Stroke & Vascular Disorders
Stroke associated with cerebral angiography
Mar. 10, 2026
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Cerebral embolism …
- Updated 12.03.2025
- Released 09.18.1995
- Expires For CME 12.03.2028
Cerebral embolism
Introduction
Overview
Cardioembolic stroke is one of the subtypes of strokes that was defined by the TOAST criteria. About 30% of all ischemic strokes are cardioembolic in etiology. It is a stroke of embolic etiology with an identifiable cardiac source. When the source of the emboli is not identified, it is defined as embolic stroke of undetermined source (ESUS) by the TOAST criteria.
In this chapter, we discuss the progress that has been made in identifying patients at high risk for cardioembolic stroke. This article provides an update on cardioembolic stroke prevention. Data from trials on stroke prevention, including information on choosing suitable anticoagulation in atrial fibrillation patients and studies on closure devices for patent foramen ovale, are reviewed.
Key points
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• Cardioembolic strokes are more clinically severe, have a higher rate of recurrence, and cause greater disability compared to other forms of stroke. | |
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• Atrial fibrillation is the leading source of cardioembolic stroke. | |
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• The proportion of cardioembolic strokes will increase with the aging of the population. | |
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• Trials have shown a modest reduction in stroke with patent foramen ovale closure, but questions remain on appropriate patient selection. |
Historical note and terminology
What is now called "stroke" was referred to as "apoplexy" in the writings of Hippocrates (460 BCE to 370 BCE). Apoplexy was defined as "to be struck down by violence or paralysis." It was probably formed from the Greek words apo ("from"), plesso ("thunderstruck"), and ia ("condition"). The term "apoplexy" was applied to myriad conditions, from illnesses affecting the level of consciousness to disorders causing a change in sensation. Apoplexy was differentiated from other conditions by its sudden onset, resulting in loss of consciousness and paralysis. During the period of the Roman Empire, Aurelius Celsus (25 BCE to 50 AD) differentiated apoplexy from paralysis. He noted that during apoplexy the entire body is paralyzed, including sensation, understanding, and movement, whereas with paralysis the effects are localized (26; 24).
There was little progress in the understanding of stroke during the Middle Ages and the Renaissance. During the 18th century, Hermann Boerhaave (1668 to 1738) and his followers returned to a more methodical and analytical approach to medicine. Van Swieten's commentaries on Boerhaave are generally believed to be the first suggestion that cerebral embolism could cause apoplexy:
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It has been established by many observations that these polyps occasionally attach themselves as excrescences to the columnae carnae of the heart, and perhaps then separate from it and are propelled, along with the blood, into the pulmonary artery or the aorta, and its branches.... were they thrown into the carotid or vertebral arteries, could disturb—or if they completely blocked all approach of arterial blood to the brain—utterly abolish the functions of the brain (26). |
During the 19th century, advances were made in understanding the pathophysiology of cerebral embolism and thrombosis. Julius Cohnhien, trained by Virchow, demonstrated the effects of embolization by producing ischemic and hemorrhagic lesions when wax globules were injected into a frog's tongue arteries (31).
The heart was established as an important source for the development of emboli when Gowers, in 1875, described a case of left middle cerebral artery and retinal artery emboli (31). The auricular appendage associated with mitral stenosis was identified as the likely origin of the emboli.
Clinical manifestations
Presentation and course
Clinical presentations of embolic strokes are often sudden and maximal in intensity at onset. Embolic material usually originates from the heart or great vessels, such as the aortic arch or carotid bifurcation. There is considerable overlap in the clinical presentation of cerebral ischemia resulting from embolic disease, large-vessel atherothrombotic disease, and small-vessel disease. The Cerebral Embolism Task Force set forth the following criteria for the diagnosis of cardiogenic cerebral embolism: (1) neurologic symptoms of abrupt onset with maximal severity at onset; (2) evidence of a potential cardiac source; (3) branch occlusions on cerebral angiography; (4) evidence of emboli to limbs or other organs; and (5) multiple infarctions involving more than one territory (13). Radiologically, they often involve multiple arterial territories or involve only one main large artery occlusion. They are often wedge-shaped, involving the cortical and subcortical white matter.
The clinical manifestations of cerebral embolism depend on the arterial territory affected and the eloquence of the ischemic tissue. A large embolism may occlude the distal internal carotid artery or the stem of the middle cerebral artery, producing findings such as contralateral hemiparesis or hemisensory deficits, a gaze preference, and, depending on the involved hemisphere, cognitive findings such as aphasia or neglect. Branch occlusions within the anterior intracranial circulation are highly suggestive of cerebral embolism. These occlusions typically manifest as restricted deficits such as fluent aphasia or monoplegia. Embolic syndromes of the posterior circulation occur less frequently. The sites most commonly obstructed are at the union of the vertebral arteries to form the basilar artery and the upper bifurcation of the basilar artery into the posterior cerebral arteries. Occlusion of a vertebral artery as it joins to form the basilar artery can produce Wallenberg syndrome or related variants. Caplan described the "top of the basilar" syndrome and its manifestations when embolism occludes the distal basilar artery. Infarction in this region may produce coma, quadriplegia, visual loss, and various behavioral syndromes (11). A unilateral posterior cerebral artery occlusion leading to an isolated hemianopsia is often embolic in origin.
