Revista Mexicana de Neurociencia

REVIEW ARTICLE

Stroke and atrial fibrillation: An update

Nicole Beaton Sur* and Jose G. Romano
School of Medicine, University of Miami Miller, Miami, Florida

Abstract
Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia encountered in clinical practice. AF is associated
with an increased risk of cardiovascular disease, heart failure, stroke, cognitive impairment and dementia, and mortality. Indi-
viduals with AF have a 5-fold risk of ischemic stroke, and AF-related strokes are associated with greater disability and
mortality compared with strokes from other causes. Moreover, the burden of AF and AF-related stroke on patients, their
caregivers, health-care systems, and society is significant and projected to increase in the coming decades due to the rap-
id growth of the ageing population. The care and management of patients with AF and AF-related stroke are challenging,
often involving complex decision-making to weigh the risks and benefits of various treatment and prevention strategies. This
topical review focuses on the latest science and advances in AF and AF-related stroke and identifies knowledge gaps and
future directions of continued research.

Keywords: Ischemic stroke. Hemorrhagic stroke. Atrial fibrillation. Prevention. Cerebrovascular disease. Anticoagulation.

Actualización en ictus y fibrilación auricular

Resumen
La Fibrilación Auricular (FA) es la arritmia sostenida mas común en la practica clínica. La FA se asocia a un riego
incrementado de enfermedad cardiovascular, falla cardiaca, enfermedad cerebrovascular, deterioro cognitivo y demencia. Los
individuos con FA tienen un riesgo cinco veces mayor de ictus, y los infartos isquémicos asociados a la FA causan mayor
discapacidad y mortalidad comparado con otras causas de ictus isquémico. Se estima que las consecuencias y la carga
de la FA y el ictus ocasionado por la FA en pacientes, sus familias, la sociedad y el sistema de salud, se incrementara de
manera importante en las próximas décadas dado el incremento de la población añosa, la cual tiene un riesgo aumentado
de FA. El manejo de los pacientes con ictus y FA es complejo dado el riesgo de hemorragia en pacientes con enfermedad
cerebrovascular, particularmente en las etapas tempranas después del ictus. Esta revisión temática se enfoca en avances
recientes en la terapéutica del ictus asociado a FA e identifica direcciones futuras de investigación.

Palabras clave: Ictus cerebral. Derrame cerebral. Fibrilación auricular. Prevención. Anticoagulación.

*Correspondence: Date of reception: 31-03-2022 Available online: 08-07-2022

Nicole Beaton Sur, Date of acceptance: 19-05-2022 Rev Mex Neuroci. 2022;23(4):149-156
E-mail: [email protected] DOI: 10.24875/RMN.22000016 www.revmexneurociencia.com
2604-6180 / © 2022 Academia Mexicana de Neurología A.C. Published by Permanyer. This is an open access article under the CC BY-NC-ND license
(http://creativecommons.org/licenses/by-nc-nd/4.0/).

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 Rev Mex Neuroci. 2022;23(4)

