Stroke associated with atrial fibrillation …

Gabriela Trifan MD

Stroke & Vascular Disorders

Updated 02.05.2025
Released 06.20.1996
Expires For CME 02.05.2028

Stroke associated with atrial fibrillation

Author: 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 (95). 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 confers a three- to five-fold increase in stroke risk and accounts for 15% to 30% of all ischemic strokes.
	• Prolonged cardiac monitoring is superior to short-term monitoring for detecting occult atrial fibrillation.
	• Patients with atrial fibrillation and an estimated annual thromboembolic risk of less than 1% per year (eg, CHA2DS2-VASc score of 0 in men and 1 in women) have a low stroke risk, and anticoagulation therapy may be omitted.
	• Patients with atrial fibrillation and an estimated annual thromboembolic risk between 1% and 2% per year (eg, CHA2DS2-VASc score of 1 in men and 2 in women) have an intermediate stroke risk, and treatment with oral anticoagulants should be initiated.
	• Patients with atrial fibrillation and an estimated annual thromboembolic risk of 2% or greater per year (eg, CHA2DS2-VASc score of 2 or higher in men and 3 or higher in women) are at high risk for stroke, and treatment with anticoagulants is recommended.
	• Direct thrombin or factor Xa inhibitors are non-inferior to warfarin in the prevention of stroke or systemic embolism, have a lower incidence of major hemorrhagic complications, and are the preferred choice of anticoagulation in patients with atrial fibrillation.
	• In addition to anticoagulation, when indicated, prescriptive focuses on healthy lifestyle and risk factor modifications, as well as early aggressive rhythm and rate control, are pillars for atrial fibrillation management.
	• Use of antiplatelets alone is not recommended for atrial fibrillation management. The addition of antiplatelets to anticoagulation in atrial fibrillation is only indicated in patients who have 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 (67); in 1874, Vulpian reported uncoordinated twitching of the atrium, "fremissement fibrillaire" after application of an electrical current (99). Nothnagel published three arterial pulse curves showing irregular heart rates in the mid-1800s and called the arrhythmia "delirium cordis" (69), 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 (21).

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 (106). 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 (104). 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 (33). 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 stroke, either due to atrial fibrillation or other causes, has similar clinical findings. Patients present with severe deficits and clinical evidence of cortical or cerebellar dysfunction, eg, sudden onset of language deficits, apraxia, unilateral weakness, sensory loss, dyscoordination, ataxia, or hemianopia (02). Other stroke subtypes, however, including large-vessel thromboembolism and lacunar infarction, can present similarly. 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 stroke 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 (62). 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 (57). 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 (43).

Biological basis

Genomic data in atrial fibrillation come from linkage analysis, genome-wide association studies using genotyping array data, and coding variations from genome sequence data (85). Both common and rare genetic variants have been implicated in the development of atrial fibrillation. Common variants have a minor allele frequency higher than 1% and modestly increase the risk of atrial fibrillation. Most of these mutations are located within intronic and intergenic regions where they can alter the function of promoters and enhancers of the nearby genes (70; 74). Single nucleotide polymorphism (SNP) associated with atrial fibrillation were identified in the PITX2, KCNN3, PRRX1, CAV1, C9orf3, SYNPO2L, SYNE2, HCN4, and ZFHX3 genes.

In comparison, rare genetic variants have a minor allele frequency of less than 1% but are highly predictive of atrial fibrillation. These mutations are associated with a gain or loss of function in genes encoding for cardiac gap junctions, signaling molecules, or sodium or potassium channels. An identified rare variant associated with loss of function of the TTN gene has been associated with earlier onset atrial fibrillation in patients younger than 30 years and leads to an earlier diagnosis (average of 5 years) than those without this mutation (17).

These genetic markers can identify individuals who have an increased risk of incidental atrial fibrillation and stroke even after adjustment for confounders (93). Data obtained in observational studies indicate that this genetic information can improve the accuracy of stroke risk stratification tools commonly used in clinical practice, such as CHA2DS2-VASc score (discussed below). However, gene sequencing data are not usually available for decision-making, and its predictive value has not been well validated in mixed cohorts.

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 usually coexists with different traditional vascular risk factors, such as advanced age, arterial hypertension, diabetes, and hypercholesterolemia. This “systemic substrate” can contribute to the development of both atrial fibrillation and thromboembolism. In addition, atrial fibrillation can be seen in association with decreased left ventricular function, atherosclerosis of the aortic arch, and occlusive disease of the extra- and intracranial arteries, which are additional sources of embolism.

