Stroke in patients with atrial fibrillation

INTRODUCTION — 

An ischemic stroke may occur in patients with atrial fibrillation (AF) either as the initial presenting manifestation of AF or despite appropriate antithrombotic prophylaxis. In such patients, a cardiac embolus, most commonly a thrombus originating from the left atrial appendage, is the cause of the ischemic stroke. (See "Clinical diagnosis of stroke subtypes", section on 'Brain ischemia'.)

Issues specific to stroke in patients with AF will be reviewed here. The risk of atheroembolism (including stroke), the role of anticoagulant prophylaxis (primary prevention) in patients with AF, and the general evaluation and management of the patient with stroke are presented elsewhere. (See "Atrial fibrillation in adults: Use of oral anticoagulants" and "Overview of the evaluation of stroke" and "Approach to reperfusion therapy for acute ischemic stroke" and "Early antithrombotic treatment of acute ischemic stroke and transient ischemic attack".)

STROKE CHARACTERISTICS — 

Strokes due to embolization of thrombus, most commonly from the left atrial appendage (LAA) in patients with AF, present with the characteristics of ischemic stroke. (See "Clinical diagnosis of stroke subtypes", section on 'Distinguishing stroke subtypes'.)

Features suggestive of cardioembolic stroke

●Increased clinical severity – Embolism from AF is associated with a predilection towards intracranial vessel occlusion, greater ischemic stroke severity, and "longer" transient ischemic attacks (TIAs) than embolism from carotid disease, presumably because of larger LAA thrombi with AF [1-4]. This relationship was illustrated in a report comparing ischemic brain events in patients with AF with those with carotid disease in two major trials. The ratio of hemispheric events to retinal events was 25:1 with AF compared with 2:1 with carotid disease [1]. As a result, patients with AF who suffer an ischemic stroke appear to have a worse outcome (more disability, greater mortality) than those who have an ischemic stroke in the absence of AF, even after adjustment for the advanced age of patients with AF-related stroke [3,5-7]. The "longer" TIAs typical in AF patients are more often associated with abnormal brain magnetic resonance diffusion imaging and would be classified as strokes by the revised American Heart Association definition [8]. (See "Definition, etiology, and clinical manifestations of transient ischemic attack".)

●Radiologic patterns – Cardioembolic stroke from AF may affect any vascular territory or multiple vascular territories of the brain, typically with one or more wedge-shaped infarcts involving the cortex and the underlying subcortical white matter. Other patterns include striatocapsular infarction from a middle cerebral artery stem occlusion and/or borderzone infarcts [9].

Silent cerebral infarction — In addition to causing symptomatic stroke with major deficits, AF is also associated with silent cerebral infarctions and TIA [10-15]. Silent cerebral infarctions are characterized by brain lesions with a radiographic appearance consistent with cerebral infarction in the absence of clinical complaints or findings. In a 2014 systematic review and meta-analysis of 17 studies, the prevalence of silent cerebral infarctions on magnetic resonance imaging and computed tomography among patients with AF was 40 and 22 percent, respectively [14]. In this review, AF was associated with more than a twofold increased risk of silent cerebral infarction in patients with no history of symptomatic stroke (odds ratio 2.62, 95% CI 1.81-3.80) in 11 studies. However, most studies pooled in this meta-analysis were cross-sectional, making the causal link between AF and silent cerebral infarction uncertain.

ACUTE ISCHEMIC STROKE — 

The initial rapid evaluation of acute ischemic stroke for patients with known or suspected AF is similar to the approach for patients with other known or suspected causes of stroke.

Is reperfusion therapy indicated? — All patients with acute ischemic stroke should be evaluated for possible reperfusion therapy, including urgent brain and neurovascular imaging. The immediate goal of reperfusion therapy is to restore blood flow to the regions of brain that are ischemic but not yet infarcted. (See "Approach to reperfusion therapy for acute ischemic stroke".)

●Intravenous (IV) thrombolysis improves functional outcome at three to six months when given within 4.5 hours of ischemic stroke symptom onset. (See "Intravenous thrombolytic therapy for acute ischemic stroke: Therapeutic use".)

However, contraindications to IV thrombolysis may be relevant for patients with AF and acute ischemic stroke (table 1):

•Current vitamin K antagonist (VKA) use (eg, warfarin) with evidence of anticoagulant effect (eg, an international normalized ratio [INR] >1.7 or prothrombin time >15 seconds).

•Direct-acting oral anticoagulant (DOAC; also referred to as non-vitamin K oral anticoagulants [NOAC]) use, unless the patient has not received a DOAC dose for more than 48 hours, assuming normal kidney function or laboratory tests such as partial thromboplastin time, INR, platelet count, ecarin clotting time, thrombin time, or appropriate direct factor Xa activity assays are normal. In most cases, only the INR is readily available for clinical decision-making.

•Evidence of intracranial hemorrhage on neuroimaging.

