Stroke associated with atrial fibrillation …

Stroke & Vascular Disorders

Updated 03.10.2026
Released 06.20.1996
Expires For CME 03.10.2029

Stroke associated with atrial fibrillation

Authors: Shivansh Desai MD, Gabriela Trifan MD

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Editor: Steven R Levine MD

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Stroke associated with atrial fibrillation

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Introduction

Overview

Stroke is the leading cause of disability in the United States, with approximately 795,000 people experiencing a new or recurrent stroke each year (100). Cardioembolism is a particularly disabling stroke subtype that accounts for 20% to 30% of all stroke cases. Observational studies demonstrated that almost half of the cardioembolic strokes are related to atrial fibrillation. In this article, the authors discuss the association of atrial fibrillation with stroke, the role of anticoagulation in stroke prevention, the available risk stratification tools, and the pathogenic mechanisms of thrombus formation associated with this cardiac arrhythmia.

Key points

	• Atrial fibrillation increases stroke risk 3- to 5-fold, accounting for 15% to 30% of all ischemic strokes.
	• Prolonged cardiac monitoring is superior to short-term monitoring for detecting occult atrial fibrillation.
	• Anticoagulation is guided by thromboembolic risk: low risk (< 1% per year; CHA2DS2-VASc score of 0 in men and 1 in women) may not require anticoagulation; intermediate risk (1% and 2% per year; CHA2DS2-VASc score of 1 in men and 2 in women) warrants oral anticoagulation; high risk (2% or greater per year; CHA2DS2-VASc score of 2 or higher in men and 3 or higher in women) requires oral anticoagulation.
	• Direct thrombin and factor Xa inhibitors are non-inferior to warfarin for stroke prevention or systemic embolism, with lower major bleeding risk, and are the preferred choice of anticoagulation in patients with atrial fibrillation.
	• In patients with contraindications to long-term anticoagulation or recurrent ischemic strokes despite anticoagulation therapy, left atrial appendage occlusion provides a safe and effective alternative to reduce stroke risk.
	• Comprehensive management includes anticoagulation, lifestyle modification, risk factor control, and early rhythm and rate management.
	• Antiplatelet monotherapy is not recommended for atrial fibrillation management; antiplatelets may be added to anticoagulation only for concomitant coronary artery disease.

Historical note and terminology

As early as 1628, Harvey had observed undulation in the right atrium of a dying animal heart (74); in 1874, Vulpian reported uncoordinated twitching of the atrium, "fremissement fibrillaire" after application of an electrical current (106). Nothnagel published three arterial pulse curves showing irregular heart rates in the mid-1800s and called the arrhythmia "delirium cordis" (76), which was defined by the complete irregularity of heartbeats continuously changing in "height and tension." However, the association between these atrial fibrillary contractions and the irregular pulse was not formally made until 1907 (23).

In 1940, Karl Paul Link synthesized dicumarol, a substance found in spoiled sweet clover known to cause hemorrhagic disease in cattle; in 1947, its use was advocated for the prevention of cardiac embolism in patients with rheumatic atrial fibrillation (113). However, the risk of stroke in patients with chronic nonvalvular atrial fibrillation was generally believed to be too small to require medication. It was not until 1978 that the results of the Framingham Study clearly demonstrated an increase in stroke incidence in patients with chronic nonrheumatic atrial fibrillation (111). Vitamin K antagonists, including warfarin, have been the treatment of choice for the prevention of stroke or systemic embolism in patients with atrial fibrillation for many decades. However, randomized placebo-control studies and large patient-level network meta-analyses demonstrated more favorable efficacy and safety profiles of different non-vitamin K antagonist oral anticoagulants in the treatment of nonvalvular atrial fibrillation compared with warfarin and are now the recommended treatment of choice.

Clinical manifestations

Presentation and course

Atrial fibrillation is the most common sustained cardiac arrhythmia and the most common cause of cardioembolism. It has been estimated that atrial fibrillation accounts for a third of ischemic strokes (36). The classic sign of atrial fibrillation is an irregular pulse; however, the pulse may be regular between atrial fibrillation episodes. Patients can have transient events of diaphoresis, lightheadedness, or palpitations. In general, cardioembolic strokes, either due to atrial fibrillation or other causes, can present similar clinical findings with other stroke subtypes, including large-vessel thromboembolism and lacunar infarction. Patients often present with severe deficits and clinical evidence of cortical or cerebellar dysfunction (eg, sudden onset of language deficits, apraxia, unilateral weakness, sensory loss, discoordination, ataxia, or hemianopia) (02). Thus, the neurologic examination has limited utility in making the diagnosis of atrial fibrillation-associated stroke. The concomitant occurrence of cerebral and systemic embolism is suggestive of cardioembolism. Brain imaging commonly shows cortical ischemia or concurrent infarction in multiple vascular territories. In the acute setting, angiographic studies typically reveal the abrupt cutoff of large vessels, such as the terminal internal carotid artery or the trunk of the middle cerebral artery, with or without evidence of atherosclerotic disease of the large cerebral arteries. Diagnosis of atrial fibrillation-related stroke is supported by the identification of abnormal cardiac rhythm on cardiac monitoring.

Prognosis and complications

Patients with atrial fibrillation have an increased risk of stroke that ranges from less than 2% to more than 10% per year. The risk of stroke increases with different traditional vascular risk factors, including age, sex, hypertension, diabetes mellitus, and previous stroke or transient ischemic attack. The deficits in cardioembolism are usually more disabling than those seen in other subtypes. As an example, the proportion of patients with increased disability, defined by a modified Rankin Scale score of 3 and above, at 6 months is 66% for cardioembolism, 32% for large artery occlusive disease, and 23% for lacunar infarction (67). Even in the setting of comparable rates of successful reperfusion for stroke, patients with atrial fibrillation have higher rates of mortality and significantly lower rates of functional independence at 3 months compared with patients with strokes related to other etiologies (62). Due to the increased disability, patients with atrial fibrillation are more likely to develop severe complications, including pneumonia, sepsis, infections, or systemic embolism. In age- and sex-adjusted analyses over a median follow-up time of 19 years, the risk of death in participants with atrial fibrillation was two-fold higher; in contrast, the risk of death was four-fold higher in participants with atrial fibrillation and stroke compared with those without atrial fibrillation (45).

Biological basis

Genomic data in atrial fibrillation are derived from linkage analysis, genome-wide association studies using genotyping array data, and coding variations from genome sequence data (91). Both common (minor allele frequency > 1%) and rare (< 1%) variants contribute to atrial fibrillation risk. Common variants modestly increase susceptibility, whereas rare variants, particularly those affecting genes involved in cardiac structure and ion channel function, are more strongly predictive for atrial fibrillation risk (77; 80). Loss-of-function variants in the TTN gene and other cardiomyopathy-related genes are associated with early-onset atrial fibrillation and highlight the overlap between atrial fibrillation and inherited cardiomyopathies (59).

Large-scale genetic studies have demonstrated a synergistic effect between common polygenic risk and rare variants, substantially increasing atrial fibrillation risk (102; 17). A large genome-wide association study meta-analysis identified more than 350 atrial fibrillation–associated genetic variants in over 180,000 cases—more than doubling the previously known at-risk genetic loci (92).

Although genetic markers may improve risk prediction for atrial fibrillation and stroke, their clinical utility remains limited by population variability and lack of routine genetic testing.

Etiology and pathogenesis

Pathogenesis of thromboembolism in atrial fibrillation. Most infarctions in patients with atrial fibrillation are believed to be caused by emboli originating in the left atrium, particularly the left atrial appendage. However, atrial fibrillation frequently coexists with traditional vascular risk factors, such as advanced age, arterial hypertension, diabetes, and hypercholesterolemia, which contribute to the development of both atrial fibrillation and thromboembolism. Additional embolic sources, including decreased left ventricular function, atherosclerosis of the aortic arch, and occlusive disease of the extra- and intracranial arteries, may also be present.

Thrombus formation in atrial fibrillation reflects the interaction between a systemic vascular substrate and an atrial substrate (atrial cardiomyopathy), consistent with the Virchow triad of thrombogenesis: blood stasis, endothelial injury, and procoagulability. Blood stasis results from atrial dilatation and loss of effective atrial contraction; endothelial dysfunction and structural remodeling further promote thrombogenesis. Inflammation and impaired fibrinolysis also contribute to a prothrombotic state (109).

These systemic and atrial factors coexist and reinforce one another leading to the formation of microemboli and increasing stroke risk (109).

Atrial fibrillation and cryptogenic stroke. Cryptogenic stroke refers to an ischemic stroke without an identified cause after standard evaluation, though definitions vary. In the TOAST classification, cryptogenic stroke is characterized under three different scenarios: strokes with incomplete evaluation, lack of cause despite an extensive assessment, or strokes with multiple plausible causes (02). Observational data suggest that atrial fibrillation accounts for a substantial proportion of cryptogenic strokes (13), and prolonged cardiac monitoring significantly increases atrial fibrillation detection in these patients (116).

Embolic stroke of undetermined source, (ESUS), a concept first introduced in 2014, is a subset of cryptogenic stroke defined as a non-lacunar ischemic stroke without a major cardioembolic source, such as atrial fibrillation, significant arterial stenosis (≥50%), or other specific causes (intracardiac thrombus, arterial dissection, or angiitis) (48). Diagnosis requires vascular imaging of both the extracranial and intracranial cerebral arteries, a transthoracic echocardiogram, and at least 24 hours of continuous heart rhythm monitoring. Although both cryptogenic stroke and ESUS show radiological evidence suggestive of an embolic mechanism, ESUS implies a more complete diagnostic evaluation.