The detrimental effect of the systemic substrate is complemented by an “atrial substrate” or “atrial cardiomyopathy,” which is represented by the elements of the Virchow triad of thrombogenesis: blood stasis, endothelial injury, and procoagulability. Blood stasis can be explained by the hemodynamic changes occuring in the fibrillating atrium. Endothelial injury in atrial fibrillation is represented by endocardial denudation and fibroelastic infiltration. In addition, observational studies have shown that enhanced inflammation, hemostatic dysfunction, and abnormal fibrinolysis, all characteristics of procoagulable states, are common in atrial fibrillation (102).

The systemic substrate contributes to the development of atrial fibrillation, which, once formed, worsens atrial contractility and furthers the progression of atrial cardiomyopathy by inducing structural remodeling. Thus, it is considered that the systemic substrate and the atrial substrate commonly coexist in patients with atrial fibrillation and interact with each other, both directly and indirectly, leading to the formation of microemboli and stroke (102).

Atrial fibrillation and cryptogenic stroke. Cryptogenic stroke refers to an embolic stroke of unknown origin. Large observational studies have shown that at least 40% of cryptogenic strokes are caused by atrial fibrillation (13). The formulation of this category, though practical from a taxonomic and investigational standpoint, is hindered by its variable and rather broad definition. As an example, 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).

Embolic stroke of undetermined source, a concept first introduced in 2014, is a subset of cryptogenic stroke and refers to a non-lacunar ischemic stroke that takes place in the absence of other well-defined stroke mechanisms, such as atrial fibrillation, atherosclerosis causing 50% or greater luminal stenosis in arteries supplying the area of ischemia, intracardiac thrombus, arterial dissection, or angiitis (46). From a pragmatic standpoint, the minimal workup necessary for diagnosing embolic stroke of an undetermined source includes a transthoracic echocardiogram, 24 hours of continuous heart rhythm monitoring, and vascular imaging of both the extracranial and intracranial cerebral arteries. Both cryptogenic stroke and embolic stroke of undetermined source have radiological evidence suggestive of an embolic mechanism. However, embolic stroke of undetermined source constitutes a subgroup of patients with cryptogenic stroke that have had sufficient workup to exclude common stroke etiologies.

Cryptogenic stroke is responsible for 30% of strokes, whereas embolic stroke of undetermined source is responsible for 15% of them. Paroxysmal atrial fibrillation is typically suspected in cryptogenic stroke or embolic stroke of undetermined source; however, observational studies demonstrate that these stroke subtypes have distinct characteristics. Patients with embolic stroke of undetermined source are usually younger, have milder stroke severity, and have smaller emboli than patients with atrial fibrillation (45). 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 at 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 (62).

The rate of detection of atrial fibrillation in patients with cryptogenic stroke increases with the length of cardiac monitoring. In the EMBRACE study, the incidence of 30-day atrial fibrillation of at least 30 seconds detected by continuous cardiac event monitoring in patients with cryptogenic stroke was 16.1% (39). In comparison, in the CRYSTAL-AF study, which utilized an implantable cardiac monitor, the rate of atrial fibrillation in patients with cryptogenic stroke was 8.6% at 6 months, 12.4% at 12 months, and 30% at 36 months (87). Similarly, in the ASSERT study, patients with a recently implanted pacemaker or defibrillator with at least one risk factor for stroke and no history of atrial fibrillation were followed for approximately 2.5 years. Among the individuals with stroke, 27% of the patients had no evidence of atrial fibrillation in the 30 days preceding the stroke, and 16% had atrial fibrillation detected only after the stroke (14).

Together, these results indicate that dysrhythmia that defines atrial fibrillation, although undoubtedly associated with cerebral ischemia, is not a necessary step in the pathogenesis of cryptogenic stroke or embolic stroke of undetermined source. These observations have led to the development of the concept of “atrial cardiomyopathy” or “atrial cardiopathy,” which refers to the anatomic and physiologic changes associated with atrial dysfunction that precede atrial fibrillation but may actively contribute to left atrial thromboembolism.

