Published online: 2021-04-13

Atrial Fibrillation and Ischemic Stroke: A Clinical

Review
Ibrahim Migdady, MD1 Andrew Russman, DO2 Andrew B. Buletko, MD2

1 Division of Neurocritical Care, Department of Neurology,
Massachusetts General Hospital, Harvard Medical School, Boston,
Massachusetts
2 Cerebrovascular Center, Neurological Institute, Cleveland Clinic,
Cleveland, Ohio
Address for correspondence Andrew B. Buletko, MD, Cerebrovascular
Center, Neurological Institute, Cleveland Clinic, 9500 Euclid Avenue,
S80, Cleveland, OH 44195-5243 (e-mail: buletka@ccf.org).

Semin Neurol

Abstract Atrial fibrillation (AF) is an important risk factor for ischemic stroke resulting in a
fivefold increased stroke risk and a twofold increased mortality. Our understanding of
stroke mechanisms in AF has evolved since the concept of atrial cardiopathy was
introduced as an underlying pathological change, with both AF and thromboembolism

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Keywords
► ischemic stroke
► atrial fibrillation
► thromboembolism
► anticoagulation
► left atrial appendage
closure
being common manifestations and outcomes. Despite the strong association with
stroke, there is no evidence that screening for AF in asymptomatic patients improves
clinical outcomes; however, there is strong evidence that patients with embolic stroke
of undetermined source may require long-term monitoring to detect silent or
paroxysmal AF. Stroke prevention in patients at risk, assessed by the CHA2DS2-VASc
score, was traditionally achieved with warfarin; however, direct oral anticoagulants
have solidified their role as safe and effective alternatives. Additionally, left atrial
appendage exclusion has emerged as a viable option in patients intolerant of anti-
coagulation. When patients with AF have an acute stroke, the timing of initiation or
resumption of anticoagulation for secondary stroke prevention has to be balanced
against the risk of hemorrhagic conversion. Multiple randomized clinical trials are
currently underway to determine the best timing for administration of anticoagulants
following acute ischemic stroke.

Stroke represents the fifth leading cause of death in the
United States, killing one person every 4 minutes.1 The global
burden of stroke is even more striking, as stroke is the second
leading cause of death worldwide after ischemic heart
disease.2 Similarly, stroke is the second largest contributor
to long-term disability in developing countries (third in
developed countries), where around 50% of stroke patients
suffer from reduced mobility, and 26% remain disabled in
basic activities of daily living (ADLs) after stroke.3 Given the
high mortality and morbidity associated with stroke, its risk
factors, such as atrial fibrillation (AF), has been studied
extensively. AF, the most common cardiac arrhythmia, has
an increasing prevalence and incidence worldwide and is
independently associated with a twofold risk of mortality.4,5
AF results in a fivefold increased risk of stroke, and ischemic
stroke or transient ischemic attack (TIA) represents the first
manifestation of AF in 2 to 5% of patients.6
This article aims to review the most current evidence
behind the association between AF and stroke: its patho-
physiology, evaluation, management, and future research
directions.
Pathophysiology of Atrial Fibrillation and
Associated Stroke
AF is a supraventricular arrhythmia characterized by rapid
and disorganized atrial activity leading to impaired atrial
contraction, manifesting on electrocardiogram (ECG) by the

Issue Theme Neurology of © 2021. Thieme. All rights reserved. DOI https://doi.org/
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Atrial Fibrillation and Ischemic Stroke Migdady et al.

absence of P-wave and irregular R-R intervals. AF represents
the final manifestation of several mechanisms that contrib-
ute to abnormal electrical generation and conduction; these
mechanisms are either structural (atrial fibrosis, dilation,
hypertrophy, and remodeling) or electrophysiological (in-
volving atrial conduction, automaticity, and intracellular
Caþ2 handling) or both.7,8 AF develops when these mecha-
nisms trigger a process of rapid electrical excitation, circuit
reentry, and left atrial dyssynchrony coupled with irregular
ventricular excitation.9,10 Multiple factors have been shown
to result in a vulnerable atrial substrate that can promote the
initiation and perpetuation of AF; these factors include
increasing age, male sex, hypertension, smoking, obesity,
diabetes mellitus, obstructive sleep apnea, sedentary life
style, and genetic predisposition.11–13
AF results in impaired atrial contraction, reduced atrial
emptying, blood stasis, thrombogenesis, and thromboembo-
lism. The association of AF with atrial fibrosis, atrial dilata-
tion, myofibrillar oxidative damage, and endothelial
dysfunction further complicates the presumed causal rela-
helpful in patients with atrial cardiopathy with or without
AF. At the time of this article preparation, the ARCADIA trial
(AtRial Cardiopathy and Antithrombotic Drugs In Prevention
After Cryptogenic Stroke) is currently underway to test this
hypothesis.21
Pattern of Stroke in Atrial Fibrillation
Infarct distribution in patients with AF is similar to other
cardioembolic etiologies such as intracardiac thrombus,
valvular heart disease, and cardiomyopathy. Neurologic def-
icits consistent with large-territory infarct may occur. Sub-
cortical infarcts can also occur and may be difficult to
differentiate from lacunar infarcts due to small vessel disease
(SVD).22 Magnetic resonance imaging (MRI) of the brain,
especially diffusion-weighted imaging (DWI), is extremely
helpful in this setting, as larger subcortical strokes (>1.5 cm)
are more suggestive of thromboembolism.23–25 It may also
be difficult to differentiate the etiology of an embolic-
appearing stroke if the patient has large-artery atheroscle-
rosis in a vessel supplying the stroke territory, as atheroem-

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tionship between AF and stroke14–16; left atrial thromboem-
bolism has been shown to occur even in the absence of
AF.17,18 While undiagnosed AF is suspected to be the cause of
many cryptogenic strokes, only one-third of patients with
cryptogenic stroke were found to have AF after long-term
follow-up with continuous implantable cardiac monitoring
(ICM).19
Atrial cardiopathy has been recognized as a host of
underlying pathological tissue changes, with both AF and
thromboembolism being common manifestations and out-
comes.20 This change of understanding in the pathophysiol-
ogy of stroke in patients with AF has clinical and treatment
implications, as it may suggest that anticoagulation could be
bolic strokes can cause similar clinical presentation and
pattern on MRI. Strokes in multiple vascular distributions
(especially in areas not supplied by the atherosclerotic
vessel) are more suggestive of a proximal, cardioembolic
source. ►Fig. 1 depicts an example of an acute ischemic
stroke due to AF.
Diagnosis of Atrial Fibrillation
AF is diagnosed when monitoring of cardiac electrical activi-
ty reveals an irregular heart rhythm with the absence of P
waves lasting  30 seconds or throughout the entire 10-
second 12-lead standard ECG.26 However, this 30-second

Fig. 1 Acute right middle cerebral artery stroke in a patient with atrial fibrillation. A 55-year-old male with history of paroxysmal atrial fibrillation
(not on anticoagulation) presented with acute onset left-sided weakness (arm affected more than leg), facial droop, hemispatial neglect,
hemianopia, and right-sided gaze preference. He presented beyond 4.5 hours; thus, he was not eligible for tissue-plasminogen activator therapy.
An emergent magnetic resonance diffusion-weighted imaging of the brain (A, B) showed a large acute infarct involving the right insular cortex,
pre- and post-central gyri and temporal operculum consistent with right middle cerebral artery (MCA) distribution stroke. An emergent cerebral
angiography (C) was performed and revealed occlusion of both M2 divisions of the right MCA (white arrows). An attempted thrombectomy failed
to retrieve the thrombi. Given the history of atrial fibrillation, large-territory cortical infarct, and the absence of proximal atherosclerotic disease,
a cardioembolic stroke due to atrial fibrillation was deemed most likely.