Cryptogenic stroke is responsible for 30% of strokes, whereas ESUS is responsible for 15%. Paroxysmal atrial fibrillation is typically suspected in cryptogenic stroke or ESUS; however, observational studies demonstrate that these stroke subtypes have distinct characteristics. Patients with ESUS are usually younger, have milder stroke severity, and have smaller emboli than patients with atrial fibrillation (47). Also, in the Oxford Vascular Study of embolic stroke of undetermined source and cryptogenic stroke, patients had a decreased prevalence of myocardial infarction, peripheral vascular disease, and asymptomatic extracranial carotid disease than patients with cardioembolism. The rate of recurrent strokes for 1 year was 2.8% for cryptogenic stroke and 35% for cardioembolic stroke. Also, the mortality at 1 year and 5 years was 6% and 25% for cryptogenic stroke and 41% and 65% for cardioembolic stroke, respectively (67). Atrial fibrillation detection increases with longer cardiac monitoring duration, reaching up to 30% at 36 months with implantable devices (94). However, temporal dissociation between atrial fibrillation episodes and stroke suggests that atrial fibrillation is not always the proximate cause (14; 116).

These aforementioned findings support the concept of “atrial cardiomyopathy” or “atrial cardiopathy,” which is defined by the presence of at least one of the following factors: (1) left atrial structural abnormalities evidenced by echocardiography or cardiac MR, such as endothelial dysfunction, fibrosis, impaired myocyte function, or chamber dilatation; (2) electrocardiographic evidence of left atrial dysfunction, including increased P-wave terminal force velocity in lead V1 (PTFV1) greater than 5000 μV·ms; or (3) increased levels of biochemical markers of cardiac dysfunction, including increased troponins or serum N-terminal pro-brain natriuretic peptide (NT-proBNP) levels greater than 250 pg/mL (57). Atrial cardiomyopathy may result from aging, hypertension, heart failure, obesity, diabetes, sleep apnea, genetic disorders, and other conditions that promote atrial fibrosis and remodeling through inflammatory and profibrotic pathways (43). Emerging evidence implicates molecular mediators, such as transforming growth factor-beta1, angiotensin II, and endothelin-1, in this process as well (118; 60; 72).

It has been observed that atrial cardiopathy is associated with cerebral embolism in 10% of cases, even in the absence of atrial fibrillation (115). Also, secondary analysis of the WARSS trial shows that patients with serologic evidence of atrial cardiopathy have a lower risk of recurrent stroke or death when treated with anticoagulation rather than aspirin (70).

Device-detected atrial-heart rate episodes (subclinical atrial tachyarrhythmias) represent another intermediate phenotype. Atrial-heart rate events are a separate entity from atrial fibrillation, although episodes lasting longer than 5 minutes increase the risk of further atrial fibrillation and stroke; however, absolute stroke remains lower than in clinical atrial fibrillation (35). Current recommendations reserve oral anticoagulation only for (1) patients with a device-detected atrial high-rate episode lasting 24 hours or longer and with a CHA2DS2-VASc score of 2 or higher or equivalent stroke risk, and (2) patients with device-detected atrial high-rate episodes lasting between 5 minutes and 24 hours and with a CHA2DS2-VASc score of 3 or higher or equivalent stroke risk, but not for those with device-detected atrial-heart rate events lasting less than 5 minutes and without another indication for oral anticoagulation (56).

Epidemiology

Atrial fibrillation is the most common sustained cardiac arrhythmia, affecting an estimated 3 to 6 million individuals in the United States alone. Over 50 years of follow-up in the Framingham Heart Study, age-adjusted prevalence and incidence of atrial fibrillation approximately quadrupled in both men (prevalence from 2% to 10%, incidence from 4 to 13 per 1000 person-years) and women (prevalence from 1% to 5%, incidence from 3 to 9 per 1000 person-years) (95). Similarly, the Rotterdam Study demonstrated a rising atrial fibrillation burden over 3 decades, with a marked increase in incidence in the 2010s (117).

Owing to the association of atrial fibrillation with age, demographic aging is expected to substantially expand disease burden. In the United States, prevalence is projected to reach 12.1 million by 2030, with annual incidence cases raising from approximately 1.2 million in 2010 to 2.6 million by 2030 (100). Atrial fibrillation prevalence is higher among White individuals; after adjustment for risk factors, Blacks (OR: 0.49; 95% CI: 0.47 to 0.52), Asian (OR: 0.68; 95% CI: 0.64 to 0.72), and Hispanic populations (OR: 0.58; 95% CI: 0.55 to 0.61) have significantly lower rates of atrial fibrillation than Whites (100).

Socioeconomic factors also influence atrial fibrillation risk and outcomes. Individuals living in intermediate-poverty neighborhoods had elevated adjusted odds of 5-year incident atrial fibrillation (OR: 1.23; 95% CI: 1.01 to 1.48), compared to individuals residing in lower-poverty neighborhoods (33). Additionally, low income in patients with prevalent atrial fibrillation (less than $40,000/y) was associated with an increased risk of heart failure and myocardial infarction (65). Data from Atherosclerosis Risk in Communities study revealed that atrial fibrillation incidence decreases with progressively increasing categories of income and education (75).

Nonvalvular atrial fibrillation is associated with a 4- to 5-fold increased risk of stroke, with the greatest attributable risk observed in the elderly (24% in those aged 80 to 89 years vs. 10% overall) (08). The risk of stroke is even higher in valvular-associated atrial fibrillation, particularly in rheumatic heart disease and mitral stenosis (16).

Differential diagnosis

Confusing conditions

Ischemic stroke remains a leading cause of morbidity and mortality worldwide, but stroke mimics form a significant proportion of acute stroke cases. With the increased availability of systemic thrombolysis and shortened door-to-needle times, the hyperacute diagnosis of stroke remains challenging, as approximately one in four stroke cases turns out to be a stroke mimic (55). Stroke mimics can be medical (when symptoms are attributable to another medical condition) or functional (when there are no organic causes for the symptoms). Among medical mimics, peripheral vertigo dysfunction (23.2%), toxic metabolic encephalopathy (13.2%), seizures (13%), and migraines (7.76%) are most common. The prevalence of functional disorders is 9.7% (84).

However, when systemic thrombolysis is administered in stroke mimics, the complication rates are low, and functional outcomes are typically good (101).

Associated or underlying disorders

Although most strokes in patients with atrial fibrillation are presumed to originate from the left atrium, other embolic sources frequently coexist. Hypertension, present in 60% to 80% of individuals with established atrial fibrillation, predisposes to small vessel occlusive disease, providing an additional non-cardioembolic mechanism of stroke (105).

Aortic arch atheroma is an important competing and potentially synergistic source of embolism. The Stroke Prevention in Atrial Fibrillation investigators reported a series of 382 patients with high-risk nonvalvular atrial fibrillation, of whom 35% had complex aortic plaques. In high-risk nonvalvular atrial fibrillation, complex aortic plaques were identified in approximately one-third of patients and were associated with substantially higher annual stroke risk (12% to 20%) compared with atrial fibrillation alone (1.2%) (03). Complex plaques are characterized by surface abnormalities (ulcerations, mobile components) and increased plaque thickness of at least 4 mm. Lesions in the ascending and transverse aorta are associated with cerebral and peripheral embolism, whereas descending aortic plaques appear more closely linked to cerebral events. Complex plaques also correlate with left atrial and endocardial abnormalities, suggesting additive thromboembolic risk (12).

Carotid atherosclerosis represents another competing mechanism for stroke in patients with atrial fibrillation. Its prevalence increases with age, affecting up to 65% of patients older than 75 years (06). In anticoagulated patients with atrial fibrillation, more than 50% carotid stenosis is associated with a modest, nonsignificant increase in stroke risk, whereas in patients not on anticoagulation, the presence of carotid changes is associated with a significant 56% increased risk of stroke, even after adjustment for CHA2DS2-VASc score (07).

Diagnostic workup

The diagnostic workup of ischemic stroke in patients with atrial fibrillation aims to identify coexistent stroke mechanisms that may alter management. Vascular imaging, such as carotid Doppler, transcranial Doppler, or other noninvasive angiographic studies (eg, magnetic resonance angiography or computed tomography angiography), is performed to exclude large artery occlusive disease. Echocardiography assesses structural heart disease, including valvular pathology (eg, mitral stenosis), left ventricular dysfunction, hypertrophy, and left atrial dilatation, and screens for other cardioembolic sources, such as cardiac tumor, interatrial septal aneurysm, and patent foramen ovale.

Transesophageal echocardiography is superior to transthoracic echocardiography for detecting left atrial appendage thrombi and is considered the gold standard in assessing aortic arch atherosclerosis. In addition, transesophageal echocardiography allows depiction of spontaneous echo contrast in the atrium and reduced left atrial appendage peak flow velocities, both being important features independently associated with increased thromboembolic risk in patients with atrial fibrillation (119). However, because anticoagulation is the treatment of choice in atrial fibrillation–related strokes, transesophageal echocardiography findings rarely change management outside selected cases.

Prolonged cardiac monitoring is standard for atrial fibrillation detection after ischemic stroke, with diagnostic yield increasing with monitoring duration. Implantable cardiac monitors substantially improve atrial fibrillation detection compared with conventional care and may facilitate earlier rhythm control and treatment initiation (10). The risk of stroke seems to increase in proportion to the atrial fibrillation burden. The rate of thromboembolic events is 1.49% per year in patients with paroxysmal atrial fibrillation, 1.95% in those with permanent atrial fibrillation, and 1.83% in persistent atrial fibrillation (68). The KP-RHYTHM study analyzed a cohort of 1965 adults with paroxysmal atrial fibrillation not on anticoagulation. Higher atrial fibrillation burden (defined as greater than 11.4% of time spent in atrial fibrillation or atrial flutter during 14 days of continuous cardiac monitoring) was associated with a three-fold increase in the risk of thromboembolic events after adjusting for known stroke risk factors (42). The results of the MONITOR AF trial, which investigated the utility of dynamic monitoring of atrial fibrillation using implantable cardiac monitoring for a mean follow-up of 24 months, showed that implantable cardiac monitoring significantly improved care pathways (tools used to guide management of complex health care decisions leading to early intervention) leading to faster onset of treatment (median time to antiarrhythmic drug therapy start was 36 days in the implantable monitor group vs. 46 days in the non-implantable cardiac monitoring group), improved rhythm control (time to first ablation, 5 vs. 14 months, respectively), and significant reduced atrial fibrillation–related morbidity and mortality (63).