Atrial cardiomyopathy 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 (54). Multiple mechanisms have been associated with the development of atrial cardiomyopathy, including: (1) hereditary muscular dystrophies cause myocyte degeneration and fatty or fibrotic changes in the atrial fibers; (2) congestive heart failure leads to atrial fibrosis and remodeling, along with calcium channel abnormalities; (3) obstructive sleep apnea is associated with slowing of cardiac conduction; (4) in the elderly there are degenerative atrial fibrotic changes; and (5) hypertension and obesity cause left atrium enlargement and P-wave abnormalities whereas diabetes and valvular diseases cause fibrotic changes and structural remodeling (41).

It has been observed that atrial cardiopathy is associated with cerebral embolism in 10% of cases, even in the absence of atrial fibrillation (108). 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 (65).

Another entity thought to be a precursor of atrial fibrillation and embolic stroke is atrial-heart rate event. Atrial-heart rate events are brief asymptomatic episodes of atrial tachyarrhythmia and can include brief episodes of atrial fibrillation or atrial flutter, detected only during prolonged use of cardiac implanted electronic devices. Atrial-heart rate events are a separate entity from atrial fibrillation, although with atrial-heart rate events longer than 5 minutes, there is a 6-fold increased risk of developing atrial fibrillation and a 2- to 2.5-fold increase in the risk of stroke; however, the overall absolute stroke risk is lower compared with patients diagnosed with atrial fibrillation (32). Treatment with oral anticoagulation is recommended 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 (53).

Epidemiology

Atrial fibrillation is the most common sustained cardiac arrhythmia. It has been estimated that atrial fibrillation affects at least 3 to 6 million people in the United States alone. Over a period of 50 years of observation from the Framingham Heart Study, the age-adjusted prevalence and incidence of atrial fibrillation approximately quadrupled for both males (prevalence from 2% to 10%, incidence from 4 to 13 per 1000 person-years) and females (prevalence from 1% to 5%, incidence from 3 to 9 per 1000 person-years) (88). Due to the increase in life expectancy, the prevalence of atrial fibrillation is estimated to rise to 12.1 million by 2030. The total incidence of atrial fibrillation in the United States adult population was estimated at 1.2 million cases in 2010, and this is expected to increase to 2.6 million by 2030 (95). The prevalence of atrial fibrillation is higher among Caucasians. After adjustment for risk factors, Blacks (OR: 0.49; 95% CI: 0.47 to 0.52), Asian people (OR: 0.68; 95% CI: 0.64 to 0.72), and Hispanic people (OR: 0.58; 95% CI: 0.55 to 0.61) have significantly lower rates of atrial fibrillation than Caucasians (95).

Owing to the association of atrial fibrillation with age, the prevalence, incidence, and proportion of strokes associated with atrial fibrillation increase sharply with age.

Social determinants of atrial fibrillation and health equity have been investigated. 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 (30). 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 (60). Data from an Atherosclerosis Risk in Communities study revealed that atrial fibrillation incidence decreases with progressively increasing categories of income and education (68).

Nonvalvular atrial fibrillation is associated with a four- to five-fold increase in the risk of stroke, with the highest proportion of stroke attributable to atrial fibrillation seen 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. As an example, although patients with rheumatic heart disease-associated atrial fibrillation may have a lower risk stratification score, they have a higher stroke event rate compared with nonvalvular atrial fibrillation (6.85 per 100 patient-years) (16). Similarly, mitral stenosis increases the risk of stroke 20 times over non-atrial fibrillation patients.

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 (52). 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% (78).

However, when systemic thrombolysis is administered in stroke mimics, the complication rates are low, and functional outcomes are typically good (96).

Associated or underlying disorders

Although most strokes in patients with atrial fibrillation are believed to originate in the left atrium, other potential causes of embolic stroke, such as carotid artery stenosis or aortic arch plaque, may coexist in these patients. About 60% to 80% of individuals with established atrial fibrillation also have hypertension, which predisposes them to small vessel occlusive disease, another common stroke mechanism (98). Of paramount clinical importance is the association of atrial fibrillation and aortic arch atheroma. 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. Patients with complex plaques and atrial fibrillation had a significantly higher stroke risk per year (12% to 20%) compared to patients with atrial fibrillation alone (1.2%), suggesting that aortic arch atheroma is an important additional source of emboli (03). Complex plaques are characterized by surface abnormalities (ulcerations, mobile components) and increased plaque thickness of at least 4 mm. Descending aorta seems to be preferentially involved in cerebral embolism, whereas complex plaques found in the ascending and transverse portions of the aorta appear to be involved in both cerebral and peripheral embolic events. Complex aortic plaques are also associated with a higher prevalence of left atrial abnormalities or endocardial abnormalities in patients with atrial fibrillation, suggesting a possible synergistic effect (12).