Seminars in Neurology © 2021. Thieme. All rights reserved.


definition has been questioned recently, as it does not appear
to relate to clinically meaningful outcomes.27 Although AF is
often asymptomatic,28 it is usually suspected when patients
present with intermittent palpitations, syncope, chest pain,
or shortness of breath that may or may not correlate to the
arrhythmia.29 Since AF could be paroxysmal (lasting <7 days)
or persistent (>7 days), it is often missed on a 10-second
standard ECG or even ambulatory (Holter) 24-hour or longer
monitoring.29 Long-standing persistent AF lasts at least
1 year. AF is termed “permanent” or “chronic” in patients
with persistent AF when the patient and physician decide not
to pursue rhythm control.
Screening in Asymptomatic Patients
At the time of this article preparation, there is no evidence to
suggest that screening for AF in asymptomatic patients (sub-
clinical or silent AF) using ECG or a wearable device results in
better clinical outcomes.30 In 2018, the United States Preven-
tative Services Task Force (USPSTF) reviewed randomized and
observational studies evaluating systematic screening with
ECG for asymptomatic patients  65 years old; while AF detec-
tion increased (from 0.6 to 2.8% over 1 year), there was
insufficient data to support a net benefit in clinical outcomes.30
The mHealth Screening to Prevent Strokes (mSToPS) trial
(2018)31 studied the use of a wearable device in asymptomatic
patients comparing immediate screening of high-risk AF
patients to delayed screening (at 4 months) and showed an
increased detection rate from 0.9 to 3.9% with immediate
monitoring. More recently, the Apple Heart Study (2019)32
monitored patients without a self-reported history of AF using
an Apple Watch sensor to detect irregular pulse rate. An
irregular pulse notification algorithm was used by wearing
an ECG patch up to 7 days. The diagnostic yield of ECG patches
was 34% (18% in patients <40 years, 35% in patients  65 years
old). Among patients who were notified of an irregular pulse
and underwent ECG, the positive predictive value for AF
detection was 84%. In both of these studies, the effect of
increased detection rate of AF on management decisions
was not thoroughly studied. The risk of ischemic stroke in
patients with subclinical (asymptomatic) AF was demonstrat-
ed in the ASSERT trial (2012)33 which evaluated older adults
(65 years old) with no known history of AF who had a
pacemaker or defibrillator inserted for other reasons. Subclin-
ical AF was detected in 10.1% of patients by 3 months, and
stroke or systemic embolism occurred in 4.2% of those with
subclinical AF detected in the first 3 months.
Diagnosis in Patients with Transient Ischemic Attack
or Stroke
It is well established that longer cardiac monitoring is often
required to confirm the diagnosis of AF in patients with history
of TIA or stroke. The EMBRACE trial (2014)34 was a multicenter,
randomized controlled trial (RCT) that assessed the detection
rate of AF in patients older than 55 years who had no history of
AF and had ischemic stroke or TIA of undetermined source,
comparing 30-day ECG monitoring (using external event-
triggered loop recorder) to conventional 24-hour monitor
(Holter). The 30-day ECG monitoring was superior to 24-
Atrial Fibrillation and Ischemic Stroke Migdady et al.
hour ECG monitoring for the detection of AF (16.1 vs. 3.2%;
p < 0.001); it was estimated that for every eight patients
monitored using the extended loop recorder, one patient
had a missed diagnosis of AF on the 24-hour monitor. The
CRYSTAL AF trial (2014)19 was also a multicenter, RCT that
assessed detection rate of AF in a similar population of patients
with AF, comparing ICM to conventional methods using Holter
monitoring or telemetry. Although the primary outcome (6-
month AF detection rate) was significantly higher in the ICM
group (12.4 vs 2%; p < 0.001), long-term follow-up (36
months) revealed a detection rate of 30% in the ICM group
compared with 3% in the control group (p < 0.001). Based on
these results, the 2019 American Heart Association (AHA)/
American College of Cardiology (ACC)/Heart Rhythm Society
(HRS) Focused Update for Management of patients with Atrial
Fibrillation recommends consideration of implantable cardiac
monitors in patients with cryptogenic stroke in whom long-
term external ambulatory monitoring is inconclusive for the
detection of AF.35
Based on our clinical experience and the aforementioned
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evidence, patients who develop embolic stroke of undeter-
mined source (ESUS)36,37 should undergo extended outpa-
tient external cardiac rhythm monitoring, followed by ICM if
AF remains strongly suspected.
Risk of Thromboembolism in Atrial
Fibrillation
The most widely used risk score for estimating the incidence
of ischemic stroke in AF is the CHA2DS2-VASc score, recom-
mended by national and international society guidelines
(►Table 1).35,38 The CHA2DS2-VASc score, which superseded
the older CHADS2 model (by assigning points to additional
risk factors, such as female gender, age 65–75, and vascular
disease), estimates the incidence of stroke at 1-year follow-
up, ranging from 0.2% in patients with a score of 0 to 14.4% in
patients with a score of 9 (assuming no aspirin or anti-
coagulation use).35,39,40 Anticoagulation should be consid-
ered for men with a score of 1 and women with a score of 2 or
greater, and is recommended in men with a score of 2 and
women with a score of 3 or greater.35
Table 1 The CHA2DS2-VASc score39,40,153
Risk factor Points
Congestive heart failure þ1
Hypertension þ1
Age  75 y þ2
Diabetes mellitus þ1
Previous stroke, TIA, or thromboembolism þ2
Vascular disease (prior MI, PAD, or aortic plaque) þ1
Age 65–74 y þ1
Female gender þ1
Abbreviations: MI, myocardial infarction; PAD, peripheral artery disease;
TIA, transient ischemic attack.
Seminars in Neurology © 2021. Thieme. All rights reserved.
Atrial Fibrillation and Ischemic Stroke Migdady et al.
The major limitation of this risk score is that it does not
account for other stroke risk factors such as left atrial
dilatation, alcohol abuse, chronic kidney disease (CKD),
obstructive sleep apnea, duration of AF episodes, and elevat-
ed high-sensitivity troponin and natriuretic peptide.41–45
Additionally, because the CHA2DS2-VASc score uses baseline
characteristics to calculate the risk of stroke, the concepts of
dynamic and “delta” CHA2DS2-VASc scores have been recent-
ly introduced to highlight the importance of follow-up
rescoring based on interval development of risk factors,
instead of reliance on baseline scores.46 The utility of this
follow-up scoring system remains under investigation.
Stroke Prevention in Atrial Fibrillation
Stroke prevention strategy in patients with AF is divided into
two main categories: antithrombotic therapy and left atrial
appendage (LAA) occlusion/exclusion.
Antithrombotic Therapy
Oral anticoagulants (OACs) are recommended for the pre-
vention of stroke in male patients with AF and CHA2DS2-VASc
score of 2, and female patients with a score of 3.35 The
decision to anticoagulate male patients with a score of 1 and
female patients with a score of 2 should be individualized, as
other factors should be taken into consideration (such as age,
bleeding risk, and patient preference). OACs to reduce risk of
stroke in patients with AF are vitamin K antagonists (specifi-
cally warfarin) and non–vitamin K oral anticoagulants (direct
oral anticoagulants [DOACs]) for nonvalvular AF. The four
DOACs used in stroke prevention in AF are factor Xa inhib-
itors (apixaban, rivaroxaban, and edoxaban) and the direct
thrombin inhibitor (dabigatran).
The benefit of warfarin in reducing the risk of stroke in
patients with AF was demonstrated in several prospective
RCTs.47–50 A meta-analysis of these studies showed a two-
third reduction in the risk of stroke with the use of warfarin
compared with placebo, and 39% reduction compared with
aspirin.47–51 Despite the benefit, there has been a rapid shift
in practice away from using warfarin to using DOACs, which
were proven in multiple clinical trials to be safer than
warfarin (especially in terms of hemorrhagic stroke risk)
and slightly more effective in stroke prevention.52–55 Addi-
tionally, DOACs have predictable effects without the need for
regular laboratory monitoring. A meta-analysis in 2014 of
four clinical trials comparing warfarin versus DOACs showed
that DOACs significantly reduced stroke or systemic embolic
events by 19% compared with warfarin; additionally, DOACs
reduced the risk of hemorrhagic stroke and all-cause mor-
tality, but increased the rate of gastrointestinal bleeding
(GIB).56 ►Table 2 summarizes the characteristics of each
DOAC and relevant stroke prevention trials. Assessing each
DOAC separately, the following major points should be
considered clinically:
1. DOACs have been approved only for the prevention of embolic
stroke in patients with nonvalvular AF, unlike warfarin which
is approved for both valvular and nonvalvular AF.
Seminars in Neurology © 2021. Thieme. All rights reserved.
2. All DOACs were associated with reduced rate of the
primary end point of stroke or systemic embolism
when compared with warfarin. Stroke was defined as
ischemic or hemorrhagic in all trials.
3. Only dabigatran 150 mg twice daily was found to be
superior to warfarin in reducing the rates of ischemic
strokes.
4. All DOACs were associated with reduced rate of hemor-
rhagic strokes.
5. All DOACs, except for rivaroxaban, were associated with
reduced rates of overall major or life-threating bleeding.
Rivaroxaban and warfarin have similar rates of major
bleeding events.
6. All DOACs, except for apixaban, were associated with
higher rates of GIB compared with warfarin. Apixaban
and warfarin have similar rates of GIB.
At the time of this article preparation, there have been no
published clinical trials assessing the efficacy and safety of
DOACs against each other. Only apixaban was compared with
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aspirin in the AVERROES trial, which randomized patients
with nonvalvular AF who are ineligible for warfarin therapy
to receive apixaban (at a dose of 5 mg twice daily) or aspirin
(81 to 324 mg per day); this trial was terminated early due to
clear benefit in favor of apixaban for reduction in stroke or
systemic embolism without increased risk of major bleeding
(including intracranial hemorrhage).57 Given the robust evi-
dence suggesting that DOACs are at least noninferior to, and
overall safer than, warfarin in the prevention of stroke and
systemic embolism, DOACs are currently recommended over
warfarin in DOAC-eligible patients, except in patients with
moderate-to-severe mitral stenosis or mechanical valves.35
It is important to note that aspirin monotherapy is con-
sidered ineffective for the reduction of stroke in patients
with AF. Although the initial SPAF trial (1991) showed a 42%
reduction in rates of ischemic stroke or systemic embolism in
patients with nonvalvular atrial fibrillation (NVAF) with
aspirin compared with placebo,58 this benefit was ques-
tioned in multiple subsequent trials with a meta-analysis
(2007) of 29 trials showing a statistically nonsignificant
stroke reduction rate of 22% with antiplatelet therapy
(DAPT) compared with placebo.51 The benefit of DAPT with
aspirin plus clopidogrel was studied in the ACTIVE W (DAPT
vs. warfarin) and the ACTIVE A trials (DAPT vs. aspirin alone
in patients ineligible for warfarin).59,60 A combined post hoc
analysis of these two trials showed a nonsignificant clinical
benefit with the addition of clopidogrel (additional 0.57
ischemic stroke equivalent per 100 patient-years; 95% con-
fidence interval [CI]: 0.12–1.24).61
Timing of Initiation or Reinitiation of Anticoagulation
after Stroke
(a) Patients with acute ischemic stroke. After a patient
suffers an acute ischemic stroke, there is often a man-
agement discussion point surrounding when to initiate
(if patient was not on OAC prior to suffering stroke) or
reinitiate (if held at the time of stroke) OAC for secondary
 Table 2 Characteristics of non–vitamin K oral anticoagulants and related stroke prevention trials