“Atrial fibrillation discovered after stroke” describes brief, device-detected episodes identified through long-term monitoring. The 3-year results from the STROKE AF trial compared the rates of atrial fibrillation detection between an insertable cardiac monitor versus site-specific usual care in patients with prior ischemic stroke attributed to either large artery atherosclerosis or small vessel disease (09). In these patients, the incidence rate of atrial fibrillation at 3 years was 21.7% in the insertable cardiac monitor group versus 2.4% in the control group (HR: 10.0; 95% CI: 4.0 to 25.2; P < 0.001). However, uncertainty remains on the clinical significance of atrial fibrillation discovered after stroke and the appropriate management.

Biomarkers, such as NT Pro‐BNP, have also been investigated for atrial fibrillation detection. Elevated NT Pro‐BNP are strongly associated with atrial fibrillation and may predict its presence independently of the left atrial size (52; 120). However, standardized strategies for diagnosing atrial cardiomyopathy after stroke, distinct from atrial fibrillation, have not yet been established.

Management

Risk stratification. Guidelines for the prevention of stroke in patients with nonvalvular atrial fibrillation recommend the use of risk stratification tools to guide management. The scores most used in clinical practice are the CHA2DS2-VASc, ATRIA, and GARFIELD-AF scores (Table 1). The CHA2DS2-VASc score is considered the most validated score; however, it has been shown to be suboptimal in selected populations (for example, patients with renal disease). This has led to the creation of new scoring systems, such as the Anticoagulation and Risk Factors in Atrial Fibrillation (ATRIA) and Global Anticoagulant Registry in the Field-Atrial Fibrillation (GARFIELD), which improve risk discrimination, although these newer scales have not been as rigorously tested as the CHA2DS2-VASc score.

A patient’s absolute stroke risk can be characterized as low (less than 1% per year), intermediate (approximately 1% to 2% per year), and high (greater than 2% per year). However, given the shortcomings of the risk stratification tools, the risk scores should be calibrated against the actual annual stroke rates in the target population to ensure an accurate, unbiased risk prediction (88).

Table 1. Validated Stroke Risk Models for Patients with Non-Valvular Atrial Fibrillation

Risk Factor	CHA2DS2-VASc	ATRIA	GARFIELD
Age 85 years or older		6	0.98
Age 75 to 84 years	2	5	0.59
Age 65 to 74 years	1	3	0.20
Female sex	1	1
Hypertension	1	1	0.16
Renal disease		1	0.35
Diabetes	1	1	0.21
Current smoking			0.48
Congestive heart failure	1	1	0.23
Previous stroke or transient ischemic attack	2	2 to 8*	0.80
Vascular disease	1		0.20
Dementia			0.51
Previous bleeding			0.30
Proteinuria		1
Low-risk score	0	0 to 5	0 to 0.89
Intermediate risk score	1	6	0.90 to 1.59
High-risk score	2 or higher	7 to 15	1.60 or higher
C-index (11)	0.63	0.66	-
C-index (13)	0.67	-	0.71
* 8 points if younger than 65 years, 4 points if aged 65 to 74 years, 2 points if aged 75 to 84 years, and 3 points if 85 years or older. ATRIA: anemia, renal disease, elderly (age 75 years or older), any previous bleeding, hypertension CHA2DS2-VASc: congestive heart failure, hypertension, age 75 years or older (doubled), diabetes mellitus, prior stroke or transient ischemic attack or thromboembolism (doubled), vascular disease, age 65 to 74 years, sex category From (56)

The 2018 American College of Chest Physicians guidelines and 2019 American College of Cardiology/American Heart Association clinical practice guidelines recommend:

	• For patients with an estimated annual thromboembolic risk of 1% or lower per year (eg, men with a CHA2DS2-VASc score of 0 and women with a score of 1), anticoagulation therapy may be omitted.
	• For patients with an estimated annual thromboembolic risk of between 1% and 2% per year (eg, CHA2DS2-VASc score of 1 in men and 2 in women), oral anticoagulation is reasonable.
	• For patients with an estimated annual thromboembolic risk of 2% or higher per year (eg, men with CHA2DS2-VASc score of 2 or higher and women with a CHA2DS2-VASc score of 3 or higher), oral anticoagulation is recommended in favor of single or combined antiplatelet therapy (69; 56).

Although the CHA2DS2-VASc score is widely used in clinical practice, a systematic review of 19 validating studies found high heterogenicity for assessing stroke risks, especially for low to intermediate-risk groups (103). This could be attributed, at least in part, to the inclusion of different populations. Also, all the risk stratification scales have well-known shortcomings. For example:

	• Several risk factors in the CHA2DS2-VASc score are given the same weight; however, their contribution to stroke may differ. A history of hypertension, for example, is associated with a higher risk of ischemic stroke than diabetes (90).
	• Female sex, in the absence of other vascular risk factors, does not seem to pose an increased risk of stroke. Thus, the risk of stroke for a patient with a score of 1 due to female sex is different than the risk of a patient with a score of 1 due to hypertension.
	• Age is a continuous variable, and establishing strict cutoffs may not accurately determine stroke risk.
	• The CHA₂DS₂-VASc score does not consider the vascular risk factor severity or how well controlled this is.
	• Risk stratification tools do not differentiate between the type and burden of atrial fibrillation (paroxysmal versus persistent or permanent).

Despite these limitations, the CHA₂DS₂-VASc score remains a fast and easy-to-use clinical risk stratification tool that reliably identifies patients at high risk who will benefit from initiating anticoagulation, as is the recommended risk stratification tool by the European and American Societies.

Table 2. CHA2DS2-VASc Score Quantification of Stroke/TE Risk for Patients with Non-Valvular Atrial Fibrillation

CHA2DS2-VASc score	Number of patients (n=1084)	Number of stroke/TE (n=25)	TE rate during 1y (95% CI)	Adjusted TE rate for aspirin prescription
0	103	0	0% (0-0)	0%
1	162	1	0.6% (0.0-3.4)	0.7%
2	184	3	1.6% (0.3-4.7)	1.9%
3	203	8	3.9% (1.7-7.6)	4.7%
4	208	4	1.9% (0.5-4.9)	2.3%
5	95	3	3.2% (0.7-9.0)	3.9%
6	57	2	3.6% (0.4-12.3)	4.5%
7	25	2	8.0% (1.0-26.0)	10.1%
8	9	1	11.1% (0.3-48.3)	14.2%
9	1	1	100% (2.5-100)	100%
TE= thromboembolic events, including ischemic stroke, peripheral embolism, or pulmonary embolism. From (Lip 2010).

Vitamin K antagonists. Randomized trials established vitamin K antagonists as superior to placebo or aspirin for primary and secondary stroke prevention in atrial fibrillation. In the Stroke Prevention in Atrial Fibrillation Studies (SPAF I and II), adjusted-dose warfarin (INR: 2.0-3.0) was more effective than aspirin, whereas fixed low-dose warfarin combined with aspirin was inferior and associated with higher embolic rates (04). Meta-analyses further demonstrated increased risk of bleeding with warfarin plus aspirin compared to warfarin alone (OR: 1.43, 95% CI: 1.00–2.02) (25). Effective vitamin K antagonist therapy requires maintaining therapeutic INR; subtherapeutic levels increase thromboembolism, whereas supratherapeutic levels increase bleeding. Poor time in therapeutic range (over 40% outside range) negates net clinical benefit (01).

Vitamin K antagonists were the standard of care for the prevention of stroke or systemic embolism in patients with atrial fibrillation until the introduction of direct oral anticoagulants, which are now considered the standard of care for the treatment of nonvalvular atrial fibrillation. Warfarin, however, remains the agent of choice in valvular heart disease conditions and in selected patients unable to receive direct oral anticoagulants.

Nonvitamin K antagonists or direct oral anticoagulants. Direct oral anticoagulants (dabigatran, apixaban, rivaroxaban, edoxaban) directly inhibit thrombin or factor Xa and are approved for stroke prevention in atrial fibrillation. Compared with warfarin, they are at least noninferior for the prevention of stroke and systemic embolism, with lower rates of intracranial hemorrhage, fixed dosing, and no routine laboratory monitoring (26).

The AVERROES trial demonstrated superiority of apixaban over aspirin for reducing stroke or systemic thromboembolism risk (HR: 0.45; 95% CI: 0.32 to 0.62; P< 0.001), without increasing the rate of hemorrhagic complications (0.4% per year) (20). However, the direct oral anticoagulant trials excluded patients with mechanical heart valves or hemodynamically significant mitral stenosis. The RE-ALIGN study showed an excess risk of thromboembolic events and hemorrhagic complications with dabigatran, compared with warfarin, in atrial fibrillation patients with mechanical heart valves (32), confirming warfarin as the treatment of choice in this population.

The term “non-valvular” atrial fibrillation has been removed from clinical practice and denotes atrial fibrillation associated with all native valvular stenosis or valvular insufficiencies and bioprosthetic valves. “Valvular” atrial fibrillation refers to atrial fibrillation due to mechanical heart valve or moderate to severe mitral stenosis (97).

The 2023 the American College of Cardiology and American Heart Association Clinical Practice Guidelines developed in collaboration with and endorsed by the American College of Clinical Pharmacy and the Heart Rhythm Society recommend using direct oral anticoagulants over warfarin in eligible patients with atrial fibrillation, except for the patients with moderate to severe mitral stenosis or mechanical heart valve for whom warfarin remains the drug of choice (56).

In patients who experience recurrent ischemic strokes due to atrial fibrillation, despite direct oral anticoagulant therapy, adherence and potential drug interactions (eg, CYP3A4 and CYP2C9 pathway, or p-glycoprotein modulators), or dietary interactions should be assessed (73).

Given the hypothesis that occult atrial fibrillation underlies embolic stroke of undetermined source, multiple trials evaluated direct oral anticoagulants in this population. The NAVIGATE-ESUS (rivaroxaban versus aspirin for stroke prevention after embolic stroke of undetermined source) (49) and RE-SPECT ESUS (dabigatran versus aspirin in the prevention of recurrent ischemic strokes after embolic stroke of undetermined source) (27) trials showed no reduction in recurrent stroke risk compared with aspirin, with increased bleeding in NAVIGATE-ESUS.