The presence of carotid atherosclerosis or plaque is another important competing mechanism for stroke in patients with atrial fibrillation. The prevalence of carotid atherosclerosis or plaque in patients with atrial fibrillation increases with age, from 38% in patients under 57- years of age (07) to 65% in patients older than 75 (06). Patients who are started on anticoagulation for atrial fibrillation and have carotid atherosclerosis changes of carotid plaque of at least 50% have a 40% nonsignificant increase in risk of stroke or transient ischemic attack compared with patients without carotid plaque (06). For 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 aim of the diagnostic workup in patients presenting with ischemic stroke and atrial fibrillation is to exclude coexistent causes of stroke that may affect management. Carotid Doppler, in addition to transcranial Doppler or other non-invasive angiographic studies, such as magnetic resonance angiography or computed tomography angiography, should be performed to rule out large artery occlusive disease. Echocardiography is recommended to assess whether cardiac disease is present or absent, in particular, valvular heart disease (eg, mitral stenosis), decreased left ventricular ejection function, left ventricular hypertrophy, or left atrial dilatation. In addition, echocardiography serves in the search for other potential sources of cardiac embolism, such as cardiac tumor, interatrial septal aneurysm, and patent foramen ovale.

Transesophageal echocardiography is clearly superior to transthoracic echocardiography for detecting left atrial thrombi (particularly in the appendage) 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 (109). Despite the diagnostic advantages of transesophageal echocardiography, the use of this relatively invasive, albeit safe, procedure may have little impact on treatment decisions except for selected cases because anticoagulation is the treatment of choice in stroke patients with atrial fibrillation.

The standard of care for identifying atrial fibrillation after an ischemic stroke involves the use of prolonged cardiac monitoring. The yield of cardiac monitoring in the detection of atrial fibrillation increases with the recording duration. In the STROKE-AF trial of patients with an implantable cardiac monitor inserted within 10 days of an index stroke, atrial fibrillation detection at 12 months lasting more than 30 seconds was significantly higher in the implantable cardiac monitor group versus the control group (12.1% vs. 1.8%; hazard ratio: 7.4 [95% CI: 2.6 to 21.3]; P < 0.001) (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 (63). 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 (40). The published 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 (58).

A newly described entity, atrial fibrillation discovered after stroke, refers to atrial fibrillation episodes that are brief and infrequent and that can be detected with greater frequency using insertable cardiac monitors. 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.

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 (82).

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 (53)

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 (64; 53).

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 (97). 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 (84).
	• 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 1c. 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. Previous trials have shown the benefits of vitamin K antagonists compared to placebo or to aspirin for primary and secondary stroke prevention. Stroke Prevention in Atrial Fibrillation Studies (SPAF I and II) investigated the effect of aspirin or placebo versus warfarin in patients with atrial fibrillation. In the first study, a direct comparison of warfarin with aspirin was limited by the small number of thromboembolic events. In the SPAF II trial, the combined use of fixed-dose warfarin (mean daily dose = 2.1 mg) with aspirin (325 mg per day) was evaluated as an alternative therapy to adjusted-dose warfarin with a target INR of 2.0 to 3.0 in patients with at least one risk factor for stroke (04). This trial was stopped early due to an elevated rate of embolism in patients treated with combination therapy (7.9% per year) as compared to those on adjusted-dose warfarin (1.9% per year). A meta-analysis of randomized trials comparing vitamin K antagonist monotherapy and vitamin K antagonist plus aspirin with the same target INR showed an increased risk of bleeding in the combined therapy arm (OR=1.43, 95% CI: 1.00 to 2.02) (22). However, when vitamin K antagonists are used, the INR must be closely monitored as subtherapeutic INR confers a greater risk of embolic events, whereas supratherapeutic INR confers a risk of major bleeding. When INR was not maintained within the therapeutic window for more than 60% of the time, there was no net benefit from anticoagulation therapy in preventing vascular events (01).

Based on these studies, vitamin K antagonists became 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 is also recommended for patients who cannot afford direct oral anticoagulants. In 2017, up to 21% of patients with nonvalvular atrial fibrillation were still receiving warfarin (110).