Prognosis and complications
Embolic stroke of cardiac origin is shown to have a higher rate of functional disability at discharge date and higher mortality risk, both due to complications or stroke itself or other systemic complications. They are also at high risk of recurrence of stroke, with a higher incidence in the acute phase. Delayed or under-anticoagulation of patients is a contributing factor, in addition to other mechanisms of stroke pathogenesis, is found to contribute to the recurrence rate.
An early complication of embolic infarction of large vessel territories is cerebral edema, as early as 24 hours, which often peaks between 3 and 5 days after an ischemic insult. Treatment with intravenous mannitol and hypertonic saline should be considered. Selected patients also benefit from decompressive craniectomy.
Seizures complicate up to 10% of strokes. Seizures following stroke are often focal but may become generalized. Persons with seizures in the acute phase of cerebral embolism may have periodic lateralized epileptiform discharges detected by EEG, but these seizures are usually self-limited and do not require treatment. Seizures that recur can be controlled with anticonvulsant monotherapy.
Skin care, nutrition, and prevention of vascular complications take priority when a patient enters convalescence. Venous thromboembolism is a common complication in stroke patients secondary to immobility (65). It is estimated that without prophylactic measures, deep venous thrombosis develops in up to 75% of hemiplegic patients, and lethal pulmonary embolism occurs in approximately 3%. Undoubtedly, the incidence of nonfatal pulmonary embolism is much higher. Prophylactic measures to prevent venous thromboembolism include early ambulation, subcutaneous administration of heparin, pneumatic compression stockings, pressure-gradient stockings, and antithrombotics (34).
Clinical vignette
A 78-year-old woman was admitted at an outside hospital with left-sided weakness of a mild degree. A carotid ultrasound and 2D echocardiogram were normal, and she was placed on aspirin. Two weeks later, she presented with expressive speech difficulty that lasted 60 minutes. There was no definite right-sided weakness. Neurologic exam revealed mild right nasolabial flattening but was otherwise normal. An MRA of the brain and neck was normal. MRI of the brain showed a small perisylvian infarct on the diffusion-weighted images and an old right middle cerebral artery infarct. A transesophageal echocardiogram was ordered, and this showed decreased contraction in the left atrial appendage and protuberant plaques in the ascending aorta. Cardiac monitoring did not show definite atrial fibrillation. The patient was placed on warfarin for presumed cardioembolic strokes and has done well for the ensuing 5 years.
Biological basis
Etiology and pathogenesis
Although embolic stroke is often suspected, the specific embolic source frequently remains unidentified even after a thorough evaluation. The heart is the most common source, particularly in atrial fibrillation, atrial flutter, structural heart disease, cardiomyopathies, valvular pathology, intracardiac tumors, and patent foramen ovale (80). However, finding a cardiac abnormality does not confirm causality, especially when competing atherosclerotic disease is present.
Large-artery atheroembolism, most notably from the aortic arch and carotid bifurcation, is another major cause of cerebral ischemia, with modern imaging highlighting the importance of complex aortic and nonstenotic carotid plaque. Embolic events may also occur peri-procedurally during cardiac catheterization or surgery. Despite advanced cardiac and vascular imaging and prolonged rhythm monitoring, many patients still have no clear source identified and are classified under the contemporary category of “embolic stroke of undetermined source.”
Atrial fibrillation. Atrial fibrillation is common in older adults and is one of the most frequent sources of cardioembolic stroke, accounting for up to 20% of ischemic strokes and approximately half of all cardioembolic events. Atrial fibrillation is categorized as valvular (mechanical valve, rheumatic mitral stenosis, or valve repair) or nonvalvular. Valvular atrial fibrillation confers the highest thromboembolic risk, up to a 17-fold increase, whereas nonvalvular atrial fibrillation carries an approximately five-fold increased risk compared with individuals in sinus rhythm.
Stroke risk in atrial fibrillation varies substantially and is determined by both clinical context and comorbid disease. Hypertension, recent heart failure, prior embolism, diabetes, vascular disease, age, and female sex are consistently associated with higher risk and form the basis of contemporary risk scores such as CHA₂DS₂-VASc. Annual stroke rates range from less than 1% in truly low-risk individuals to upwards of 7% to 15% in those with multiple risk factors. Young patients with lone atrial fibrillation, typically under 60 years of age with no structural heart disease, have a very low stroke risk, often lower than 0.5% per year (Fonseca 2023; 40). Atrial fibrillation may coexist with other conditions, such as congestive heart failure and obstructive sleep apnea (48).
Most thromboemboli in nonvalvular atrial fibrillation originate in the left atrial appendage, making it a key target for management. Oral anticoagulation remains the cornerstone of stroke prevention, whereas left atrial appendage occlusion provides an alternative strategy in select patients who cannot tolerate long-term anticoagulation.
Myocardial infarction. A recent myocardial infarction is an important cause of cerebral embolism, primarily due to left ventricular thrombus formation resulting from intracavitary stasis and regional wall-motion abnormalities during left ventricular dysfunction. The risk is highest in the early postmyocardial infarction period, with most embolic strokes occurring within the first 4 to 12 weeks; estimated risks are approximately 0.9% in the first month and up to 3% to 4% within the first year (63). Contemporary registry and cohort data show that in-hospital stroke after myocardial infarction occurs in approximately 0.5% to 0.8% of patients, with reported ranges from 0.3% to 1.4% across large studies (52; 60; 37). Risk is higher in older individuals, women, and patients with heart failure, atrial fibrillation, or those undergoing coronary artery bypass grafting (10; 52). Early coronary revascularization is associated with a reduced stroke risk following myocardial infarction (76). Additional mechanisms of postmyocardial infarction embolism include delayed-onset atrial fibrillation, atrial ectopy, and atrial cardiomyopathy, even in the absence of clinically apparent arrhythmia (63).