Apixaban Rivaroxaban Dabigatran Edoxaban

Mechanism Anti-Xa Anti-Xa Antithrombin Anti-Xa
Half-life (h) 12 5–9a 12–17 10–14
b
Time to Cmax 3–4 2–4 1–3 1–2
Metabolism/interactions CYP3A4 CYP3A4/5 Pro-drug Minimal CYP3A4
P-gp and Bcrp substrate CYP2J2 P-gp substrate P-gp substrate
P-gp and Bcrp substrate
Renal clearance (%) 27 36 80 50
Full dose for stroke 5 mg twice daily 20 mg once daily 150 mg twice daily 60 mg once daily
prevention and Reduce to 2.5 mg twice daily with any Reduce to 15 mg once daily if CrCl Reduce to 75 mg twice daily if Reduce to 30 mg once daily if
dosage adjustments 2 of the following: 15–50 CrCl 15–30 CrCl 15–50
• Age  80 y Avoid use with severe (CrCl <15) or Edoxaban should not be used if
• Body weight 60 kg end-stage chronic kidney disease CrCl >95
• sCr 1.5 mg/dL
Reduce to 2.5 mg twice daily when
apixaban is administered with strong
dual inhibitors CYP3A4 and P-gp
Reversal agent Andexanet alfa Andexanet alfa Idarucizumab Andexanet alfa
52 54 53
Stroke prevention ARISTOTLE (2011) ROCKET-AF (2011) RE-LY (2009) ENGAGE AF-TIMI 48 (2013)154
trials and their - Apixaban superior to warfarin in - Rivaroxaban noninferior to warfarin in - Dabigatran 150 mgc twice - Edoxaban d superior to warfa-
main results NVAF in reducing incidence of: reducing incidence of: daily superior to warfarin in rin in reducing incidence of:
• Stroke or systemic embolism • Stroke or systemic embolism reducing incidence of: • Stroke or systemic embo-
• Hemorrhagic stroke • Hemorrhagic stroke • Stroke or systemic embo- lism
• Ischemic stroke with hemor- • Fatal bleeding lism • Hemorrhagic stroke and
rhagic conversion - Purely ischemic strokes occurred • Ischemic stroke other ICH
• Stroke morbidity and mortality with similar rates on both drugs • Hemorrhagic stroke • Major bleeding
• All-cause mortality - Similar rates in overall major bleed- • Vascular death • Fatal and life-threaten-
• Major bleeding ing events. Rivaroxaban had higher • Life-threatening major ing bleeding
- Purely ischemic strokes occurred risk of major GIB bleeding • Cardiovascular death
with similar rates on both drugs - No significant difference in all- • All-cause mortality - Purely ischemic stroke oc-
- Similar rates of GIB cause mortality or stroke outcome - Higher rates of MI occurred in curred with similar rates in
- Subjects with apixaban and DM bled the dabigatran group both groups
more than subjects with apixaban - Higher rates of GIB occurred in - Edoxaban group had higher
without DM the dabigatran group rates of major GIB
- No significant difference in all-

Seminars in Neurology
cause mortality

Abbreviations: Bcrp, breast cancer resistance protein; Cmax, maximum serum concentration; CrCl, creatinine clearance (mL/min); CYP, cytochrome P450 enzyme; DM, diabetes mellitus; GIB, gastrointestinal
bleeding; ICH, intracranial hemorrhage; MI, myocardial infarction; NVAF, nonvalvular atrial fibrillation; P-gp, P-glycoprotein; sCr, serum creatinine (mg/dL).
Atrial Fibrillation and Ischemic Stroke

a
The half-life of rivaroxaban is longer (11–13 hours) in elderly population.
b
The time to peak plasma concentration of dabigatran is 1 hour if fasting, and delayed by 2 hours after a fatty meal.
c
In the RE-LY trial, two doses of dabigatran (110 and 150 mg, twice daily) were compared against warfarin and each other. Dabigatran 110 mg twice daily maintained risk reduction of primary end point of stroke or
systemic embolism, hemorrhagic stroke, and life-threatening bleed but had similar rates of ischemic stroke, vascular death, and all-cause mortality as warfarin. There was no increased risk of GIB in the reduced
dose of dabigatran group. In the RELY-ABLE study, longitudinal follow-up of patients taking both doses of dabigatran showed that there is no difference in stroke or mortality, but there was a higher rate of major
bleeding with the higher dabigatran dose.53,155
d
In the ENGAGE trial, a reduced dose of edoxaban (30 mg once daily) was used if CrCl <50 mL/min, weight 60 kg, or concomitant use of P-gp inhibitors. Lower dose of edoxaban maintained risk reduction of

© 2021. Thieme. All rights reserved.

