of anticoagulation. The dashed vertical lines delimit the typical therapeutic range for warfarin therapy. Reprinted with permission from European Heart Rhythm Association, et al, J Am Coll Cardiol.9 B 2006 American College of Cardiology Foundation. content.onlinejacc.org/ article.aspx?articleID=1137853.
provides additional efficacy for stroke prevention in AF (2.4% annual risk) over aspirin alone (3.3% annual risk; relative risk of stroke for aspirin compared with aspirin and clopidogrel is 1.6; 95% CI 1.3 to 1.9), but this benefit appears to be offset by a higher risk of major bleeding (2.0% versus 1.3% annual risk) that is similar to warfarin.12 Therefore, national guidelines recommend aspirin alone rather than the combination of aspirin and clopidogrel for patients with AF and clear contraindications to oral anticoagulation therapy, particularly in patients with hemorrhagic risks.11 Apixaban 5 mg twice daily may be a potential alterative for high-risk patients (see the section on novel oral anticoagulants).13 For patients with AF and ischemic stroke despite therapeutic anticoagulation, the optimal management strategy is not defined. Most patients with ischemic stroke while on warfarin therapy are found to have a subtherapeutic INR. The risk of ischemic stroke rapidly rises as the INR 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 the appropriate 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 for secondary 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.
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Cardioembolic Stroke KEY POINT
spend in the therapeutic range may be 60% to 70% at most. For selected patients, an increased INR goal could be considered, but bleeding risks are increased and direct evidence of benefit is lacking.
h Potential 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).
Timing of Initiating Anticoagulation After Acute Stroke During the first few weeks after a new ischemic stroke, the risks of hemorrhagic transformation, particularly for patients with large-territory infarcts or with evidence of associated hemorrhage, likely outweigh the potential benefits of anticoagulation to prevent early recurrent cardioembolic events for most patients. For high-risk patients with smaller strokes, well-controlled blood pressure, and no evidence of bleeding, earlier initiation of anticoagulation can be considered, particularly with warfarin since the achieving a full therapeutic effect typically takes several days anyway. Novel Oral Anticoagulants The intensive laboratory monitoring, narrow therapeutic range, and numerous drug interactions associated with warfarin have prompted the development of alternative oral anticoagulants. As of December 2013, the US
Food and Drug Administration (FDA) has approved the direct thrombin inhibitor dabigatran15,16 and two factor Xa inhibitors (rivaroxaban17,18 and apixaban19,20) for prevention of stroke in nonvalvular AF (Table 3-4). These agents have fixed dosing, do not require frequent laboratory monitoring, have a rapid onset of anticoagulant effect, and have fewer drug interactions than warfarin. All were found to be noninferior to warfarin for stroke and systemic embolism (Rivaroxaban Versus Warfarin in Nonvalvular Atrial Fibrillation [ROCKET-AF],18 Randomized Evaluation of LongTerm Anticoagulant Therapy [RE-LY],15 and Apixaban for the Prevention of Stroke in Subjects With Atrial Fibrillation [ARISTOTLE] 20). Dabigatran (150 mg dose) and apixaban also met superiority end points. Apixaban showed a mortality benefit over warfarin. Intracranial hemorrhage rates were lower for all three agents compared with warfarin, but major gastrointestinal bleeding was higher with dabigatran and rivaroxaban compared with warfarin. As illustrated in Case 3-2, these agents can be considered as an alternative to warfarin in most patients with AF and stroke, particularly given the lower intracranial hemorrhage rates seen in these initial studies. But
TABLE 3-4 Properties of Oral Anticoagulant Therapies
314
Warfarin
Rivaroxaban
Mechanism
Vitamin K antagonist
Factor Xa inhibitor
Typical Dose for Atrial Fibrillation
Variable
Renal Dose Adjustment
Dabigatran Etexilate
Apixaban
20 mg daily
Direct thrombin inhibitor 150 mg twice daily
Factor Xa inhibitor 5 mg twice daily
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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April 2014
KEY POINTS
Case 3-2
h Potential drawbacks
A 65-year-old man with a history of paroxysmal atrial fibrillation and a right middle cerebral artery stroke 1 year ago had been maintained on warfarin therapy. He reported good medication adherence, and his international normalized ratio was usually between 2 and 3 at his follow-up visits to the anticoagulation clinic. Renal function was normal. He would like to discuss whether he is a candidate for a novel oral anticoagulant. Comment. For patients who are already well managed on warfarin, continuing warfarin therapy may be reasonable. However, the lower risks of intracranial hemorrhage that have been reported with the novel oral anticoagulants could justify making the transition from warfarin to a novel oral anticoagulant in carefully selected patients. Renal disease, liver disease, medication interactions, medication adherence, availability of reversal agents, and cost are all considerations when choosing an oral anticoagulant.