Atrial cardiomyopathy and ventricular dysfunction. The dilated cardiomyopathies are characterized by global ventricular dysfunction and are highly associated with arrhythmias. It is this combination that leads to chronic intracavitary stasis and is responsible for the conditions conducive to cerebral embolism. The presence of cardiomyopathy in the absence of arrhythmia has also been found to be associated with embolic strokes. Observational studies have shown that blood biomarkers, such as N-terminal pro B-type natriuretic peptide and high-sensitivity troponin, are associated with stroke risk. The ARCADIA study compared stroke risk with anticoagulation versus antiplatelet therapy. This study, however, has negative results, which did not show a reduction of stroke risk with anticoagulation. Despite epidemiological evidence of cardiomyopathy being associated with stroke risk, it is likely due to the underdetection of occult atrial fibrillation in this patient population in the study.
Valvular disease. Stroke due to valvular disease can be due to infectious or noninfectious native valvular disease. Noninfectious valvular diseases can be from either native or prosthetic valve pathology. Among native valve disorders, mitral stenosis, most often a sequela of rheumatic fever, remains a significant embolic source. Left atrial enlargement and atrial fibrillation are common, and left atrial thrombus formation is frequent, creating a strong substrate for embolism (73). Embolic events may also occur in mixed mitral valve disease, stenosis with regurgitation, whereas isolated mitral regurgitation is rarely a direct cause of stroke. Mitral valve prolapse, despite being common in young adults, carries a very low annual stroke risk, approximately 0.02% per year, and should only be considered after exclusion of more likely etiologies (73). Mitral annular calcification, often seen in older adults, is associated with increased embolic risk, primarily when accompanied by atrial fibrillation, and may function more as a marker of systemic atherosclerosis than a direct source of emboli (73). Calcific embolism from aortic stenosis is possible but uncommon (73).
Cerebral embolism is also a major complication of prosthetic cardiac valves, with risk varying by valve type and position. Mechanical valves are highly thrombogenic in the absence of anticoagulation. Annual embolic rates are estimated at 13% to 18% for mechanical mitral valves and 8% to 10% for mechanical aortic valves (73; 45). In contrast, bioprosthetic valves have substantially lower thromboembolic risk without anticoagulation, approximately 1.7% to 2.4% per year in the mitral position and 1.3% to 1.9% per year in the aortic position, with the highest risk occurring in the first 3 postoperative months (73; 45). In patients with bioprosthetic valves who are in sinus rhythm and have no additional risk factors, annual stroke risk may be as low as 0.7% (73). These marked differences form the basis of current ACC/AHA guideline recommendations, which stress lifelong anticoagulation for all mechanical valves and more selective, risk-based anticoagulation for bioprosthetic valves (79; 57; 40).
Infective endocarditis, resulting from bacterial infection and diagnosed according to modified Duke’s criteria, can cause cerebral embolism. Treatment focuses on appropriate antimicrobial therapy rather than anticoagulation or antiplatelet therapy. Clinical manifestations of septic cerebral emboli range from subtle symptoms, such as encephalopathy and headache, to catastrophic intracranial hemorrhage and death. Intracranial hemorrhage in endocarditis occurs due to rupture of mycotic aneurysms or septic arteritis (51; 51). The presentation depends on the size and number of emboli: large emboli can obstruct major vessels, causing ischemia or suppuration, leading to abscess formation, whereas multiple microemboli often produce an encephalopathic presentation. A combination of these mechanisms is not uncommon. In a 15-year review of 707 endocarditis cases, stroke occurred in 68 patients (9.6%), more frequently with mitral valve involvement (17%) than aortic (9%) (06). Embolization risk is highest during the first week of antimicrobial therapy and in patients with mobile vegetations or vegetations greater than 10 mm on the anterior mitral leaflet (19). A meta-analysis of 21 studies confirmed that vegetations larger than 10 mm significantly increase stroke risk (54). Endocarditis is a more common cause of stroke in patients undergoing hemodialysis; a single-center review found that 12% of strokes in these patients were linked to endocarditis (39). Right-sided infectious endocarditis rarely causes cerebral embolization but may do so via paradoxical embolism through a patent foramen ovale.
Noninfective endocarditis, including Libman-Sacks endocarditis in systemic lupus erythematosus and antiphospholipid syndrome, as well as marantic endocarditis associated with Trousseau syndrome in malignancy, can also cause embolic stroke. MRI findings may reveal the triple territory sign, with strokes in bilateral anterior and posterior circulation, which has high specificity (96.4%) for distinguishing Trousseau syndrome-related embolic stroke from atrial fibrillation-related cardioembolism (75).
Patent foramen. The most common occult cardiac source of embolism is a patent foramen ovale, present in roughly 20% of the general population. Given its high prevalence, attributing a stroke to a patent foramen ovale requires careful consideration. Stroke is thought to occur via paradoxical embolism, where a venous thrombus crosses the patent foramen ovale through a right-to-left shunt, typically when right-sided heart pressures exceed left-sided pressures. In a single-center review of 1,689 patients with stroke or transient ischemic attack, several factors were associated with patent foramen ovale, including a history of deep vein thrombosis or pulmonary embolism, prolonged travel, migraine, preceding Valsalva maneuvers, and awakening with stroke symptoms (58).