●Mechanical thrombectomy is indicated for selected patients with acute ischemic stroke caused by an intracranial large artery occlusion who can be treated within 24 hours of the time last known to be well (algorithm 1), when performed at centers with appropriate expertise. (See "Mechanical thrombectomy for acute ischemic stroke".)

Specific data on the effectiveness of thrombolytic therapy in ischemic stroke are limited for patients with AF, although such patients account for 20 to 30 percent of those participating in clinical trials [16,17]. As an example, the National Institute of Neurological Disorders and Stroke (NINDS) trial included 115 patients with AF (18 percent) [16]. No subgroup analysis of these patients has been reported, although there was no evidence of a treatment interaction between history of AF and benefit from alteplase. The large size and worse prognosis of AF-associated acute ischemic stroke accentuate both the risks and the benefits of fibrinolysis [17]. (See "Approach to reperfusion therapy for acute ischemic stroke".)

Diagnostic approach

Comprehensive evaluation — Patients with AF who suffer an ischemic stroke are likely to have had a cardioembolic event. On the other hand, AF is common in older adults, who often are at risk for other types of stroke. Thus, the presence of AF in a stroke patient does not always mean that there is a causal relationship [18]. Therefore, all patients with a stroke, even in the setting of AF, need a complete evaluation for other causes of stroke, since the findings might result in a different treatment.

The evaluation is generally the same as in other patients with acute stroke, including brain and neurovascular imaging, cardiac rhythm monitoring during the acute phase, and echocardiography. As for other patients with a suspected embolic stroke, transesophageal echocardiography (TEE) may be used to identify embolic sources (intracardiac or aortic), which may be particularly helpful for patients at increased risk for complications of anticoagulation. However, a TEE is not used to exclude AF as the cause of embolic stroke, since residual atrial thrombi may or may not be present. (See "Overview of the evaluation of stroke", section on 'Ischemia' and "Overview of the evaluation of stroke", section on 'Confirming the diagnosis'.)

Source of embolism — For those patients with AF in whom an embolic stroke seems likely, sources other than the left atrial appendage (LAA) need to be considered. Embolism refers to particles of debris originating elsewhere that block arterial access to a particular brain region. Embolic strokes may arise from a source in the heart, aorta, or large vessels (table 2). (See "Stroke: Etiology, classification, and epidemiology", section on 'Embolism' and "Clinical diagnosis of stroke subtypes", section on 'Brain ischemia'.)

Thromboembolism of aortic atheroma is discussed separately. (See "Thromboembolism from aortic plaque".)

Brain and neurovascular imaging — Neuroimaging should be obtained for all patients suspected of having acute ischemic stroke or transient ischemic attack (TIA). Brain and neurovascular imaging play an essential role in acute stroke by:

●Differentiating ischemia from hemorrhage

●Excluding stroke mimics, such as tumor

●Assessing the status of large cervical and intracranial arteries

●Estimating the volume of brain tissue that is irreversibly infarcted (ie, infarction "core")

●Estimating the extent of potentially salvageable brain tissue that is at risk for infarction (ie, ischemic "penumbra")

●Guiding acute interventions, including patient selection for reperfusion therapies (ie, intravenous thrombolysis and mechanical thrombectomy)

Imaging of acute ischemic stroke is reviewed in detail elsewhere. (See "Neuroimaging of acute stroke".)

Cardiac monitoring — For patients in sinus rhythm without a history of AF, cardiac rhythm monitoring is recommended for at least the first 24 to 48 hours after the onset of ischemic stroke to identify AF or atrial flutter [19]. However, paroxysmal AF may not be detected on short-term cardiac monitoring such as continuous telemetry and 24- or 48-hour Holter monitors. To increase the likelihood of detecting AF, ambulatory cardiac monitoring for two to four weeks is suggested for all adult patients with a cryptogenic ischemic stroke or cryptogenic TIA. (See "Overview of the evaluation of stroke", section on 'Monitoring for subclinical atrial fibrillation'.)

Echocardiography — Transthoracic echocardiographic (TTE) evaluation is recommended for most patients presenting with ischemic stroke, primarily to investigate the conditions associated with AF (but not to identify LAA thrombi). Because chronic anticoagulation with a DOAC or warfarin is recommended in all eligible patients with AF and stroke, echocardiography often will not have a significant impact on anticoagulant management decisions. (See "Role of echocardiography in atrial fibrillation" and "Epidemiology, risk factors, and prevention of atrial fibrillation" and "Atrial fibrillation in adults: Use of oral anticoagulants".)

The LAA and thus LAA thrombus are rarely seen on TTE but are easily visualized and assessed by TEE. Approximately 45 percent of patients presenting with an acute embolic event in the setting of new-onset AF will have residual LAA thrombus [20,21]. Even when not seen on TEE, an intracardiac thrombus is presumed to have been present in all patients with AF who have had a recent thromboembolic event independent of anticoagulation status. This hypothesis is based in part upon the observations that microscopic thrombus can be identified in most patients with chronic sustained AF at autopsy [22] and that patients with a recent thromboembolism and newly recognized AF are significantly more likely to have spontaneous echocardiography contrast (a marker of stasis) than similar patients without a thromboembolic event (87 versus 48 percent) [21].