patients with renal impairment, liver disease, mechanical valves or other valvular disease, or an anticipated need for reversal of anticoagulant effect for gastrointestinal bleeding (for dabigatran and rivaroxaban) may be well served to remain on warfarin. A validated reversal strategy and a laboratory test of anticoagulant effect are not yet available for these novel anticoagulants. Poor adherence to a twice-daily dosing schedule could result in a subtherapeutic anticoagulant effect more quickly compared with warfarin. Higher drug costs and controversy regarding whether patients on these agents could be candidates for acute thrombolytic therapy are also relevant considerations. Underutilization of Anticoagulation Up to two-thirds of patients with AF, particularly those at highest risk of stroke, are not on appropriate anticoagulation therapy.21 The underuse of anticoagulation for AF is based, in part, on the challenges of warfarin therapy; however, other significant barriers remain. The bleeding risks associated with frequent falls or advanced age are often outweighed by the stroke-prevention Continuum (Minneap Minn) 2014;20(2):309–322
benefits of anticoagulation. Patients at risk for falls with a CHADS2 score of 2 or higher generally benefit from anticoagulation therapy, even when there is an increased risk of hemorrhage from falls.22 Although elderly patients have higher risks for both ischemic and hemorrhagic stroke, a meta-analysis of 12 clinical trials found that the benefits of anticoagulation appear to extend to elderly patients. This benefit was driven by hemorrhage rates that were similar with aspirin and with warfarin therapy.23 Ultimately though, the decision to initiate anticoagulation is often complex and should incorporate patient preferences. The HAS-BLED (Hypertension, Abnormal liver or renal function, Stroke, Bleeding, Labile INR, Elderly age, Drug or alcohol use) scale was developed to estimate the risk of hemorrhage with anticoagulation and to highlight modifiable factors that are associated with increased risk such as concomitant antiplatelet therapy or alcohol intake (Table 3-5 24,25 ). 24 HAS-BLED can provide additional information for clinical decision making, but should not be used as the sole reason to withhold anticoagulation
of novel oral anticoagulants compared to warfarin include 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 from anticoagulation 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.
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TABLE 3-5 HAS-BLEDa,bScore to Estimate the Risk of Hemorrhage With Warfarin HAS-BLED Score
Bleeding Risk %
95% Confidence Interval
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
4
8.9
5.2Y14.0
Caution warranted
5
9.1
1.1Y29.2
Caution warranted
Insufficient data
Insufficient data
Caution warranted
Q6 a b
Data from Pisters R, et al, Chest,24 journal.publications.chestnet.org/article.aspx?articleid=1045174. and Lip GY, et al, J Am Coll Cardiol.25 www.sciencedirect.com/science/article/pii/S0735109710043378. HAS-BLED Hypertension 1 point Systolic blood pressure 9160 mm Hg Abnormal renal and/or liver function 1 or 2 points Renal: dialysis, kidney transplant, or creatinine Q2.6 mg/dL (1 point) Liver: cirrhosis or bilirubin 92 normal; or AST, ALT, or AlkPhos 93 normal (1 point) Stroke 1 point Bleeding predisposition or history 1 point Labile international normalized ratio (INR) 1 point Time spent in therapeutic range G60% Elderly 1 point Age 965 years Drugs and/or excess alcohol use 1 or 2 points Antiplatelet agents or nonsteroidal anti-inflammatory drugs Maximum HAS-BLED Score is 9 points AST = aspartate aminotransferase; ALT = alanine aminotransferase; AlkPhos = alkaline phosphatase.
