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Contents lists available at ScienceDirect

Trends in Cardiovascular Medicine

journal homepage: www.elsevier.com/locate/tcm

Atrial fibrillation and stroke: A review and new insights

Irene Escudero-Martínez a,b,∗, Lluis Morales-Caba a,b, Tomás Segura c,d
a
Stroke Unit, Department of Neurology, Hospital Universitari i Politècnic La Fe, Valencia, Spain
b
Instituto de Investigación Sanitaria La Fe - Universidad de Valencia, Valencia, Spain
c
Department of Medical Sciences, Faculty of Medicine of Albacete, University of Castilla-La Mancha, Albacete, Spain
d
Stroke Unit, Department of Neurology, Hospital General Universitario de Albacete, Spain

a r t i c l e i n f o a b s t r a c t

Keywords: The link between heart and brain continues to be a matter of great interest for the scientific commu-
Atrial fibrillation nity. One of the most established associations between the two is that the heart is a significant source
Ischemic stroke
of emboli and is responsible for 20-25% of all ischemic strokes. The most frequent underlying cause of
Prevention
cardioembolic stroke is atrial fibrillation (AF), a disease that affects almost 3 million people in the USA
and 4.5 million in Europe. AF increases the risk of ischemic stroke by a factor of 3 to 5 times. It is esti-
mated that AF is responsible for 15% of all strokes worldwide. A more comprehensive understanding of
this association and development of intensive stroke prevention measures are needed, as we know that
AF incidence and prevalence will increase over the coming years, becoming one of the largest epidemics
and public health challenges we face.
© 2021 Elsevier Inc. All rights reserved.

Epidemiological association of AF and stroke a cortical cardiac pacing site in the insular cortex that may partic-
ipate in an inappropriate sympathomimetic discharge when dam-
AF is the most common arrhythmia encountered in clinical aged. [9, 10]
practice, with a pooled incidence in community-based studies av-
eraging 4.70 per 10 0 0 person-years, and a prevalence ranging from
Thrombogenesis and embolism: mechanistic hypothesis
2% in people < 65 years to 9% in those > 65 years and almost 18%
in the elderly (> 85 years). [1, 2] It has been identified as one of
The classical model of embolic stroke in AF patients is that
the main sources of embolism in patients admitted for ischemic
fibrillation of the atrium produces ineffective contraction leading
stroke in stroke units since the early1970s. [3]
to stasis of blood, which favors thrombus formation and subse-
The causal association of atrial fibrillation and stroke has been
quent embolization to the brain. This classical pathophysiological
supported by a series of cohort-based studies. [4] Incidence of is-
model has been questioned in the last two decades. Failure to
chemic stroke in patients with AF without anticoagulation ranges
prove a temporal relationship between episodes of paroxysmal AF
from 7.7 to 30.8 per 10 0 0 person-years. [5, 6]
and stroke in patients with cardiac implantable electronic devices
AF is also considered to be highly prevalent among patients ad-
has contradicted one of the principles of causality. Therefore, this
mitted in stroke units due to strokes arising from other mecha-
has led investigators to search for additional factors that might be
nisms. 10% of patients with lacunar stroke also present with AF,
responsible for or contribute to AF-related strokes. [11]
and large artery atherosclerosis is twice as common in patients
Current models advocate for an interplay between abnormal
with AF as in those without. [7, 8]
atrial contractility (that is, AF itself) and other atrial factors such
Finally, AF can present as an acute complication of the stroke
as endothelial dysfunction, fibrosis, impaired myocyte function,
itself. Acute ischemic stroke and transient ischemic attack (TIA)
chamber dilatation and left atrial appendage mechanical dysfunc-
are followed by electrocardiographic abnormalities in up to 75% of
tion. These pathophysiological mechanisms have been reported in
cases, with AF being the most frequent arrhythmia. Although the
humans and experimental animal models, and they constitute the
mechanism by which stroke can produce cardiac rhythm distur-
more recent concept of atrial myopathy. [12]
bances is not fully understood, it has been postulated that there is
Endothelial dysfunction in AF manifests as decreased expres-
sion of nitric oxide (NO) synthase in the endocardium. Loss of
∗
Corresponding author at: Stroke Unit, Department of Neurology, Hospital Uni- laminar flow and cyclic stretch would result in downregulation of
versitari i Politècnic La Fe, Av. Fernando Abril 106, 46026 Valencia, Spain. this enzyme. The decrease in NO also facilitates an increase in the
E-mail address: escudero_ire@gva.es (I. Escudero-Martínez). production of adhesion molecules that would facilitate the forma-

https://doi.org/10.1016/j.tcm.2021.12.001
1050-1738/© 2021 Elsevier Inc. All rights reserved.

