Drugs

https://doi.org/10.1007/s40265-018-0912-8

REVIEW ARTICLE

Management of Embolic Stroke of Undetermined Source (ESUS)

Tobias Geisler1 • Annerose Mengel2 • Ulf Ziemann2 • Sven Poli2

 Springer International Publishing AG, part of Springer Nature 2018

Abstract According to the Trial of ORG 10172 in Acute

Stroke Treatment (TOAST) classification, embolic stroke
of undetermined source (ESUS) has refined the old defi-
nition of cryptogenic stroke. More sophisticated criteria
and a well-defined diagnostic workup point out the embolic
nature of this disease. Because ESUS is associated with a
high stroke recurrence, a clear risk prediction and man-
agement is of utmost importance to improve prognosis. To
date, standard pharmacotherapy consists of antiplatelet
drugs and statins. This review attempts to provide an
overview on the diagnostic criteria, prognosis, and current
clinical trials evaluating the value of direct oral anticoag-
ulants for secondary prevention after ESUS.
Key Points
Patients with embolic stroke of undetermined source
(ESUS) represent a heterogeneous group with a high
likelihood of an occult embolic source of stroke.
A more resolute risk stratification, e.g. by screening
for subclinical atrial fibrillation, or a risk factor-
based enrichment of the targeted ESUS population,
will become necessary to determine the optimal
medical secondary prevention.
The safety and efficacy of antithrombotic treatment
is currently being investigated in major randomized
clinical trials comparing direct oral anticoagulants
against antiplatelet therapy.

1 Introduction

The underlying courses of embolic stroke of undetermined

source (ESUS) are manifold and a differentiated diagnostic
approach is warranted to determine the optimal pharma-
cological and/or interventional strategy. Subsequently, we
inform readers about diagnosis, etiopathology and treat-
ment of underlying causes, with a focus on pharma-
cotherapy, on the basis of a systematic search of available
guideline recommendations and literature.
& Tobias Geisler
tobias.geisler@med.uni-tuebingen.de
2 Methods
1
Department of Cardiology, University Hospital Tübingen,
Otfried-Müller-Straße 10, 72076 Tübingen, Germany
We performed a search for stroke and ESUS management
2
Department of Neurology and Stroke, University Hospital in international stroke guidelines, including the guidelines
Tübingen, Hoppe-Seyler-Straße 3, 72076 Tübingen,
Germany
of the European Stroke Organisation (ESO), the European