The ARCADIA trial was another major trial that investigated the use of anticoagulation versus antiplatelets in embolic stroke of an undetermined source with evidence of atrial cardiopathy (58). ARCADIA enrolled patients diagnosed with embolic stroke of undetermined source in the past 6 months who had evidence of atrial cardiopathy defined by one of three biomarkers (ECG marker reflective of left atrial abnormalities, an enlarged left atrium on echocardiography, or a serum NT-proBNP level above 250 pg/mL). Patients were randomized to apixaban 5 mg (or 2.5 mg, if indicated) twice daily plus placebo or aspirin 81 mg daily plus placebo. The study failed to show a benefit for preventing recurrent strokes with the use of apixaban compared to aspirin (4.4% rate in both groups for an HR of 1.00; 95% CI: 0.64 to 1.55), and recruitment was terminated early. The all-cause mortality rate was slightly higher in the apixaban group (1.8% vs. 1.2%), but the difference was not significant (HR 1.53; 95% CI: 0.63 to 3.74). The Apixaban Versus Aspirin for Embolic Stroke of Undetermined Source (ATTICUS) trial, which randomized 352 patients to receive either apixaban (178 patients) or aspirin (174 patients) within a median of 8 days after an embolic stroke of undetermined source, also demonstrated no reduction in recurrent ischemia with apixaban (39).

In contrast, Apixaban for Stroke Prevention in Subclinical Atrial Fibrillation (ARTESIA) trial, showed that individuals with short-duration (6 minutes to less than 24 hours) asymptomatic subclinical atrial fibrillation detected by an implanted pacemaker, defibrillator, or cardiac monitor and with a CHA2DS2-VASc score of 3 or higher who were treated with apixaban had a lower risk of stroke or systemic embolism (HR, 0.63; 95% confidence interval [CI], 0.45 to 0.88; P=0.007) compared to participants treated with aspirin only. However, the risk of major bleeding over a mean follow-up period of 3.5±1.8 years was higher in the apixaban groups compared to the aspirin group (HR, 1.80; 95% CI, 1.26 to 2.57; P=0.001) (50).

Collectively, current evidence does not support routine embolic stroke of undetermined source, including in individuals with atrial cardiopathy.

Antiplatelet agents. Multiple studies have shown the superiority of anticoagulation compared to antiplatelets alone for managing atrial fibrillation-related complications; therefore, using antiplatelets alone is not recommended for atrial fibrillation management (61). Combined antiplatelet-anticoagulant therapy may only be indicated for patients with atrial fibrillation who also have acute coronary syndromes or those who undergo percutaneous coronary intervention with or without stenting.

Initiation of anticoagulation after acute stroke. The timing of anticoagulation after acute ischemic stroke in atrial fibrillation remains individualized and requires balancing the risk of recurrent cardioembolism against hemorrhagic transformation. In general, the American Heart Association/American Stroke Association guidelines recommend anticoagulation within 4 to 14 days after a stroke (61). However, different factors can influence this decision, including the size of the stroke or the presence of hemorrhagic conversion. Earlier initiation is favored in patients at high risk of recurrent embolism (eg, valvular heart disease, intracardiac thrombus, or congestive heart failure), whereas delaying anticoagulation is appropriate in large infarcts, uncontrolled hypertension, or hemorrhagic conversion.

European guidance proposes a severity-based “1-3-6-12 day” rule according to the neurologic deficit, and emerging data suggest that early direct oral anticoagulant initiation is safe in patients with mild to moderate strokes (34).

Failure of anticoagulation therapy. In patients who experience recurrent ischemic strokes despite appropriate direct oral anticoagulant therapy, switching to a different direct oral anticoagulant or to warfarin has not consistently demonstrated improved outcomes and may increase bleeding risk. A study showed that in patients experiencing breakthrough ischemic stroke while on dual oral anticoagulants, switching to warfarin was associated with significantly worse outcomes compared to dual oral anticoagulant-based strategies, including a 1.80-fold higher risk of recurrent ischemic stroke and 2.90-fold higher risk of intracranial hemorrhage, whereas continuing the same dual oral anticoagulant or switching to a different dual oral anticoagulant yielded similar outcomes for both efficacy and safety endpoints (86). Alternative strategies, particularly left atrial appendage occlusion, have shown benefit in selected patients with recurrent events despite anticoagulation. Left atrial appendage occlusion combined with continued oral anticoagulation has been shown to significantly reduce recurrent ischemic stroke risk by 67% compared to oral anticoagulation alone (HR: 0.33, 95% CI: 0.19–0.58), with annualized stroke rates of 2.8% versus 8.9%, respectively, and demonstrated a 79% relative risk reduction compared to predicted event rates based on CHA₂DS₂-VASc scores (71). In the LAAOS III trial, surgical left atrial appendage occlusion reduced stroke and systemic embolism by 33% compared to no occlusion (HR: 0.67, 95% CI: 0.53–0.85), with this benefit remaining consistent regardless of whether patients were receiving oral anticoagulation or not (22).

Rhythm- and rate-control. One of the largest trials of rate versus rhythm control in atrial fibrillation, the AFFIRM trial showed that achieving a normal sinus rhythm does not significantly reduce the risk of stroke (114). Most strokes occurred in patients who stopped anticoagulation, suggesting that the treatment of atrial dysrhythmia may not completely eliminate the thrombogenic substrate observed in atrial fibrillation. However, the RAFAS Trial, which investigated early rhythm control versus standard care in patients with newly documented atrial fibrillation during an acute ischemic stroke, showed that at 12 months follow-up, the rates of ischemic stroke recurrence were lower than the standard care group (HR: 0.251 [log‐rank P=0.034]), with similar rates for adverse outcomes (81). Other clinical trials have also shown the benefit of rhythm control in patients with heart failure (87). Current guidelines do not account for attributing ischemic stroke to atrial cardiomyopathy rather than atrial fibrillation. There is, however, significant ongoing research for various types of therapies to treat atrial cardiomyopathy.

Nonpharmacological treatments. Nonpharmacological treatments for stroke prevention in atrial fibrillation include catheter ablation therapies, pulsed-field ablation, or percutaneous closure of the left atrium appendage. In the CABANA catheter, ablation significantly reduced atrial fibrillation recurrence compared to medical therapy (HR: 0.52, 95% CI: 0.45–0.60; P< 0.001) but did not significantly reduce the primary composite endpoint of death, disabling stroke, serious bleeding, or cardiac arrest (HR: 0.86, 95% CI: 0.65–1.15; P = .30), indicating that rhythm control alone does not eliminate thromboembolic risk (79).

Percutaneous left atrial appendage occlusion has also been evaluated as an alternative to anticoagulation. In the PROTECT atrial fibrillation trial (WATCHMAN), which randomized patients with atrial fibrillation and a CHADS2 score of 1 or greater to percutaneous closure of the left atrium appendage versus warfarin, percutaneous closure of the left atrium appendage was noninferior to warfarin for prevention of stroke and systemic embolism (53). In the extended period of 4 years, the device was associated with a significant reduction in the composite outcome of stroke, systemic embolism, and cardiovascular/unexplained death, compared with warfarin (8.4% vs. 13.9%) (89). However, this benefit was largely driven by a reduction in the rate of hemorrhagic stroke, with no effect on the occurrence of ischemic stroke. Additionally, the PREVAIL trial showed that left atrial appendage occlusion was non-inferior to warfarin for ischemic stroke prevention or side effects more than 7 days post-procedure (rate ratio: 1.07; 95% CI: 0.57 to 1.89).

The PRAGUE-17 trial further demonstrated noninferiority of percutaneous closure of the left atrium appendage compared with direct oral anticoagulants in high-risk patients with nonvalvular atrial fibrillation. At a median follow-up time of 19.9 months, the annual rates of the primary outcome (defined as a composite outcome of stroke, transient ischemic attack, systemic embolism, cardiovascular death, major or nonmajor clinically relevant bleeding, or procedure- or device-related complications) were similar between groups (10.99% with left atrial appendage closure and 13.42% with direct oral anticoagulants for a subdistribution hazard ratio of 0.84, 95% CI: 0.53 to 1.31; P=0.44; P=0.004 for noninferiority) (78).

Current guidelines recommend considering the use of left atrial appendage closure in patients with contraindication to long-term oral anticoagulation due to nonreversible causes and in patients with moderate to high risk of stroke and a high risk of significant bleeding on oral anti-coagulation (56).

Surgical left atrial appendage occlusion performed during cardiac surgery also reduces thromboembolic events. The LAAOS III trial enrolled 4770 patients with a CHA2DS2-VASc score of 2 or higher who underwent cardiac surgery (coronary artery bypass graft surgery or valve surgeries) and were continued in oral anticoagulation postoperatively (110). The trial showed that surgical left atrial appendage occlusion provided additional benefit to oral anticoagulation without increasing the risk of adverse events (HR: 0.67, 95% CI:0.53–0.85; P=0.001).

Overall, left atrial appendage occlusion, percutaneous or surgical, provides an alternative or adjunct to anticoagulation in carefully selected patients, whereas catheter ablation primarily improves rhythm control without replacing stroke prevention therapy.

Health inequalities and barriers to atrial fibrillation management. Women and individuals from underrepresented racial and ethnic groups, although often having worse quality of life and increased symptoms, are less likely to receive guideline-concordant therapy (11; 99). Lower socioeconomic status, lack of supplemental insurance coverage, and known sex and racial or ethnic inequities led to delays in diagnosing and managing atrial fibrillation (31). The “2023 ACC/AHA/ACCP/HRS Guideline for the Diagnosis and Management of Atrial Fibrillation” emphasizes the need to address these health inequalities and provide standardized care to all individuals (56).