Introduction setting of AF include increased age, female sex, hyper-

tension, heart failure, diabetes, and history of cardio-
Atrial fibrillation (AF) is common, affecting an vascular or cerebrovascular ischemic events. Women
estimated 37.6 million individuals globally in 20171, an with AF have a higher risk of stroke compared with
increase from 33.5 million individuals in 20102. The men, which is thought to be mediated by increased age
prevalence of AF increases with age, nearly doubling and vascular risk factors10-14. Moreover, AF-related
every decade after age 60 years3. As people are living stroke tends to be more severe in women, and more
longer and the ageing population continues to grow women than men die or are disabled from AF-related
rapidly, the prevalence of AF is projected to nearly triple stroke every year15.
by the year 20504. Similarly, the burden of AF posed Risk stratification schemes, such as the CHA2DS2-VASc
by the increased risk of cardiovascular disease, heart score, assist in assessing the risk of stroke and systemic
failure, stroke, cognitive impairment and dementia, and embolism in AF patients, giving weight to common risk
mortality is also expected to increase in parallel over factors (Table 1). The American Heart Association and
the ensuing decades4. American Stroke Association guidelines recommend
The treatment of patients with AF and AF-related using the CHA2DS2-VASc score for risk stratification to
stroke is complex, and the burden on patients, caregiv- guide the use of anticoagulants for the prevention of
ers, health-care systems, and society is high. Although stroke and systemic embolism16.
there have been significant scientific advances in the
area of AF and cardioembolic stroke recently, many key
Mechanisms and clinical presentation of
knowledge gaps remain. In this topical review, an over-
stroke in AF
view of AF and AF-related stroke will be discussed, with
an emphasis on treatment, prevention, screening, spe- AF is characterized by irregular atrial activity, result-
cial considerations, and future research directions. ing in abnormal and irregular atrial contractions. Sev-
eral factors, such as enlarged atrial size, atrial fibrosis,
chronic inflammation, and upregulation of ion channel
Risk factors for AF and stroke
subunits, contribute to the development and mainte-
Increased age and male sex are the strongest nance of AF. Irregularities in atrial contraction associ-
non-modifiable risk factors for AF. Male sex is associat- ated with AF increase the risk of stasis of blood flow
ed with a 1.5-fold risk of developing AF and 2-fold higher and thrombus formation, thereby predisposing to stroke
incidence compared with female sex5,6. Although the and systemic embolism. Over 90% of thrombi second-
overall incidence, prevalence, and age-adjusted lifetime ary to AF arise from the left atrial appendage17. There
risk of AF is higher in men, there are more women than is emerging evidence suggesting that atrial cardiopa-
men with AF due to differences in Regarding other thy, characterized by structural, contractile, architectur-
non-modifiable risk factors, the literature suggests that al, or electrophysiological changes within the atria, may
white men have a higher incidence of AF; however, black contribute to stroke through thrombus formation even
patients have a higher risk of death related to AF and a in the absence of AF18,19. The lack of temporal associ-
higher risk of AF-related stroke7. ation between implantable device-detected AF and
Common modifiable risk factors for AF include hyper- stroke events supports the notion that the thrombi may
tension, diabetes, obesity, cardiovascular disease, smok- arise from the dysfunctional atria and atrial appendage
ing, and alcohol use. Similarly, these same risk factors rather than from the AF itself20,21. In some cases, the
increase the risk of stroke in patients with AF. Women stroke itself may contribute to the development of AF,
with AF tend to be older and have more hypertension, and AF detected after stroke may have a different risk
hyperlipidemia, and obesity, while men with AF tend to profile for recurrent thromboembolic events19,22.
have more coronary artery disease, left ventricular dys- AF can be paroxysmal or sustained; however, the risk
function, and chronic obstructive pulmonary disease5. of stroke is similar regardless of AF type. Although gen-
AF is associated with a 5-fold risk of ischemic stroke8, erally considered a “silent” condition, up to 60% of in-
one of the most feared and debilitating sequelae of the dividuals report symptoms such as fatigue, dizziness,
arrhythmia. AF accounts for approximately 20-25% of palpitations, dyspnea, chest pain, generalized weak-
all ischemic strokes, though the frequency of AF in- ness, and other less common symptoms23. Women tend
creases to approximately 40% in ischemic stroke pa- to be more symptomatic compared with men and they
tients ≥ 80  years old9. Risk factors for stroke in the report higher burden of symptoms and lower quality of
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 N.B. Sur, J.G. Romano: Stroke and AF

Table 1. The CHA2DS2‑VASc score components and estimated yearly risk of stroke and systemic embolism
CHA2DS2‑VASc Points CHA2DS2‑VASc score Yearly risk of ischemic Yearly risk of stroke/TIA and
Risk Factor stroke (%) systemic embolism (%)

Congestive heart failure +1 0 0.2 0.3

Hypertension +1 1 0.6 0.9

Age < 65 years 0 2 2.2 2.9

Age 65‑74 years +1 3 3.2 4.6

Age ≥ 75 years +2 4 4.8 6.7

Diabetes +1 5 7.2 10.0

Vascular disease +1 6 9.7 13.6

Male sex 0 7 11.2 15.7

Female sex +1 8 10.8 15.2

Stroke/TIA/thromboembolism +2 9 12.2 17.4

Adapted from Friberg et al. 201211. TIA signifies transient ischemic attack.