Society of Cardiology (ESC), and the American Heart
Association (AHA)/American Stroke Association (ASA).
In addition, we searched for ongoing clinical trials on
ClinicalTrials.gov using the keywords ‘ESUS’, ‘crypto-
genic stroke’, ‘cardioembolic stroke’, ‘subclinical atrial
fibrillation’ and ‘non-vitamin K antagonist oral anticoag-
ulants/NOAC/direct oral anticoagulants/DOAC and
stroke’. A review of the current literature was also per-
formed on PubMed.gov using the search terms ‘pharma-
cotherapy of stroke’, ‘antithrombotic therapy of stroke’,
‘cryptogenic stroke’, ‘embolic stroke of undetermined
source’, ‘ESUS’, ‘cardioembolic stroke’, ‘patent foramen
ovale’, ‘PFO’, ‘subclinical atrial fibrillation and stroke’,
‘secondary prevention of stroke’, and ‘NOAC/DOAC and
stroke’.
3 Diagnosis and Prognosis of Embolic Stroke
of Undetermined Source (ESUS)
Criteria for the diagnosis of ESUS have evolved to better
confine the embolic nature of non-lacunar cryptogenic
ischemic stroke. In 2014, these new criteria were set up
(Table 1) [1].
According to the Trial of ORG 10172 in Acute Stroke
Treatment (TOAST) classification, ESUS is a subgroup of
cryptogenic strokes. The definition of ESUS uses more
restrictive criteria to distinguish embolic stroke from other
causes of stroke, but does not surpass the old definition in
whole; other cryptogenic strokes also include cases with
two or more causes identified and with incomplete evalu-
ation. Recent registries reported a rate of 9–25% of all
stroke patients meeting the ESUS criteria (Fig. 1) [2, 3].
Per definition, the origin of embolism in ESUS remains
unclear. Potential sources include yet undetected paroxys-
mal AF, paradoxical venous thromboembolism via a per-
sistent foramen ovale (PFO), substenotic atherosclerotic
plaques in brain-supplying arteries or the aortic arch
potentially causing ischemic stroke by plaque rupture and
consecutive arterioarterial embolization, hypercoagulable
states due to inherited or acquired coagulopathies (e.g. due
to concomitant malignant disease), migraine, non-bacterial
thrombotic endocarditis, or other rare causes such as
genetic, autoimmune, or rheumatologic diseases.
According to registry data, ESUS patients are younger
[4] and suffer less often from classical cardiovascular risk
factors compared with non-ESUS ischemic stroke patients.
Risk factors, as well as potential embolic sources, signifi-
cantly differ between younger and older ESUS patients [5].
The average risk of stroke recurrence after ESUS is
approximately 4.5% per year [3, 6]., Importantly, the risk
of stroke recurrence after ESUS increases with patients’
load of those cardiovascular risk factors that are also
T. Geisler et al.
Table 1 Embolic stroke of undetermined source criteria according to
Hart et al. [1]
Diagnostic criteria for the definition of ESUS
Stroke detected by CT or MRI that is not lacunara
Absence of extracranial or intracranial atherosclerosis causing
more than 50% luminal stenosis in arteries supplying the area of
ischemia
No major-risk cardioembolic source of embolismb
No other specific cause of stroke identified (e.g. arteritis,
dissection, migraine/vasospasm, drug misuse)
Diagnostic assessment for definition of ESUS
Brain CT or MRI
12-lead electrocardiogram
Precordial echocardiography
Cardiac monitoring for more than 24 h with automated rhythm
detection
Imaging of both the extracranial and intracranial arteries
supplying the area of brain ischemia (catheter, MRI, or CT
angiography, or cervical duplex plus transcranial Doppler
ultrasonography)
ESUS embolic stroke of undetermined source, CT computed tomog-
raphy, MRI magnetic resonance imaging
a
A lacunar infarct is defined as a subcortical infarct smaller than or
equal to 1.5 cm on CT or 2.0 cm on diffusion-weighted MRI in its
largest dimension; visualization by CT usually needs delayed imaging
24–48 h after stroke onset
b
Permanent or paroxysmal atrial fibrillation, sustained atrial flutter,
intracardiac thrombus, prosthetic cardiac valve, atrial myxoma or
other cardiac tumors, mitral stenosis, myocardial infarction within
4 weeks, left ventricular ejection fraction \ 30%, valvular vegeta-
tions, or infective endocarditis
included in the CHADS2 and CHA2DS2-VASc scores.
Both scores were primarily developed for stroke risk
stratification in patients with atrial fibrillation (AF) and for
guiding clinicians to choose the appropriate antithrombotic
regimen for primary stroke prevention in AF patients [7].
Apart from the high incidence of clinically apparent strokes
in ESUS patients, the incidence of so-called ‘silent’
ischemic lesions (SILs) is even higher. SILs can be
detected by brain imaging, i.e. computed tomography or,
ideally, magnetic resonance imaging (MRI) (Fig. 2). New
SILs have been reported in 14.5% of patients at 90 days
after cryptogenic stroke [8]. SILs on brain imaging are of
clinical relevance as they predict subsequent clinical vas-
cular events [9, 10]. In addition, they are associated with
neurocognitive decline [11].
4 Role of Atrial Fibrillation in ESUS/Stroke
Patients
Known or first-detected AF is common in stroke patients.
In a Swedish nationwide population-based registry, the
prevalence of AF was approximately one-third of all stroke
Management of ESUS

Fig. 1 Prevalence of ESUS in

comparison with other stroke
etiologies. Other cryptogenic
strokes include cases with two
or more mechanisms identified,
as well as those with incomplete
evaluation. ESUS embolic
stroke of undetermined source