Thus, diagnostic evaluation by TEE to search for a residual intraatrial thrombus is not essential for patients with AF, since the absence of a thrombus will not alter the long-term clinical (anticoagulation) management. However, TEE to confirm absence of residual thrombus before cardioversion may be reasonable for those in whom an AF rhythm strategy will be pursued. (See "Role of echocardiography in atrial fibrillation" and "Management of atrial fibrillation: Rhythm control versus rate control".)

Managing antithrombotic therapy acutely

●Stop anticoagulation temporarily – For most patients on anticoagulant therapy at the time of stroke onset, anticoagulation is temporarily withheld during the acute phase of ischemic stroke due to the risk of hemorrhagic transformation of the brain infarction.

●Acute antiplatelet therapy – In patients with AF who experience an ischemic stroke, acute antiplatelet therapy (algorithm 2) may be warranted to reduce both disability and the risk of early recurrent stroke, which is 3 to 5 percent in the first two weeks [23,24]. These benefits must be balanced against the risk of intracranial bleeding with antithrombotic therapy.

●Starting or resuming oral anticoagulation – Once the stroke evaluation is complete, antithrombotic therapy may be modified according to the ischemic stroke mechanism (algorithm 3). For patients with AF, long-term oral anticoagulation is started (or resumed) once the risk of hemorrhagic transformation has diminished, usually within the first days to two weeks after stroke onset, as guided mainly by the size of the ischemic infarct. (See 'Timing after acute ischemic stroke' below.)

The management of acute antithrombotic therapy in patients with stroke is discussed in detail elsewhere. (See "Early antithrombotic treatment of acute ischemic stroke and transient ischemic attack".)

RISK OF RECURRENT STROKE

●Known AF – Patients with AF who have had a prior embolic event already have the most potent risk factor for recurrent stroke. The risk of recurrent stroke in the first few weeks after the presenting event is 3 to 5 percent, based upon large numbers of patients observed in the control arms of older randomized trials [23,24]. Risk of stroke and all-cause mortality after transient ischemic attack alone was not significantly increased in the GARFIELD-AF registry [25].

Due to the high risk of recurrent embolism, lifelong anticoagulation is recommended for secondary prevention (these patients have a minimum CHA₂DS₂-VASc score (calculator 1) of 2 for which chronic anticoagulation is strongly recommended). (See "Atrial fibrillation in adults: Selection of candidates for long-term anticoagulation".)

●Atrial fibrillation detected after stroke (AFDAS) – Accumulating evidence suggests that patients with AFDAS have a lower prevalence of cardiovascular disease and a lower risk of recurrent stroke than patients with AF known at the time of stroke occurrence [26-31]. One hypothesis is that some cases of AFDAS may be due to neurogenic mechanisms such as autonomic dysregulation, while others are due to cardiogenic mechanisms [29]. However, anticoagulation management does not distinguish between these two groups. The category of AFDAS applies when AF is detected beyond the acute phase of ischemic stroke by prolonged cardiac monitoring, but does not apply when AF is detected during the acute stroke admission [28].

LONG-TERM ANTICOAGULATION

Indications — For most patients with ischemic stroke and AF, chronic oral anticoagulation (direct-acting oral anticoagulant [DOAC] generally preferred) is recommended to reduce the risk of thromboembolism and recurrent ischemic stroke, independent of the cause of the stroke and independent of whether AF is detected before or after the stroke presentation.

Contraindications to anticoagulation include acute intracranial hemorrhage. Patients with a previous intracranial hemorrhage may be candidates for anticoagulation, depending upon their risk of recurrent ischemic stroke and intracranial bleeding. (See "Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis", section on 'Anticoagulation'.).

Patients who are acceptable candidates for short-term antithrombotic therapy may benefit from left atrial appendage (LAA) occlusion.(See "Atrial fibrillation: Left atrial appendage occlusion".)

Benefit — In patients with AF, randomized trials have shown that therapeutic oral anticoagulant with a DOAC or a vitamin K antagonist (VKA; eg, warfarin) reduces the risk of ischemic stroke and other embolic events by approximately two-thirds compared with placebo (or aspirin) irrespective of baseline risk. (See "Atrial fibrillation in adults: Selection of candidates for long-term anticoagulation", section on 'General efficacy'.)

●DOACs – Most patients with AF with an indication for anticoagulation are treated with a DOAC rather than a VKA. Randomized trials have demonstrated that DOACs are either superior (apixaban and dabigatran) or noninferior (edoxaban or rivaroxaban) to VKAs for stroke prevention. Studies have also shown that DOACs have less bleeding side effects than VKAs among patients with AF and ischemic stroke or transient ischemic attack (TIA). (See "Atrial fibrillation in adults: Use of oral anticoagulants", section on 'Choice of anticoagulant'.)