Migdady et al.

primary end point of stroke or systemic embolism in addition to hemorrhagic stroke; however, risk of pure ischemic stroke was higher compared with warfarin. Low-dose edoxaban was associated with lower risk
of all subtypes of bleeding and all-cause mortality.

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Atrial Fibrillation and Ischemic Stroke
stroke prevention in patients with AF. This decision is
often made by weighing the risk of symptomatic hemor-
rhagic transformation with anticoagulation versus the
risk of recurrent ischemic stroke without anticoagula-
tion. Predictors for hemorrhagic transformation include
large infarct, previous intracranial hemorrhage, throm-
bocytopenia, mechanical thrombectomy, and lobar cere-
bral microhemorrhages (given the association with
cerebral amyloid angiopathy).62
A meta-analysis (2007) looked at comparison of intrave-
nous (IV) unfractionated heparin or low-molecular-
weight heparin (LMWH) initiated within 48 hours of a
cardioembolic stroke versus other treatments (aspirin or
placebo). IV anticoagulation was associated with an
increase in symptomatic intracerebral hemorrhage
(ICH; 2.5 vs. 0.7%, odds ratio [OR]: 2.89, 95% CI:
1.19–7.01), though with similar rate of death or disability
at follow-up, and a nonsignificant trend toward reduc-
tion in recurrent ischemic stroke within 7 to 14 days (3.0
vs. 4.9%, OR: 0.68, 95% CI: 0.44–1.06).63 Given the in-
creased risk of symptomatic ICH, IV anticoagulants were
not recommended as an acute treatment of ischemic
stroke due to AF.
At the time of this article preparation, there are no
published RCTs addressing when to initiate or reinitiate
long-term OACs for secondary stroke prevention after an
acute ischemic stroke due to cardioembolism. The trials
comparing each DOAC to warfarin excluded acute ische-
mic stroke patients within 7 (ARISTOTLE) and 14 days
(RE-LY and ROCKET-AF).52–54 Based on expert consensus,
the AHA/American Stroke Association recommend start-
ing OAC within 4 to 14 days after an acute ischemic stroke
for most patients; however, OAC should be delayed for
patients with hemorrhagic transformation.64 These rec-
ommendations were largely adopted based on the results
of the prospective observational study, Early Recurrence
and Cerebral Bleeding in Patient With Acute Stroke and
Atrial Fibrillation (RAF), which showed that high
CHA2DS2-VASc score, high National Institutes of Health
Stroke Scale (NIHSS), large ischemic lesions, and choice of
OAC each independently led to greater risk of both
recurrent ischemic stroke and major bleeding at
90 days. This study supported prior literature showing
better outcomes in patients treated with OAC compared
with LMWH either alone or as a bridging therapy, and the
best time for initiation of OAC was between 4 and 14 days
from ischemic stroke (significant reduction in composite
stroke, TIA, symptomatic systemic embolism, symptom-
atic bleeding, and major extracranial bleeding; hazard
ratio 0.53; 95% CI: 0.30–0.93).65 The European Society of
Cardiology (ESC) and European Heart Rhythm Associa-
tion (EHRA) recommend initiation of OAC 1 day after TIA,
3 days after stroke with NIHSS < 8, 6 days after stroke
with NIHSS 8 to 15, and 12 days after stroke with NIHSS
> 15.66,67 Many observational studies suggest that clini-
cians initiate OAC earlier than guideline recommenda-
tions in certain patient populations who may be at low
Seminars in Neurology © 2021. Thieme. All rights reserved.
Migdady et al.
risk of hemorrhagic transformation, especially when
using DOACs.68 There are at least four clinical trials
currently in progress which aim to compare early versus
late anticoagulation after acute cardioembolic ischemic
stroke: ELAN (NCT03148457; Switzerland), OPTIMAS
(EudraCT, 2018–003859–38; UK), TIMING
(NCT02961348; Sweden), and START (NCT03021928;
the United States).
(b) Patients with ICH. As with the initiation of OAC after an
acute ischemic stroke, there are no published RCTs at the
time of this article preparation addressing the questions
of whether or not, and when, to initiate or resume OAC for
stroke prevention due to AF after ICH. This leaves a great
deal of uncertainty in this patient population. An alter-
native approach to stroke prevention in high-risk
patients with AF who have contraindications to OAC is
LAA closure device, which is discussed further later in
this review. Evaluating individual risk of thromboembo-
lism and hemorrhage, optimal OAC choice and timing,
and management of other modifiable risk factors should
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all be taken into account when making decisions about
OAC after ICH.69 A systematic and multidisciplinary
approach is needed in making this complex decision.66
In 2017, a systematic review and meta-analysis looked at
eight studies comparing thromboembolic events (stroke
and myocardial infarction) and recurrent ICH. The study
reported lower risk of thromboembolic complications
with OAC (though almost exclusively vitamin K antago-
nists) without an increased risk of ICH after OAC initiation
(pooled relative risk: 0.34; 95% CI: 0.25–0.45; Q ¼ 5.12, p
for heterogeneity ¼ 0.28). The majority of patients were
prescribed OAC in the first 3 months (range between
10 days and 6 months; time was not reported in four
studies). Some obvious limitations include studies al-
most exclusively using vitamin K antagonists, significant
heterogeneity in risk of recurrent ICH (pooled relative
risk: 1.01; 95% CI: 0.58–1.77; Q ¼ 24.68, p for heteroge-
neity < 0.001), and absence of specific analysis regarding
the timing of initiation of OAC after ICH.70 Though we
currently have very limited evidence-based guidelines at
this time, several RCTs are ongoing to hopefully help
provide more information to this topic in the future
including APACHE-AF (NCT02565693; the Netherlands),
SoSTART (NCT03153150; UK), ASPIRE (NCT03907046;
the United States), and A3ICH (NCT03243175; France).
Anticoagulation in Specific Populations
(a) Patients with valvular AF. Patients with valvular heart
disease and AF are thought to have a higher risk of
thromboembolism compared with those with AF
alone.71,72 Although AF often exists with other valve
disease, the term “valvular AF” is currently narrowly
defined as AF in the setting of moderate-to-severe mitral
stenosis or mechanical heart valve.35 This distinction is
important because the pivotal DOAC trials excluded
patients with valvular AF (rheumatic or moderate-severe
mitral stenosis and mechanical valve). Patients with