Fig. 3 Incidence of AF in 75 patients undergoing cardiac monitoring

Fig. 2 Diffusion-weighted magnetic resonance imaging reveals a with an insertable loop recorder after embolic stroke or TIA of
silent ischemic lesion in the right frontal cortex, leading to the undetermined source; included patients had to have at least one
diagnosis of embolic stroke of undetermined source in a patient additional risk factor predictive for AF.23 AF atrial fibrillation, TIA
presenting with a right-sided hemiparesis transient ischemic attack

patients [12], and cardioembolic strokes have a worse
prognosis, with increased mortality and unfavorable neu-
rological outcome [13, 14]. Despite electrocardiogram
(ECG) monitoring on stroke units, or the conduction of at
least one 24-h Holter ECG after ischemic stroke, AF
remains undetected in a considerable fraction of stroke
patients. By using prolonged screening methods, e.g. non-
invasive or insertable loop recorders, subclinical AF can be
detected in a much higher number of patients. In the
Cryptogenic Stroke and Underlying AF (CRYSTAL-AF)
trial, 441 patients with cryptogenic stroke (according to the
TOAST definition) were randomized to either conventional
intermittent ECG monitoring or to an insertable loop
recorder for continuous ECG monitoring [15]. With the
help of continuous ECG monitoring, AF episodes lasting at
least 30 s were detected in 12.4% versus only 2.0% of
patients during the 12-month follow-up period (hazard
ratio 7.3, 95% confidence interval 2.6–20.8; p \ 0.001).
Similarly, continuous ECG monitoring in the 30-day Car-
diac Event Monitor Belt for Recording Atrial Fibrillation
After a Cerebral Ischemic Event (EMBRACE) trial, which
was realized using a non-invasive 30-day event-triggered
recorder, revealed 16.1% compared with only 3.2% AF
detection after 90 days of repeated conventional 24-h ECG
monitoring [16].
In a pooled analysis of trials using different methods of
cardiac monitoring, the detection rate in patients with
ischemic stroke/transient ischemic attack (TIA) undergoing
implantable loop recording was 16.9% [17]. Consistently,
in the Find-AF randomized trial, the detection rate of AF
episodes lasting 30 s or longer was 14% after 6 months in
patients with stroke of any etiology undergoing repeated
10-day Holter ECG [18]. The impact of the standardized
MONitoring for Detection of Atrial Fibrillation in Ischemic
Stroke (MonDAFIS) trial is investigating the impact of
prolonged and systematic ECG monitoring and will pro-
vide important information about the prevalence of AF in
the acute stroke setting and among different types of stroke
[19]. The role of distinct ECG parameters to predict the
occurrence of AF episodes and stroke risk has previously
been discussed [20–22].
Focusing on ESUS patients only and applying additional
clinical, ECG, or echocardiographic criteria predictive for
cardiac embolism due to occult AF (i.e. CHA2DS2-Vasc
score C 4, detection of atrial runs in 24-h Holter ECG, size
of left atrium in transthoracic echocardiography parasternal
axis [ 45 mm, or decreased flow in the left atrial appen-
dage [LAA] documented by transesophageal echocardiog-
raphy [TOE]), we were able to increase the AF detection
rate to 30% after 1 year of continuous ECG monitoring
using an insertable loop recorder (Fig. 3) [23]. Other
population-based cohort studies and registries suggested an
enhanced association of distinct ECG and TOE parameters
T. Geisler et al.
(i.e. LAA contraction and filling velocity) suggestive of left
atriopathy and risk for non-lacunar stroke [24, 25]. Still
under debate remains the association between the risk for
recurrent stroke or SILs and the AF burden, i.e. the
cumulative and single episode AF duration and frequency.
In a post hoc analysis of the ASymptomatic AF and Stroke
Evaluation in Pacemaker Patients and the AF Reduction
Atrial Pacing Trial (ASSERT) investigating the prevalence
of subclinical AF detected by cardiac pacemakers or
implantable cardioverter defibrillators in a primarily non-
stroke cohort, the highest association with stroke incidence
was found for AF episodes lasting longer than 24 h [26].
There are currently no data on AF burden thresholds
defining the risk for recurrent stroke/SILs in patients after
ESUS; however, with the help of continuous ECG moni-
toring, the Apixaban for TreatmenT of embolIc Stroke of
Undetermined Source (ATTICUS) randomized controlled
trial might answer this important question [27].
5 Role of Antiplatelet Agents
The current standard antithrombotic treatment for sec-
ondary prevention in patients with ischemic stroke without
overt AF is mono antiplatelet therapy. The role of dual
antiplatelet therapy (DAPT) in stroke patients has been
investigated in a number of randomized clinical trials.
Whereas first trials could not document a benefit of DAPT
versus mono antiplatelet therapy [28, 29], a recent trial
suggests that short-term DAPT provides additional risk
reduction when initiated early after TIA or minor stroke
[30, 31]. Some guidelines also recommend combination of
low-dose aspirin and dipyridamole as secondary prevention
[48]. To date, no trials investigated dual versus mono anti-
platelet therapy specifically in ESUS patients. Mono ther-
apy with ticagrelor was not superior to aspirin in unselected
ischemic stroke/TIA patients regarding the endpoints of
stroke, myocardial infarction, or death at 90 days in the
Acute Stroke or Transient Ischaemic Attack Treated with
Aspirin or Ticagrelor and Patient Outcomes (SOCRATES)
trial [32]. A post hoc analysis of ESUS patients revealed no
interaction on treatment effect by ticagrelor compared with
aspirin, except that patients with a low-grade (\ 50%)
stenosis ipsilateral to the index stroke/TIA, or patients with
aortic arch atherosclerosis, seemed to gain benefit by the
intensified antiplatelet therapy with ticagrelor [33].
6 Role of Oral Anticoagulants in ESUS
Based on the hypothesis that thromboembolism is the
underlying cause of cryptogenic stroke/ESUS [34], and due
to the fact that subclinical AF is frequently detected in
Management of ESUS