In the ARISTOTLE trial, among 3436 participants with stroke or systemic embolism, apixaban was found to be superior to adjusted-dose warfarin in preventing recurrent stroke or systemic embolism (2.5 versus 3.2 percent; hazard ratio [HR] 0.79, 95% CI 0.66-0.95) [32]. Apixaban also caused less major bleeding compared with warfarin (2.1 versus 3.1 percent; HR 0.69, 95% CI 0.60-0.80) and resulted in lower overall mortality (3.5 versus 3.9 percent). In a separate trial, among patients with prior stroke, dabigatran had a larger protective effect on stroke as compared with warfarin but had similar rates of major hemorrhage [33]. In other clinical trials of patients with prior stroke or TIA, both edoxaban [34] and rivaroxaban [35] were found to be noninferior to warfarin for future stroke prevention.

●Vitamin K antagonist – Selected patients with AF are anticoagulated with a VKA (eg, warfarin) rather than a DOAC. This includes patients with mechanical valves, clinically significant rheumatic mitral stenosis, or who are at risk for a drug interaction with DOAC agents (table 3A). (See "Atrial fibrillation in adults: Use of oral anticoagulants", section on 'Choice of anticoagulant'.)

The efficacy of a VKA for patients with AF was illustrated by a pooled individual participant analysis of six randomized trials [36]. Treatment with adjusted-dose warfarin (international normalized ratio 2 to 3) reduced stroke risk from an average of 10 percent per year with aspirin to 4 percent per year.

In an analysis from the EAFT and SPAF III trials of 834 patients with prior nondisabling ischemic stroke or prior TIA at study entry, the long-term risk of recurrent stroke was lower in patients with a prior TIA than in those with a prior ischemic stroke [37]. However, the reduction in recurrent stroke risk with warfarin therapy was comparable in both groups: 3 versus 7 percent per year with aspirin in patients with a TIA and 4 versus 11 percent per year in those with ischemic stroke.

Anticoagulated patients with AF who experience ischemic stroke typically have smaller infarcts with a lower mortality rate compared with patients with AF and stroke who are not anticoagulated [38,39]. This is likely explained by a higher fraction of nonembolic strokes and small size of embolic strokes among anticoagulated AF patients. Anticoagulation greatly reduces the likelihood of large stroke due to LAA thromboembolism, so that the remaining strokes are from cerebral small artery disease or other mechanisms [38].

Risk — The most feared complication of anticoagulant therapy is major bleeding, as reviewed separately. (See "Atrial fibrillation in adults: Selection of candidates for long-term anticoagulation", section on 'Bleeding risk' and "Risks and prevention of bleeding with oral anticoagulants".)

For patients with AF who are candidates for short-term antithrombotic therapy (eg, 45 days) but not long-term anticoagulation, LAA occlusion should be considered. (See "Atrial fibrillation: Left atrial appendage occlusion".)

Whether to use chronic oral anticoagulants must consider both benefit and risk through shared decision-making with the patient. However, the benefit of oral anticoagulants far outweighs the risk for nearly all patients with ischemic stroke and AF [40]. (See "Atrial fibrillation in adults: Selection of candidates for long-term anticoagulation".)

Choice of anticoagulant — For most patients with stroke or TIA and AF who do not have a specific indication for VKA therapy, a DOAC is preferred to a VKA, as discussed separately. (See "Atrial fibrillation in adults: Use of oral anticoagulants", section on 'Choice of anticoagulant'.)

Clinical settings in patients with AF in which a VKA is indicated (rather than a DOAC) include the following (see "Atrial fibrillation in adults: Use of oral anticoagulants", section on 'Choice of anticoagulant'):

●Mechanical heart valve of any type in any location. (See "Antithrombotic therapy for mechanical heart valves".)

●Rheumatic mitral stenosis that is severe or clinically significant (mitral valve area ≤1.5 cm²). (See "Rheumatic mitral stenosis: Overview of management", section on 'Prevention of thromboembolism'.)

●Patients for whom the DOAC agents are avoided due to drug interactions (eg, those receiving P-glycoprotein drug efflux pump [P-gp] inducers, which can decrease the anticoagulant effect of DOACs and chronic antiviral agents, which may increase the anticoagulant effect of DOACs) (table 3A-C) [41]. (See "Atrial fibrillation in adults: Use of oral anticoagulants", section on 'Drug interactions' and "Direct oral anticoagulants (DOACs) and parenteral direct-acting anticoagulants: Dosing and adverse effects".)

●Additional clinical settings in which VKA use may be reasonable or preferable to DOAC, as discussed separately. This may include patients with chronic severe kidney disease with creatinine clearance (by Cockcroft-Gault equation) less than 25 to 30 mL/min. Apixaban is generally preferred in this setting, although some clinicians prescribe warfarin for selected patients in this setting, as described separately. (See "Atrial fibrillation in adults: Use of oral anticoagulants", section on 'Chronic kidney disease'.)

