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Stroke in patients with atrial fibrillation

author: Warren J Manning, MD
section editors: Peter J Zimetbaum, MD, Scott E Kasner, MD
deputy editors: Susan B Yeon, MD, JD, John F Dashe, MD, PhD

All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: Feb 2024.

This topic last updated: Jul 21, 2023.

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 (LAA), 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".)

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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 – AF is associated with more severe ischemic strokes and "longer" transient ischemic
attacks (TIAs) than emboli from carotid disease, presumably due to embolization of larger thrombi with AF [1,2]. 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]. The "longer" TIAs typical in AF patients are more often associated
with abnormal magnetic resonance diffusion imaging and would be classified as strokes by the revised American Heart
Association definition [6]. (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 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 [7].

Silent cerebral infarction — In addition to causing symptomatic stroke with major deficits, AF is also associated with silent
cerebral infarctions (SCIs) and TIA [8-13]. SCI is characterized by brain lesions that have 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 SCI lesions on magnetic resonance imaging and computed tomography among patients with AF
was 40 and 22 percent, respectively [12]. In this review, AF was associated with more than a twofold increased risk of SCI in

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

However, contraindications to IVT 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 renal 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 select patients with acute ischemic stroke caused by an intracranial large
artery occlusion in the proximal anterior circulation who can be treated within 24 hours of the time last known to be

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well ( algorithm 1). (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 [14,15]. As an example, the National Institute of
Neurological Disorders and Stroke (NINDS) trial included 115 patients with AF (18 percent) [14]. 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 [15]. (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 [16]. As a result, all patients with a stroke, even in the
setting of AF, need a complete evaluation for other causes of stroke, especially if they would result in different treatment.

The evaluation is generally the same as the evaluation 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, other sources 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'.)

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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 [17]. 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 several 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. Because chronic anticoagulation with warfarin or
one of the DOACs 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/detected 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 [18,19].

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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 [20] 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)
[19].

Thus, for patients with AF, diagnostic evaluation by TEE to search for a residual intraatrial thrombus is not essential since the
absence of a thrombus will not alter the long-term clinical (anticoagulation) management. However, TEE to confirm absence
of residual thrombus prior to cardioversion may be reasonable for those in whom a rhythm strategy is going to 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 [21,22]. 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.)

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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

Patients who have had a prior embolic event already have the most potent risk factor for subsequent stroke. The risk of
recurrent stroke in the first few weeks after the initial event is 3 to 5 percent based upon large numbers of patients observed
in the control arms of randomized trials [21,22]. In addition, a risk of up to 12 percent per year has been reported in
nonanticoagulated patients in the first two to three years after a stroke [23,24].

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).

LONG-TERM ANTICOAGULATION

Indications — For most patients with ischemic stroke and AF, chronic oral anticoagulation is recommended to reduce the
risk of thromboembolism and recurrent ischemic stroke, independent of the cause of the stroke.

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'.)

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

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● DOACs – 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). DOACS
are also preferred over VKAs for patients with AF and other indications for anticoagulation. (See "Atrial fibrillation in
adults: Use of oral anticoagulants".)

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) [25]. 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 [26]. In other clinical trials of patients with prior stroke or TIA, both edoxaban [27] and
rivaroxaban [28] were found to be noninferior to warfarin with respect to future stroke prevention.

● Warfarin – Aspirin alone offers inadequate protection, with a stroke risk that averaged 10 percent per year in a pooled
analysis of individual participants from six randomized trials [29]. Compared with aspirin, treatment with adjusted-dose
warfarin (international normalized ratio 2 to 3) reduced this risk 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 [30]. 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.

In addition, 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 [31,32]. This is likely explained by a
higher fraction of nonembolic strokes among anticoagulated AF patients and small size of embolic strokes. Anticoagulation
greatly reduced the likelihood of large stroke due to left atrial emboli, so that the remaining strokes are from cerebral small
artery disease or other mechanisms [31].

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

The decision of whether to use chronic oral anticoagulants must take both benefit and risk into account 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 [33]. (See "Atrial fibrillation in adults: Selection of candidates for anticoagulation".)

Choosing between direct-acting oral anticoagulants and warfarin — For most patients with stroke or TIA and AF who do
not have a specific indication for warfarin or another VKA, a DOAC is preferred to a VKA. (See "Atrial fibrillation in adults: Use
of oral anticoagulants" and "Atrial fibrillation in adults: Use of oral anticoagulants", section on 'Approach to anticoagulation'.)