Please cite this article as: I. Escudero-Martínez, L. Morales-Caba and T. Segura, Atrial fibrillation and stroke: A review and new insights,
Trends inDescargado
Cardiovascular Medicine,
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I. Escudero-Martínez, L. Morales-Caba and T. Segura
tion of intracavitary thrombi. In addition, all cardiac output passes
through the left atrium, and the atrial endocardium represents, in
fact, an endocrine organ that produces NO and provides circulating
NO to the systemic circulation. Thus, dysfunction of the atrial en-
docardium may have an adverse effect on systemic vessel function
as a whole. [13]
Atrial fibrosis may occur in the context of systemic disease
(such as hyperthyroidism or amyloidosis), mitral valve disease, a
long history of hypertension, or simply due to aging. Common
histopathological findings are an accumulation of collagen, atro-
phy, and vacuolar degeneration of myocytes with accumulation of
lipofuscins, an increase in the quantity of adipose tissue, and grad-
ual loss in nodal fibers with fibrofatty substitution of the sinoatrial
node. This may represent a structural substrate reentry circuit (AF
genesis) and lack of NO production, thus providing a potential sub-
strate for thrombus formation. [14]
Atrial fibrosis can be observed by gadolinium enhanced cardiac
MRI even before the development of AF itself. This fact could ex-
plain auricular thrombus formation in subjects in sinus rhythm but
with atrial fibrosis alone. [15] All those changes also lead to cham-
ber dilatation, which is a known and strong predictor of AF. [16]
Transesophageal echocardiography (TEE) measurement of the
flow pattern by pulse wave Doppler has shown an irregular AF
phenotype in the left atrium, despite simultaneous surface ECG
showing sinus rhythm. These findings would help to explain the
occurrence of embolic phenomena during periods of sinus rhythm
in these patients. [17]
Clinical and radiological characteristics of ischemic stroke due
to AF
AF is associated with more severe strokes than those caused by
atheromatous disease, and one of the hypotheses is that cardioem-
bolic strokes are presumably due to embolization of large thrombi.
AF has also been associated with silent cerebral infarctions (SBI)
and TIA. [18]
Regarding neuroimaging characteristics, multiterritorial em-
bolisms are more frequently seen in cardioembolic stroke due to
AF. Additionally, there is a higher probability of DWI lesions after
TIA due to AF embolism than those due to other etiologies.
Stroke risk assessment and need for treatment in patients with
AF
Stroke prevention is the main management priority in patients
with AF. To stratify embolic risk in AF patients, the CHADS2 scale
was developed based on multiple clinical variables. It is widely
employed due to its simplicity and ease of use. [19, 20]
More recently, the CHA2 DS2 -VASc score was developed. This
score considers patients with a prior stroke/TIA or patients > 75
years as high-risk patients and therefore should receive oral an-
ticoagulation (OAC) for stroke prevention. Furthermore, a combi-
nation of at least two risk factors from the following - hyper-
tension, heart failure, diabetes, age 65 to 75, female gender, and
pre-existing vascular disease - are also considered to be high risk.
[21] CHA2 DS2 -VASc provides a more accurate risk estimation in the
group of intermediate risk from CHADS2 , for whom OAC recom-
mendations were not clear. It is also suggested that CHA2 DS2 -VASc
is a better discriminator of ‘true low-ri’sk patients when compared
with CHADS2 . [22]
With direct oral anticoagulants (DOACs), which reduce the rate
of major bleeding complications when compared to vitamin K an-
tagonists (VKA), physicians are less reluctant to initiate oral antico-
agulation. [23] Nowadays, the focus of stroke prevention in NVAF
patients has shifted from predicting high-risk patients to identify
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Trends in Cardiovascular Medicine xxx (xxxx) xxx
patients at truly low risk of ischemic stroke, in whom OAC has no
net clinical benefit. [24]
Because OAC is a double-edged sword, with both benefits and
associated risks, the decision-making process requires a defined
and reliable, evidence-based foundation. Blood biomarkers can pro-
vide information on prognosis and risk stratification. [25] The most
widely studied for this purpose are mentioned below but many
others have also been investigated.
Von Willebrand factor (VWF) elevation is one of the best-
known biomarkers: high VWF levels are suggestive of endothe-
lial dysfunction. [26] Its elevation is correlated with left atrial
blood stasis in NVAF. In several cohort studies, patients who devel-
oped thromboembolic events had significantly higher VWF activity
and total concentration compared to those without demonstrated
thromboembolism. [27]
An increase in other circulating factors, such as PAI-1 (plas-
minogen activation inhibitor), TAT (thrombin-antithrombin com-
plex III) and D-dimer, has been reported as leading to decreased
fibrinolytic activity and an increase in thrombotic state in patients