Dosing — Dosing recommendations for DOACs (table 4) are reviewed in detail elsewhere. (See "Direct oral anticoagulants (DOACs) and parenteral direct-acting anticoagulants: Dosing and adverse effects".)

There are legitimate reasons for DOAC dose reductions, which differ according to the specific agent. Clinical settings in which dose modification may be indicated include older age, low body weight, kidney function impairment, and/or concomitant use of interacting drugs. (See "Direct oral anticoagulants (DOACs) and parenteral direct-acting anticoagulants: Dosing and adverse effects".)

For patients with AF treated with a VKA (eg, warfarin), an international normalized ratio (INR) between 2 and 3 is generally recommended (except for those with a bileaflet mechanical mitral valve, for whom the INR target would be 2.5 to 3.5), with an average annual time in the therapeutic range >70 percent. (See "Atrial fibrillation in adults: Use of oral anticoagulants", section on 'Vitamin K antagonist'.)

Timing after acute ischemic stroke — For medically stable patients with AF and a small- or moderate-sized infarct with no intracranial bleeding, warfarin can be initiated soon (24 hours after admission) with minimal risk of transformation to hemorrhagic stroke. We prefer to wait 48 hours to start a DOAC in these patients, as DOACs have a more rapid anticoagulant effect.

Withholding anticoagulation for one week has been generally recommended for those with large ischemic stroke, symptomatic hemorrhagic transformation, or poorly controlled hypertension [42-46]. However, some studies suggest that DOAC administration within the first four to seven days of ischemic stroke onset is safe, even in patients with larger nonhemorrhagic strokes [47,48], as reviewed separately. (See "Early antithrombotic treatment of acute ischemic stroke and transient ischemic attack", section on 'Timing of anticoagulation after acute ischemic stroke or TIA in patients with atrial fibrillation'.)

Patients may benefit from aspirin until therapeutic anticoagulation is achieved [49].

Although once widely practiced, early treatment with heparin for patients with AF who have an acute cardioembolic stroke should generally be avoided, as studies have shown that such treatment causes more harm than good. (See "Early antithrombotic treatment of acute ischemic stroke and transient ischemic attack", section on 'Atrial fibrillation'.)

Specific patient groups

Patients with another potential stroke mechanism — In some patients with ischemic stroke and AF, the work-up will identify a noncardioembolic stroke mechanism (eg, large artery atherosclerosis, small vessel disease, other determined etiology) as the potential cause of the stroke.

●Lacunar infarction – The optimal therapy is not known for patients with AF who experience a small subcortical "lacunar" infarct deemed as likely to be due to cerebral small artery disease as opposed to a cardiac embolus [50]. Anticoagulation is recommended for these patients even though the stroke mechanism is uncertain. This is because in randomized trials, these patients would have been categorized as having a history of stroke; these trials have consistently shown that patients with a history of stroke benefit from VKA and DOACs.

●Large artery stenosis – Some patients with AF have a significant ipsilateral stenosis of a large artery that supplies the territory of the acute ischemic stroke. In such cases, it is usually impossible to determine which mechanism was causative. Anticoagulation for AF is recommended, and the large artery stenosis should be treated appropriately (eg, revascularization for cervical internal carotid artery stenosis) as a separate cause.

Older age — Older age is a risk factor for stroke in patients with AF and is generally cited as a risk factor for bleeding. The risk increase with age is approximately linear. However, the risk of bleeding attributable to older age is often overestimated, and anticoagulants are underused in older individuals who are at the highest risk of stroke and may derive more benefit than younger individuals [40]. (See "Risks and prevention of bleeding with oral anticoagulants", section on 'Age, race, and sex'.)

Fall risk — Among patients with a history of falls or at high risk of falling, the risk of intracranial hemorrhage is increased among patients on anticoagulation, aspirin, or no antithrombotic therapy. However, the absolute increased risk of intracranial hemorrhage related to anticoagulation is small. In particular, anticoagulation increases the risk of subdural hemorrhage (SDH), which is often due to falls, but the absolute risk with VKA therapy is approximately two additional SDHs per 1000 patients [51], which is much lower compared with the risk of cardioembolic stroke due to AF [40].

Nonrandomized studies suggest that for patients with AF and high risk of falls, the benefit of anticoagulation (ie, a reduced risk of ischemic stroke and consequent disability) outweighs the risk of intracranial bleeding from a fall. (See "Risks and prevention of bleeding with oral anticoagulants", section on 'Risk factors for bleeding in specific sites'.)

Another option for high fall risk patients who are candidates for short-term antithrombotic therapy is LAA occlusion. (See "Atrial fibrillation: Left atrial appendage occlusion".)