The Risk of Paradoxical Embolism (ROPE) score and PASCAL Classification have been proposed to help identify patients in whom a patent foramen ovale is likely causal for stroke (42). This score incorporates factors such as an absence of conventional vascular risk factors and the presence of a cortical infarct on neuroimaging. Transesophageal echo with bubble study is considered the gold standard for diagnosing patent foramen ovale and allows for direct visualization of patent foramen ovale and assessment of size and high-risk anatomical features, such as atrial septal aneurysm. Other sensitive screening tests include transcranial Doppler (44).
Other causes. Transesophageal echocardiography has also provided evidence that the aortic arch is a common source of embolic material (32). The risk of cerebral embolism appears to be directly related to the size of atherosclerotic plaques visualized. Other rare causes include primary cardiac tumors, such as atrial myxoma and fibroelastoma.
Pathophysiology
The underlying mechanism of cerebral infarction from embolism is occlusion of cerebral vessels with debris from a proximal source. An embolus may consist of platelet aggregates, thrombus, platelet-thrombi, cholesterol, calcium, bacteria, neoplastic cells, air, or any other foreign substance.
Most embolic debris contains platelet aggregates (07). Red thrombus may be more likely in conditions causing blood stasis, eg, atrial fibrillation and myocardial infarction. A thrombus may also form on an ulcerated internal carotid artery plaque or occur with intraplaque hemorrhage and rupture, leading to distal embolism.
Epidemiology
Cerebral embolism accounts for approximately 20% of the 730,000 strokes that occur in the United States each year. Risk factors associated with an increased risk of cerebral embolism include atrial fibrillation, myocardial infarction, and valvular heart disease. The prevalence of atrial fibrillation increases with age, and approximately half of atrial fibrillation-related strokes occur in patients over 75 years of age. It is estimated that chronic atrial fibrillation affects more than 2 million Americans. The number of patients with chronic atrial fibrillation is estimated to increase to over 5 million by 2050. Population-based studies have associated atrial fibrillation with a 5-fold increase in stroke risk. Atrial fibrillation is associated with a stroke recurrence rate of 15% in the first year and 5% yearly thereafter. The risk of recurrence is strongly linked to the presence and type of underlying structural cardiac disorders. A statement from the American College of Cardiology, American Heart Association, and European Society of Cardiology identified the following risk factors for stroke with atrial fibrillation: (1) previous stroke or transient ischemic attack, (2) hypertension, (3) congestive heart failure, (4) advanced age, (5) diabetes, and (6) coronary artery disease. High emphasis on prior stroke or transient ischemic attack and age greater than 75 years is reflected in the assigned double weight in the CHA2DS2-VASc score. Additional risk factors include persistent or permanent atrial fibrillation, obesity, renal dysfunction, and left atrial enlargement (40).
Over 1 million Americans have a myocardial infarction each year. Acute myocardial infarction is complicated by stroke within 2 to 4 weeks of onset in 2.5% of patients. Factors that increase the risk of cerebral embolism in this population include transmural anterior wall infarcts, left ventricular thrombus, and advanced age.
Congestive heart failure affects 5.1 million people in the United States (29). The number of people who have had congestive heart failure is increasing due to the aging of the population.
When one considers the mortality according to stroke subtype, it is clear that cardioembolic strokes carry a high mortality. In a study following 998 patients with a first cerebral infarct, the 30-day mortality was 2% for lacunar strokes, 10% for atherothrombotic strokes, and 23% for cardioembolic strokes (18). Patients with cardioembolic stroke have a lower rate of recurrent stroke at 1 month compared to patients with large vessel atherosclerosis (46).
Prevention
Prevention includes secondary prevention of stroke. Therefore, there must be a high index of suspicion based on clinical and radiological findings for cerebral embolism as an etiology of the stroke mechanism.
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• MRI with strokes in multiple vascular territories must raise suspicion. | |
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• Telemonitoring, event monitor, or implantable loop recorders can help rule out atrial fibrillation. | |
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• Transthoracic echocardiography is the minimal recommendation to rule out intracardiac thrombus and is less invasive than transesophageal echocardiography. | |
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• Anticoagulation for underlying atrial fibrillation. | |
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• Atrial appendage closure for surgical candidates. |
Detection of atrial fibrillation. With the increasing availability of prolonged cardiac monitoring, it has been noted that some patients with a stroke of unknown cause (cryptogenic stroke) have intermittent atrial fibrillation during follow-up. Two studies, CRYSTAL-AF and EMBRACE, have found that prolonged monitoring can detect a 5- or 6-fold higher rate of intermittent atrial fibrillation, compared to usual care (28; 68). The studies differed in the length of follow-up (90 days vs. 12 months) and the method for cardiac monitoring (external monitoring vs. an implanted device). In EMBRACE, there was a nearly 2-fold higher rate of anticoagulant use in patients who underwent prolonged monitoring. Therefore, if a patient with a cryptogenic stroke is a potential candidate for anticoagulation, prolonged cardiac monitoring should be considered.