Situations where a VKA is indicated (rather than a DOAC) include the following [33]:

● Moderate to severe mitral stenosis

● Mechanical heart valve in any location

Warfarin is generally preferred for patients with severely impaired kidney function, since all DOACs are excreted by the kidney
to some degree. (See "Direct oral anticoagulants (DOACs) and parenteral direct-acting anticoagulants: Dosing and adverse
effects", section on 'Chronic kidney disease'.)

Dosing — Dosing recommendations for DOACs ( table 3) are reviewed in detail elsewhere. (See "Direct oral anticoagulants
(DOACs) and parenteral direct-acting anticoagulants: Dosing and adverse effects".)

Note that there are legitimate reasons for DOAC dose reductions, which differ according to the specific agent. In general,
clinical settings in which dose modification may be indicated include older age, low body weight, renal insufficiency, 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 INR between 2 and 3 is recommended, with an average annual time

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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 (after 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 to two weeks is generally recommended for those with large ischemic stroke,
symptomatic hemorrhagic transformation, or poorly controlled hypertension [34-38]. Patients may benefit from aspirin until
therapeutic anticoagulation is achieved [39]. (See "Early antithrombotic treatment of acute ischemic stroke and transient
ischemic attack".)

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 [40].
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

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territory of the acute ischemic stroke. In such cases, it is usually impossible to determine with certainty 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 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 [33]. (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, but 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 [41], which is much lower compared with the risk of cardioembolic stroke due to AF [33].

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'.)

Anticoagulant-intolerant patients — Left atrial appendage (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.

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

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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 left atrial appendage (LAA) thrombus and other potential
cardiac sources of embolism. (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 [42-44]. 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 [44,45].

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 [44]:

● 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 [44]:

● 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

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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 [46]. 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 despite appropriate dosing and compliance, it is reasonable to change to another DOAC, but optimal treatment is
uncertain, and no consensus exists. A retrospective study suggested that for patients with left ventricular thrombus, warfarin
may be superior to DOAC for reducing the risk of stroke or systemic embolism [47]. Analogous data for AF patients with LAA
thrombi are not available.

Regardless, 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.

Warfarin treatment failure — In patients with AF who suffer ischemic stroke during warfarin anticoagulation, the intensity
of anticoagulation is most often subtherapeutic (INR less than 2), and continuing warfarin after one to two weeks of
temporary interruption for patients with large infarcts or shorter interruption with small infarcts with renewed efforts to
keep the INR in the 2 to 3 therapeutic range or consideration of a change to a DOAC is advised.

When ischemic stroke occurs with a therapeutic INR (2 to 3), we favor increasing the target INR to 2.5 to 3.5, or switching
from warfarin to a DOAC rather than routine addition of antiplatelet therapy. The addition of antiplatelet therapy is known to
increase major hemorrhage (and particularly brain hemorrhage), and the benefit is less well defined.

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

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"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
[48]. 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 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) [49]. (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 [50].
However, there was a significant 38 percent reduction in all major vascular events (one major vascular event prevented
in every 11 patients treated for five years), providing a strong rationale for blood pressure lowering.

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● 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
neurological 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, although this approach is empiric, without good supporting evidence,
and the use of 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 statin therapy. Statin therapy reduces the risk of
recurrent ischemic stroke and cardiovascular events among patients with stroke of atherosclerotic origin, although the
efficacy of statin therapy specifically for patients with ischemic stroke attributed to AF has not been well studied.
However, 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 (INR)
among patients with AF taking warfarin [51]. Many patients with AF have 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 – A number of 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

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prevention of ischemic stroke", section on 'Lifestyle modification'.)

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 echocardiography. Paroxysmal AF may not be detected on short-term cardiac monitoring; thus,
ambulatory cardiac monitoring for several 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 to two weeks (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.)

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● 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.)

● 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, it is important to verify that the correct DOAC dose is prescribed and that
the patient is compliant. 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, options include increasing the target INR to 2.5 to 3.5, switching to a
DOAC, 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 if the annual time in therapeutic range has been less than 70 percent.

● 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

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prognosis".)

Use of UpToDate is subject to the Terms of Use.