Table 2 Subgroup analyses of patients with a history of stroke or transient ischemic attack from the five landmark trials evaluating direct oral
anticoagulants in atrial fibrillation
NOAC Comparator No. of Annual event rates for Annual event rates for Annual event rates for References
stroke recurrent stroke and major bleeding intracranial bleeding
patients systemic embolism

Rivaroxaban Warfarin 7468 2.79% on rivaroxaban vs.
2.96% on warfarin (HR
0.94, 95% CI 0.77–1.16)
Dabigatran Warfarin 3623 2.32% on dabigatran
110 mg bid vs. 2.78% on
warfarin (RR 0.84, 95%
CI 0.58–1.20), and 2.07%
on dabigatran 150 mg bid
(RR 0.75, 95% CI
0.52–1.08)
Apixaban Warfarin 3436 2.46% on apixaban vs.
3.24% on warfarin (HR
0.76, 95% CI 0.56–1.03)
Aspirin 2.39% on apixaban vs.
9.16% on aspirin (HR
0.29, 95% CI 0.15–0.60)
Edoxaban Warfarin 5973 2.44 on edoxaban 60 mg qd
vs. 2.85 on warfarin (HR
0.86, 95% CI 0.67–1.09)
bid twice daily, CI confidence interval, HR hazard ratio, qd once daily, RR relative risk, NOAC non-vitamin K antagonist oral anticoagulant
3.13% on rivaroxaban vs. 0.59% on rivaroxaban vs. [40]
3.22% on warfarin (HR 0.80% on warfarin (HR
0.97, 95% CI 0.79–1.19) 0.57, 95% CI 0.34–0.97)
2.74% on dabigatran 0.25% on dabigatran [41]
110 mg bid vs. 4.15% on 110 mg bid vs. 1.28% on
warfarin (RR 0.66, 95% warfarin (RR 0.20, 95%
CI 0.48–0.90), and 4.15% CI 0.08–0.47), and 0.53%
on dabigatran 150 mg bid on dabigatran 150 mg bid
(RR 1.01, 95% CI (RR 0.41, 95% CI
0.77–1.34) 0.21–0.79)
2.84% on apixaban vs. 0.55% on apixaban vs. [42]
3.91% on warfarin (HR 1.49% on warfarin (HR
0.73, 95% CI 0.55–0.98) 0.37, 95% CI 0.21–0.67)
4.10% on apixaban vs. 1.17% on apixaban vs. [39]
2.89% on aspirin (HR 1.56% on aspirin (HR
1.28, 95% CI 0.58–2.82) 0.80, 95% CI 0.22–2.99)
3.25% on edoxaban 60 mg 0.62% on edoxaban 60 mg [43]
qd vs. 3.86% on warfarin qd vs. 1.09% on warfarin
(HR 0.84, 95% CI (HR 0.57, 95% CI
0.67–1.06) 0.36–0.92)