Outcomes

The selection of antithrombotic agents in atrial fibrillation depends on the predicted risk of thromboembolism and hemorrhagic complications. When anticoagulation is warranted, direct oral anticoagulants are usually preferred over warfarin, given the same proven efficacy as vitamin K antagonists and a lower risk for bleeding. Several scales exist to quantify bleeding risk: (1) HEMORR2HAGES, (2) ATRIA, and (3) HAS-BLED. The 2012 AMADEUS trial compared the predictive abilities of these scales for clinically relevant intracranial bleeding, and HAS-BLED demonstrated superiority over the other scales (05). Both HEMORR2HAGES and HAS-BLED scores are being used in clinical practice.

The HEMORR2HAGES score is calculated by adding 1 point for each of the following factors: hepatic or renal disease, ethanol abuse, malignancy, old age (older than 75 years), reduced platelet counts or platelet dysfunction, uncontrolled hypertension, anemia, genetic factors, elevated fall risk, or stroke; 2 points were added for rebleeding (38). HAS-BLED score has fewer components and adds 1 point for each of these factors: hypertension, abnormal renal and liver function (1 or 2 points), stroke, bleeding, labile INRs, elderly, and drugs or alcohol (1 or 2 points) (83).

Table 3a. Incidence of Major Bleeding Stratified by the HEMORR2HAGES Score

HEMORR2HAGES score	Number of patients	Number of bleeding	Bleeding per 100 patient-years warfarin (95% CI)
0	209	4	1.9 (0.6-4.4)
1	508	11	2.5 (1.3-4.3)
2	454	20	5.3 (3.4-8.1)
3	240	15	8.4 (4.9-13.6)
4	106	9	10.4 (5.1-18.9)
5 or greater	87	8	12.3 (5.8-23.1)
Any score	1604	67	4.9 (3.9-6.3)
Data from the National Registry of Atrial Fibrillation (38).

Table 3b. Incidence of Major Bleeding Stratified by HAS-BLED Score

HAS-BLED score	Number of patients	Number of bleeding	Bleeding per 100 patient-years (%)
0	798	9	1.13
1	1286	13	1.02
2	744	14	1.88
3	187	7	3.74
4	46	4	8.70
5	8	1	12.50
6	2	0	0.0
7	0	-	-
8	0	-	-
9	0	-	-
Any score	3 071	48	1.56
From (83).

The annual rate of major hemorrhage is estimated at 1% for aspirin and 3% to 4% for warfarin (04). Direct oral anticoagulants have a 30% to 50% reduced risk of major bleeding, including intracranial hemorrhage, compared to warfarin. However, in patients with prior intracranial hemorrhage, direct oral anticoagulants may not be safe. The 2025 PRESTIGE-AF trial reported intracerebral hemorrhage rates of 5.00 (95% CI: 2.68–8.39) per 100 patient years in the factor Xa inhibitor group versus 0.82 (0.14–2.53) per 100 patient years in the no anticoagulant group (104). Although direct oral anticoagulants lowered ischemic stroke risk compared to no anticoagulation, the benefit was offset by increased recurrent intracerebral hemorrhage and major bleeding events. A 2025 meta-analysis confirmed reduced ischemic stroke risk (RR: 0.23, 95% CI: 0.06–0.91) but increased recurrent intracerebral hemorrhage risk (RR: 3.60, 95% CI: 1.40-9.30), with no significant difference in all-cause mortality or net clinical benefit (24).

Combination antithrombotic therapy further increases bleeding risk: dual therapy (warfarin plus clopidogrel) and triple therapy (warfarin, aspirin, and clopidogrel) increases major bleeding 1.7- to 3.7-fold compared to warfarin, respectively (46), and adding aspirin to direct oral anticoagulants has an additive bleeding risk (98). Such combinations are generally reserved for patients with coronary artery disease or stenting.

Emergency reversal is possible: the effect of warfarin can be reverted using intravenous vitamin K and prothrombin complex concentrate (37). In the case of dabigatran, the monoclonal antibody fragment idarucizumab reverses the anticoagulant effect completely and durably within minutes of administration (85), whereas a single bolus of andexanet alfa can be used for reversal of apixaban and rivaroxaban (19).

Special considerations

Perioperative management of antithrombotics in atrial fibrillation. The question of holding anticoagulation perioperatively and using other protective agents (eg, low molecular weight heparin) is still a matter of debate. Existing data suggest that the risk of stroke increases significantly in the first 2 weeks after stopping the anticoagulant (15). The BRIDGE trial concluded that holding warfarin for elective procedures without any bridging was non-inferior to using low molecular weight heparin for arterial thromboembolism prevention (28). The risk of bleeding was reduced in patients without bridging compared with patients who were bridged (RR 0.41; 95% CI, 0.20 to 0.78). Findings are similar when direct oral anticoagulants are used: a subgroup analysis of the RE-LY trial looked at patients who interrupted dabigatran before surgery and used bridging anticoagulation versus no bridging and found no significant differences in the rates of thromboembolism or systemic emboli among groups (29). Bridging anticoagulation is not recommended for unselected cases but is advised for patients at high risk for thromboembolism (eg, mechanical heart valve, atrial fibrillation, venous thromboembolism) (30).

Secondary atrial fibrillation. Secondary atrial fibrillation refers to the cases of atrial fibrillation that occur during active medical conditions or surgical procedures. Typical scenarios include infections, pulmonary embolism, hyperthyroidism, or cardiac surgery. A substantial number of patients with secondary atrial fibrillation will spontaneously convert to sinus rhythm on correction of the underlying process. This has led to the notion that secondary atrial fibrillation is a self-limited condition that carries a more benign prognosis than primary atrial fibrillation. However, there is growing evidence that challenges this concept. New-onset atrial fibrillation during sepsis and perioperative atrial fibrillation has been associated with an increased risk of stroke (107; 40). It is plausible that patients with secondary atrial fibrillation constitute a selected group of individuals with genetic or atrial factors that predispose them to develop atrial fibrillation. Guidelines do not give specific recommendations in terms of anticoagulation for patients with secondary atrial fibrillation (56). However, it is reasonable to consider active surveillance for recurrent atrial fibrillation and tailor the use of anticoagulation based on individual risk of thromboembolism.

COVID-19 and atrial fibrillation. Arrhythmias have been reported in cases of COVID-19 infection, with COVID-19-positive patients having slightly higher odds of developing atrial fibrillation compared to matched COVID-19-negative patients (OR: 1.19; 95% CI: 1.00 to 1.41; p=0.0495) (112). In a large cohort of patients across the United States, the incidence of new-onset atrial fibrillation during COVID-19 hospitalization was 5.4%, and these patients had higher rates of death (45.2% vs. 11.9%) and major cardiovascular events (23.8% vs. 6.5%) compared to patients without new-onset atrial fibrillation. However, the adjusted rates of death were similar between groups (HR: 1.10; 95% CI: 0.99 to 1.23), whereas rates for major cardiovascular events, including stroke, remained elevated in the atrial fibrillation group (HR: 1.31; 95% CI: 1.14 to 1.50) (93). The association between atrial fibrillation, COVID-19 disease, and stroke risk is complex and needs further investigation.

Management of atrial fibrillation in renal patients. Approximately 15% to 20% of the patients with chronic kidney disease have atrial fibrillation. The dose adjustments recommended for patients with chronic kidney disease are shown in Table 4. A large retrospective study looking into the use of apixaban versus aspirin in dialysis patients found that patients with atrial fibrillation on dialysis who took apixaban had a 28% lower rate of bleeding events compared to patients taking warfarin (HR: 0.72; 95% CI: 0.59 to 0.87; P< 0.001), with similar risks of stroke/systemic embolism (HR: 0.88; 95% CI: 0.69 to 1.12; P=0.29) (96). Therefore, apixaban is now considered an alternative to warfarin in patients with atrial fibrillation on dialysis.

Table 4. Dose Adjustment of Direct Oral Anticoagulants in Patients with Chronic Kidney Disease

	RE-LY	ROCKET-AF	ARISTOTEL	ENGAGE AF-TIMI
Drug	Dabigatran	Rivaroxaban	Apixaban	Edoxaban
Renal clearance	80%	35%	25%	50%
Exclusion criteria for chronic kidney disease	CrCl<30 mL/min	CrCl<30 mL/min	Serum creatinine>2.5 mg/dL or CrCl<25 mL/min	CrCl<30 mL/min
Renal function
Normal or mild impairment (CrCl 51-80 mL/min)	150 mg twice daily	20 mg once daily	5 mg once daily	60 mg (or 30 mg) once daily
Moderate impairment
(CrCl 30-50 mL/min)	150 mg twice daily	15 mg once daily	5 mg once daily*	30 mg (or 15 mg) once daily
Severe impairment
(CrCl 15-29 mL/min)	75 mg twice daily**	15 mg once daily	Not recommended	30 mg (or 15 mg) once daily
End-stage chronic kidney disease (with or without dialysis)	Not recommended	Not recommended	Not recommended***	Not recommended
CrCl: creatinine clearance * Use 2.5 mg twice daily if two of the following: serum creatinine 1.5 or higher, age 80 years or older, or weight 60 kg or less. Dose determined based on modeling studies; however, this dose was not properly investigated in randomized trials. * In patients with end-stage chronic kidney disease on stable hemodialysis, prescribing information suggests using apixaban 5 mg twice daily with dose reduction to 2.5 mg twice daily if the patient is 80 years of age or older or weight is 60 kg or less. From (21; 44; 82; 41).

Although the ARISTOTEL trial excluded patients with creatinine clearance lower than 25 mL/min, further studies investigating this population led to FDA-approved labeling of apixaban to include patients with end-stage renal failure and hemodialysis (108).

Pregnancy

In general, atrial fibrillation is uncommon during pregnancy (66). In cases where anticoagulation is indicated, low molecular weight heparin should be used throughout pregnancy. Warfarin therapy in the first trimester of pregnancy is associated with fetal anomalies and is, therefore, not recommended. Similarly, limited evidence exists on the use of direct oral anticoagulants in pregnancy. Studies have shown that rivaroxaban was associated with an increased risk of miscarriages and a 4% rate of anomalies and is, therefore, not recommended (64).