therapy for patients who have other indications for anticoagulation for stroke secondary prevention. Surgical Procedures for Atrial Fibrillation Left atrial appendage closure devices and left atrial appendage excision or exclusion procedures as well as Cox maze procedures (a series of surgical incisions to the atria to interrupt atrial reentry) and radioablation have been developed to treat AF. For most patients, these procedures do not obviate the need for long-term anticoagulation therapy because a continued risk for recurrent AF remains even after treatment, and the risk of recurrent stroke for patients with AF who have already had a stroke or TIA is high. Therefore, the precise role for these procedural approaches to
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Recommendation
prevent stroke with AF has not been established. VALVULAR DISEASE Infective Endocarditis Stroke is often the primary presenting symptom of infective endocarditis. Although direct infection of normal valves can occur, the risk of endocarditis is much higher when the native valve is compromised. Although rheumatic heart disease is uncommon in developed counties, it is still the most common cause of valvular disease globally. Bicuspid aortic valve and prosthetic valve implantation confer higher risks for infection as well. IV drug use is more commonly associated with right-sided valvular disease (eg, tricuspid valve) and typically results in septic embolization to the lungs rather
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than ischemic stroke, but IV drug use still confers a higher risk for left-sided endocarditis. Staphylococcus aureus, Streptococcus viridans, and Enterococcus are the most common organisms.26 Endocarditis is suggested by fever, weight loss, a history of IV drug use or other source of bacteremia, a new murmur on physical examination, or evidence of systemic embolization to other vascular territories. Multiple blood cultures, serial ECG (to evaluate for myocardial infarction, heart block, or conduction delay), and TEE are critical elements of the diagnostic workup. TTE is not adequate to exclude the possibility of valvular vegetations when endocarditis is suspected.27 An elevated erythrocyte sedimentation rate or C-reactive protein, and a leukocytosis, which is not always present, support this diagnosis but are relatively nonspecific. Brain MRI is better suited than head CT for demonstrating the multiple foci of ischemia and cerebral microbleeds that are typical for endocarditis. The lesions in endocarditis are classically of differing ages and in multiple vascular distributions or in a watershed distribution; subclinical brain lesions are common. Antibiotic therapy may reduce the risk of continued embolization. Antithrombotic therapy in the acute setting is associated with an increased risk of hemorrhage. For patients with AF or mechanical heart valve prostheses who present with endocarditis and stroke, short-term interruption of anticoagulation therapy may be necessary in some cases, despite the high risks of thrombosis and recurrent stroke during the period that anticoagulation is withheld. Nonbacterial Thrombotic Endocarditis Nonbacterial thrombotic endocarditis (marantic endocarditis) involves the aggregation of sterile vegetations along the Continuum (Minneap Minn) 2014;20(2):309–322
edge of heart valves and is primarily associated with systemic malignancy. Heparin or low-molecular-weight heparin rather than warfarin is generally recommended.28 Libman-Sacks endocarditis, which is associated with systemic lupus erythematosus and the antiphospholipid antibody syndrome, involves a similar deposition of immune complexes that result in small inflammatory vegetations. Direct evidence is lacking, but antiplatelet therapy for primary prevention or anticoagulation for secondary prevention is reasonable. Rheumatic Heart Disease Rheumatic heart disease, a complication of Group A streptococcal infection, most commonly affects the mitral valve. Concurrent AF is common.11 The risk of stroke remains even after successful valvuloplasty, so continued anticoagulation to a goal INR of 2.0 to 3.0 is recommended.
KEY POINTS
h A transthoracic echocardiogram is not adequate to exclude the possibility of valvular vegetations 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 heart valves.