other types of valvular disease in the DOAC trials main-
tained similar stroke risk reduction, with no evidence to
suggest a need for a different anticoagulation regimen.
Unacceptable thromboembolic and bleeding risk was
seen in the dabigatran arm of the RE-ALIGN trial
(2013),73 which compared dabigatran versus warfarin
in patients with mechanical heart valves. Although the
study did not primarily look at prevention of stroke due
to AF in patients with mechanical valves, the results of
the RE-ALIGN trial prompted abandonment of all DOACs
in patients with mechanical valves. Thus, it is currently
recommended that patients with valvular AF receive
warfarin instead of DOACs for stroke prevention.35 At
the time of this article preparation, there have been no
published randomized clinical trials primarily evaluating
the efficacy and safety outcomes of DOACs versus warfa-
rin for patients with valvular AF.
(b) Patients with CKD. Although CKD is not included in the
CHA2DS2-VASc score, it has been shown to be indepen-
dently associated with increased risk of thromboembo-
lism in AF patients. In the ATRIA (Impact of Proteinuria
and Glomerular Filtration Rate on Risk of Thromboem-
bolism in Atrial Fibrillation) study,74 patients with esti-
mated glomerular filtration rate (eGFR) <45 mL/min had
significantly higher risk of thromboembolism, even when
adjusted for other baseline variables such as age; gender;
history of stroke, hypertension, heart failure diabetes
mellitus, or coronary artery disease; and socioeconomic
status (adjusted hazard ratio: 1.39, 95% CI: 1.13–1.72).
This relationship was confirmed in a meta-analysis
(2015) which again showed that AF patients who have
eGFR <60 mL/min experienced significantly increased
risk of thromboembolic events than those with eGFR
60 mL/min (relative risk: 1.62, 95% CI: 1.40–1.87), in
addition to a linear increase in the annual rate of throm-
boembolic events with decreasing renal function.75 The
mechanism of increased risk of thromboembolism in
CKD patients is thought to be due to a prothrombotic
state related to elevated von Willebrand factor, endothe-
lial injury, inflammation, and elevated coagulation fac-
tors, especially in patients with end-stage renal disease
requiring dialysis.76–78 That being said, severe renal
impairment (eGFR < 30 mL/min) increases the risk of
major bleeding, most notably because of resultant plate-
let dysfunction.79 Anticoagulation is still recommended
in patients with CKD and high CHA2DS2-VASc score,35
and the choice of OAC is based on the degree of kidney
injury. For patients with mild to moderate CKD
(eGFR > 30 mL/min), the approach to anticoagulation is
similar to that of those without CKD, taking into consid-
erations the dosage adjustments for DOACs, if chosen. In
the latest AHA/ACC/HRS Focused Update for Manage-
ment of Patients with Atrial Fibrillation, the following
recommendations were made based on the stage of
CKD35:
1. Moderate-to-severe CKD (defined as serum creatinine
1.5 mg/dL for apixaban, CrCl 15–30 mL/min for dabi-
Atrial Fibrillation and Ischemic Stroke Migdady et al.
gatran, CrCl  50 mL/min for rivaroxaban, or CrCl 15–-
50 mL/ min for edoxaban): DOACs are acceptable.
2. End-stage renal disease (CrCl < 15 mL/min) or dialy-
sis: Warfarin or apixaban can be used, but rivaroxa-
ban, edoxaban, and dabigatran are not recommended
because of the lack of evidence from clinical trials that
benefit exceeds risk.
However, the dose of apixaban in patients on dialysis is
controversial. Based on limited pharmacokinetic data,
the U.S. Food and Drug Administration (FDA) has recom-
mended full-dose apixaban (5 mg twice daily) for
patients with ESRD on dialysis, unless other reasons for
dose reduction exist (such as age 80 years or weight
60 kg).35,80
(c) Patients with acute coronary syndrome (ACS) or per-
cutaneous coronary intervention (PCI). Patients with AF
requiring anticoagulation who develop ACS or undergo
PCI (especially with stenting) pose a management dilem-
ma. The majority of these patients require DAPT with
aspirin and a P2Y12 inhibitor (typically clopidogrel) to
Downloaded by: Rutgers University. Copyrighted material.
prevent stent thrombosis in the post-PCI period.81 Treat-
ment of AF in this population is challenging because
multiple retrospective and prospective studies showed
a significantly elevated bleeding risk in patients on triple
therapy with a combination of warfarin, aspirin, and
P2Y12 inhibitors (up to 44% risk of any bleeding by
1 year in one trial).82 In 2013, the WOEST trial was the
first RCT to show that in patients with an indication for
OAC undergoing PCI, dual therapy (OAC plus clopidogrel)
was associated with a lower risk (25% absolute risk
reduction) of bleeding than triple therapy (OAC plus
clopidogrel plus aspirin). This reduction in bleeding
events was observed without a significant increase in
thrombotic events. The WOEST trial did not assess the
safety of DOACs in this setting, prompting the PIONEER
AF-PCI (2016), RE-DUAL PCI (2017), and most recently
the AUGUSTUS (2019) and ENTRUST-AF-PCI (2019) trials
which primarily evaluated the safety of rivaroxaban,
dabigatran, apixaban, and edoxaban, respectively, versus
warfarin in patients with AF who had recent ACS or PCI
requiring DAPT.83–87 These trials (summarized
in ►Table 3) uniformly showed that the use of a DOAC
plus a P2Y12 inhibitor is safer than (for apixaban, rivar-
oxaban, and dabigatran), or at least as safe as (for
edoxaban), warfarin plus DAPT in the post-PCI period.
In all of these trials, the risk of thrombotic outcomes
(including stent thrombosis) was not significantly in-
creased with early withholding of aspirin in the immedi-
ate post-PCI period; however, none of these trials were
powered enough to evaluate for thrombotic outcomes. In
the 2019 AHA/ACC/HRS Focused Update, the use of dual
therapy with low-dose rivaroxaban (15 mg daily) or
dabigatran (150 mg twice daily) with P2Y12 inhibitor
(clopidogrel) was considered reasonable alternatives to
triple therapy involving warfarin and DAPT. This update
was published in January 2019, before the AUGUSTUS
and the ENTRUST-AF PCI trials were published.35 Of note,
Seminars in Neurology © 2021. Thieme. All rights reserved.
 Table 3 Clinical trials evaluating the use of non–vitamin K oral anticoagulants in atrial fibrillation patients with acute coronary syndrome or undergoing percutaneous coronary
intervention
Apixaban
Trial name AUGUSTUS (2019) 83
Seminars in Neurology
Design Open label, 2  2 factorial design
Inclusion criteria NVAF (requiring AC) and recent ACS or
requiring PCI (or both) and planned treat-
ment with P2Y12 inhibitor for at least 6 mo
Sample size 4,614
Randomization groups • Apixaban vs. warfarin
• Aspirin vs. placebo
Follow-up 7 mo
© 2021. Thieme. All rights reserved.
Results of primary ISTH major or CRNM bleeding
endpoint, HR • Apixaban vs. warfarin: 0.69
(95% CI) (0.58–0.81)
• Aspirin vs. placebo: 1.89 (1.59–2.24)
Results of select Death or hospitalization
secondary endpoints, • Apixaban vs. warfarin 0.83 (0.74–0.93)
HR (95% CI) • Aspirin vs. placebo: 1.08 (0.96–1.21)
Stroke
• Apixaban vs. warfarin 0.50 (0.26–0.97)
• Aspirin vs. placebo 1.06 (0.56–1.98)
Stent thrombosis
• Apixaban vs. warfarin 0.77 (0.38–1.56)
• Aspirin vs. placebo 0.52 (0.25–1.08)
Major conclusions • Apixaban reduces risk of bleeding in post-
PCI AF patients compared with warfarin
• Triple therapy with warfarin is associated
with substantial increase in bleeding risk
without improving thrombotic protection
• Nonsignificant increase in risk of stent
thrombosis in patients not on aspirin
• Dual therapy with apixaban plus aspirin is
reasonable regimen in AF post-PCI patients
Abbreviations: AC, anticoagulation; ACS, acute coronary syndrome; CI, confidence interval; CRNM, clinically relevant nonmajor bleeding; DAPT, dual-antiplatelet therapy; G1, group 1; G2, group 2; G3, group 3;
HR, hazard ratio; ISTH, International Society on Thrombosis and Haemostasis; NVAF, nonvalvular atrial fibrillation; PCI, percutaneous coronary intervention.
Rivaroxaban
PIONEER AF-PCI (2016) 87
Open label, 3-parallel-group design
NVAF (requiring AC) and recent PCI with
stent placement
2,124
• G1: rivaroxaban (15 mg daily) þ P2Y12
inhibitor
• G2: rivaroxaban (2.5 mg twice daily) þ
aspirin þ P2Y12 inhibitor
• G3: warfarin þ aspirin þ P2Y12 inhibitor
3y
Clinically significant bleeding
• G1 vs. G3: 0.59 (0.47–0.76)
• G2 vs. G3: 0.63 (0.5–0.8)
• G1 and G2 vs. G3: 0.61 (0.5–0.75)
Major adverse cardiovascular event
• G1 vs. G3: 1.08 (0.69–1.68)
• G2 vs. G3: 0.93 (0.59–0.1.48)
Stroke
• G1 vs. G3: 1.07 (0.39–2.96)
• G2 vs. G3: 1.36 (0.52–3.58)
Stent thrombosis
• G1 vs. G3: 1.20 (0.32–4.45)
• G2 vs. G3: 1.44 (0.40–5.09)
• Dual therapy with low-dose rivaroxaban
(15 mg daily) plus P2Y12 inhibitor or very
low dose rivaroxaban (2.5 mg twice daily)
plus DAPT is associated with lower risk of
bleeding when compared with triple ther-
apy with warfarin
• The rates of major cardiovascular events
(including stroke) and stent thrombosis
were similar among the three treatment
groups
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Dabigatran
RE-DUAL PCI (2017)85
Open label, 3-parallel-group design
NVAF (requiring AC) and recent PCI with
stent placement
2,725
• G1: warfarin þ aspirin þ P2Y12 inhibitor
• G2: dabigatran (110 mg twice daily) þ
P2Y12 inhibitor
• G3: dabigatran (150 mg twice daily) þ
P2Y12 inhibitor
14 mo
ISTH major or CRNM bleeding
• G2 vs. G1: 0.52 (0.42–0.63)
• G3 vs. G2: 0.72 (0.58–0.88)
Thromboembolic events or death
• G2 vs. G1: 1.30 (0.98–1.73)
• G3 vs. G2: 0.97 (0.68–1.39)
Stroke
• G2 vs. G1: 1.30 (0.63–2.67)
• G3 vs. G2: 1.09 (0.42–2.83)
Definite stent thrombosis
• G2 vs. G1: 1.86 (0.79–4.40)
• G3 vs. G1: 0.99 (0.35–2.81)
• Dual therapy with dabigatran (110 or
150 mg twice daily) plus P2Y12 inhibitor
reduces the risk of major bleeding com-
pared with triple therapy with warfarin
• Dual therapy with dabigatran is noninfe-
rior to triple therapy with warfarin with
respect to efficacy of reducing thrombo-
embolic events (including stroke), death,
and stent thrombosis
Edoxaban
ENTRUST-AF PCI (2019) 84
Open label, 1:1 design
NVAF (requiring AC) and recent PCI
1,506
Edoxaban plus P2Y12 inhibitors vs. warfarin
plus aspirin plus P2Y12 inhibitor
Atrial Fibrillation and Ischemic Stroke
12 mo
ISTH major or CRNM bleeding
• Edoxaban regimen vs. warfarin regi-
men: 0.83 (0.65–1.05)
Composite of cardiovascular death, stroke,
systemic embolic event, myocardial infarc-
Migdady et al.
tion, or stent thrombosis
• Edoxaban regimen vs. warfarin regi-
men: 1.06 (0.71–1.69
Stroke
• Edoxaban regimen vs. warfarin regi-
men: 0.84 (0.36–1.95)
Definite stent thrombosis
• Edoxaban regimen vs. warfarin regi-
men: 1.32 (0.46–3.79)
• Dual therapy with edoxaban plus P2Y12
results in similar rates of major bleeding
and reduction of death from cardiovascular
causes, stroke, myocardial infarction, or
definite stent thrombosis