Anticoagulant-intolerant patients — LAA occlusion or dual antiplatelet therapy may be reasonable alternatives to therapy with aspirin alone in high-risk patients with AF who cannot be treated with long-term warfarin or DOAC, or because of strong patient preference following careful consideration of the advantages of oral anticoagulation. However, LAA occlusion requires a minimum 45 days of antithrombotic therapy after implantation to allow time for endothelialization of the device. LAA occlusion is discussed separately. (See "Atrial fibrillation: Left atrial appendage occlusion".)

ANTICOAGULATION FAILURE

Determining the cause of recurrent stroke — All patients with AF who have an ischemic stroke despite oral anticoagulation with a vitamin K antagonist (VKA) or a direct-acting oral anticoagulant (DOAC) should have a thorough evaluation to determine if the most likely stroke mechanism is cardioembolic due to AF or noncardioembolic due to large artery atherosclerosis, small vessel disease, or another cause of ischemic stroke. Note that patients with ischemic stroke and AF will still need chronic oral anticoagulation even if a competing stroke mechanism is found.

Transesophageal echocardiogram (TEE) is useful to assess for residual left atrial appendage (LAA) thrombus and other potential cardiac sources of embolism (eg, complex aortic plaque [52]). (See "Overview of the evaluation of stroke", section on 'Ischemia' and "Overview of the evaluation of stroke", section on 'Confirming the diagnosis'.)

Missed doses should be suspected in patients taking a DOAC, and subtherapeutic intensity of anticoagulation is a very common cause of treatment failure for patients taking a VKA [53-55]. For patients with stroke on DOACs with good compliance or while on warfarin anticoagulation with a therapeutic international normalized ratio (INR), a noncardioembolic stroke mechanism (eg, lacunar, large artery stenosis, malignancy) is often the cause, although cardioembolism may account for the majority [55,56].

In an analysis of patients with ischemic stroke despite oral anticoagulation, the stroke etiology for 1674 patients taking a DOAC was due to the following factors [55]:

●Cardioembolism - 49 percent

●Poor adherence or insufficient dose – 23 percent

●A competing mechanism – 28 percent

For 1274 patients taking a VKA, the stroke etiology was due to the following factors [55]:

●Cardioembolism – 37 percent

●Poor adherence or insufficient dose – 43 percent

●A competing mechanism – 20 percent

Direct-acting oral anticoagulant treatment failure — While data are limited, ischemic stroke that occurs during therapy with a DOAC (eg, apixaban, dabigatran, edoxaban, or rivaroxaban) for AF has been associated with several factors, including treatment at doses lower than recommended and/or poor adherence.

LAA thrombus, if present, suggests the need to reassess dosing and compliance. One study compared 713 cases of ischemic stroke or transient ischemic attack (TIA) during DOAC treatment with unmatched controls (consecutive outpatients with AF) who did not have cerebrovascular events during DOAC treatment [57]. In multivariable analysis, ischemic cerebrovascular events were associated with off-label under-dosing of DOAC, atrial enlargement, hyperlipidemia, and higher CHA₂DS₂-VASc score.

It is important to verify that the correct DOAC dose was prescribed and that the patient was compliant. If a thrombus is present and DOAC compliance with twice-daily dosing is uncertain, it may be reasonable to change to a once-daily DOAC, but optimal treatment is uncertain, and no consensus exists. (See "Atrial fibrillation in adults: Use of oral anticoagulants", section on 'Anticoagulant failure'.)

Changing DOAC therapy is not without risk, as suggested by a population-based retrospective cohort study of 2337 patients with AF who developed a first ischemic stroke or TIA despite DOAC treatment [58]. Compared with patients who remained on unchanged DOAC therapy after the first ischemic event, the risk of recurrent ischemic stroke was higher for patients who switched to another DOAC (adjusted hazard ratio [aHR] 1.62, 95% CI 1.25-2.11) or switched to warfarin (aHR 1.96, 95% CI 1.27-3.02).

Regardless of which oral anticoagulant is chosen, resuming oral anticoagulation therapy for patients with AF is generally indicated after one to two weeks of temporary interruption with large infarcts or shorter interruption with small infarcts. (See "Early antithrombotic treatment of acute ischemic stroke and transient ischemic attack", section on 'Timing of anticoagulation after acute ischemic stroke or TIA in patients with atrial fibrillation'.)

A pooled analysis with individual patient data (n = 5314) from seven prospective cohort studies found that patients with AF and ischemic stroke despite oral anticoagulation had a higher risk of recurrent ischemic stroke than patients with a similar CHA₂DS₂-VASc score but without prior oral anticoagulation [59].

Warfarin treatment failure — When ischemic stroke occurs with a therapeutic INR (2 to 3), we favor switching from warfarin to a DOAC rather than routine addition of antiplatelet therapy. If DOAC therapy is contraindicated (eg, in patients with a mechanical valve), alternative options include increasing the target INR to 2.5 to 3.5 or LAA occlusion. The addition of antiplatelet therapy is known to increase major hemorrhage (and particularly brain hemorrhage), and the benefit is less well defined than the benefit of optimizing anticoagulation.

