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 (29). The classic sign of atrial fibrillation is an irregular pulse; however, between atrial fibrillation episodes, the pulse may be regular. 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 ranging 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 (56). 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 (51). 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 2-fold higher, whereas in participants with atrial fibrillation and stroke, the risk of death was 4-fold higher compared with participants without atrial fibrillation (39).

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 (76). 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 (65; 67). 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 gain or loss of function of 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 (14).

These genetic markers can identify individuals who have an increased risk of incidental atrial fibrillation and stroke even after adjustment for confounders (84). 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 the CHADS₂ and CHA₂DS₂-VASc scores (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

5.1 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 that occur 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 characteristic of procoagulable states, are common in atrial fibrillation (91).

The systemic substrate contributes to the development of atrial fibrillation, which, once formed, worsens atrial contractility and furthers the progression of the 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 (61).

5.2 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 the cryptogenic strokes are caused by atrial fibrillation (11). 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 stroke 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 nonlacunar 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 (42). From a pragmatic standpoint, the minimal workup necessary for the diagnosis of embolic stroke of undetermined source includes 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 (41). Also, in the Oxford Vascular Study embolic stroke of undetermined source and cryptogenic stroke patients had decreased prevalence of myocardial infarction, peripheral vascular disease, and asymptomatic extracranial carotid disease than patients with cardioembolism. The rate of recurrent stroke 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 (56).

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% (35). In comparison, in the CRYSTAL-AF study, which utilized an implantable cardiac monitoring, 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 (78). 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 (12). Together, these results indicate that the 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 (48). 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 (37).

It has been observed that atrial cardiopathy is associated with cerebral embolism in 10% of cases, even in the absence of atrial fibrillation (96). Also, secondary analysis of the WARSS trials 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 (60).

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 considered to be a separate entity from atrial fibrillation, although presence of atrial-heart rate event longer than 5 minutes has a 6-fold increased risk of developing atrial fibrillation and a 2- to 2.5-fold increase in the risk of stroke. The overall absolute stroke risk is lower though compared with patients diagnosed with atrial fibrillation (28). There is uncertainty on best management for atrial-heart rate events.

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) (79). 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 (85). 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 (85).

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 an 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 (26). Additionally, low income in patients with prevalent atrial fibrillation (< $40,000/y) was associated with increased risk of heart failure and myocardial infarction (54). Data from an Atherosclerosis Risk in Communities study revealed that atrial fibrillation incidence decreases with progressively increasing categories of income and education (63).

Nonvalvular atrial fibrillation is associated with a 4- to 5-fold increase in the risk of stroke across all age groups (92). The risk of stroke is even higher in valvular-associated atrial fibrillation. As an example, patients with rheumatic heart disease-associated atrial fibrillation have a 17-fold increase in the risk of stroke (93). Similarly, mitral stenosis increases the risk of stroke 20 times over nonatrial fibrillation patients.

Prevention

Traditional vascular risk factors, including age, male sex, hypertension, congestive heart disease, diabetes mellitus, coronary artery disease, and sleep apnea, are associated with both atrial fibrillation and stroke. Five borderline or abnormal risk factors explain approximately 65% of the population-attributable risk for atrial fibrillation: hypertension (24%), BMI 25 or greater (18%), smoking (12%), cardiac disease (5%), and diabetes mellitus (4%) (46). However, the studies investigating the prevention of atrial fibrillation by using different strategies, including lifestyle interventions, glycemic control, treatment of sleep apnea, and use of statins or renin-angiotensin blockers have yield mixed results. The most current guidelines for the prevention of stroke recommend the correction of modifiable vascular risk factors (47). Antithrombotics are considered the mainstay for primary and secondary stroke prevention.

Differential diagnosis

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 (88). Of major 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 (10).

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-old (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, presence of carotid changes is associated with 56% significant 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 the detection of 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 (97). 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 use of prolonged cardiac monitoring. The yield of cardiac monitoring in 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) (09). 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 (57). 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 3-fold increase in the risk of thromboembolic events after adjusting for known stroke risk factors (36). 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 (52).

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 monitors versus site-specific usual care in patients with prior ischemic stroke attributed to either large artery atherosclerosis or small vessel disease (08). 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

14.1 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 commonly used in clinical practice are the CHADS₂ and the CHA₂DS₂-VASc scores. The CHADS₂ score (Table 1a) incorporates five conditions: (1) recent congestive heart failure, (2) hypertension, (3) age of 75 years or older, (4) diabetes, and (5) prior stroke or transient ischemic attack. Each condition is given 1 point except for the composite of stroke or transient ischemic attach, which receives 2 points.