with AF. [28, 29] Elevation of NT-proBNP (N-terminal pro–B-type
natriuretic peptide) and hs-TnT (high-sensitivity cardiac troponin
T), both linked to myocardial damage and heart failure, can add
strong prognostic information, and indicate an increase in em-
bolic risk in AF patients. Those biomarkers also show independent
prognostic value after risk stratification by other known factors
(CHAD2s2-VASc, male sex, higher body mass index…) [30, 31, 32,
33]
Other biomarkers such as mean platelet volume, IL-6 and TNF-α
have been studied as novel thrombotic risk predictors. They appear
to be increased in some patients with AF independently of antico-
agulation treatment and it may reflect an underlying inflammatory
state that has previously been related to thrombogenesis and en-
dothelial activation. These findings are reported in a limited num-
ber of studies with heterogeneous populations, so the data should
be interpreted cautiously. [34, 35]
It has been suggested that the implementation of all these
biomarkers would provide highly individualized embolic risk es-
timation in AF patients, and consequently personalized prevention
treatment and strategies. Examples of clinical scales that include
biomarkers are the ATRIA score, the Intermountain risk score, and
the ABC-Stroke scale [36, 37, 38] Moreover, adding these biomark-
ers to CHA2 DS2 -VASc score may help identify patients in an en-
hanced thrombotic or decreased fibrinolytic state among patients
initially classified as low risk patients. [39]
AF as a cause of silent brain infarction (SBI)
SBI are defined as cerebral infarcts that are observed on neu-
roimaging in the absence of any neurological symptoms referable
to the corresponding area. [40]
Nowadays, epidemiological research and neuroimaging, espe-
cially MRI, has proved that SBI contributes to neurocognitive de-
cline, cardiovascular events including an increased risk of first
stroke (10% per year and two-to-threefold of those without SBI),
as well as disability, gait instability, depression, and death. Hence
the term silent is misleading and the term covert brain infarction
(CBI) is considered more appropriate. [41, 42]
Prevalence of SBI in the general population ranges from 8 to
28% according to epidemiological studies and has been consistently
associated with age and hypertension in large population studies.
[43] AF has been postulated as a cause of SBI. A recent systematic
review and meta-analysis showed that AF was associated with SBI
(OR 2.62, 95% CI 1.81–3.80) independently of AF type (paroxysmal,
persistent, or permanent). [44] SBI can also occur after AF ablation
due to the potential thromboembolic risk of the procedure. SBI rate
JID: TCM
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I. Escudero-Martínez, L. Morales-Caba and T. Segura
varies according to the technique, being significantly higher after
thoracoscopic epicardial ablation than after catheter ablation. [45]
The AHA-ASA published a scientific statement on the man-
agement of patients with covert cerebrovascular disease in 2017.
This document recommends assessing common vascular risk fac-
tors and pulse for AF in patients with SBI and consider echocardio-
graphy when there is a pattern of SBI which appears to be embolic
in origin. Regarding prevention of stroke in patients with SBI, there
is no clear recommendation, but the statement suggests that it
is reasonable to consider this information when making decisions
about anticoagulation for those with atrial fibrillation. However, it
also states that the role of SBI in prevention strategies has not been
fully studied in RCTs and that further investigation is needed. [46]
Diagnosis of AF as a cause of stroke
AF: to screen or not to screen?
The evidence for AF screening in the general population as a
primary prevention strategy for cardioembolic stroke is quite lim-
ited. According to the AHA/ASA guidelines, screening all patients
aged 65 years and older using pulse palpation to detect AF fol-
lowed by ECG is recommended. More recently, the recommenda-
tion to perform systematic AF screening in individuals aged > 75
years of age has been upgraded from class IIb to class IIa in the
2020 ESC AF guidelines. [47, 48]
Systematic opportunistic screening is more likely to be cost-
effective than systematic population screening. Nurse pulse palpa-
tion or modified blood pressure monitors (if available) would be
appropriate screening tests followed by a diagnostic 12-lead ECG
interpreted by a trained general practitioner in those who screen
positive, with referral to a specialist for cases in which diagnosis is
unclear. [49]
Nowadays, smartphones and smartwatches offer the possibility
of AF screening and monitoring. Although AF detection via these
smart devices may represent an inexpensive, noninvasive approach
to long-term AF surveillance and management, more studies are
needed to clearly identify the ideal population for the use of these
systems as well as adopt the best technology and strategy in con-
junction with the medical community. [50, 51]
Screening for AF is attractive because most consequences can