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38. Kirchhof P, Benussi S, Kotecha D, et al. 2016 ESC Guidelines for the management of atrial fibrillation developed in
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44. Polymeris AA, Meinel TR, Oehler H, et al. Aetiology, secondary prevention strategies and outcomes of ischaemic stroke
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45. Freedman B, Martinez C, Katholing A, Rietbrock S. Residual Risk of Stroke and Death in Anticoagulant-Treated Patients
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47. Robinson AA, Trankle CR, Eubanks G, et al. Off-label Use of Direct Oral Anticoagulants Compared With Warfarin for Left
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GRAPHICS

Eligibility criteria for the treatment of acute ischemic stroke with intravenous thrombolysis
(recombinant tissue plasminogen activator or tPA)

Inclusion criteria

▪ Clinical diagnosis of ischemic stroke causing measurable neurologic deficit

▪ Onset of symptoms <4.5 hours before beginning treatment; if the exact time of stroke onset is not known, it is defined as the last time
the patient was known to be normal or at neurologic baseline
▪ Age ≥18 years

Exclusion criteria
Patient history
▪ Ischemic stroke or severe head trauma in the previous three months
▪ Previous intracranial hemorrhage
▪ Intra-axial intracranial neoplasm
▪ Gastrointestinal malignancy
▪ Gastrointestinal hemorrhage in the previous 21 days
▪ Intracranial or intraspinal surgery within the prior three months

Clinical
▪ Symptoms suggestive of subarachnoid hemorrhage
▪ Persistent blood pressure elevation (systolic ≥185 mmHg or diastolic ≥110 mmHg)
▪ Active internal bleeding
▪ Presentation consistent with infective endocarditis
▪ Stroke known or suspected to be associated with aortic arch dissection
▪ Acute bleeding diathesis, including but not limited to conditions defined under 'Hematologic'

Hematologic
▪ Platelet count <100,000/mm 3 *

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▪ Current anticoagulant use with an INR >1.7 or PT >15 seconds or aPTT >40 seconds*
▪ Therapeutic doses of low molecular weight heparin received within 24 hours (eg, to treat VTE and ACS); this exclusion does not apply
to prophylactic doses (eg, to prevent VTE)
▪ Current use (ie, last dose within 48 hours in a patient with normal renal function) of a direct thrombin inhibitor or direct factor Xa
inhibitor with evidence of anticoagulant effect by laboratory tests such as aPTT, INR, ECT, TT, or appropriate factor Xa activity assays

Head CT
▪ Evidence of hemorrhage
▪ Extensive regions of obvious hypodensity consistent with irreversible injury

Warnings ¶

▪ Only minor and isolated neurologic signs or rapidly improving symptoms Δ

▪ Serum glucose <50 mg/dL (<2.8 mmol/L) ◊
▪ Serious trauma in the previous 14 days §
▪ Major surgery in the previous 14 days ¥
▪ History of gastrointestinal bleeding (remote) or genitourinary bleeding ‡
▪ Seizure at the onset of stroke with postictal neurologic impairments †
▪ Pregnancy**
▪ Arterial puncture at a noncompressible site in the previous seven days ¶¶
▪ Large (≥10 mm), untreated, unruptured intracranial aneurysm ¶¶
▪ Untreated intracranial vascular malformation ¶¶

Additional warnings for treatment from 3 to 4.5 hours from symptom onset ΔΔ
▪ Age >80 years
▪ Oral anticoagulant use regardless of INR
▪ Severe stroke (NIHSS score >25)
▪ Combination of both previous ischemic stroke and diabetes mellitus

ACS: acute coronary syndrome; aPTT: activated partial thromboplastin time; ECT: ecarin clotting time; INR: international normalized ratio;
PT: prothrombin time; NIHSS: National Institutes of Health Stroke Scale; tPA: tissue plasminogen activator (alteplase or tenecteplase); TT:
thrombin time; VTE: venous thromboembolism.

* Although it is desirable to know the results of these tests, thrombolytic therapy should not be delayed while results are pending unless

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(1) there is clinical suspicion of a bleeding abnormality or thrombocytopenia, (2) the patient is currently on or has recently received
anticoagulants (eg, heparin, warfarin, a direct thrombin inhibitor, or a direct factor Xa inhibitor), or (3) use of anticoagulants is not known.
Otherwise, treatment with intravenous tPA can be started before availability of coagulation test results but should be discontinued if the
INR, PT, or aPTT exceed the limits stated in the table, or if platelet count is <100,000 mm 3 .