Table 1a. CHADS2 Score Quantification of Stroke Risk for Patients with Non-Valvular Atrial Fibrillation

One of the drawbacks of the CHADS₂ score is that almost 30% of the general population falls in the undetermined category, raising the question of whether these patients should be treated with anticoagulants or not. The CHA₂DS₂-VASc score (Table 1b, 1c), which is an extension of the CHADS₂ score, incorporates presence of vascular disease, age 65 to 74, and female sex as prognostic factors for stroke.

Table 1b. CHA2DS2-VASc Score

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

Although the CHA₂DS₂-VASc score is widely used in clinical practice, a systematic review of 19 validating studies found high heterogenicity for the assessment of stroke risks, especially for low to intermediate risk groups (87). 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:

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 currently 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

14.2 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, direct comparison of warfarin with aspirin was limited by the small number of thromboembolic events. In 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 the 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) (19). 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 the prevention of 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 the 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.

14.3 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 noninferior 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 (20). The rates of embolism and cerebral hemorrhage observed with each of these agents are shown in Table 2.

Table 2. Direct Oral Anticoagulants

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 the reduction of 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) (15).

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. Based on subgroup analysis of randomized trials it was suggested that direct oral anticoagulants can potentially be used in atrial fibrillation patients with mild aortic stenosis, aortic regurgitation, and mitral regurgitation (66). 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 (25).

The 2019 American College of Cardiology/American Heart Association Clinical Practice Guidelines and the Heart Rhythm Society Guideline for the Management of Patients with Atrial Fibrillation 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, where warfarin remains the drug of choice (47). These guidelines are in line with the 2021 European Heart Rhythm Association Practical guide. 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 (82).

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 aspiring (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) (43). 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) (21).

ARCADIA was another major trial that investigated the use of anticoagulation versus antiplatelets in embolic stroke of undetermined source with evidence of atrial cardiopathy (49). The trial’s interim results were recently presented at the 2023 European Stroke Conference. 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 benefit for preventing recurrent strokes with 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 rate of all-cause mortality 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).

Based on these trials, the use of anticoagulation in unselected cases of embolic stroke of undetermined source is not currently recommended.

14.4 Antiplatelet agents. Multiple studies have shown the superiority of anticoagulation compared to antiplatelets alone for the management of atrial fibrillation–related complication; therefore, use of antiplatelets alone is not currently recommended for atrial fibrillation management (50). 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.

14.5 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 post stroke (50). However, different factors can influence this decision, including size of stroke or 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, timing of resuming anticoagulation needs to balance the risk for recurrent ischemic events with the risk for hemorrhagic transformation. The 2018 American Heart Association/American Stroke Association guidelines recommend starting anticoagulation within 4 to 14 days post ischemic stroke (72; 80). 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 8-15), and 12 days after a large stroke (NIHSS more than 15) (44). A study has also shown that for patients with mild to moderate strokes, early direct oral anticoagulation initiation appears safe (27).

14.6 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 (86). The majority of 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 (68). Other clinical trials have also shown the benefit of rhythm control in patients with heart failure (73).

14.7 Nonpharmacological treatments. Besides anticoagulation, other nonpharmacological strategies are available for prevention of stroke in atrial fibrillation patients, including catheter ablation therapies, pulsed field ablation, or percutaneous closure of the left atrium appendage. 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 noninferior 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 (45). 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%) (74). 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 noninferior 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). Current guidelines recommend considering the use of left atrial appendage closure in patients at high bleeding risk from oral anticoagulation (50).

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 (32). 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) (70).

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

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

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 (40). Also, the addition of aspirin to direct oral anticoagulants has an additive effect on the risk of bleeding (83). 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 (30). In the case of dabigatran, the monoclonal antibody fragment idarucizumab reverses the anticoagulant effect in a complete and durable fashion within minutes of administration (71), whereas a single bolus of andexanet alfa can be used for reversal of apixaban and rivaroxaban (17).

Special considerations

16.1 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 (13). The BRIDGE trial concluded that holding warfarin for elective procedures without any bridging was noninferior to using low molecular weight heparin for arterial thromboembolism prevention (22). 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 (23). 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) (24).

16.2 Secondary atrial fibrillation. Secondary atrial fibrillation refers to the cases of atrial fibrillation that take place during the course of 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 increased risk of stroke (90; 33). 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 (47). However, it is reasonable to consider active surveillance for recurrent atrial fibrillation and tailor the use of anticoagulation based on individual risk of thromboembolism.

16.3 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) (94). 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) (77). The association between atrial fibrillation, COVID-19 disease, and stroke risk is complex and needs further investigation.

16.4 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) (81). 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

Pregnancy

In general, atrial fibrillation is uncommon during pregnancy (55). 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 currently recommended (53).