be prevented. The optimal screening procedure, however, is not
yet defined. Several ongoing studies [GUARD AF (NCT04126486),
STROKESTOP 1 (NCT01593553) & 2 (NCT02743416) and the LOOP
study (NCT02036450)] will report data within a few years on hard
endpoints after randomization to arms undergoing AF screening or
not. [52]
ESUS
The term ESUS (embolic stroke of undetermined source) was
introduced in 2014 to identify patients with non-lacunar crypto-
genic ischemic strokes in whom embolism was the likely stroke
mechanism. [53] The frequency of ESUS varies depending on the
population, with most of the studies reporting a frequency of ESUS
ranging from 9% to 25%. [54] The optimal preventive treatment in
these patients remains unclear. Two large randomized clinical tri-
als (NAVIGATE-ESUS and RESPECT-ESUS) failed to demonstrate the
efficacy of OAC in the prevention of stroke recurrences in these pa-
tients. [55, 56]
In patients presenting with an ESUS, AF is an important cause
that should be investigated due to its potential benefit in stroke
prevention with OAC. But not all ESUS patients present the same
risk for AF. In the NAVIGATE-ESUS trial that included 7112 ESUS pa-
tients, AF was ultimately detected in only 3.4% of the whole group
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Trends in Cardiovascular Medicine xxx (xxxx) xxx
during a mean follow-up time of 11 months. [57] In this study, ad-
vanced age, left atrium enlargement and frequent supraventricular
extrasystole were predictive of a higher risk of developing AF. In
the RESPECT-ESUS trial, 5390 patients were enrolled, and AF was
found in 7.5%. They found that advanced age and elevation of NT-
proBNP (when available) were associated with a higher risk of de-
veloping AF. [58]
These findings may help clinicians identify patients who may
benefit from more intense, long-term cardiac monitoring. Figure 1
proposes an algorithm to select stroke patients for prolonged car-
diac monitoring.
Long-term cardiac monitoring
There are different prolonged monitoring strategies available in
clinical practice to detect AF in stroke patients: 12-lead electrocar-
diogram (ECG), inpatient ECG telemetry during stroke admission
to the Stroke Unit/ICU, ECG Holter from 24 hours to 7 days after
discharge, external long-term ECG recordings that can register up
to 30 days and cardiac implantable devices, including pacemakers,
defibrillators and implantable loop recorders, which are small de-
vices that are inserted subcutaneously on the chest and are used
for long-term ECG event recording, up to several years. [59]
The selection of a specific tool in clinical practice should con-
sider different factors that include the sensitivity, the cost, or the
invasiveness of the test. Table 1 summarizes the main characteris-
tics of each strategy.
Each tool records different events: while surface ECG detects
supraventricular irregular heart rhythm without p waves, im-
plantable devices monitor the electrical activity of the atria and
can detect high-rate atrial activity, also defined as Atrial High-Rate
Episodes (AHRE). These AHREs have been found to be present in
most cases of AF or flutter, and they imply a higher risk of stroke
than sinus rhythm. However, the best strategy for stroke preven-
tion in this group remains unclear. [60] AF burden has also been
postulated as a marker of thromboembolic risk, but this has not
been proved by prospective studies. [60]
In this past year, 6 RCTs evaluating long-term cardiac monitor-
ing have been published. On balance, these trials have confirmed
that long-term cardiac monitoring is associated with increased de-
tection of AF, but overall, there was no difference between the con-
trol group of patients and those receiving long-term cardiac mon-
itoring in terms of OAC use or rates of recurrent stroke. Further
studies are needed to fill this knowledge gap. [61]
Secondary stroke prevention in AF patients
Antithrombotic therapy
In patients with valvular AF, oral anticoagulation (OAC) for
stroke prevention with vitamin K antagonists (VKA) is indicated.
For those with non-valvular AF (NVAF), direct oral anticoagulants
(DOACs) are considered by AF guidelines world-wide as the pre-
ferred choice of anticoagulant treatment to prevent stroke. [47, 62,
63, 64]
In secondary stroke prevention, the main controversy is the
time point at which OAC should be (re-)started after a stroke.
Regarding ischemic stroke, 2021 EHRA-ESC guidelines recommend
OAC initiation within the first 24-72 hours in patients with tran-
sient ischemic attack (TIA). In patients with acute ischemic stroke
(AIS), if infarct size is not expected to substantially increase the
risk of hemorrhagic transformation, OAC could be (re-)initiated ≥
3 days if mild stroke, 6-8 days after if moderate stroke and in pa-
tients with severe stroke at 12–14 days, after excluding secondary
hemorrhagic transformation by repeating brain imaging studies.
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I. Escudero-Martínez, L. Morales-Caba and T. Segura Trends in Cardiovascular Medicine xxx (xxxx) xxx