¶ With careful consideration and weighting of risk-to-benefit, patients may receive intravenous thrombolysis despite one or more
warnings.

Δ Patients who have a persistent neurologic deficit that is potentially disabling, despite improvement of any degree, should be treated
with intravenous thrombolysis in the absence of other contraindications. Any of the following should be considered disabling deficits:
▪ Complete hemianopia: ≥2 on NIHSS question 3, or
▪ Severe aphasia: ≥2 on NIHSS question 9, or
▪ Visual or sensory extinction: ≥1 on NIHSS question 11, or
▪ Any weakness limiting sustained effort against gravity: ≥2 on NIHSS question 5 or 6, or
▪ Any deficits that lead to a total NIHSS >5, or
▪ Any remaining deficit considered potentially disabling in the view of the patient and the treating practitioner using clinical
judgment

◊ Patients may be treated with intravenous thrombolysis if glucose level is subsequently normalized.

§ The potential risks of bleeding with tPA from injuries related to the trauma should be weighed against the anticipated benefits of
reduced stroke-related neurologic deficits.

¥ The increased risk of surgical site bleeding with tPA should be weighed against the anticipated benefits of reduced stroke-related
neurologic deficits.

‡ There is a low increased risk of new bleeding with tPA in the setting of past gastrointestinal or genitourinary bleeding. However, tPA
administration within 21 days of gastrointestinal bleeding is not recommended.

† Intravenous thrombolysis is reasonable in patients with a seizure at stroke onset if evidence suggests that residual impairments are
secondary to acute ischemic stroke and not to a postictal phenomenon.

** tPA can be given in pregnancy when the anticipated benefits of treating moderate or severe stroke outweigh the anticipated increased
risks of uterine bleeding.

¶¶ The safety and efficacy of administering tPA is uncertain for these relative exclusions.

ΔΔ Although these were exclusions in the trial showing benefit in the 3 to 4.5 hour window, intravenous tPA appears to be safe and may
be beneficial for patients with these criteria, including patients taking oral anticoagulants with an INR <1.7.

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Adapted from:
1. Hacke W, Kaste M, Bluhmki E, et al. Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. N Engl J Med 2008; 359:1317.
2. Del Zoppo GJ, Saver JL, Jauch EC, et al. Expansion of the time window for treatment of acute ischemic stroke with intravenous tissue plasminogen activator. A
science advisory from the American Heart Association/American Stroke Association. Stroke 2009; 40:2945.
3. Re-examining Acute Eligibility for Thrombolysis (TREAT) Task Force:, Levine SR, Khatri P, et al. Review, historical context, and clarifications of the NINDS rt-PA stroke
trials exclusion criteria: Part 1: rapidly improving stroke symptoms. Stroke 2013; 44:2500.
4. Demaerschalk BM, Kleindorfer DO, Adeoye OM, et al. Scientific rationale for the inclusion and exclusion criteria for intravenous alteplase in acute ischemic stroke: A
statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2016; 47:581.
5. Powers WJ, Rabinstein AA, Ackerson T, et al. Guidelines for the Early Management of Patients With Acute Ischemic Stroke: 2019 Update to the 2018 Guidelines for
the Early Management of Acute Ischemic Stroke: A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association. Stroke
2019; 50:e344.

Graphic 71462 Version 27.0

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Patient selection for mechanical thrombectomy to treat acute ischemic stroke

MT should be performed at a stroke center with appropriate neurointerventional expertise. The TLKW is judged to be the time of stroke

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symptom onset (if known), or the time the patient was last seen at their baseline for patients with wake-up stroke or those found down.
The ASPECTS method is used to assess the extent of ischemic changes on head CT or DWI. Refer to UpToDate topics for a full discussion
of MT, including calculation of ASPECTS, NIHSS, and mRS, and other clinical issues pertaining to MT.

ACA: anterior carotid artery; ASPECTS: Alberta Stroke Program Early CT Score; CT: computed tomography; CTA: computed tomography
angiography; CTP: computed tomography perfusion; DSA: digital subtraction angiography; DWI: diffusion-weighted magnetic resonance
imaging; ICA: internal carotid artery; LVO: large vessel (artery) occlusion; MCA: middle cerebral artery; MRA: magnetic resonance
angiography; MRI: magnetic resonance imaging; mRS: modified Rankin Scale; MT: mechanical thrombectomy; NIHSS: National Institutes
of Health Stroke Scale; PWI: perfusion-weighted magnetic resonance imaging.