References

01: ACTIVE Writing Group of the ACTIVE Investigators, Connolly S, Pogue J, et al. Clopidogrel plus aspirin versus oral anticoagulation for atrial fibrillation in the Atrial fibrillation Clopidogrel Trial with Irbesartan for prevention of Vascular Events (ACTIVE W): a randomised controlled trial. Lancet 2006;367:1903-12. PMID 16765759
02: Adams HP, Bendixen BH, Kappelle LJ, et al. Classification of subtype of acute ischemic stroke. Definitions for use in a multicenter clinical trial. TOAST. Trial of Org 10172 in Acute Stroke Treatment. Stroke 1993;24(1):35-41. PMID 7678184
03: Anonymous. Transesophageal echocardiographic correlates of thromboembolism in high-risk patients with nonvalvular atrial fibrillation. The Stroke Prevention in Atrial Fibrillation Investigators Committee on Echocardiography. Ann Intern Med 1998;128(8):639-47. PMID 9537937
04: Anonymous. Warfarin versus aspirin for prevention of thromboembolism in atrial fibrillation: Stroke Prevention in Atrial Fibrillation II Study. Lancet 1994;343(8899):687-91. PMID 7907677
05: Apostolakis S, Lane DA, Guo Y, Buller H, Lip GY. Performance of the HEMORR(2)HAGES, ATRIA, and HAS-BLED bleeding risk-prediction scores in patients with atrial fibrillation undergoing anticoagulation: the AMADEUS (evaluating the use of SR34006 compared to warfarin or acenocoumarol in patients with atrial fibrillation) study. J Am Coll Cardiol 2012;60(9):861-7. PMID 22858389
06: Becattini C, Dentali F, Camporese G, et al. Carotid atherosclerosis and risk for ischemic stroke in patients with atrial fibrillation on oral anticoagulant treatment. Atherosclerosis 2018;271:177-81. PMID 29524860
07: Bekwelem W, Jensen PN, Norby FL, et al. Carotid atherosclerosis and stroke in atrial fibrillation: the atherosclerosis risk in communities study. Stroke 2016;47(6):1643-6. PMID 27217511
08: Benjamin EJ, Blaha MJ, Chiuve SE, et al. Heart Disease and Stroke Statistics-2017 Update: A Report From the American Heart Association. Circulation 2017;135(10):e146-e603. PMID 28122885
09: Bernstein RA, Kamel H, Granger CB, et al. Atrial fibrillation in patients with stroke attributed to large- or small-vessel disease: 3-year results from the STROKE AF Randomized Clinical Trial. JAMA Neurology 2023:e233931.** PMID 37902733
10: Bernstein RA, Kamel H, Granger CB, et al. Stroke of Known Cause and Underlying Atrial Fibrillation (STROKE-AF) randomized trial. JAMA 2021;325(21):2169-77 PMID 34061145
11: Bhave PD, Lu X, Girotra S, Kamel H, Vaughan Sarrazin MS. Race- and sex-related differences in care for patients newly diagnosed with atrial fibrillation. Heart Rhythm 2015;12(7):1406-12. PMID 25814418
12: Blackshear JL, Pearce LA, Hart RG, et al. Aortic plaque in atrial fibrillation: prevalence, predictors, and thromboembolic implications. Stroke 1999;30(4):834-40. PMID 10187888
13: Brachmann J, Morillo CA, Sanna T, et al. Uncovering atrial fibrillation beyond short-term monitoring in cryptogenic stroke patients: three-year results from the cyptogenic stroke and underlying atrial fibrillation trial. Circ Arrhythm Electrophysiol 2016;9(1):e003333. PMID 26763225
14: Brambatti M, Connolly SJ, Gold MR, et al. Temporal relationship between subclinical atrial fibrillation and embolic events. Circulation 2014;129(21):2094-9. PMID 24633881
15: Broderick JP, Bonomo JB, Kissela BM, et al. Withdrawal of antithrombotic agents and its impact on ischemic stroke occurrence. Stroke 2011;42(9):2509-14. PMID 21719769
16: Chang SN, Wang CH, Waranugraha Y, et al. Left atrial dimension and CHA2DS2-VASc score in predicting stroke in patients with rheumatic atrial fibrillation. JACC Adv 202430;3(12):101343. PMID 39817065
17: Choi SH, Jurgens SJ, Xiao L, et al. Sequencing in over 50,000 cases identifies coding and structural variation underlying atrial fibrillation risk. Nat Genet 2025;57(3):548-62. PMID 40050430
18: Choi SH, Weng LC, Roselli C, et al. Association between titin loss-of-function variants and early-onset atrial fibrillation. JAMA 2018;320(22):2354-64. PMID 30535219
19: Connolly SJ, Crowther M, Eikelboom JW, et al. Andexanet alfa for acute major bleeding associated with factor Xa inhibitors. N Engl J Med 2019;380:1326-35. PMID 30730782
20: Connolly SJ, Eikelboom J, Joyner C, et al. Apixaban in patients with atrial fibrillation. N Engl J Med 2011;364(9):806-17. PMID 21309657
21: Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009;361(12):1139-51. PMID 19717844
22: Connolly SJ, Healey JS, Belley-Cote EP, et al. Oral anticoagulation use and left atrial appendage occlusion in LAAOS III. Circulation 2023;148(17):1298-304. PMID 37732457
23: Cushny AR, Edmunds CW. Paroxysmal irregularity of the heart and auricular fibrillation. Am J Med Sci 1907;133:66-77.
24: D'Anna L, Bax F, Abu-Rumeileh S, et al. Oral anticoagulation versus no anticoagulation for stroke prevention in patients with intracranial haemorrhage and atrial fibrillation: an updated meta-analysis of randomised controlled trials. J Neurol Neurosurg Psychiatry 2025;96(10):919-27. PMID 40695584
25: Dentali F, Douketis JD, Lim W, Crowther M. Combined aspirin-oral anticoagulant therapy compared with oral anticoagulant therapy alone among patients at risk for cardiovascular disease: a meta-analysis of randomized trials. Arch Intern Med 2007;167:117-24. PMID 17242311
26: Dentali F, Riva N, Crowther M, Turpie AG, Lip GY, Ageno W. Efficacy and safety of the novel oral anticoagulants in atrial fibrillation: a systematic review and meta-analysis of the literature. Circulation 2012;126(20):2381-91.** PMID 23071159
27: Diener HC, Easton JD, Granger CB, et al. Design of randomized, double-blind, evaluation in secondary stroke prevention comparing the efficacy and safety of the oral thrombin inhibitor dabigatran etexilate vs. acetylsalicylic acid in patients with embolic stroke of undetermined source (RE-SPECT ESUS). Int J Stroke 2015;10(8):1309-12. PMID 26420134
28: Douketis JD, Healey JS, Brueckmann M, et al. Perioperative bridging anticoagulation during dabigatran or warfarin interruption among patients who had an elective surgery or procedure. Substudy of the RE-LY trial. Thromb Haemost 2015a;113:625-32. PMID 25472710
29: Douketis JD, Spyropoulos AC, Kaatz S, et al. Perioperative Bridging Anticoagulation in Patients with Atrial Fibrillation. N Engl J Med 2015b;373(9):823-33. PMID 26095867
30: Douketis JD, Spyropoulos AC, Spencer FA, et al. Perioperative management of antithrombotic therapy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012;141(2 Suppl):e326S-50S.** PMID 22315266
31: Eberly LA, Garg L, Yang L, et al. Racial/ethnic and socioeconomic disparities in management of incident paroxysmal atrial fibrillation. JAMA Netw Open 2021;4(2):e210247. PMID 33635328
32: Eikelboom JW, Connolly SJ, Brueckmann M, et al. Dabigatran versus warfarin in patients with mechanical heart valves. N Engl J Med 2013;369(13):1206-14. PMID 23991661
33: Essien UR, McCabe ME, Kershaw KN, et al. Association between neighborhood-level poverty and incident atrial fibrillation: a retrospective cohort study. J Gen Intern Med 2022;37(6):1436-43. PMID 34240286
34: Fischer U, Koga M, Strbian D, et al. Early versus later anticoagulation for stroke with atrial fibrillation. N Engl J Med 2023;388(26):2411-21. PMID 37222476
35: Freedman B, Boriani G, Glotzer TV, Healy JS, Kirchhof P, Potpara TS. Management of atrial high-rate episodes detected by cardiac implanted electronic devices. Nat Rev Cardiol 2017;14(12):701-14. PMID 28682320
36: Freedman B, Potpara TS, Lip GY. Stroke prevention in atrial fibrillation. Lancet 2016;388(10046):806-17. PMID 27560276
37: Frontera JA, Lewin JJ 3rd, Rabinstein AA, et al. Guideline for Reversal of Antithrombotics in Intracranial Hemorrhage: A Statement for Healthcare Professionals from the Neurocritical Care Society and Society of Critical Care Medicine. Neurocrit Care 2016;24(1):6-46.** PMID 26714677
38: Gage BF, Yan Y, Milligan PE, et al. Clinical classification schemes for predicting hemorrhage: results from the National Registry of Atrial Fibrillation (NRAF). Am Heart J 2006;151:713-9. PMID 16504638
39: Geisler T, Keller T, Martus P, et al. Apixaban versus aspirin for embolic stroke of undetermined source. NEJM Evid 2024;3(1):EVIDoa2300235. PMID 38320511
40: Gialdini G, Nearing K, Bhave PD, et al. Perioperative atrial fibrillation and the long-term risk of ischemic stroke. JAMA 2014;312(6):616-22. PMID 25117130
41: Giugliano RP, Ruff CT, Braunwald E, et al. Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2013;369(22):2093-104. PMID 24251359
42: Go AS, Reynolds K, Yang J, et al. Association of burden of atrial fibrillation with risk of ischemic stroke in adults with paroxysmal atrial fibrillation: The KP-RHYTHM Study. JAMA Cardiol 2018;3(7):601-8. PMID 29799942
43: Goette A, Kalman JM, Aguinaga L, et al. EHRA/HRS/APHRS/SOLAECE expert consensus on Atrial cardiomyopathies: definition, characterisation, and clinical implication. J Arrhythm 2016;32(4):247-78. PMID 27588148
44: Granger C, Alexander J, McMurrau J, et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2011;365(11):981-92. PMID 21870978
45: Hald EM, Lochen ML, Mathiesen EB, et al. Atrial fibrillation, venous thromboembolism, ischemic stroke, and all‐cause mortality: the Tromsø study. Res Pract Thromb 2020;4(6):1004-12. PMID 32864551
46: Hansen ML, Sørensen R, Clausen MT, et al. Risk of bleeding with single, dual, or triple therapy with warfarin, aspirin, and clopidogrel in patients with atrial fibrillation. Arch Intern Med 2010;170(16):1433-41. PMID 20837828
47: Hart RG, Catanese L, Perera KS, Ntaios G, Connolly SJ. Embolic stroke of undetermined source: a systematic review and clinical update. Stroke 2017;48(4):867-72. PMID 28265016
48: Hart RG, Diener HC, Coutts SB, et al. Embolic strokes of undetermined source: the case for a new clinical construct. Lancet Neurol 2014;13(4):429-38.** PMID 24646875
49: Hart RG, Sharma M, Mundl M, et al. Rivaroxaban for stroke prevention after embolic stroke of undetermined source (NAVIGATE-ESUS). N Engl J Med 2018;378(23):2191-201. PMID 29766772
50: Healey JS, Lopes RD, Granger CB, et al. Apixaban for stroke prevention in subclinical atrial fibrillation. N Engl J Med 2024;390(2):107-17. PMID 37952132
51: Heidbuchel H, Verhamme P, Alings M, et al. EHRA practical guide on the use of new oral anticoagulants in patients with non-valvular atrial fibrillation: executive summary. Eur Heart J 2013;34(27):2094-106. PMID 23625209
52: Hijazi Z, Wallentin L, Siegbahn A, et al. N-terminal pro-B-type natriuretic peptide for risk assessment in patients with atrial fibrillation: insights from the ARISTOTLE Trial (Apixaban for the Prevention of Stroke in Subjects With Atrial Fibrillation). J Am Coll Cardiol 2013;61(22):2274-84. PMID 23563134
53: Holmes DR, Reddy VY, Turi ZG, et al. Percutaneous closure of the left atrial appendage versus warfarin therapy for prevention of stroke in patients with atrial fibrillation: a randomised non-inferiority trial. Lancet 2009;374(9689):534-42. PMID 19683639
54: Huxley RR, Lopez FL, Folsom AR, et al. Absolute and attributable risks of atrial fibrillation in relation to optimal and borderline risk factors: the Atherosclerosis Risk in Communities (ARIC) study. Circulation 2011;123(14):1501-8. PMID 21444879
55: Jones AT, O'Connell NK, David AS. Epidemiology of functional stroke mimic patients: a systematic review and meta-analysis. Eur J Neurol 2020;27(1):18-26. PMID 31448489
56: Joglar JA, Chung MK, Armbruster AL, et al. 2023 ACC/AHA/ACCP/HRS Guideline for the Diagnosis and Management of Atrial Fibrillation: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation 2024;149(1):e1-156. PMID 38033089
57: Kamel H, Okin PM, Longstreth WT Jr, Elkind MS, Soliman EZ. Atrial cardiopathy: a broadened concept of left atrial thromboembolism beyond atrial fibrillation. Future Cardiol 2015;11(3):323-31. PMID 26021638
58: Kamel H, Longstreth WT, Tirschwell DL, et al. Apixaban to Prevent Recurrence After Cryptogenic Stroke in Patients With Atrial Cardiopathy: The ARCADIA Randomized Clinical Trial. JAMA 2024;331(7):573-81. PMID 38324415