patients after ESUS, benefits of therapeutic anticoagulation
seem likely. The efficacy of anticoagulation for stroke
prevention in subclinical AF is currently unclear. Ongoing
randomized clinical trials are investigating the impact of
anticoagulation using NOACs in device-detected subclini-
cal AF/atrial high-rate episodes (AHRE) [Apixaban for the
Reduction of Thrombo-Embolism in Patients With Device-
Detected Sub-Clinical Atrial Fibrillation (ARTESIA) trial,
NCT01938248, and Non-vitamin K antagonist Oral anti-
coagulants in patients with Atrial High rate episodes
(NOAH)-AFNET6 trial, NCT02618577]. The situation is
different in patients after stroke/ESUS in whom the
causality, as well as the recurrent stroke risk, is higher.
However, the anticipated risk reduction for recurrent stroke
risk has to be weighed against the risk of hemorrhagic
transformation and intracranial bleedings, which is cer-
tainly higher in stroke patients, in particular in the early
phase after stroke compared with non-stroke patients
treated with oral anticoagulation.
Vitamin K antagonists (VKAs) have not been systemi-
cally investigated in randomized trials specifically focusing
on patients with cryptogenic stroke or ESUS. In the War-
farin-Aspirin Recurrent Stroke Study (WARSS), adjusted-
dose warfarin (international normalized ratio [INR]
1.4–2.8) was compared with aspirin (325 mg/day) for the
endpoint of ischemic stroke recurrence or death within
2 years. A post hoc analysis revealed that in the
cryptogenic stroke subgroup, warfarin was associated with
worse outcomes among those patients with moderate stroke
severity, and with better outcomes in patients without
baseline hypertension or with posterior circulation infarcts
sparing the brainstem [35]. NOACs have been shown to be
at least as effective as warfarin for recurrent stroke pre-
vention in the subgroup of patients with a history of
ischemic stroke/TIA in a pooled analysis of randomized
controlled AF trials [36] and in a recent meta-analysis of
real-world registries [37]. They are recommended as first
choice in patients with AF according to the most recent
guidelines [38]. Furthermore, compared with warfarin,
these compounds are associated with a reduced rate of
intracranial bleeding in AF patients with previous stroke
(Table 2). Apixaban is the only NOAC that has been tested
against aspirin in AF patients with contraindications for
VKAs (Apixaban Versus Acetylsalicylic Acid [ASA] to
Prevent Stroke in Atrial Fibrillation Patients Who Have
Failed or Are Unsuitable for Vitamin K Antagonist
Treatment [AVERROES] trial). In the subgroup of AF
patients with previous stroke, apixaban led to a pronounced
reduction of recurrent stroke and systemic embolism
without increasing the rate of major bleeding [39].
Three randomized trials have been initiated to evaluate
the value of NOACs compared with standard aspirin in
ESUS (Fig. 4). The double-blinded Randomized Evalua-
tion in Secondary Stroke Prevention Comparing the