* All patients with acute ischemic stroke should be simultaneously evaluated for treatment with intravenous thrombolysis; refer to
UpToDate topics for details.

¶ Urgent imaging is usually done with CT and CTA, less often with MRI and MRA.

Δ Advanced imaging is not essential but can be used at centers with CTP or DWI/PWI and automated software imaging analysis to
determine infarct volume; patients can be selected for MT if they have salvageable brain tissue with a mismatch between a relatively
larger area of hypoperfusion (ischemic penumbra) and a smaller area of irreversibly injured brain tissue (infarct core). Refer to UpToDate
text for details.

◊ There is intracranial arterial occlusion of the distal ICA, or the M1 or proximal M2 segment of the MCA, as shown by CTA, MRA, or DSA.

§ MT may be a treatment option at expert stroke centers for patients with basilar artery LVO, but benefit is uncertain.

Graphic 141874 Version 2.0

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Pathophysiologic ischemic stroke classification

Large vessel atherothrombotic stroke

More common

Bifurcation of the common carotid artery

Siphon portion of the common carotid artery

Middle cerebral artery stem

Intracranial vertebral arteries proximal to middle basilar artery

Origin of the vertebral arteries

Less common

Origin of the common carotid artery

Posterior cerebral artery stem

Origin of the major branches of the basilar-vertebral arteries

Origin of the branches of the anterior, middle, and posterior cerebral arteries

Small vessel (lacunar) stroke

Mechanism

Lipohyalinotic occlusion

Less frequently proximal atherothrombotic occlusion

Least likely embolic occlusion

Most common locations

Penetrating branches of the anterior, middle, and posterior cerebral and basilar arteries

Cardioaortic embolic stroke

Cardiac sources definite - antithrombotic therapy generally used

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Left atrial thrombus

Left ventricular thrombus

Atrial fibrillation and paroxysmal atrial fibrillation

Sustained atrial flutter

Recent myocardial infarction (within one month)

Rheumatic mitral or aortic valve disease

Bioprosthetic and mechanical heart valve

Chronic myocardial infarction with ejection fraction <28 percent

Symptomatic heart failure with ejection fraction <30 percent

Dilated cardiomyopathy

Cardiac sources definite - anticoagulation hazardous

Bacterial endocarditis (exception nonbacterial)

Atrial myxoma

Cardiac sources possible

Mitral annular calcification

Patent foramen ovale

Atrial septal aneurysm

Atrial septal aneurysm with patent foramen ovale

Left ventricular aneurysm without thrombus

Isolated left atrial spontaneous echo contrast ("smoke") without mitral stenosis or atrial fibrillation

Mitral valve strands

Ascending aortic atheromatous disease (>4 mm)

True unknown source embolic stroke

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Other
Dissection

Moyamoya

Binswanger's disease

Primary thrombosis

Cerebral mass

Graphic 55099 Version 4.0

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Immediate antithrombotic treatment of acute ischemic stroke

This algorithm is intended to provide basic guidance regarding the immediated use of antithrombotic therapy for patients with an acute
ischemic stroke. For further details, including scoring of the NIHSS and suggested dosing regimens of antithrombotic agents, refer to the
relevant UpToDate topic reviews.

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OA: oral anticoagulants; IVT: intravenous thrombolysis; MT: mechanical thrombectomy; NIHSS: National Institutes of Health Stroke Scale;
DAPT: dual antiplatelet therapy (eg, aspirin and clopidogrel, or aspirin and ticagrelor).

* Refer to text and associated algorithm for details.

¶ Brain and large vessel imaging, cardiac evaluation, and (for select patients) other laboratory tests.

Δ For severe systemic or symptomatic intracranial bleeding, withhold all anticoagulant and antiplatelet therapy for one to two weeks or
until the patient is stable.

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Antithrombotic therapy according to cause of acute ischemic stroke

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This algorithm is intended to provide basic guidance regarding the immediate use of antithrombotic therapy for patients with an acute
ischemic stroke. For further details, including scoring of the NIHSS and suggested dosing regimens of antithrombotic agents, refer to the
relevant UpToDate topic reviews.