all these trials showed numerically more (though sta-
tistically nonsignificant) myocardial infarctions and
stent thromboses in patients with very early withdrawal
of aspirin therapy. Thus, the 2019 AHA/ACC/HRS guide-
lines currently recommend that if triple therapy is used,
it should be minimized to a period of 4 to 6 weeks (period
of greatest risk for stent thrombosis), especially in
patients with ACS.
(d) Patients undergoing cardioversion. Indications for car-
dioversion (electrical or pharmacological) of AF generally
have new onset or newly diagnosed AF, hemodynamic
instability, severe acute heart failure, or symptomatic AF
despite adequate rate control.38 Cardioversion of AF
carries the risk of stroke and other systemic embolic
events due to left atrial stunning and subsequent clot
dislodgement with return of mechanical function.88 This
risk was shown to be more significant when AF is
chronic.89 Thus, for patients with AF duration 48 hours
(or when the duration of AF is unknown) who are
scheduled to undergo cardioversion, anticoagulation is
recommended for 3 weeks before and at least 4 weeks
after cardioversion. If cardioversion is emergent, such as
in patients with hemodynamic instability, anticoagula-
tion should be started as soon as possible and continued
for at least 4 weeks.35 This is irrespective of the baseline
risk for stroke and prior need for anticoagulation. For
patients who need to be cardioverted before 3 weeks of
the completion of therapeutic anticoagulation, a combi-
nation of anticoagulation and a transesophageal echo-
cardiogram (TEE), to evaluate for left atrial thrombus, can
be used to expedite cardioversion.89 Patients who have
intracardiac thrombus should not undergo cardioversion.
For patients with AF duration <48 hours, there is cur-
rently no strong prospective data for or against the use of
anticoagulation prior to and after cardioversion. Retro-
spective data showed that in patients with AF duration
<48 hours, those with higher CHA2DS2-VASc score (2
for men and 3 for women) are at a higher risk of
thromboembolism after cardioversion than those with
a lower CHA2DS2-VASc score; thus, the decision about
anticoagulation should be personalized based on throm-
boembolic and bleeding risk.90,91
Traditionally, anticoagulation was performed with war-
farin or heparin, however; three recent RCTs evaluating
the safety and efficacy of apixaban (EMANATE, 2018),92
rivaroxaban (X-VERT, 2014)93 and edoxaban (ENSURE-
AF, 2016)94 showed these DOACs to be effective and safe
alternatives for patients with AF undergoing cardiover-
sion. Additionally, post hoc analysis of the RE-LY trial
(which included a large number of cardioversions)
showed no difference in the rates of stroke and throm-
boembolism between those who received dabigatran or
warfarin.53,95 The most recent 2019 AHA/ACC/HRS
guidelines recommend using either warfarin or one of
the DOACs when anticoagulation is needed for AF car-
dioversion.35 It is important to note that cardioversion of
AF back into sinus rhythm does not negate the need for
Atrial Fibrillation and Ischemic Stroke Migdady et al.
chronic anticoagulation beyond the post–cardioversion
anticoagulation period, and is based on CHA2DS2-VASc
score. In other words, patients with AF who need anti-
coagulation (based on CHA2DS2-VASc score) will still
need chronic anticoagulation beyond 4 weeks after
cardioversion.
(e) Patients undergoing catheter ablation for AF. Catheter
ablation (using radiofrequency ablation or cryotherapy)
is indicated in patients with symptomatic AF pursuing a
rhythm control strategy to improve quality of life, and in
patients with heart failure with reduced ejection frac-
tion, as it may lower mortality, reduce heart failure
hospitalization rate, and maintain sinus rhythm longer
when compared with cardioversion.35 Similar to cardio-
version, patients undergoing AF ablation are at risk of
thromboembolism and stroke (during and following the
procedure) that is higher than their baseline risk, which
can last for months after the procedure.96,97 This risk is
thought to be, in part, related to left atrial endothelial
injury that can precipitate thrombus formation, in addi-
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tion to stunning of the myocardial tissue as a result of
catheter ablation, and dislodgement of a preexisting clot
is also possible.98,99 Thromboembolic phenomenon after
ablation procedures can be asymptomatic—thought to be
related to microemboli causing asymptomatic ischemic
lesions than can be seen on MRI of the brain, and was
linked to long-term neurocognitive dysfunction.100
Given this risk of thromboembolism and stroke, it is current-
ly recommended that patients planned to undergo AF abla-
tion procedure to be on therapeutic anticoagulation for
3 weeks prior and 8 weeks after the ablation.101 Preproce-
dural TEE is necessary in patients with inadequate or inter-
rupted anticoagulation prior to the procedure, and is
strongly considered even in patients with adequate anti-
coagulation prior to the AF ablation. This is based on retro-
spective data revealing evidence of left atrial thrombus or
sludge prior to AF ablation despite adequate preprocedural
anticoagulation; evidence is less robust for patients with
paroxysmal AF who present with sinus rhythm on the day of
procedure and in patients with CHA2DS2-VASc of zero.101,102
All patients undergoing AF ablation receive intraprocedural
heparin with a loading dose prior or immediately following
transseptal puncture followed by heparin infusion to main-
tain an activated clotting time (ACT) of 300 seconds
throughout the procedure.101 The choice of pre- and post-
procedural anticoagulation varies and is mainly dependent
on the patient’s preprocedural anticoagulant regimen. For
patients on warfarin prior to the ablation procedure, unin-
terrupted warfarin was shown to be superior to periproce-
dural bridging with heparins, as long as the international
normalized ratio (INR) is within the therapeutic range.103,104
For patients on DOACs, clinical trials evaluating uninterrupt-
ed rivaroxaban (VENTURE-AF, 2015),105 dabigatran (RE-CIR-
CUIT, 2017),106 apixaban (AXAFA-AFNET 5, 2018),107 and
edoxaban (ELIMINATE-AF, 2019)108 versus uninterrupted
warfarin showed that DOACs are as at least safe and effective
Seminars in Neurology © 2021. Thieme. All rights reserved.
Atrial Fibrillation and Ischemic Stroke
as warfarin in patients undergoing AF ablation; dabigatran
was associated with fewer bleeding complications than
warfarin. In these trials, the once-daily DOACs (dabigatran
and edoxaban) were given in the evening on the day of the
procedure; at least 6 hours post–sheath removal after achiev-
ing adequate hemostasis. For the twice-daily DOACs (apix-
aban and dabigatran), the morning dose on the day of
procedure was given as scheduled; the evening dose of
dabigatran was given at least 3 hours after sheath removal
and achievement of hemostasis (no delay period in the
apixaban study).105–108 Patients who were not on AC prior
to the procedure can be started on one of the DOACs 3 weeks
prior and continued for 8 weeks after, because of easier
dosing and no need for monitoring. The decision to continue
AC beyond 8 weeks after the procedure is based on the
patient’s baseline stroke risk factors (i.e., CHA2DS2-VASc
score) and has little to do with the clinical outcome of the
ablation procedure, as recurrences of AF are common after
catheter ablation, especially asymptomatic AF.101
Percutaneous Left Atrial Appendage Closure
The LAA, an ear-shaped tubular structure in the wall of the
left atrium, is thought to be the source of the majority of
thromboembolic events in patients with AF. In one review,
91% of nonrheumatic AF-related left atrial thrombi were
isolated to, or originated in, the LAA.109 While OAC is the
gold standard for stroke prevention in patients with AF,
patients who have high risk of bleeding on anticoagulation
can benefit from nonpharmacological methods of stroke
prevention, such as percutaneous or surgical (open) LAA
closure. Although multiple devices were designed for LAA
closure, only the Watchman device (Boston Scientific) has
been studied extensively in clinical trials and is approved in
the United States; it is currently indicated for patients with
increased risk of stroke or systemic embolism (using
CHA2DS2-VASc score) who have an appropriate rationale to
seek a nonpharmacological alternative to OAC.
The Watchman device, first introduced in 2005, is a self-
expanding nitinol structure designed to permanently im-
plant at, or slightly distal to, the ostium of the LAA to trap
potential emboli before they exit the LAA. It is inserted
using a standard percutaneous technique via the femoral
vein into the right atrium (under fluoroscopy and TEE
guidance), followed by transseptal rupture and deployment
of the Watchman device in the LAA. Heart tissue grows over
the implant and the LAA is permanently sealed, resulting in
a fully endothelialized device. After the procedure, patients
remain on therapeutic warfarin (INR: 2–3) and aspirin
(81–100 mg daily) for at least 45 days, followed by DAPT
(clopidogrel 75 mg and aspirin 300–325 mg daily) until
6 months, followed by ongoing aspirin (300–325 mg daily)
therapy. The initial anticoagulation period (45 days) is
meant to ensure adequate seal and endothelialization of
the device prior to withdrawal of anticoagulation and
prevent development of device-related thrombosis (DRT).
Thus, a TEE is performed at 45 days to ensure an adequate
seal, which has to be repeated at 6 months if the initial TEE
reveals >5 mm leak. This anticoagulation regimen is based
Seminars in Neurology © 2021. Thieme. All rights reserved.
Migdady et al.
on the clinical trials leading to the FDA approval of the
device in March, 2015.110
Evidence Supporting the Watchman Device
The PROTECT AF (2009)111 was a multicenter, open-label,
controlled noninferiority trial that randomized 707 patients
with NVAF to LAA closure with the Watchman device
(n ¼ 463) versus warfarin (n ¼ 244) and followed up patients
for a mean of 16 months. The device demonstrated non-
inferior rate of the primary end point of ischemic or hemor-
rhagic stroke, cardiovascular death, or systemic embolization
compared with warfarin alone (3 events per 100 patient-
years [PY] in the device group vs. 4.9 events per 100 PY in the
control group [p for noninferiority >0.99]). While the rates of
all strokes (ischemic and hemorrhagic) were noninferior
between the groups (2.3 events/100 PY vs. 3.2 events/100
PY [p ¼ 0.99 for noninferiority]), there was significantly less
hemorrhagic strokes in the device group (one hemorrhagic
stroke in the device group versus six in the warfarin group).
There were more adverse outcomes in the device group
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because of high occurrence of pericardial effusion. Given
this periprocedural safety hazard and to confirm findings
from the PROTECT AF trial, a 2014 study, the PREVAIL trial,112
randomized 407 patients with NVAF to percutaneous LAA
closure with the Watchman device (n ¼ 269) versus long-
term warfarin therapy (n ¼ 138) and followed up them for a
median of 12 months. There were less periprocedural com-
plications in the PREVAIL trial compared with the PROTECT
AF trial (likely related to the procedure being performed by
more experienced operators), and the device demonstrated
noninferior rate of stroke or systemic embolism from 7 days
to 18 months; however, noninferiority was not achieved in
regard to rates of cardiovascular or unexplained death,
stroke, or systemic embolism at 18 months (i.e., more events
in the device arm), which was thought to be due to a low
event rate in the control arm. A patient-level meta-analysis
combining the 5-year outcomes of the PROTECT-AF and
PREVAIL trials revealed that LAA closure with the Watchman
device provided significant reductions in cardiovascular and
all-cause mortality. While maintaining equivalent rates of
all-cause and ischemic strokes, there was reduction in
hemorrhagic and disabling/fatal stroke.113 Based on the
results of the PROTECT AF and PREVAIL trials, the Watchman
device acquired the FDA approval in March, 2015.
Following these two trials, two single-arm (Continued
Access to PROTECT AF [CAP] and Continued Access to PRE-
VAIL [CAP2]), multicenter, prospective nonrandomized reg-
istry studies with entry criteria similar to the PROTECT AF
and PREVAIL trials, respectively, collected data during regu-
latory review of the premarket application for the Watchman
device and showed similar primary effectiveness and safety
endpoints to the original trials.114 Most recently, long-term
analysis of patients enrolled in CAP and CAP2 registries (all
with Watchman device) showed that compared with the
accompanying RCTs, the registry patient population was at
slightly higher risk of adverse events (defined as a composite
of stroke, systemic embolism, and CV/unexplained death);
3.05 events/100 PY in CAP versus 2.24/100 PY in the device