Prosthetic Mechanical Valves and Bioprosthetic Valves Prosthetic mechanical valves present a high risk for thromboembolization, especially for devices with caged-ball or tilting-disc mechanisms and for devices in the mitral position. Anticoagulation is indicated for all patients with mechanical valves; the intensity of anticoagulation therapy and the specific indications for concomitant antiplatelet therapy are based on the type and position of the prosthetic valve. For patients with prosthetic valves that present with embolic events such as stroke despite adequate antithrombotic therapy, national guidelines provide comprehensive suggestions on intensifying antithrombotic therapy for various clinical scenarios, although definitive data to support these recommendations are admittedly sparse (Table 3-629). Bioprosthetic valves do not present the same degree of embolic www.ContinuumJournal.com
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Cardioembolic Stroke
TABLE 3-6 Suggested Intensification of Antithrombotic Therapy for Stroke With Prosthetic Valve Replacementa Therapy on Presentation With New Stroke Warfarin, international normalized 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
Data from Bonow RO, et al, J Am Coll Cardiol.29 www.sciencedirect.com/science/article/pii/S0735109708018330.
risk as mechanical valves and can generally be managed with antiplatelet therapy. However, warfarin is recommended for the first 3 months after implantation of a mitral bioprosthetic valve. Dabigatran is not recommended for use in patients with mechanical heart valves, and rivaroxaban and apixaban have not been evaluated for this indication. Therefore, warfarin remains the preferred treatment for this indication. Mitral Valve Prolapse Mitral valve prolapse is a largely echocardiographic diagnosis that is characterized by abnormal movement of one or more valve leaflets into the left atrium during systole. Data on the relationship between mitral valve prolapse and stroke are conflicting. Most patients with stroke and mitral valve prolapse can be managed with antiplatelet therapy.30 CARDIOMYOPATHY AND STRUCTURAL HEART LESIONS Heart Failure Heart failure is associated with an increased risk of stroke from altered flow within dilated heart chambers, relative stasis of blood, increased risk of concomitant AF, and an associated relative prothrombotic state. For pa-
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Dose Adjustment Option
tients with associated AF or left ventricular thrombus, anticoagulation is generally preferred over antiplatelet therapy. As illustrated in Case 3-3, for patients with heart failure and sinus rhythm, the optimal choice of antiplatelet or anticoagulation therapy is uncertain. In the Warfarin and Antiplatelet Therapy in Chronic Heart Failure (WATCH) study, patients with symptomatic heart failure, sinus rhythm, and a left ventricular ejection fraction of 35% or less were randomized to aspirin (162 mg/d), clopidogrel (75 mg/d), or warfarin (INR 2.5 to 3.0).32 There were no significant differences between the three treatment arms for the risk of the composite primary end point of death, myocardial infarction, or stroke. Similarly, in the Warfarin and Aspirin in Patients With Heart Failure and Sinus Rhythm (WARCEF) study, patients with an ejection fraction below 35% with sinus rhythm were randomized to aspirin 325 mg/d or adjusted-dose warfarin (goal INR of 2.75; range 2.0 to 3.5).31 Anticoagulation did not provide an overall benefit: a reduction in ischemic stroke was offset by an increase in major hemorrhage. For secondary prevention, warfarin, aspirin, clopidogrel, or aspirin plus extended dipyridamole are all reasonable
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KEY POINTS
Case 3-3
h For patients with
A 64-year-old woman with a history of congestive heart failure presented with an acute right middle cerebral stroke. Her echocardiogram showed biatrial enlargement and a left ventricular ejection fraction of 30%; no thrombus or valvular disease was seen. ECG showed sinus rhythm. A brain MRI showed multiple foci of restricted diffusion in the right middle cerebral artery territory, as well as three small foci of restricted diffusion in the left hemisphere. The patient was discharged home on antiplatelet therapy, but, given the suspicion for a cardioembolic source, she was referred for extended cardiac monitoring. One week later, she had an asymptomatic 5-minute episode of atrial fibrillation noted on cardiac monitoring and returned to clinic to transition to anticoagulation therapy. Comment. This case illustrates the initial management of a stroke patient with a history of congestive heart failure with a reduced ejection fraction and sinus rhythm with antiplatelet therapy based on the Warfarin and Aspirin in Patients With Heart Failure and Sinus Rhythm (WARCEF) study.31 However, the distribution of the infarcts suggested a cardioembolic source, and the documented paroxysmal atrial fibrillation demonstrated in follow-up provided a clear justification for anticoagulation therapy.