HTN: hypertension; SBP: systolic blood pressure; DBP: diastolic blood pressure; ICA: internal carotid artery; CEA: carotid endarterectomy;
OA: oral anticoagulation; CAS: carotid artery stenting; DAPT: dual antiplatelet therapy (eg, aspirin and clopidogrel, or aspirin and
ticagrelor); NIHSS: National Institutes of Health Stroke Scale; CT: computed tomography; MRI: magnetic resonance imaging.

* Brain and neurovascular imaging, cardiac evaluation, and (for select patients) other laboratory tests.

¶ Indications for long-term oral anticoagulation include atrial fibrillation, ventricular thrombus, mechanical heart valve, and treatment of
venous thromboembolism.

Δ "Large" infarcts are defined as those that involve more than one-third of the middle cerebral artery territory or more than one-half of
the posterior cerebral artery territory based upon neuroimaging with CT or MRI. Though less reliable, large infarct size can also be
defined clinically (eg, NIHSS score >15).

◊ Long-term aspirin therapy is alternative (though less effective) if OA contraindicated or refused.

§ Direct oral anticoagulant agents have a more rapid anticoagulant effect than warfarin, a factor that may influence the choice of agent
and timing of OA initiation.

¥ Some experts prefer DAPT, based upon observational evidence.

‡ Long-term single-agent antiplatelet therapy for secondary stroke prevention with aspirin, clopidogrel, or aspirin-extended-release
dipyridamole.

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Standard dosing of direct oral anticoagulants

Nonvalvular AF - stroke
Anticoagulant VTE treatment ¶ VTE primary prophylaxis Δ
prophylaxis*

Dabigatran (Pradaxa) 150 mg twice daily Parenteral anticoagulation for 5 110 mg for the first day, then
to 10 days; then dabigatran 150 220 mg once daily
mg twice daily

Apixaban (Eliquis) 5 mg twice daily 10 mg twice daily for one week, 2.5 mg twice daily
then 5 mg twice daily

Edoxaban (Savaysa, Lixiana) 60 mg once daily Parenteral anticoagulation for 5

to 10 days; then edoxaban 60
mg once daily

Rivaroxaban (Xarelto) 20 mg once daily with the 15 mg twice daily with food for 10 mg once daily, with or
evening meal three weeks; then 20 mg once without food
daily with food

This is a simplified table that lists the most common dosing in individuals with normal renal function, normal weight, and lack of
concomitant interacting medications (eg, P-glycoprotein inhibitors or inducers). Refer to UpToDate topics on AF, VTE treatment, VTE
prophylaxis, and DOAC dosing for possible changes based on impaired renal function or extremes of weight. Other factors may influence
dosing in individual patients.

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AF: atrial fibrillation; VTE: venous thromboembolism, includes deep vein thrombosis and pulmonary embolism; DOAC: direct oral
anticoagulant.

* Dosing may be reduced for certain drugs in certain settings (eg, use of dabigatran 110 mg twice daily for individuals who are at
increased risk of bleeding; refer to UpToDate topic on anticoagulation for atrial fibrillation for other examples).

¶ Treatment for acute VTE typically refers to the first three to six months of administration; continued treatment beyond six months may
be done with a lower dose for some anticoagulants (eg, apixaban, rivaroxaban); the dose is not lowered when therapy is continued using
dabigatran or edoxaban. Refer to the latest prescribing information for each individual anticoagulant.

Δ Prophylaxis refers to primary prophylaxis in settings such as after knee or hip surgery.

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Contributor Disclosures
Warren J Manning, MD Equity Ownership/Stock Options: Pfizer [Anticoagulants]. All of the relevant financial relationships listed have
been mitigated. Peter J Zimetbaum, MD Consultant/Advisory Boards: Abbott Medical [Lead extraction]. All of the relevant financial
relationships listed have been mitigated. Scott E Kasner, MD Grant/Research/Clinical Trial Support: Bayer [Stroke]; Bristol Meyers Squibb
[Stroke]; Diamedica [Stroke]; Genentech [Stroke]; WL Gore and Associates [Stroke]. Consultant/Advisory Boards: Abbvie [Stroke];
AstraZeneca [Stroke]; NovoNordisk [Stroke]. All of the relevant financial relationships listed have been mitigated. Susan B Yeon, MD, JD No
relevant financial relationship(s) with ineligible companies to disclose. John F Dashe, MD, PhD No relevant financial relationship(s) with
ineligible companies to disclose.

Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a
multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced
content is required of all authors and must conform to UpToDate standards of evidence.

Conflict of interest policy

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