arm of PROTECT-AF, and 4.80/100 PY in CAP2 versus 3.65/100
PY in the device arm of PREVAIL. This was likely related to
more severe and extensive comorbidities in the registry
patients. There were consistent reductions in stroke rates
in the device group in all four studies compared with
warfarin.115
It is important to note that the FDA labeling still requires
patients to be eligible for short-term OAC after Watchman
implantation. The main reason to use anticoagulation after
implantation is due to the risk of DRT, which was present in
3.74% of patients at 12 months in the pooled analysis of
PROTECT-AF, PREVAIL, CAP, and CAP2 studies, and was found
to be predictive of stroke or systemic embolism.116,117
Because some patients have absolute contraindication to
anticoagulation (such as certain patients at high risk of
life-threatening bleeds and cerebral amyloid angiopathy),
several studies investigated the feasibility of antiplatelet
therapy in this population. The ASAP study (2013)118 was
a single-arm multicenter, nonrandomized study of the
Watchman device in warfarin-ineligible patients with
NVAF that assigned patients to aspirin and clopidogrel for
6 months followed by aspirin alone. After a mean follow-up
of 1.2 years, the postimplantation annual ischemic stroke
rate was 1.7%, which was thought to be 77% fewer ischemic
strokes than expected for the population enrolled based on
CHADS2 score (if treated by aspirin alone). A recent 5-year
follow-up analysis of ASAP revealed an annual rate of ische-
mic stroke or systemic embolism of 1.8%, not different from
the original ASAP results, and this was consistent with
ischemic stroke rates in the device arms of PROTECT-AF
(1.7%) and PREVAIL trials (1.6%).118,119 The EWOLUTION trial
(2019) was a single-arm, multicenter, prospective, nonran-
domized cohort study that enrolled a total of 1,020 subjects
undergoing Watchman device implantation in 13 countries,
to evaluate real-life clinical outcomes over 2 years.120,121 In
this study, 72% of patients were not suitable for OAC and were
using only antiplatelet therapy or nothing immediately after
implantation (85% were using single-antiplatelet therapy or
nothing at the end of the 2-year follow-up period). Despite
the low rates of anticoagulation, the overall observed ische-
mic stroke rate was 1.3/100 PY, conferring an 83% reduction
compared with expected risk by CHA2DS2-VASc. In EWOLU-
TION, the DRT was observed in 4.1% of patients at 2 year, 2.6%
in the first 3 months, without a statistically significant
relationship found between the incidence of DRT and the
type of postimplantation anticoagulation. A propensity-ad-
justed analysis was performed in the patients receiving DAPT
to compare outcomes of DAPT 105 days versus DAPT >105
days and showed lower bleeding rates in early discontinua-
tion without significant difference in thromboembolic risks.
Additionally, the discontinuation of DAPT and OACs in 85% of
all patients at 2 years was associated with a 46% lower major
bleeding rates compared with historic controls.
Following data from the ASAP and EWUOLUTION studies,
the European Heart Rhythm Society Survey revealed that less
than 10% of European centers actually follow the PROTECT AF
and PREVAIL protocols for postprocedural anticoagulation.122
The most recent EHRA and the European Association of
Atrial Fibrillation and Ischemic Stroke Migdady et al.
Percutaneous Cardiovascular Intervention (EAPCI) expert con-
sensus statement on catheter-based LAA occlusions (Au-
gust 2019) recommended DAPT (aspirin and clopidogrel) for
1 to 6 months as a possible alternative after Watchman
implantation in patients not suitable for long-term oral anti-
coagulation therapy.123 Additionally, DOACs were considered
possible alternatives to warfarin in the postimplantation
period123; similar guidelines have not yet been adopted in
the United States.35 The ASAP-TOO trial is currently underway
to establish the safety and effectiveness of the Watchman
device in NVAF patients who are ineligible for OACs.124
Other LAA Closure Devices
The first LAA closure system, the PLAATO device (Appriva
Medical), was introduced in 2001.125–127 Despite initial
promising results, the device was withdrawn in 2007 by
the manufacturer due to commercial reasons.128 In addition
to the Watchman device (which is approved in both the
United States and Europe), six other LAA closure systems are
currently approved in Europe. The Amplatzer cardiac plug
Downloaded by: Rutgers University. Copyrighted material.
(ACP, St. Jude Medical) and the second-generation Amplatzer
Amulet were introduced in 2008 and 2013, respective-
ly.129–131 Although this is the second-most commonly used
device globally after the Watchman device and it has prom-
ising results, it is not yet approved in the United States; the
PRAGUE 17 trial is currently underway to compare outcomes
of LAA closure using Amulet or Watchman device versus
DOACs.128 The Lariat device (SentreHeart) was first intro-
duced in 2009 and is different from other closure devices
because it utilizes both an endocardial and epicardial ap-
proach to permanently exclude the LAA. It is currently
approved in the United States for soft-tissue closure, but
not LAA closure, given reported cases of death and serious
complications such as heart perforation or complete LAA
detachment, limiting its “off-label” use to certain cases
where other endovascular LAA closure methods are not
feasible.132–135 Its efficacy and safety as an adjunct to AF
ablation is currently being studied in the aMAZE trial.136,137
The WaveCrest device (Coherex Medical) was introduced in
2010 and acquired European approval in 2013. This device is
different from other occlusion devices because of its flexible
design that can accommodate a wide range of LAA anato-
mies, since it relies on proximal deployment in the LAA
instead of deeper deployment, making it more suitable for
patients with small LAA. Approval for use in the United States
is pending as well as the results of the WaveCrest 1 (nonran-
domized safety and efficacy trial) and WaveCrest 2 (random-
ized trial of WaveCrest vs. Watchman devices) trials.138,139
The LAmbre (Lifetech Scientific) device is a fully retrievable
and repositionable special device for multilobed or small
anatomies.140 Lastly, Occlutech LAA Occluder (Occlutech
International) is unique given its adaptiveness to the LAA
anatomy.141 Both LAmbre and Occlutech have been studied
only in small series.142,143
Surgical LAA Closure
The primary goal of surgical LAA closure is to completely
exclude the LAA to prevent thrombus formation. This can be
Seminars in Neurology © 2021. Thieme. All rights reserved.
Atrial Fibrillation and Ischemic Stroke Migdady et al.