In patients with AF who suffer ischemic stroke during warfarin anticoagulation, the intensity of anticoagulation is most often subtherapeutic (INR less than 2). Continuing warfarin (after one to two weeks of temporary interruption for patients with large infarcts or shorter interruption with small infarcts) and renewed efforts to keep the INR in the 2 to 3 therapeutic range or consideration of a change to a DOAC is advised. (See "Early antithrombotic treatment of acute ischemic stroke and transient ischemic attack", section on 'Timing of anticoagulation after acute ischemic stroke or TIA in patients with atrial fibrillation'.)

HEMORRHAGIC STROKE — 

For patients with AF on anticoagulation who develop a hemorrhagic stroke, anticoagulation and antiplatelet drugs should be discontinued, and medications to reverse the effects of anticoagulant drugs should be given immediately. These and other management issues are discussed separately.(See "Reversal of anticoagulation in intracranial hemorrhage" and "Spontaneous intracerebral hemorrhage: Acute treatment and prognosis".)

ADDITIONAL SECONDARY PREVENTION STRATEGIES

●Early rhythm control – One trial suggested a benefit of early rhythm control among patients with AF who had a stroke [60]. In this study, 300 patients with AF and acute ischemic stroke were randomly assigned to early rhythm control or usual care. The rate of ischemic stroke was lower in the rhythm control group at 12 months (1.7 versus 6.3 percent); rates of mortality and hospitalizations did not differ. Rates of sustained AF were lower in the early rhythm control group compared with usual care (34 versus 63 percent) at 12 months. A potential limitation of this study was that it was non-blinded. Further randomized studies in other populations are needed before we can recommend the widespread use of early rhythm control for thromboembolism prevention in patients with stroke and AF.

●Control of hypertension – Blood pressure control is an important component of the management of patients with AF who have had a stroke. Antihypertensive therapy, preferably including an angiotensin-converting enzyme inhibitor, reduces the risk of vitamin K antagonist (VKA)-associated intracranial hemorrhage and may reduce the rate of recurrent stroke. (See "Reversal of anticoagulation in intracranial hemorrhage".)

The latter benefit was suggested in a secondary analysis from the PROGRESS trial, which demonstrated the benefit of blood pressure lowering (using perindopril-indapamide) among both hypertensive and nonhypertensive patients who had a previous stroke or transient ischemic attack (TIA) [61]. (See "Antihypertensive therapy for secondary stroke prevention".)

Among the subset of 476 patients with AF, perindopril-based therapy produced a mean 7.3/3.4 mmHg reduction in blood pressure compared with placebo and a 34 percent reduction in the incidence of recurrent stroke (13.6 versus 18.9 percent), a difference that was not statistically significant because of the small number of recurrent events [62]. However, a significant 38 percent reduction in all major vascular events (one major vascular event prevented in every 11 patients treated for five years) provides a strong rationale for lowering blood pressure.

●Revascularization for carotid artery stenosis – About 10 percent of patients with AF with ischemic stroke or TIA have a cervical carotid stenosis of 50 percent or greater diameter, slightly more than half of which are ipsilateral to the neurologic symptoms. Based on estimates of attributable risk, ipsilateral stenosis of at least 70 percent stenosis is equally likely to be the cause of cerebral ischemia as is cardiogenic embolism. Consequently, carotid revascularization with endarterectomy or stenting seems reasonable for AF patients with high-grade ipsilateral stenosis, followed by chronic anticoagulation and antiplatelet therapy. However, this approach is empiric, without good supporting evidence, and combined antiplatelet and anticoagulant therapy increases bleeding risk. The management of symptomatic carotid artery disease is discussed elsewhere. (See "Management of symptomatic carotid atherosclerotic disease".)

●Statin therapy – For most patients with ischemic stroke, we start high-intensity statin therapy. Statin therapy reduces the risk of recurrent ischemic stroke and cardiovascular events among patients with stroke of atherosclerotic origin. However, the efficacy of statin therapy specifically for patients with ischemic stroke attributed to AF has not been well studied. A report of 6116 patients with ischemic stroke who were discharged on a statin found that outpatient adherence to statin therapy was associated with a reduced risk of recurrent ischemic stroke for patients with AF as well as those without AF, even after adjustment for time in the therapeutic range of the international normalized ratio among patients with AF taking warfarin [63]. A majority of patients with AF have some concomitant atherosclerotic disease, and statin therapy is recommended for patients with atherosclerotic cardiovascular disease (such as prior acute coronary syndrome, myocardial infarction, stable or unstable angina, coronary or other arterial revascularization, ischemic stroke, TIA, or peripheral arterial disease) (see "Overview of secondary prevention of ischemic stroke", section on 'LDL-C lowering therapy'). In addition, and in the absence of defined atherosclerotic cardiovascular disease, many patients are at high risk for a cardiovascular disease event due to age and the presence of hypertension. (See "Low-density lipoprotein cholesterol-lowering therapy in the primary prevention of cardiovascular disease", section on 'Age >75 years'.)