life compared with men. Accordingly, women are more have been steadily increasing over the past decade9,27.
likely than men to seek care for AF5. Given the relatively Thrombolytic therapy and endovascular therapy remain
silent and potentially paroxysmal nature of AF, it can be the hallmark of acute ischemic stroke treatment for el-
challenging to detect. It is estimated that approximately igible patients, regardless of the presence of AF. One
13% of individuals with AF have undetected AF24. caveat is that patients with known AF who are on anti-
In up to 37% of cases, stroke is the first sign of AF25. coagulation for stroke prevention may not be eligible for
The symptoms of stroke secondary to AF are character- intravenous thrombolysis, thus endovascular therapy
ized by the sudden onset of neurological deficits that are may be the only acute treatment option. In addition,
typically maximal at onset. The course of symptoms is blood pressure management, heart rate and rhythm
less likely to be progressive or stuttering as is sometimes control, and management of post-stroke complications
the case in strokes due to small or large vessel disease. are crucial to in-hospital treatment of AF-related stroke.
Patients with AF-related stroke present with greater se-
Several studies have shown that rate control is not in-
verity and higher frequency of large vessel occlusion
ferior to rhythm control regarding cardiovascular out-
strokes compared to strokes from other causes.
comes and mortality for the treatment of AF28,29, and
Infarct patterns in AF-related stroke include large ter-
the focus of this section will be the use of anticoagu-
ritory wedge-shaped infarcts and/or smaller multifocal
lants for stroke prevention.
infarcts in multiple arterial territories (Fig. 1). In addition,
patients with AF tend to have a higher burden of white
matter hyperintensities and evidence of cerebral small Oral anticoagulants (OACs) for secondary
vessel disease, including microhemorrhages26. Vessel stroke prevention
imaging in the acute stroke setting may show large ves-
sel occlusion. Hemorrhagic transformation of the infarct- Initiation of anticoagulation therapy in patients with
ed tissue is more common in cardioembolic strokes, AF-related stroke is paramount for secondary stroke
likely due to larger infarct size and increased patient age. prevention. Decision-making in this setting is challeng-
ing, given the risk of hemorrhage in the immediate
post-stroke period, weighed against the risk of recur-
Treatment and outcomes of AF-related rent ischemic stroke, or other ischemic events. The
stroke estimated risk of a recurrent ischemic stroke is 1.5%
Population-based studies in the US and Canada sug- per day in the first 2  weeks after an acute stroke30,
gest that ischemic stroke admissions with comorbid AF while the risk of any radiographic hemorrhagic

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 Rev Mex Neuroci. 2022;23(4)

favorable safety profile and do not require constant

A B
blood level monitoring, making them easier to use. In
2019, the American College of Cardiology and Ameri-
can Heart Association published updated guidelines
recommending DOACs as first line for eligible patients
with AF23. The main contraindication to DOACs in-
cludes patients with mechanical heart valves and mod-
erate-to-severe mitral valve stenosis23.

C
Timing of initiation of OACs
The timing of initiation of OACs for secondary stroke
prevention after acute stroke depends on many factors,
mainly the size of the infarct and the presence of hem-
orrhage on brain imaging. One decision-making algo-
rithm is illustrated in figure  2. As patients with recent
ischemic stroke were excluded from the clinical trials
on anticoagulation, much of the evidence is based on
observational studies and robust evidence is lacking in
Figure 1. Imaging patterns in AF-related stroke. A: A non- this patient population. The AHA/ASA guidelines sug-
contrast head CT in a 85-year-old woman presenting with
aphasia and right-sided weakness, demonstrating a gest initiation of OACs immediately after TIA and
wedge-shaped infarct in the left middle cerebral artery 14 days after acute ischemic stroke event in most cas-
distribution. B: The digital subtraction angiogram for the es, apart from very large infarcts (defined as either
same patient demonstrating an acute left middle cerebral NIHSS > 15 or an infarct involving the complete territory
artery occlusion. C: A T2 FLAIR MRI in a 58-year-old man of a vessel) with severe hemorrhagic transformation in
with new onset AF and a large left hemispheric acute
infarct, as well as evidence of hyperintensities in bilateral
which delaying OAC initiation beyond 2  weeks is rea-
hemispheres suggestive of small vessel disease. sonable. European guidelines from the pre-DOAC era
suggest a more granular approach to initiating OACs
depending on stroke severity, recommending initiation
of OACs 1 day after a transient ischemic attack, 3 days
transformation ranges from 3.2% to 44% in the first after minor stroke (NIHSS < 8), 6  days in mild stroke
5  days depending on the use of thrombolytic (NIHSS 8-15), and 12 days after severe stroke (NIHSS
therapy31. > 15)38.
Vitamin K antagonists (VKAs) and direct OACs Data from observational studies suggest that in clin-
(DOACs) are the mainstay of stroke prevention in pa- ical practice, DOACs are started on average 4-11 days
tients with AF, each with their unique set of advantages after ischemic stroke. Early start of DOACs in these
and risks (Table 2)32-36. Although VKAs, such as warfarin, studies was associated with an average risk of intrace-
have been used for decades and are associated with a rebral hemorrhage (ICH) of 2.2% per year, which was
two-thirds relative risk reduction of stroke and systemic 3-fold lower than the risk of ischemic stroke events over
embolism compared with aspirin, the need for constant the same time39.
serum level monitoring and multiple food and drug in- Despite current guidelines, an estimated 50% of pa-
teractions makes warfarin difficult to use. Patients with tients with acute stroke and AF are discharged from the
AF on warfarin tend to have suboptimal time in the hospital without OAC, with evidence of sex and
therapeutic range37, and women tend to be more at risk race/ethnic differences in OAC utilization40. Risk of
of stroke than men while on warfarin due to differences bleeding, risk for falls, and goals of care (comfort mea-
in metabolism5. sures/hospice care) are commonly cited reasons for not
DOACs, such as dabigatran, rivaroxaban, apixaban, starting OACs at stroke hospital discharge, and the rate
and edoxaban, have emerged into clinical practice in of OAC use may increase over time after hospital
the past decade. DOACs are as effective, if not more discharge.
effective, than warfarin for stroke and systemic embo- At present, there are several randomized controlled
lism prevention33-36. In addition, DOACs have a more trials underway evaluating various OAC initiation
152
 N.B. Sur, J.G. Romano: Stroke and AF