options, but comparative data are lacking. Data on the use of novel oral anticoagulants in this setting are not available. Myocardial Infarction and Left Ventricular Thrombus Left ventricular thrombus, a complication of myocardial infarction, presents a high risk for embolization and subsequent stroke. Left ventricular thrombus is more common with anterior ST-segment elevation myocardial infarction because of the relative stasis of blood within the ventricle. Therefore, for patients at high risk of developing left ventricular thrombus, a screening TTE is recommended. For patients with documented left ventricular thrombus and myocardial infarction, at least 3 months of anticoagulation is recommended.11 Follow-up TTE to evaluate left ventricular ejection fraction and residual thrombus may help with individualized decisions on the optimal duration of anticoagulation therapy. Again, novel oral anticoagulants have not been evaluated in this setting and are not recommended. Continuum (Minneap Minn) 2014;20(2):309–322
congestive heart failure with sinus rhythm, the choice of anticoagulation 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.
Other Cardiac Lesions Atrial myxoma, a tumor of mesenchymal cells of the heart, is a rare cause of cardioembolic stroke that is seen most often in younger patients. An atrial mass is seen on echocardiography and can be present even without a mitral stenosis murmur or a tumor plop on auscultation. Papillary fibroelastoma is a rare cause of stroke that is also apparent on echocardiography. For both lesions, the ongoing risk of embolization typically warrants surgical resection. AORTIC ARCH ATHEROSCLEROSIS Aortic arch atherosclerosis confers a risk for both systemic and cerebrovascular embolization. This commonly occurs via thromboembolism of larger clots that lodge and fragment in medium and large vessels. However, cholesterol embolization from the plaque itself may also occur and typically showers much smaller emboli into the arterioles in multiple vascular territories. Cholesterol embolization from the plaque itself can shower much smaller emboli into arterioles in multiple vascular territories. www.ContinuumJournal.com
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Cardioembolic Stroke
TEE is generally preferred over TTE for assessing the aortic arch. Plaque thickness greater than 4 mm, ulceration, and actively mobile elements have been implicated as potential risk factors for embolization.33Y35 Increased plaque thickness suggests a complex plaque with overlying thrombus. Ulceration is thought to increase the risk of thrombus formation. Mobile elements suggest that a thrombus is superimposed on an unstable plaque. Aortic arch atherosclerosis shares risk factors in common with stroke more generally, so these patients often have clear indications for aggressive risk factor modification and antiplatelet therapy for secondary prevention irrespective of aortic arch disease. Statins may have the potential to stabilize or even regress plaques. The Aortic Arch Related Cerebral Hazard Trial (ARCH) trial compared the combination of aspirin and clopidogrel with adjusted-dose warfarin to prevent recurrent vascular events in patients with significant aortic arch disease and a recent TIA or minor stroke.36 The final results of this study are not yet available; however, the trial was recently and prematurely terminated for futility. SUMMARY Cardioembolism is an important cause of stroke that requires an initial clinical suspicion, a tailored diagnostic workup, particularly for atrial fibrillation, and a prevention strategy that draws upon current clinical evidence and therapeutic options. REFERENCES 1. Lin HJ, Wolf PA, Kelly-Hayes M, et al. Stroke severity in atrial fibrillation. The Framingham Study. Stroke 1996;27(10):1760Y1764. 2. Pearson AC, Labovitz AJ, Tatineni S, Gomez CR. Superiority of transesophageal echocardiography in detecting cardiac source of embolism in patients with cerebral
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