Nonvitamin K antagonists or direct oral anticoagulants. Direct oral anticoagulants are non-vitamin K antagonists that have been approved by the United States Food and Drug Administration as alternatives to warfarin in the prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation. The anticoagulant effect of these agents is exerted by either direct inhibition of thrombin (dabigatran) or factor Xa (apixaban, rivaroxaban and edoxaban). In general, these agents are considered non-inferior to warfarin, with the advantage of having a lower rate of intracerebral hemorrhage. In addition, they are administered as a fixed dose, do not require laboratory monitoring, and have very limited drug interactions (23).

The AVERROES trial compared apixaban to aspirin (81- to 324 mg/day) in atrial fibrillation patients who had failed vitamin K antagonist treatment or were deemed unsuitable to be treated with warfarin. This study was terminated early as apixaban proved its superiority to aspirin for reducing stroke or systemic thromboembolism (HR 0.45; 95% CI: 0.32 to 0.62; P< 0.001). The rate of hemorrhagic complications was similar between both groups (0.4% per year) (18).

It should be emphasized that the studies that investigated the efficacy of direct oral anticoagulants in atrial fibrillation excluded patients with mechanical heart valves or hemodynamically significant mitral stenosis. A subgroup analysis of randomized trials suggested that direct oral anticoagulants can potentially be used in atrial fibrillation patients with mild aortic stenosis, aortic regurgitation, and mitral regurgitation (72). However, the RE-ALIGN study showed that dabigatran was associated with an excess risk of thromboembolic events and hemorrhagic complications compared with warfarin in atrial fibrillation patients with mechanical heart valves (29). 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 (91).

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 (53).

For patients with ischemic strokes due to atrial fibrillation treated with direct oral anticoagulants who experience recurrent ischemic strokes and are compliant with the prescribed anticoagulant, drug interactions between direct oral anticoagulants and drugs affecting the CYP3A4 and CYP2C9 pathway, or p-glycoprotein inhibitors or inducers, or dietary interactions should be closely monitored (66).

Understanding that undiagnosed atrial fibrillation may be the culprit of stroke in individuals with cryptogenic ischemia, two large, randomized studies investigated the beneficial effect of direct oral anticoagulants for the prevention of recurrent ischemic strokes in patients with embolic stroke of undetermined source. NAVIGATE-ESUS (rivaroxaban for stroke prevention after embolic stroke of undetermined source) evaluated the efficacy of rivaroxaban 15 mg daily versus 100 mg aspirin daily for preventing recurrent strokes or systemic embolism in patients with recent embolic stroke of undetermined source. The trial was terminated early due to an increased risk of bleeding seen with rivaroxaban (1.8% annual rate) compared to aspirin (0.7% annual rate). The trial also failed to demonstrate the benefit of using rivaroxaban for preventing recurrent ischemic strokes (4.7% annual rate of recurrent strokes for both rivaroxaban and aspirin groups) (47). The RE-SPECT ESUS trial compared the efficacy and safety of dabigatran 150 mg twice daily versus aspirin 100 mg daily in the prevention of recurrent ischemic strokes after embolic stroke of undetermined source. The annual rate of recurrent stroke was similar in patients treated with dabigatran (4.1%) and aspirin (4.8%). The rates of major bleeding were similar between both groups (1.7% annual rate for dabigatran vs. 1.4% annual rate for aspirin) (24).

ARCADIA was another major trial that investigated the use of anticoagulation versus antiplatelets in embolic stroke of an undetermined source with evidence of atrial cardiopathy (55). 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).

Results from another randomized clinical trial, Apixaban for Stroke Prevention in Subclinical Atrial Fibrillation (ARTESIA), 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) (48).

The Apixaban Versus Aspirin for Embolic Stroke of Undetermined Source (ATTICUS) trial 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. At 1 year follow-up, odds of recurrent ischemia were similar between groups (adjusted odds ratio, 0.79; 95% confidence interval, 0.42 to 1.48; P=0.57), without an increased risk of major and nonmajor bleeding (HR, 0.68; 95% CI, 0.22 to 2.16) (36).

Based on these trials, the use of anticoagulation in unselected cases of embolic stroke of undetermined source is not recommended, 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 (56). 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. Timing to initiate anticoagulation therapy in atrial fibrillation patients with acute ischemic stroke is controversial.