59: Kany S, Jurgens SJ, Rämö JT, et al. Genetic testing in early-onset atrial fibrillation. Eur Heart J 2024;45(34):3111-23. PMID 39028637
60: Karakasis P, Theofilis P, Vlachakis PK, et al. Atrial fibrosis in atrial fibrillation: mechanistic insights, diagnostic challenges, and emerging therapeutic targets. Int J Mol Sci 2024;26(1):209. PMID 39796066
61: Kleindorfer DO, Towfighi A, Chaturvedi S, et al. 2021 Guideline for the Prevention of Stroke in Patients with Stroke and Transient Ischemic Attack: a guideline from the American Heart Association/American Stroke Association. Stroke 2021;52(7):e364-467.** PMID 34024117
62: Kobeissi H, Ghozy S, Seymour T, et al. Outcomes of patients with atrial fibrillation following thrombectomy for stroke: a systematic review and meta-analysis. JAMA Network Open 2023;6(1):e2249993. PMID 36607633
63: Lakkireddy DR, Garg J, Ahmed A, et al. LB-456091-2 Dynamic data driven management of atrial fibrillation using implantable cardiac monitors – the MONITOR AF study. Heart Rhythm 2023;20(7):1085-6.
64: Lameijer H, Aalberts JJJ, van Veldhuisen DJ, Meijer K, Pieper PG. Efficacy and safety of direct oral anticoagulants during pregnancy; a systematic literature review. Thromb Res 2018;169:123-7. PMID 30036784
65: LaRosa AR, Claxton J, O’Neal WT, et al. Association of household income and adverse outcomes in patients with atrial fibrillation. Heart 2020;106(21):1679-85. PMID 32144188
66: Lee MS, Chen W, Zhang Z, et al. Atrial fibrillation and atrial flutter in pregnant women--a population-based study. J Am Heart Assoc 2016;5(4):e003182. PMID 27076563
67: Li L, Yiin GS, Geraghty OC, et al. Incidence, outcome, risk factors, and long-term prognosis of cryptogenic transient ischaemic attack and ischaemic stroke: a population-based study. Lancet Neurol 2015;14(9):903-13. PMID 26227434
68: Link MS, Giugliano RP, Ruff CT, et al. Stroke and Mortality Risk in Patients With Various Patterns of Atrial Fibrillation Results From the ENGAGE AF-TIMI 48 Trial (Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation–Thrombolysis in Myocardial Infarction 48). Circ Arrhythm Electrophysiol 2017;10(1):pii:e004267. PMID 28077507
69: Lip GY, Banerjee A, Boriani G, et al. Antithrombotic therapy for atrial fibrillation: CHEST guideline and expert panel report. Chest 2018;154(5):1121-1201. PMID 30144419
70: Longstreth WT Jr, Kronmal RA, Thompson JL, et al. Amino terminal pro-B-type natriuretic peptide, secondary stroke prevention, and choice of antithrombotic therapy. Stroke 2013;44(3):714-9. PMID 23339958
71: Maarse M, Seiffge DJ, Werring DJ, et al. Left atrial appendage occlusion vs standard of care after ischemic stroke despite anticoagulation. JAMA Neurol 2024;81(11):1150-8. PMID 39374446
72: Martignani C, Spadotto A, Carelli M, et al. Atrial cardiomyopathy: a "distinct clinical entity" for a deeper understanding of atrial fibrillation and cardioembolic stroke. J Clin Med 2025;14(23):8363. PMID 41375667
73: Mar PL, Gopinathannair R, Gengler BE, et al. Drug interactions affecting oral anticoagulant use. Circ Arrhythm Electrophysiol 2022;15(6):e007956. PMID 35622425
74: McMichael J. History of atrial fibrillation 1628–1819 Harvey-de Senac-Laënnec. Br Heart J 1982;48:193-7. PMID 7049202
75: Mou L, Norby FL, Chen LY, et al. Lifetime risk of atrial fibrillation by race and socioeconomic status: ARIC Study (Atherosclerosis Risk in Communities). Circ Arrhythm Electrophysiol 2018;11(7):e006350. PMID 30002066
76: Nothnagel H. Ueber arythmische Herzthätigkeit. Dtsch Arch Klin Med 1876;17:190-220.
77: Olesen MS, Nielsen MW, Haunsø S, Svendsen JH. Atrial fibrillation: the role of common and rare genetic variants. Eur J Hum Genet 2013;22(3):297-306. PMID 23838598
78: Osmancik P, Herman D, Neuzil P, et al. Left atrial appendage closure versus direct oral anticoagulants in high-risk patients with atrial fibrillation. J Am Coll Cardiol 2020;75(25):3122-35. PMID 32586585
79: Packer DL, Mark DB, Robb RA, et al. Effect of catheter ablation vs antiarrhythmic drug therapy on mortality, stroke, bleeding, and cardiac arrest among patients with atrial fibrillation: The CABANA Randomized Clinical Trial. JAMA 2019;321(13):1261-74. PMID 30874766
80: Paludan-Muller C, Svendsen JH, Olesen MS. The role of common genetic variants in atrial fibrillation. J Electrocardiol 2016;49(6):864-70. PMID 27624063
81: Park J, Shim J, Lee JM, et al. Risks and benefits of early rhythm control in patients with acute strokes and atrial fibrillation: a multicenter, prospective, randomized study (the RAFAS trial). J Am Heart Assoc 2022;11(3):e023391. PMID 35043663
82: Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011;365(10):883-91. PMID 21830957
83: Pisters R, Lane DA, Nieuwlaat R, de Vos CB, Crijns HJ, Lip GY. 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):1093-100. PMID 20299623
84: Pohl M, Hesszenberger D, Kapus K, et al. Ischemic stroke mimics: a comprehensive review. J Clin Neurosci 2021;93:174-82. PMID 34656244
85: Pollack CV Jr, Reilly PA, van Ryn J, et al. Idarucizumab for Dabigatran Reversal - Full Cohort Analysis. N Engl J Med 2017;377(5):431-41. PMID 28693366
86: Romoli M, Paciaroni M, Marrone N, et al. Anticoagulation strategies following breakthrough ischemic stroke while on direct anticoagulants: a meta-analysis. Neurology 2025;105(4):e213964. PMID 40758940
87: Prystowsky EN. Rate versus rhythm control for atrial fibrillation: has the debate been settled? Circulation 2022;146(21):1561-3. PMID 36409779
88: Quinn GR, Severdija ON, Chang Y, Singer DE. Wide variation in reported rates of stroke across cohorts of patients with atrial fibrillation. Circulation 2017;135(3):208-19. PMID 27799272
89: Reddy VY, Sievert H, Halperin J, et al. Percutaneous left atrial appendage closure vs. warfarin for atrial fibrillation: a randomized clinical trial. JAMA 2014;312(19):1988-98. PMID 25399274
90: Romero JR, Morris J, Pikula A. Stroke prevention: modifying risk factors. Ther Adv Cardiovasc Dis 2008;2(4):287-303. PMID 19124428
91: Roselli C, Rienstra M, Ellinor PT. Genetics of atrial fibrillation in 2020:GWAS, genome sequencing, polygenic risk, and beyond. Circ Res 2020;127(1):21-33. PMID 32716721
92: Roselli C, Surakka I, Olesen MS, et al. Meta-analysis of genome-wide associations and polygenic risk prediction for atrial fibrillation in more than 180,000 cases. Nat Genet 2025;57(3):539-547. PMID 40050429
93: Rosenblatt AG, Ayers CR, Rao A, et al. New-onset atrial fibrillation in patients hospitalized with COVID-19: results from the American Heart Association COVID-19 Cardiovascular Registry. Circ Arrhythm Electrophysiol 2022;15(5):e010666. PMID 35475654
94: Sanna T, Diener HC, Passman RS, et al. Cryptogenic stroke and underlying atrial fibrillation. N Engl J Med 2014;370(26):2478-86. PMID 24963567
95: Schnabel RB, Yin X, Gona P, et al. 50 year trends in atrial fibrillation prevalence, incidence, risk factors, and mortality in the Framingham Heart Study: a cohort study. Lancet 2015;386(9989):154-62. PMID 25960110
96: Siontis KC, Zhang X, Eckard A, et al. Outcomes associated with apixaban use in patients with end-stage kidney disease and atrial fibrillation in the United States. Circulation 2018;138(15):1519-29. PMID 29954737
97: Steffel J, Collins R, Antz M, et al. 2021 European Heart Rhythm Association practical guide on the use of non-vitamin K antagonist oral anticoagulants in patients with atrial fibrillation. Europace 2021:23(10):1612-76. PMID 33895845
98: Steinberg BA, Peterson ED, Kim S, et al. Use and outcomes associated with bridging during anticoagulation interruptions in patients with atrial fibrillation: findings from the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF). Circulation 2015;131(5):488-94. PMID 25499873
99: Thompson LE, Maddox TM, Lei L, et al. Sex differences in the use of oral anticoagulants for atrial fibrillation: a report from the National Cardiovascular Data Registry (NCDR®) PINNACLE Registry. J Am Heart Assoc 2017;6(7):e005801. PMID 28724655
100: Tsao CW, Aday AW, Almarzooq ZI, et al. Heart disease and stroke statistics—2023 update: a report from the American Heart Association. Circulation 2023;147(8):e93-621. PMID 36695182
101: Tsivgoulis G, Alexandrov AV, Chang J, et al. Safety and outcomes of intravenous thrombolysis in stroke mimics: a 6-year, single-care center study and a pooled analysis of reported series. Stroke 2011;42(6):1771-4. PMID 21493900
102: Vad OB, Monfort LM, Paludan-Müller C, et al. Rare and common genetic variation underlying atrial fibrillation risk. JAMA Cardiol 2024;9(8):732-40. PMID 38922602
103: van Doorn S, Debray TPA, Kaasenbrood F, et al. Predictive performance of the CHA2DS2-VASc rule in atrial fibrillation: a systematic review and meta-analysis. J Thromb Haemost 2017;15(6):1065-77. PMID 28375552
104: Veltkamp R, Korompoki E, Harvey KH, et al. Direct oral anticoagulants versus no anticoagulation for the prevention of stroke in survivors of intracerebral haemorrhage with atrial fibrillation (PRESTIGE-AF): a multicentre, open-label, randomised, phase 3 trial. Lancet 2025;405(10482):927-36. PMID 40023176
105: Verdecchia P, Angeli F, Reboldi G. Hypertension and atrial fibrillation. Circ Res 2018;122(2):352-68. PMID 29348255
106: Vulpian A. Note sur les effets de la faradisation directe des ventricules du coeur chez le chien. Arch Phys Norm Pathol 1874; 6:975.
107: Walkey AJ, Hammill BG, Curtis LH, Benjamin EJ. Long-term outcomes following development of new-onset atrial fibrillation during sepsis. Chest 2014;146(5):1187-95. PMID 24723004
108: Wang X, Tirucherai G, Marbury TC, et al. Pharmacokinetics, pharmacodynamics, and safety of apixaban in subjects with end-stage renal disease on hemodialysis. J Clin Pharmacol 2016;56(5):628-36. PMID 26331581
109: Watson T, Shantsila E, Lip G. Mechanisms of thrombogenesis in atrial fi brillation: Virchow’s triad revisited. Lancet 2009;373(9658):155-66. PMID 19135613
110: Whitlock RP, Belley-Cote EP, Paparella D, et al. Left atrial appendage occlusion during cardiac surgery to prevent stroke. N Engl J Med 2021;384(22):2081-91. PMID 33999547
111: Wolf PA, Dawber TR, Thomas HE Jr, Kannel WB. Epidemiologic assessment of chronic atrial fibrillation and risk of stroke: the Framingham study. Neurology 1978;28(10):973-7. PMID 570666
112: Wollborn J, Karamnov S, Fields KG, Yeh T, Muehischlegel JD. COVID-19 increases the risk for the onset of atrial fibrillation in hospitalized patients. Sci Rep 2022;12(1):12014. PMID 35835807
113: Wright IS, Foley WT. Use of anticoagulants in the treatment of heart disease with special reference to coronary thrombosis, rheumatic heart disease with thromboembolic complications and subacute bacterial endocarditis. Am J Med 1947; 3:718-39. PMID 20272357
114: Wyse DG, Waldo AL, DiMarco JP, et al. A comparison of rate control and rhythm control in patients with atrial fibrillation. N Engl J Med 2002;347(23):1825-33. PMID 12466506
115: Yaghi S, Boehme AK, Hazan R, et al. Atrial cardiopathy and cryptogenic stroke: a cross-sectional pilot study. J Stroke Cerebrovasc Dis 2016;25(1):110-4. PMID 26476588
116: Yaghi S, Sposato LA, Shu L, et al. Device-detected atrial fibrillation in patients with and without cryptogenic ischemia: the ANTARCTICA pooled analysis. Stroke 2025;56(10):2895-903. PMID 40765508
117: Yang S, De Kruijf N, Zhu F, van Oortmerssen JAE, de Groot NMS, Kavousi M. Trends in burden of atrial fibrillation over three decades: a population-based study. Heart 2025:heartjnl-2025-326510. PMID 41015500
118: Yao C, Veleva T, Scott L Jr, et al. Enhanced cardiomyocyte NLRP3 inflammasome signaling promotes atrial fibrillation. Circulation 2018;138(20):2227-42. PMID 29802206
119: Zabalgoitia M, Halperin JL, Pearce LA, Blackshear JL, Asinger RW, Hart RG. Transesophageal echocardiographic correlates of clinical risk of thromboembolism in nonvalvular atrial fibrillation. J Am Coll Cardiol 1998;31(7):1622-6. PMID 9626843
120: Zhao X, Li H, Liu C, Ren Y, Sun C. NT Pro-BNP can be used as a risk predictor of clinical atrial fibrillation with or without left atrial enlargement. Clin Cardiol 2022;45(1):68-74. PMID 34952980