Fig. 4 Current randomized
clinical trials investigating the
efficacy of direct oral
anticoagulants after ESUS
according to Geisler et al. [27],
Diner et al. [44] and Hart et al.
[45]. ESUS embolic stroke of
undetermined source, ECG
electrocardiogram
Thrombin Inhibitor Dabigatran Etexilate Versus Aspirin in
Embolic Stroke of Undetermined Source (RE-SPECT
ESUS) trial compares standard-dose dabigatran, i.e. 110 or
150 mg twice daily, with aspirin 100 mg once daily for
secondary stroke prevention after mild to moderate ESUS,
defined as a score of three or less on the modified Rankin
Scale (mRS). Medication needs to be started within
6 months after the index stroke and is evaluated for up to
3 years [44]. The primary efficacy endpoint is the time to
first recurrent stroke (ischemic, hemorrhagic, or unspeci-
fied), and the primary safety endpoint is the time to first
major bleed. After randomization of 5390 patients, enrol-
ment has recently been completed and the first results are
expected in late 2018. The double-blinded Rivaroxaban
Versus Aspirin in Secondary Prevention of Stroke and
Prevention of Systemic Embolism in Patients With Recent
Embolic Stroke of Undetermined Source (NAVIGATE
ESUS) trial compares reduced-dose rivaroxaban, i.e.
15 mg once daily, with aspirin 100 mg once daily in a
similar population, i.e. patients with an mRS \ 4 within 6
months after ESUS, with the major difference being that
patients planned for continuous ECG monitoring were
excluded from participation [45]. The primary endpoint
additionally includes MRI-positive TIA, and systemic
embolism. After enrolment of 7214 patients at an interim
analysis in October 2017, NAVIGATE ESUS was prema-
turely terminated due to the lack of efficacy of rivaroxaban
over aspirin. In the open-label, and still actively recruiting,
ATTICUS trial, full-dose apixaban, i.e. 5 mg twice daily, is
T. Geisler et al.
compared with aspirin 100 mg once daily, initiated within
4 weeks after ESUS. According to the latest amendment
(1.5) patients with both minor and major stroke might be
enrolled. In case of major stroke, defined as a stroke vol-
ume of more than one-third of the middle cerebral artery
territory, randomization needs to be delayed to more than
14 days after the index stroke. Only patients with initiated
or planned continuous, or at least daily, ECG monitoring
are allowed to be enrolled in order to alleviate the detection
of subclinical AF. The primary endpoint will be the
prevalence of new ischemic lesions on fluid attenuation
inversion recovery MRI at 12 months compared with
baseline [27]. Of note, compared with aspirin, apixaban led
to a reduction of new ischemic lesions, as well as lesion
volume, in the MRI substudy of the AVERROES trial,
without increasing microbleeds [46].
7 Treatment Recommendations in Cryptogenic
Stroke Patients with Patent Foramen Ovale
In a recent meta-analysis including 2385 patients, VKAs
were not superior to antiplatelet therapy in the subgroup of
cryptogenic stroke patients with patent foramen ovale
(PFO) [47]. Current guidelines recommend antiplatelet
therapy in cryptogenic stroke or ESUS patients with PFO
but without evidence of venous thrombosis [48]. However,
in case the PFO is combined with an atrial septal aneurysm,
patients are at a substantially higher risk for recurrent
Management of ESUS
stroke, and preventive strategies other than antiplatelet
therapy might be considered (e.g. PFO closure or oral
anticoagulation) [49]. To date, guideline recommendations
regarding PFO closure have been solely restricted to PFO
patients with documented venous thrombosis. Two recent
trials (the Patent Foramen Ovale Closure or Anticoagulants
versus Antiplatelet Therapy to Prevent Stroke Recurrence
[CLOSE] trial, and the Gore REDUCE Clinical Study
[REDUCE]) [50, 51], as well as the extended analysis of
the Randomized Evaluation of Recurrent Stroke Compar-
ing PFO Closure to Established Current Standard of Care
Treatment (RESPECT) trial, over a median of 5.9 years
[52], have shown a benefit of PFO closure compared with
antiplatelet medical therapy. These results will probably
change guidelines in the near future and lead to a less-
restrictive indication of PFO closure in selected ESUS
patients with PFO (e.g. patients \ 60 years of age, patients
with an associated atrial septal aneurysm, or patients with a
large interatrial shunt). However, the interventional
approach has not yet been compared to oral anticoagulation
with NOACs.
8 Gaps of Evidence and Future Directions
In particular, knowledge gaps exist regarding the
following:
• The optimal antithrombotic strategy for preventing
ESUS recurrence.
• The timing and duration of antithrombotic therapy after