Table 2. Oral anticoagulants recommended for stroke prevention in AF

Anticoagulant Benefits Disadvantages

Vitamin K antagonists 67% relative risk reduction versus aspirin Significant food and drug interactions
– Warfarin 26% reduction in mortality versus aspirin Need for blood level monitoring
Can be used in patients with mechanical Suboptimal time in therapeutic range
valves and mod‑severe mitral stenosis Low patient adherence
Point of care confirmation of anticoagulation
Reversible

Direct oral anticoagulants (DOACs) About 19% relative risk reduction compared Contraindicated in mechanical valves and
Direct thrombin inhibitors with warfarin moderate‑to‑severe mitral stenosis
– Dabigatran 10% reduction in mortality compared with Reversal agents less readily available, costly
Factor Xa inhibitors warfarin Caution in renal and hepatic impairment
– Apixaban Easy to use, less food/drug interactions
– Rivaroxaban Lower rates of hemorrhage
– Edoxaban Reversible

Figure 2. One evaluation and management algorithm for decision-making in patients with acute stroke with indications
for anticoagulation. AC: anticoagulation; OAC: oral anticoagulation; CAA: cerebral amyloid angiopathy; CMB: cerebral
microbleed; HAS-BLED: Hypertension, abnormal liver/renal function, stroke history, bleeding history or predisposition,
labile INR, elderly, and drug/alcohol usage; ICH: intracerebral hemorrhage; IVC: inferior vena cava; DVT: deep venous
thrombosis; PE: pulmonary embolism; NIHSS: National Institutes of Health Stroke Scale.

protocols after acute ischemic stroke for patients with [United  Kingdom, EduraCT 2018-003859-38]; START
AF (ELAN, [Switzerland/International NCT03148457]; [United States, NCT03021928]; and AREST [United
TIMING [Sweden, NCT02961348]; OPTIMAS States, NCT02283294]).
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 Rev Mex Neuroci. 2022;23(4)