Fig. 1. Proposed algorithm to select stroke patients for prolonged cardiac monitoring. Adapted from reference [59].

Table 1
Long-term monitoring devices main characteristics. Table adapted from reference [59]

Technique Recording time Invasiveness Cost

Holter Monitoring Days Non invasive Low

Wearable long term outpatient telemetry (NUUBO®) Weeks Non invasive Intermediate
Insertable cardiac monitors (Reveal®) Years Minimally invasive High
Pacemakers and implantable cardioverter defibrillators Years Invasive High

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Table 2
Summary of ongoing RCTs regarding time of re/starting OAC after an ischemic stroke or ICH. Data from reference [65]

ISCHEMIC STROKE

Clinical trial Arms of treatment Estimated Main outcome Result

enrollment
ELAN (NCT03148457) Early vs standard NOAC onset, 2000 Composite of major bleed, stroke Ongoing. October 2021.
stratified by stroke severity. ∗ recurrence, systemic embolism,
vascular death at 30 days.
OPTIMAS (NCT03759938) Early NOAC onset (within 96 hours of 3478 Composite of stroke recurrence, Ongoing. September 2022.
stroke) vs standard (between days 7 intracranial bleed, systemic embolism
and 14). at 90 days.
TIMING (NCT02961348) Early NOAC onset (day 1 to 4) vs late 888 Composite of stroke recurrence, Ongoing. December 2021.
onset (day 5 to 10) after ischemic intracerebral bleed, any cause death at
stroke.
START (NCT03021928) Time-to-treatment interval with NOAC 1000 Composite of stroke recurrence, To be published. Recruited until
either 60, 132, 228 and 324 hours systemic embolism, intracerebral August 2021.
after index stroke. bleed, systemic major bleeding and
any cause death at 30 days.
AREST (NCT02283294) Apixaban vs warfarin stratified: TIA - 91 Composite endpoint of fatal stroke, Early onset of apixaban does not
small - medium stroke. recurrent ischemic stroke, or TIA. increase the risk of intracerebral
hemorrhagic complications.
HEMORRHAGIC STROKE
PRESTIGEAF (NCT03996772) NOAC vs antiplatelet after intracranial 654 Time to first first incident ischemic Proposed February 2021. Still
haemorrhage. Stratified by stroke or recurrent haemorrhage. recruiting.
lobar/non-lobar and gender.
APACHE-AF (NCT02565693) Apixaban (5 mg or 2.5 mg twice daily) 101 Number of patients who experience High subsequent annual risk of
vs single antiplatelet vs no the combination of vascular death or non-fatal stroke or vascular death,
antithrombotic. non-fatal stroke (follow up of 12 to 72 whether allocated to apixaban or to
months). avoid anticoagulation.
NASPAF-ICH (NCT02998905) NOAC vs aspirin (81 mg). 30 Composite of ischemic stroke and No cases of recurrent ICH or fatal
recurrent cerebral haemorrhage stroke were documented.
through study completion (one year).
Recruitment rate in study.
ASPIRE (NCT03907046) Apixaban (5 mg or 2.5 mg twice daily) 700 Incidence of ischemic or hemorrhagic Ongoing. October 2021.
vs aspirin (81 mg). stroke or death at 3 years follow up.
SoSTART (NCT03153150) NOAC vs VitK antagonist 203 Rate of intracranial haemorrhage Inconclusive. Lack of statistical power.
anticoagulants vs no antithrombotic. recurrence in the first year of follow
up. Recruitment rate per site-month.
A3ICH (NCT03243175) Apixaban (5 mg twice daily) vs left 300 Composite of fatal and non-fatal Ongoing. December 2023.
appendage closure. intracranial and extracranial embolic
and haemorrhagic events.
ENRICH-AF (NCT03950076) Edoxaban (60 mg or 30 mg) 1200 Stroke or major haemorrhage in Proposed February 2021. Still
median 2 years follow-up. recruiting.