Screening for atrial fibrillation has also been investigated in patients in whom the index stroke is either lacunar or due to large vessel atherosclerosis. In a multicenter study with stroke due to these mechanisms and in which an implanted loop recorder was placed within 10 days of the index stroke, atrial fibrillation was detected in 12.1% of patients, compared to 1.8% in the usual care group (08). In another trial, an implantable loop recorder was compared to an external 4-week loop recorder (09). The implanted device detected atrial fibrillation in 15.4% of patients, compared to 4.7% with the 4-week recording. Although these results might push some clinicians to utilize the implantable loop recorder more frequently, at present, it has not been shown that atrial fibrillation monitoring decreases stroke. A trial from Europe enrolled over 6000 individuals with atrial fibrillation risk factors and compared implantable loop recorder placement with usual care (74). The implantable loop recorder device detected more atrial fibrillation than usual care (31.8% vs. 12.2%), but there was no difference in the stroke rates over 64.5 months of follow-up. This raised questions about whether all atrial fibrillation detected with monitors is of clinical significance.
Anticoagulation for atrial fibrillation. The 1990s produced several clinical trials devoted to the prevention of stroke due to cerebral embolism, largely targeting nonvalvular atrial fibrillation. These studies compared aspirin, warfarin, or a combination of both and emphasized the importance of patient selection in guiding therapy. Overall, warfarin was more effective than aspirin for stroke prevention, with pooled analyses showing a 65% risk reduction compared with 20% with aspirin (33). Aspirin was compared to placebo or no treatment in eight trials; only the SPAF-1 (Stroke Prevention in Atrial Fibrillation) study showed modest benefit but was limited by low power, selection bias, and its primary-prevention design.
Subsets of patients may derive sufficient benefit from aspirin while avoiding anticoagulation risks. Aspirin may be reasonable for patients with atrial fibrillation who are younger than 75 years without cardiac comorbidities, whereas approximately 30% in this age group with risk factors--left ventricular dysfunction, systolic hypertension, prior transient ischemic attack or stroke--benefit more from warfarin. Among patients over 75, only 30% are free of cardiac comorbidities, but anticoagulation risks also increase. Aspirin may also be effective in patients with atrial fibrillation presenting with lacunar stroke syndrome (22).
Guidelines emphasize risk stratification based on age, hypertension, ejection fraction less than 35%, heart failure, and diabetes (33; 25). CHADS or CHA₂DS₂-VASc scores are recommended to identify patients likely to benefit from anticoagulation (17).
For secondary prevention after a transient ischemic attack or stroke, warfarin is clearly superior. In the European Atrial Fibrillation Trial, annual stroke rates were 12% with placebo, 10% with aspirin, and 4% with warfarin (21). Aspirin was also compared directly to apixaban in the AVERROES study (15), which was terminated early due to the clear benefit of apixaban over aspirin.
Despite its efficacy, warfarin remains underused; only 52.6% of patients with atrial fibrillation in the Cardiovascular Health Study received it (41), and many older patients are contraindicated or deemed ineligible (38). Intracranial hemorrhage risk with warfarin is low (less than 0.5% per year) until age 80 (23). Concerns regarding elderly patients have been addressed; the Birmingham Atrial Fibrillation Treatment of the Aged study randomized 974 patients 75 years or older (mean 81) to warfarin (INR 2 to 3) or aspirin 75 mg/day. Warfarin reduced annual stroke risk from 3.8% to 1.8% without increasing major extracranial hemorrhage (47).
Novel oral anticoagulants offer effective alternatives. They are first-line oral anticoagulants in patients with atrial fibrillation (except moderate to severe mitral stenosis, mechanical heart valves, and mechanical heart devices). FDA-approved anticoagulants include dabigatran, rivaroxaban, apixaban, edoxaban, and betrixaban.
Dabigatran. In the RE-LY study, over 18,000 patients were assigned to treatment with two doses of dabigatran (110 or 150 mg twice daily) or warfarin adjusted to an international normalized ratio of 2 to 3. Patients were followed for an average of 2 years (16). The rate of the primary endpoint (stroke or systemic embolism) was similar between the lower dose of dabigatran (1.53%) and warfarin (1.69%), with a lower rate of major bleeding with dabigatran. The 150-mg dose of dabigatran had a lower rate of embolism (1.11%) compared to warfarin (p< 0.001). Bleeding events were similar in the two groups. There were no major concerns about liver toxicity with dabigatran. Dosage of dabigatran requires adjustment for patients with impaired renal function (creatinine clearance less than 30 mg/dl).
Rivaroxaban. Rivaroxaban is an oral factor Xa inhibitor that was compared to warfarin in the ROCKET study (59). Over 14,000 patients were randomly assigned to receive warfarin (INR 2 to 3) or rivaroxaban 20 mg per day. Stroke or systemic embolism occurred at a rate of 1.7% per year in the rivaroxaban group and 2.2% per year in the warfarin group (p< 0.001 for noninferiority). There was no difference in the rates of major bleeding.
Apixaban. A third oral anticoagulant is apixaban, a factor Xa inhibitor. Over 18,000 patients were enrolled in the ARISTOTLE study comparing warfarin (INR 2 to 3) and apixaban 5 mg twice per day (30). The endpoint of stroke or systemic embolism occurred at a rate of 1.3% per year in the apixaban group and 1.6% per year in the warfarin group (p=0.01 for superiority). Major bleeding was reduced with apixaban (hazard ratio 0.69, p< 0.001). Finally, mortality was also lower with apixaban compared to warfarin (hazard ratio 0.89, p=0.047).