●Lifestyle modification – Several behavioral and lifestyle modifications may be beneficial for reducing the risk of ischemic stroke and cardiovascular disease. These include smoking cessation, limited alcohol consumption, weight control, regular aerobic physical activity, salt restriction, and a Mediterranean diet. (See "Overview of secondary prevention of ischemic stroke", section on 'Lifestyle factors'.)

SUMMARY AND RECOMMENDATIONS

●Features suggestive of cardioembolic stroke – Cardioembolic stroke from atrial fibrillation (AF) is generally associated with increased severity compared with embolic stroke from carotid disease. Cardioembolic stroke may affect single or multiple vascular territories of the brain and appear as wedge-shaped infarcts involving cortex and adjacent white matter. (See 'Features suggestive of cardioembolic stroke' above.)

●Evaluation for reperfusion therapy – All patients with acute ischemic stroke should be assessed to see if they are eligible for reperfusion therapy. (See 'Is reperfusion therapy indicated?' above.)

●Comprehensive stroke evaluation – All patients with acute stroke, even in the setting of AF, need a complete evaluation for other causes of stroke; the work-up should include brain and neurovascular imaging, cardiac rhythm monitoring, and transthoracic echocardiography (TTE). Paroxysmal AF may not be detected on short-term cardiac monitoring; thus, ambulatory cardiac monitoring for two to four weeks is suggested for all adult patients with a cryptogenic ischemic stroke or cryptogenic transient ischemic attack (TIA). (See 'Diagnostic approach' above.)

●Antithrombotic therapy during the acute phase of stroke – Anticoagulation is usually temporarily withheld immediately after ischemic stroke, due to the risk of hemorrhagic transformation, and restarted within the first days to two weeks, as guided mainly by the size of the ischemic infarct. (See 'Timing after acute ischemic stroke' above.)

For patients with AF and large acute infarctions, symptomatic hemorrhagic transformation, or poorly controlled hypertension, we suggest withholding oral anticoagulation for one week (Grade 2C). (See 'Timing after acute ischemic stroke' above.)

However, early acute antiplatelet therapy (algorithm 2) may be warranted to reduce both disability and the risk of early recurrent stroke, which is 3 to 5 percent in the first two weeks. (See 'Managing antithrombotic therapy acutely' above.)

●Long-term anticoagulation – For most patients with an ischemic stroke or TIA and AF, we recommend a direct-acting oral anticoagulant (DOAC) rather than a vitamin K antagonist (VKA) (Grade 1A). DOACs are more efficacious at preventing recurrent stroke and have lower rates of major hemorrhage. However, a VKA is indicated for patients with moderate to severe mitral stenosis or any mechanical heart valve and is generally preferred for patients with severely impaired kidney function. (See 'Long-term anticoagulation' above.)

●When long-term anticoagulation is not an option – Left atrial appendage (LAA) occlusion should be considered for patients who can tolerate short-term (45-day) antithrombotic therapy. (See 'Anticoagulant-intolerant patients' above.)

●Anticoagulation treatment failure

•Determining the cause – For patients with AF who develop an ischemic stroke while on anticoagulation, subtherapeutic intensity of anticoagulation (eg, inappropriate low-dose DOAC, missed DOAC doses, or low international normalized ratio [INR] on warfarin) at the time of stroke is the most common cause of treatment failure. Nevertheless, all such patients should have a thorough evaluation (including brain and neurovascular imaging, and echocardiography) to determine if the most likely cause of stroke is cardioembolic due to AF, or noncardioembolic due to another mechanism. (See 'Determining the cause of recurrent stroke' above.)

•DOAC treatment failure – In this setting, verifying that the correct DOAC dose is prescribed and that the patient is compliant is important. If a thrombus is present despite appropriate dosing and compliance, it is reasonable to change to another DOAC, but optimal treatment is uncertain. (See 'Direct-acting oral anticoagulant treatment failure' above.)

•Warfarin treatment failure – In this setting with a therapeutic INR, options include switching to a DOAC (if not contraindicated), increasing the target INR to 2.5 to 3.5, or considering LAA occlusion. For patients with a subtherapeutic INR at the time of the stroke, an attempt should be made to identify the cause (eg, poor compliance, drug or food interaction) and to consider switching to a DOAC.

●Hemorrhagic stroke on anticoagulation – For patients on anticoagulation who develop a hemorrhagic stroke, anticoagulation and antiplatelet drugs should be discontinued, and medications to reverse the effects of anticoagulant drugs should be given immediately. These and other measures are reviewed separately. (See "Reversal of anticoagulation in intracranial hemorrhage" and "Spontaneous intracerebral hemorrhage: Acute treatment and prognosis".)