Left atrial appendage occlusion (LAAO) there was no significant difference in ICH recurrence,
the mortality in the start-OAC group was twice that in
Since approximately 90% of thrombi in AF arise from
the avoid-OAC group48. Several randomized clinical
the left atrial appendage, LAAO is an attractive ap-
trials are currently underway and expected to provide
proach to secondary prevention in patients with AF in
more robust data on outcomes after resumption of
which long-term anticoagulation is contraindicated. The
OAC initiation and LAAO versus best medical care
PROTECT AF trial showed non-inferiority of LAAO with
after ICH: ASPIRE (NCT03968393); PRESTIGE-AF
the WATCHMAN device compared with warfarin for the
(NCT03996772); STATICH (NCT03186729); A3ICH
endpoint of stroke, systemic embolism, and cardiovas-
(NCT03243175); and ENRICH-AF (NCT03950076);
cular death41. Similarly, the PREVAIL trial showed sig-
STROKECLOSE (NCT02830152).
nificantly lower complication rates (2.2%), and non-in-
feriority of the WATCHMAN device for LAAO versus
warfarin for stroke and systemic embolism > 7  days Screening for AF
post-randomization. Although there is an upfront risk of
Current US Preventive Services Task Force recom-
periprocedural complications (such as cardiac tampon-
mendations state that there is an insufficient evidence
ade) and a long-term risk of ischemic stroke with LAAO,
to support widespread screening given the low frequen-
the overall risk seems to be offset by significantly lower
cy of AF in the general unselected population and in
rates of hemorrhage in the long-term39. In patients with
individuals over age 50 years49-51. Nevertheless, signif-
AF undergoing cardiac surgery for other reasons, sur-
icant technological advances over the past decade
gical LAAO has also been shown to reduce the risk of
have yielded newer devices which are easy to use,
stroke and systemic embolism compared to those ran-
commercially available and have high sensitivity and
domized not to have LAAO, though the majority of
specificity for detecting AF52.
these patients also remained on anticoagulation during
follow-up42. The updated American and European Given that the risk factors for stroke and AF are sim-
guidelines indicate LAAO as a Class IIb indication for ilar, the role of screening for AF in high-risk populations
stroke prevention in AF patients undergoing cardiac (increased age and high-risk CHA2DS2-VASc score)
surgery or with a contraindication to long-term antico- has become a recent research focus, especially in
agulation23,43. It remains challenging to identify those post-stroke patients with various stroke subtypes. The
patients at such a high risk of stroke in whom LAAO is CRYSTAL-AF study of cryptogenic stroke patients
preferred to anticoagulation. For example, recent data (mean age 62  years) showed an AF detection rate of
suggest that even patients with AF and falls44, demen- 12% at 1  year with implantable loop recorders versus
tia45, or microhemorrhages46 have a relatively low risk 2% with standard of care53. In the EMBRACE trial, also
of subsequent ICH and a greater risk of recurrent isch- in patients with cryptogenic stroke with a mean age of
emic stroke. 73 years, the AF detection rate with a 30-day external
monitor was 16% versus 3% in the control group54.
More recently, the STROKE-AF and PER DIEM studies
ICH and anticoagulants in AF have shown significantly higher AF detection rates with
The management of ICH in patients with AF who the use of implantable loop recorders in post-stroke
require anticoagulation is another challenging scenar- patients with various non-AF stroke etiologies, com-
io, specifically if and when to resume anticoagulants. pared with the standard of care or 30-day external loop
Observational data suggest that resumption of OAC recorder monitoring, respectively55,56. Several studies
after ICH is associated with reduced ischemic events have also shown favorable results in screening high-
and mortality, without a significant increase in hemor- risk patients for AF in the absence of recent stroke with
rhagic events47. Moreover, observational studies sug- various protocols, from intermittent electrocardiogram
gest that the optimal timing of resumption of OAC after screening to implantable loop recorders50,51. One ques-
ICH is within 4-8  weeks, depending on individual pa- tion that remains to be answered, however, is the
tient characteristics, the size, and location of the ICH amount or burden of device-detected AF that would
(Fig.  2). However, the SoSTART randomized trial of warrant initiation of anticoagulation. In other words, is
203 participants in the UK was unable to show the risk-benefit balance the same for a patient with a
non-inferiority for resumption versus avoidance of OAC 30-s episode of AF compared with a patient with > 24 h
after ICH (median time 115  days post-ICH): although of AF detected during screening?
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 N.B. Sur, J.G. Romano: Stroke and AF

Future directions Independent Data Monitoring Committee for a clinical

trial (Genentech).
Significant scientific advances have been made in the
past few decades regarding the screening, prevention,
and treatment of patients with AF and AF-related stroke. Ethical disclosures
Nevertheless, the prevalence of both AF and AF-related Protection of human and animal subjects. The
stroke, and the burden associated with each, are steadi- authors declare that the procedures followed were in
ly increasing with the rapid growth of the ageing popu- accordance with the regulations of the Relevant Clinical
lation. Several questions remain unanswered and are Research Ethics Committee and with those of the Code
the focus of ongoing and future clinical trials. First, is of Ethics of the World Medical Association (Declaration
screening for AF in high-risk populations for the primary of Helsinki).
prevention of stroke effective and cost-efficient? Sec- Confidentiality of data. The authors declare that
ond, what is the minimum burden of device-detected AF they have followed the protocols of their work center on
necessary to warrant anticoagulation? Third, should all the publication of patient data.
non-AF post-stroke patients be screened for AF with Right to privacy and informed consent. The au-
implantable loop recorders, regardless of stroke sub- thors have obtained approval from the Ethics Commit-
type? Fourth, when is the optimal time to initiate oral tee for analysis and publication of routinely acquired
anticoagulation in patients with recent AF-related stroke clinical data and informed consent was not required for
(both ischemic and hemorrhagic stroke)? Finally, the this retrospective and observational study.
association between AF, stroke, and the development of
cognitive impairment and dementia has been well es-
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