Contributors

All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.

Authors

Shivansh Desai MD

Dr. Desai of the University of Illinois Chicago has no relevant financial relationships to disclose.
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Gabriela Trifan MD

Dr. Trifan of The University of the Illinois College of Medicine has no relevant financial relationship 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.
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Former Authors

Gregory W Albers MD
Helmi L Lutsep MD
Yvonne Schwammenthal MD
Ehud Schwammenthal MD
David Tanne MD
Salvador Cruz-Flores MD
Tagann Chaisam MD
Gabriela Trifan MD
Neelofer Shafi MD
Fernando Testai MD PhD

Patient Profile

Age range of presentation: 6 to 65+ years
Sex preponderance: female>male
Heredity: Heredity may be a factor
Population groups selectively affected: Caucacians

Elderly
Occupation groups selectively affected: none selectively affected

ICD & OMIM codes

ICD-10: Atrial fibrillation and flutter: I48

Cerebral infarction due to embolism of cerebral arteries: I63.4
ICD-11: Atrial fibrillation, unspecified: BC81.3Z

Cerebral ischaemic stroke due to cardiac embolism: 8B11.20

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Stroke associated with atrial fibrillation

Associated Disorders

Small vessel occlusive disease
Aortic arch atheroma
Carotid atherosclerosis

Differential Diagnosis

stroke associated with carotid artery stenosis
stroke associated with aortic arch plaque
stroke associated with small-vessel ischemic disease
aortic arch atheroma
procoagulability
- carotid atherosclerosis or plaque

Also Relevant

Aortic atherosclerosis and stroke
Cerebral embolism
Ischemic stroke
Pregnancy and stroke
Stroke associated with myocardial infarction

Stroke associated with atrial fibrillation

Cite this article

Introduction

Overview

Key points

Historical note and terminology

Clinical manifestations

Presentation and course

Prognosis and complications

Biological basis

Etiology and pathogenesis

Epidemiology

Prevention

Differential diagnosis

Confusing conditions

Associated or underlying disorders

Diagnostic workup

Management

Table 1. Validated Stroke Risk Models for Patients with Non-Valvular Atrial Fibrillation

Table 2. CHA2DS2-VASc Score Quantification of Stroke/TE Risk for Patients with Non-Valvular Atrial Fibrillation

Outcomes

Table 3a. Incidence of Major Bleeding Stratified by the HEMORR2HAGES Score

Table 3b. Incidence of Major Bleeding Stratified by HAS-BLED Score

Special considerations

Table 4. Dose Adjustment of Direct Oral Anticoagulants in Patients with Chronic Kidney Disease

Pregnancy

References

Contributors

Authors

Editor

Former Authors

Patient Profile

ICD & OMIM codes

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Questions or Comment?

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