Edoxaban. A fourth option for a direct-acting oral anticoagulant is edoxaban. Edoxaban is also a factor Xa inhibitor. Over 21,000 patients were enrolled in the ENGAGE-AF study comparing warfarin (INR 2-3) and edoxaban (two different once-daily regimens) (27). The primary endpoint was stroke or systemic embolism, which occurred at an annual rate of 1.50% in the warfarin group, compared with 1.18% in the higher dose edoxaban patients (hazard ratio 0.79, p< 0.001 for noninferiority). The corresponding rate for the primary endpoint in the low-dose edoxaban group was 1.61%. The annual rates of major bleeding were 3.43% with warfarin, 2.75% with high-dose edoxaban, and 1.61% with low-dose edoxaban.
No head-to-head non-vitamin K antagonist oral anticoagulant (NOAC) comparisons exist. Dabigatran is the only agent proven superior to warfarin for ischemic stroke prevention, and apixaban is the only NOAC to reduce all-cause mortality. All NOACs lower intracerebral hemorrhage risk relative to warfarin (17).
Dual antiplatelet therapy with aspirin and clopidogrel is an alternative for patients unsuitable for warfarin. The ACTIVE-W trial found warfarin superior to dual therapy (3.9% vs. 5.6% per year) with similar major bleeding (03). In ACTIVE-A, aspirin plus clopidogrel modestly reduced major vascular events compared to aspirin alone (6.8% vs. 7.6%) but slightly increased major bleeding (02). Dual therapy may be considered in patients with low bleeding risk.
Surgical management. For patients with atrial fibrillation who are not candidates for long-term anticoagulation, left atrial appendage closure offers a potential alternative for stroke prevention. Additional indications for left atrial appendage occlusion include absolute contraindications to chronic anticoagulation, a history of systemic thromboembolism despite therapeutic oral anticoagulation, and situations in which bleeding risk clearly outweighs the risk of systemic embolism.
A pivotal randomized trial compared the WATCHMAN left atrial appendage closure device with warfarin (INR 2 to 3) (64). After a mean follow-up of 3.8 years, the composite primary endpoint of stroke, systemic embolism, or cardiovascular death occurred at 2.3 events per 100 patient-years in the device group versus 3.8 events per 100 patient-years with warfarin (rate ratio 0.60). Surgical left atrial appendage closure also showed benefit in a large randomized controlled trial, reducing the risk of stroke and systemic embolism by 33% (78). However, device-based left atrial appendage closure carries potential complications, most notably pericardial tamponade, and further studies are needed to clarify safety and efficacy compared with direct oral anticoagulants.
The AFFIRM trial evaluated rate versus rhythm control strategies in atrial fibrillation and found no significant difference in major outcomes between the two approaches, while reaffirming a 69% relative reduction in stroke with therapeutic warfarin (69). Similarly, a randomized trial in patients with atrial fibrillation and heart failure showed no difference in stroke risk between rate and rhythm control strategies (67).
Long-term oral anticoagulation is also recommended in several other high-risk settings, such as rheumatic mitral stenosis with atrial fibrillation and mechanical heart valves (66). Shorter anticoagulation courses (3 to 6 months) are advised following acute myocardial infarction when left ventricular thrombus or significant wall-motion abnormalities are present. Most patients with bioprosthetic valves do not require long-term anticoagulation beyond the initial three postoperative months unless there are additional risk factors, such as left atrial thrombus, prior embolic events, or multiple valve replacements. Thromboembolic risk is higher for bioprosthetic mitral valves than for bioprosthetic aortic valves (73).
Patent foramen ovale. For patients with a patent foramen ovale, treatment options include (1) antiplatelet agents, (2) warfarin, (3) percutaneous closure, and (4) open surgical closure. Only if the patent foramen ovale was associated with an atrial septal aneurysm or large shunt size was there a markedly higher rate of recurrent stroke (50). Most studies have shown that patent foramen ovale is not a major risk factor for stroke in the general population, when one includes subjects older than 50 years (61).
Patent foramen ovale closure studies utilized a device known as the Amplatzer occluder. The RESPECT trial enrolled 980 patients between the ages of 18 and 60 with a cryptogenic stroke and evidence of a patent foramen ovale by transesophageal echocardiogram (12). Patients were randomly assigned to patent foramen ovale closure or antithrombotic therapy. After a mean follow-up period of 2.6 years, the closure group had a stroke rate of 1.8% (nine events), and the medical therapy group had a rate of 3.3% (16 events). In the intention-to-treat analysis, the hazard ratio was 0.49 (p=0.08). There was a 4.2% risk of serious adverse events with the closure device, including two cases of pericardial tamponade. There was no difference in major bleeding. Atrial fibrillation rates were 3.0% in the closure group and 1.5% in the medical therapy group (p=0.13).
The PC Trial Investigators enrolled 414 patients and followed them for an average of 4 years (53). Nonfatal stroke occurred in one patient in the closure group and in five patients in the medical therapy group (hazard ratio 0.20, 0.02 to 1.72, p=0.14).