Fig. 2 Annual rates of ischemic stroke in different studies of stroke prevention in patients with atrial fibrillation. Event rates of the intervention
groups are based on ARISTOTLE (for apixaban), 52 ROCKET-AF (for rivaroxaban), 54 RE-LY (for dabigatran), 53 ENGAGE AF-TIMI 48 (for edoxaban), 154
meta-analysis of PROTECT AF, and PREVAIL by Reddy et al (for Watchman), 113 and meta-analysis of warfarin randomized clinical trials by Agarwal
et al (for warfarin).156 This graph is only descriptive and does not provide statistical comparisons between event rates (intervention vs. expected)
or between different intervention groups. The reference populations vary widely and there are no trials comparing DOACs with each other or
with Watchman. Expected event rates were based on mean CHADS 2 or CHA2DS 2-VASc scores as reported in the population of each intervention
group in the aforementioned studies. Scores were then compared with published validation cohorts by Gage et al (for CHADS2) 157 and Friberg
et al (for CHA2 DS2-VASc) 40 which represent the annual risk without use of anticoagulation. To calculate expected event rates, mean CHADS2 and
CHA2DS2-VASc scores were rounded to the lowest integer to avoid overestimation of stroke risk. For example, mean CHADS 2 in the rivaroxaban

Downloaded by: Rutgers University. Copyrighted material.

arm of ROCKET-AF was 3.48; because there is no way to estimate the true expected stroke based on the available studies, this was rounded to 3.

performed through endocardial or epicardial LAA ligation
(exclusion), suture or stapler excision, epicardial clips, and
other methods.144–146 This is typically performed in patients
undergoing cardiac surgery for other indications. Concomi-
tant surgical LAA closure during cardiac surgery was shown
to reduce rates of postoperative thromboembolism in retro-
spective studies.147,148 In a small randomized prospective
References
pilot trial comparing three atrial appendage elimination
techniques (internal ligation, stapled excision, and surgical
excision), surgical (suture) excision has been shown to
outperform other techniques.149,150 The main limitation of
surgical closure is that it is often incomplete (often exceeding
50% of cases), which necessitates a postoperative TEE to
confirm LAA closure, as incomplete closure increases the
risk of thromboembolism.149,151,152 The 2019 AHA/ACC/HRS
guidelines state that surgical closure of the LAA may be
“considered” in patients with AF undergoing cardiac
surgery.35
►Fig. 2 summarizes annual rates of ischemic stroke in
different methods of stroke prevention in patients with AF
compared with expected risk based on respective CHADS2 or
CHA2DS2-VASc scores.
Conclusion
In conclusion, the close relationship between AF and stroke
requires physicians caring for patients with stroke to (1) be
familiar with AF diagnosis, monitoring, and assessment of
thromboembolic risk; and (2) have an in-depth knowledge of
the underlying mechanisms of stroke in patients with AF to
choose the best method of stroke prevention, taking other
comorbidities into account. Multiple studies are currently
underway to better understand these aspects of this preva-
lent and important stroke risk factor.
Conflict of Interest
None declared.
Acknowledgments
None.
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