ESUS to safeguard an optimal risk–benefit ratio.
• Optimal screening methods and algorithms to detect
subclinical atrial fibrillation.
• The association of AF burden and the degree of
atriopathy and the risk of ESUS, and the definition of
cut-off values of AF duration to indicate
anticoagulation.
• Identification/design and validation of risk factor-based
models that increase the likelihood of an underlying
thromboembolic mechanism compared with non-em-
bolic causes, as well as non-thrombotic embolic sources
(e.g. infectious disease/endocarditis, cancer). In this
context, two classification schemes (Atherosclerosis,
Small-vessel disease, Cardiac pathology, Other causes,
or Dissection [ASCOD] [53] and Causative Classifica-
tion of Stroke [CCS] [54]) have been previously
published that account for the multiplicity of stroke
causes. These scoring systems allow for weighing the
different underlying causes of stroke to better define the
probability of stroke mechanisms.
Advances in these fields of ongoing research will
facilitate personalized, risk factor-based pharmacotherapy
in this heterogenous group of patients. Given that stroke is
a leading course of mortality and disability, individual
approaches will likely contribute to a reduction of mor-
bidity/mortality and health economic costs.
9 Conclusions
Patients with ESUS represent a heterogeneous group of
patients with a high likelihood of an occult embolic source
of stroke [55–57]. These patients include individuals with
undetected paroxysmal AF, PFO-associated ESUS, aortic
arch plaque-associated ESUS, cardiac valve-associated
ESUS, or even occult cancer. The safety and efficacy of
antithrombotic treatment is currently being investigated in
major randomized clinical trials comparing NOACs against
antiplatelet therapy. The heterogeneity of the embolic
source and the time-dependent risk after ESUS might be
reasons that make a general recommendation for
antithrombotic therapy challenging. This heterogeneity is
also suggested by the premature termination of a recent
trial showing the lack of efficacy with the factor Xa inhi-
bitor rivaroxaban compared with aspirin in ESUS patients.
Results of further clinical trials will shed more light into
the optimal management of this risk group. Possibly, a
more resolute risk stratification, e.g. by screening for sub-
clinical AF, or a risk factor-based enrichment of the tar-
geted ESUS population, will become necessary in order to
identify the optimal pharmacological or interventional
treatment strategy, depending on the most probable nature
of the underlying embolic source. Based on the available
evidence, a generalist approach of anticoagulation cannot
be recommended for treatment after ESUS. (Temporary)
off-label NOACs might be considered in high-risk patients,
e.g. in case of recurrent ESUS. However, intensified
screening for atrial fibrillation, either by Holter monitoring
(30 days) or implantable loop recorders, should be
mandatory in order to confirm the indication for (contin-
ued) anticoagulation. Although the cut-off for relevant AF
(e.g. short episodes of AF/AHRE lasting 2 min, or AF
episodes of several hours’ duration) is unclear, in our
opinion, the threshold for anticoagulation for secondary
stroke prevention should be more rigid than in a non-stroke
population.
Compliance with Ethical Standards
Funding No external funding was used in the preparation of this
manuscript.
Conflicts of interest Tobias Geisler reports personal fees from
AstraZeneca, Boehringer Ingelheim, Pfizer, and MSD; grants and
personal fees from Bayer Healthcare, Bristol Myers Squibb, Daiichi
Sankyo, Eli Lilly, and The Medicines Company; and grants from
Siemens Healthcare and Spartan Bioscience, outside the submitted

work. Annerose Mengel has no conflicts of interest relevant to the
presented work. Ulf Ziemann has received speaker honoraria and/or
travel compensation from Bayer Vital GmbH, Biogen Idec GmbH,
Bristol Myers Squibb GmbH, Medtronic GmbH, and Pfizer GmbH;
and grants from Biogen Idec GmbH, Servier, and Janssen Pharma-
ceuticals NV. He serves on the advisory board of CorTec GmbH.
None of the above are related to the submitted work. Sven Poli has
received speaker’s honoraria and consulting honoraria from Bayer,
Boehringer Ingelheim, Bristol-Myers Squibb/Pfizer, Daiichi Sankyo
and Werfen; reimbursement for congress traveling and accommoda-
tion from Bayer and Boehringer Ingelheim; and research support from
Bristol-Myers Squibb/Pfizer, Boehringer-Ingelheim, Daiichi Sankyo
and Helena Laboratories. None of the above are related to the sub-
mitted work.
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