These timelines have been suggested according to expert recom-
mendations and should always be individualized for each patient
taking into consideration individual thrombotic and hemorrhagic
risks. [65]
The 2019 AHA/ASA guidelines conclude that ‘for most patients
with an acute ischemic stroke in the setting of AF, it is reasonable
to initiate OAC between 4 and 14 days after the onset of neurolog-
ical symptoms’. [66]
After an intracranial hemorrhage (ICH), a case-by-case consider-
ation is needed to determine whether to (re-)start anticoagulation,
according to individual risks and ICH etiology. The generic recom-
mendation for these patients is to (re-)start OAC 4–8 weeks after
the ICH if the individual risk of cardio-embolic stroke is high and
the risk of recurrent ICH is estimated to be lower.
The safety of oral anticoagulation in the setting of cerebral amy-
loid angiopathy and in the presence of cerebral microbleeds (CMB)
remains unclear and merits further study. In patients with CMB,
observational studies have shown that are they are associated with
a greater relative hazard for subsequent ICH than for ischemic
stroke, but the absolute risk of ischemic stroke is higher than that
of ICH. [67]
Table 2 summarizes ongoing RCTs regarding time of re/starting
OAC after an ischemic stroke or ICH.
Other therapeutic interventions
Left atrial appendage (LAA) occlusion is a potential alternative
strategy to long-term anticoagulation in AF patients post ICH af-
ter careful weighing of risks and benefits. However, this strategy
requires a period of antiplatelet or anticoagulant treatment post-
deployment, which also carries a risk of recurrent ICH. [68] Pa-
tients with AF after ICH in whom LAA occlusion is being consid-
ered should ideally be included into an ongoing RCT. [65]
More recently, a novel, permanent, bilateral pair of common
carotid artery (CCA) filters has been developed to capture big em-
boli, thereby preventing major cerebral stroke in patients with
high-risk AF who may or may not be receiving OAC. [69]
Conclusion
AF is the most common tachyarrhythmia and an important
cause of covert and clinical stroke. The relationship between AF
and cerebral ischemia is bidirectional and nowadays we better un-
derstand the pathophysiology of thrombosis and other mechanisms
related to AF. An early diagnosis of AF is important due to the ther-
apeutic implications, mainly stroke prevention. OAC is the standard
of care for these patients, and novel strategies with new devices
are being developed as an alternative for patients in whom OAC is
contraindicated.
Key trends
- AF and stroke incidence and prevalence will increase over the
next years, becoming one of the largest epidemics and public
health challenges.

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JID: TCM
ARTICLE IN PRESS
I. Escudero-Martínez, L. Morales-Caba and T. Segura
- An increasing number of AF detection tools are available, so
the best strategy in each population (general population vs pa-
tients with previous stroke) should be defined according to
cost-effectiveness.
- OAC is the cornerstone of stroke prevention in AF patients.
However, in patients at high risk of ICH other strategies such
as LAA might be an alternative.
Declaration of Competing Interest
None.
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