In most cases, anticoagulation can be safely resumed 14 days after a stroke (56). However, different factors can influence this decision, including the size of stroke or the presence of hemorrhagic conversion. For patients at high risk of recurrent cardiogenic embolism, including those with valvular heart disease, intracardiac thrombus, or congestive heart failure, early anticoagulation is generally advised. In patients with large infarcts, uncontrolled hypertension, or those at relatively low risk for early recurrence, delaying anticoagulation for several days to a week may reduce the risk of hemorrhagic transformation. Following significant hemorrhagic infarction, anticoagulation should generally be delayed.

With the widespread use of direct oral anticoagulants for stroke prevention in patients with atrial fibrillation, the timing of resuming anticoagulation needs to balance the risk of recurrent ischemic events with the risk of hemorrhagic transformation. The 2018 American Heart Association/American Stroke Association guidelines recommend starting anticoagulation within 4 to 14 days after an ischemic stroke (80; 89). In comparison, the European Heart Rhythm Association of the European Society of Cardiology recommends using the “1-3-6-12 days” rule. This means that anticoagulation can be resumed 1 day after a transient ischemic attack, 3 days after a minor ischemic stroke (defined as NIHSS less than 8), 6 days after a mild stroke (defined as NIHSS between 8 and 15), and 12 days after a large stroke (NIHSS more than 15) (49). A study has also shown that early direct oral anticoagulation initiation appears safe for patients with mild to moderate strokes (31).

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 (107). 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 (75). Other clinical trials have also shown the benefit of rhythm control in patients with heart failure (81).

Nonpharmacological treatments. Besides anticoagulation, other nonpharmacological strategies are available for the prevention of stroke in atrial fibrillation patients, including catheter ablation therapies, pulsed-field ablation, or percutaneous closure of the left atrium appendage. The CABANA trial randomized patients with atrial fibrillation and one or more risk factors for stroke to catheter-based treatment or rhythm- or rate-control drug therapy. Catheter ablation was associated with a nearly 50% reduction in recurrent atrial fibrillation (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) (73). The PROTECT atrial fibrillation trial (WATCHMAN) randomized patients with atrial fibrillation and a CHADS2 score ≥1 to percutaneous closure of the left atrium appendage versus warfarin. Patients assigned to percutaneous closure of the left atrium appendage had to be able to tolerate warfarin for 45 days after the procedure, at which time warfarin therapy was discontinued. The surgical procedure was non-inferior to warfarin and had a 3 per 100 patient-year efficacy rate compared with 4.9 per 100 patient-year efficacy in the warfarin group (50). 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%) (83). 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 randomized control trial compared percutaneous closure of the left atrium appendage with direct oral anticoagulants in inpatients with nonvalvular atrial fibrillation and high risk for stroke. 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) (71).

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 (53).

Another possible procedure for atrial fibrillation management to reduce the thromboembolic risk is surgical left atrial appendage occlusion. 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 (103). 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).

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; 94). 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 (28). 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 (53).

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 (35). 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) (77).

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 (35).

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 (77).

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. The use of dual therapy (warfarin and clopidogrel) or triple therapy (warfarin, aspirin, and clopidogrel) increases the risk of fatal and nonfatal bleeding 1.7 to 3.7 times compared to warfarin, respectively (44). Also, the addition of aspirin to direct oral anticoagulants has an additive effect on the risk of bleeding (92). In general, the combination of antithrombotics is not recommended for patients with atrial fibrillation. However, this may be indicated in patients with coronary artery disease or those undergoing cardiac stent procedures.

In case of emergency, the effect of warfarin can be reverted using intravenous vitamin K and prothrombin complex concentrate (34). In the case of dabigatran, the monoclonal antibody fragment idarucizumab reverses the anticoagulant effect completely and durably within minutes of administration (79), whereas a single bolus of andexanet alfa can be used for reversal of apixaban and rivaroxaban (20).

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 (25). 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 (26). 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) (27).

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 (100; 37). 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 (53). 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) (105). 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) (86). 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) (90). 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 (19; 42; 76; 38).

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 (101).

Pregnancy

In general, atrial fibrillation is uncommon during pregnancy (61). 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 (59).

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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.

Author

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

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 1c. 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

Author

Editor

Former Authors

Patient Profile

ICD & OMIM codes

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Questions or Comment?

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Lobar hemorrhage

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