Publications such as the CLOSE and REDUCE trials did identify a small stroke reduction with patent foramen ovale closure. In the CLOSE trial, 663 patients with a recent stroke and patent foramen ovale were enrolled if they also had an atrial septal aneurysm or large interatrial shunt (49). After a mean follow-up of 5.3 years, there were no strokes in the patent foramen ovale closure group compared to 14 with antiplatelet therapy (p < 0.001). The incidence of atrial fibrillation was higher in the patent foramen ovale closure group compared to medical therapy (4.6% vs. 0.9%, p = 0.02). Similar results were seen in the REDUCE trial (70). In 664 randomized patients, the stroke risk was lower with patent foramen ovale closure compared to antiplatelet therapy (1.4% vs. 5.4%, p = 0.002). Atrial fibrillation was higher in the device-treated patients, with a rate of 6.6%. An updated meta-analysis found that the number needed to treat with patent foramen ovale closure to prevent one stroke is 46.5 for 3.7 years. This analysis also found an increase in atrial fibrillation with device closure and no difference in all-cause mortality or transient ischemic attack (56). In addition to the RoPE score, the PASCAL classification system may also be useful in decision-making. This system looks for the coexistence of a RoPE score of 7 or more along with either a large shunt or atrial septal aneurysm. If both a high score and a high-risk anatomic feature are present, then the patent foramen ovale relation to the stroke is considered “probable”, whereas it is considered “possible” if either a high score or an anatomic feature is present. A pooled analysis with close to 5 years of follow-up found that the absolute risk reduction with patent foramen ovale closure was 2.1% if the patent foramen ovale relation was probable or possible, but there was no benefit if the patent foramen ovale relation was judged as unlikely (43).
These studies show that the recurrent stroke rate for patients with a patent foramen ovale treated medically is quite low, approximately 1% per year. Further, recurrent events are not always due to the patent foramen ovale. There may be a slight stroke risk reduction in individual patients, but patients should be selected carefully, and they must be carefully evaluated for other stroke mechanisms (intermittent atrial fibrillation, arterial dissection, etc.) before patent foramen ovale closure is considered.
As the population ages and cardiac care improves, there is a growing number of patients living with reduced cardiac ejection fraction.
The Warfarin Aspirin Reduced Cardiac Ejection Fraction (WARCEF) trial enrolled 2305 patients with ejection fraction less than 35% who were in sinus rhythm (35). Patients were randomly assigned to warfarin (INR 2.0 to 3.5) or aspirin 325 mg per day. Patients were followed for an average of 3.5 years. The primary endpoint was stroke or death from any cause. There was no difference between the warfarin and aspirin groups with respect to the primary endpoint. During follow-up, the rate of stroke was reduced with warfarin (0.72 events per 100 patient-years vs. 1.36, hazard ratio 0.52, p=0.005). However, major bleeding was also increased with warfarin (1.78 per 100 patient-years vs. 0.87, p< 0.001). There was no difference in the two groups with respect to intracranial hemorrhage. The authors concluded that the choice between warfarin and aspirin should be individualized, with consideration of stroke and bleeding risks. There may be a benefit with anticoagulation in patients below age 60 years, but this requires further study (36).
Long-term anticoagulant therapy (warfarin) is best monitored with the international normalization ratio time. The international normalization ratio takes into account the differing sensitivities of the thromboplastin reagent used in the standard prothrombin time test and minimizes fluctuations in test results with subsequent dosing changes. In most patients with atrial fibrillation, the international normalization ratio is kept between 2.0 and 3.0.
Differential diagnosis
The differential diagnosis of cerebral embolism is that for any acute focal neurologic deficit. Transient focal ischemia must be distinguished from focal seizures and migraine. In the acute phase of a stroke, an intracerebral hemorrhage must be excluded by CT. Headache and depressed level of consciousness should suggest an intracranial hemorrhage. Embolism may be clinically difficult to distinguish from any other mechanism of stroke. Pure sensory or pure motor syndromes involving one half of the body point to small-vessel occlusive disease but can be caused by emboli, and the clinical syndromes are of limited diagnostic specificity without corroborating laboratory studies.
The causes of focal brain ischemia are myriad. The vast majority of infarctions, however, are related either to atherosclerosis of extracranial or intracranial arteries, or to common cardiac sources of embolism. Inflammatory causes of stroke include the antiphospholipid antibody syndrome, Takayasu disease, granulomatous arteritis, aortoarteritis, infective arteritis, and systemic arteritis (Wegener granulomatosis, rheumatoid arthritis, sarcoidosis, polyarteritis nodosa, and Behçet disease). Nonatherosclerotic causes of stroke include arterial dissection, fibromuscular dysplasia, moyamoya syndrome, and vasospasm in subarachnoid hemorrhage.
Less common types of embolism include fat after long bone fractures, fibrocartilaginous, air in Caisson disease (in divers), amniotic fluid, tumor, and iatrogenic foreign particle.
Diagnostic workup
One of the first diagnostic tests when evaluating a patient suspected of stroke is a nonenhanced CT of the head, which distinguishes nonhemorrhagic from hemorrhagic stroke. CT findings suggestive of cerebral embolism include "wedge-shaped" low-attenuation defects at the gray-white cortical junction, multiple strokes crossing arterial territories, a hyperdense middle cerebral artery sign, and early conversion of a "bland" infarct to a hemorrhagic infarct. At least 40% of embolic infarctions eventually have CT evidence of hemorrhage that is usually of no clinical significance.
Prompt evaluation of the cervical carotid arteries with ultrasound or MRA helps identify occlusive arterial disease, potential candidates for endarterectomy, and patients with intracranial atherosclerosis. Transcranial Doppler may also identify middle cerebral artery occlusion, which often suggests embolism. An electrocardiogram may reveal potential sources of the stroke, such as atrial fibrillation or myocardial infarction. Transthoracic echocardiography can confirm the presence of an akinetic or dyskinetic left ventricular wall, mural thrombus, valvular disorders, and other intracardiac masses. It is of limited use for viewing the left atrium and left atrial appendage, which are often the sites of a thrombus. In an echocardiographic study of 846 patients with ischemic stroke, among patients in sinus rhythm, 37.2% had findings that potentially might lead to a beneficial response from anticoagulation, such as dilated cardiomyopathy, previous anterior wall myocardial infarction, or depressed ejection fraction (01). Transesophageal echocardiography is superior to transthoracic echocardiography for imaging these structures. A number of potential sources of emboli, such as patent foramen ovale, atrial septal aneurysm, atrial "smoke," aortic atherosclerosis, and congenital anomalies, may be identified by transesophageal echocardiography. Routine use of transthoracic echocardiography is unlikely to be useful in elderly patients (77). In patients with a stroke and patent foramen ovale, it may be worthwhile to check for conditions associated with an increased risk of venous thrombosis, such as the factor V Leiden mutation and anticardiolipin antibodies (14).
Transesophageal echocardiography is also potentially useful in risk stratification for patients with atrial fibrillation. In the SPAF III trial, transesophageal echocardiography was carried out in 786 patients. Dense, spontaneous echo contrast and left atrial appendage thrombus were present in 20% and 15% of patients, respectively, and each was associated with a 3-fold increased risk of stroke (33). Left atrial thrombus documentation has also been associated with an increased risk of transient ischemic attack (71).
Management
Once the diagnosis of cerebral embolism has been established, thrombolytic therapy with intravenous tissue plasminogen activator can improve the long-term prognosis if treatment can be initiated within 3 hours (NINDS Study group 1995). Guidelines from the American Heart Association/American Stroke Association also indicate that select patients with cardioembolic stroke can benefit from mechanical thrombectomy (62). Heparin anticoagulation is sometimes initiated in the acute setting to lower the risk of recurrence if a nonseptic cardiac source of embolism persists, although the benefits are unproven (05). Decisions regarding choice of long-term antithrombotic therapy need to be based on the clinical status of the patient, comorbidities, and echocardiographic variables (04).
The baseline laboratory evaluation should include a complete blood count with differential, platelet count, prothrombin time, partial thromboplastin time, erythrocyte sedimentation rate, serum glucose, electrolytes, lipids, and a VDRL test. Urinalysis, 12-lead ECG, and plain chest radiograph should also be performed.
Some patients require supplemental oxygen or intravascular volume expansion with colloid solutions if dehydration is suspected. Fever should be carefully monitored and aggressively evaluated and treated. There is experimental evidence to suggest that hyperthermia may increase infarct size. Fever may be the clue to another complication, such as aspiration pneumonia, endocarditis, or deep venous thrombosis. Both hyperglycemia and hypoglycemia can exacerbate ischemic brain damage. Blood glucose levels that exceed 200 mg/dL should be treated with insulin, and glucose levels below 60 mg/dL should be avoided.
Rehabilitation plans should begin on the first day of hospitalization and should include a physiatrist, physical and occupational therapists, a social worker, a dietitian, and, if indicated, a speech pathologist.
Special considerations
Pregnancy
Pregnancy increases the likelihood of cerebral infarction to approximately 10 times that of the expected incidence in nonpregnant young women (20). Cardioemboli are responsible for the majority of ischemic infarctions of arterial origin during pregnancy. Most strokes during pregnancy affect the anterior circulation, especially the middle cerebral artery. Cardiac conditions frequently associated with cerebral embolism during pregnancy include atrial arrhythmias, congenital disorders (eg, atrial septal defects), and acquired disorders (eg, peripartum cardiomyopathy).
Venous infarction also occurs in the peripartum period (20).
The consequences of atrial fibrillation during pregnancy are potentially life-threatening. Atrial fibrillation may be chronic as a consequence of rheumatic mitral stenosis, or it may develop de novo during the course of the pregnancy. Congestive heart failure occurs more frequently with de novo atrial fibrillation during pregnancy than with chronic atrial fibrillation (20). Women with chronic atrial fibrillation who are treated with warfarin should take contraceptive precautions to avoid exposing the fetus to the potential teratogenic effects of warfarin. If pregnancy is desired, alternative anticoagulation methods such as subcutaneous heparin should be implemented prior to conception and continued through the first trimester.
Anesthesia
Patients with a history of cerebral embolism often are treated with oral anticoagulants. Prior to any surgical procedure, these patients require conversion from oral anticoagulants to intravenous anticoagulants. The risk of cerebral embolism increases if there is a definite source of embolism during the period of time when anticoagulation is reversed. However, in most patients, warfarin can be safely withheld for 1 or 2 weeks to permit elective or emergent surgery.
Media
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Contributors
All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.
Authors
-
Varsha Muddasani MD
Dr. Muddasani of University of Texas Health Science Center at Houston has no relevant financial relationships to disclose.
See Profile -
Aparna M Prabhu MD MRCP
Dr. Prabhu of Thomas Jefferson University and Jefferson Einstein Medical Center has no relevant financial relationships to disclose.
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Editor
-
Steven R Levine MD
Dr. Levine of the SUNY Health Science Center at Brooklyn has no relevant financial relationships to disclose.
See Profile
Former Authors
- Daryl W Thompson MD
- Anthony J Furlan MD
- Seemant Chaturvedi MD
Patient Profile
- Age range of presentation
-
- 0 months to 65+ years
- Sex preponderance
-
- female>male, >1:1
- Heredity
-
- none
- Population groups selectively affected
-
- none selectively affected
- Occupation groups selectively affected
-
- none selectively affected
ICD & OMIM codes
- ICD-10
-
- Occlusion and stenosis of other cerebral artery: I66.8
- ICD-11
-
- Cerebral venous thrombosis: 8B22.1
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