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Protected by copyright.
Advances in the management of cardioembolic
stroke associated with patent foramen ovale
Brian Mac Grory,1,2 E Magnus Ohman,2,3 Wuwei Feng,1 Ying Xian,4 Shadi Yaghi,5 Hooman Kamel,6
Michael E Reznik5
1
Department of Neurology,
Duke University School of
Medicine, Durham, NC, USA
2
Duke Clinical Research
Institute, Durham, NC, USA
3
Division of Cardiology,
Department of Medicine, Duke
University School of Medicine,
Durham, NC, USA
4
Department of Neurology, UT
Southwestern Medical Center,
Dallas, TX, USA
5
Department of Neurology,
Warren Alpert Medical School of
Brown University, Providence,
RI, USA
6
Department of Neurology, Weill
Cornell Medicine, New York,
NY, USA
Correspondence to:
B Mac Grory
brian.macgrory@duke.edu
Cite this as: BMJ 2022;376:e063161
http://dx.doi.org/10.1136/
bmj‑2020‑063161
Series explanation: State of the
Art Reviews are commissioned
on the basis of their relevance
to academics and specialists
in the US and internationally.
For this reason they are written
predominantly by US authors.
the bmj | BMJ 2022;376:e063161 | doi: 10.1136/bmj-2020-063161
State of the Art REVIEW
A BST RAC T
Patent foramen ovale (PFO) describes a valve in the interatrial septum that permits
shunting of blood or thrombotic material between the atria. PFOs are present in
approximately 25% of the healthy population and are not associated with any
pathology in the vast majority of cases. However, comparisons between patients
with stroke and healthy controls suggest that PFOs may be causative of stroke in
certain patients whose stroke is otherwise cryptogenic. Options for the diagnosis of
PFO include transthoracic echocardiography, transesophageal echocardiography,
and transcranial Doppler ultrasonography. PFOs associated with an interatrial septal
aneurysm seem to be more strongly linked to risk of recurrent stroke. Therapeutic
options for secondary stroke prevention in the setting of a PFO include antiplatelet
therapy, anticoagulation, and percutaneous device closure. Recent randomized
clinical trials suggest that percutaneous closure reduces the subsequent risk of
stroke in appropriately selected patients, with a large relative benefit but small
absolute benefit. Referral for percutaneous PFO closure should therefore be
considered in certain patients after a multidisciplinary, patient centered discussion.
Areas for future study include structural biomarkers to aid in determining the role of
PFO closure in older people with possible PFO associated stroke, the role of direct
oral anticoagulants, and very long term outcomes after device closure.
Introduction cryptogenic stroke (a subclass of ischemic stroke
Arterial ischemic stroke associated with patent for which no cause can be identified).4-11 These
foramen ovale (PFO) is an important cause of trials identified “PFO-associated stroke”12 as a
disability and death and represents a challenging therapeutically relevant entity and have prompted
clinical scenario for the practicing stroke physician, further studies into optimal strategies for secondary
internist, or cardiologist. The foramen ovale is prevention of stroke. These include investigations
a conduit between the right and left sides of the on expanding percutaneous PFO closure beyond
heart that is present in all humans during fetal narrowly defined eligibility criteria from existing
development (supplementary figure). This conduit clinical trials and the development of biomarkers
persists beyond infancy in approximately 25% of that more accurately predict future risk of stroke
people,1 2 which translates to approximately 1.9 in patients with PFO. In this review, we critically
billion people globally. Given its high prevalence evaluate the literature on the management of stroke
and that it is clinically silent in the vast majority associated with PFO, with a particular emphasis on
of cases, PFO is specifically not classified as a form recent literature. We also outline persistent areas of
of congenital heart disease.3 Thus, determining uncertainty in this field and opportunities for future
whether a PFO is pathologic (that is, implicated in an research.
ischemic stroke) represents a major challenge, and
a potential to impose harm through indiscriminate Sources and selection criteria
treatment exists. We searched PubMed, Embase, Medline, Web of
Six recent randomized controlled trials (RCTs) Science, and the Cochrane Database of Systematic
reported across eight publications showed that Reviews for articles published between 1 January
percutaneous closure of a PFO is associated with a 2000 and March 2021. We used the keyword terms
reduced risk of subsequent cerebrovascular events “patent foramen ovale”, “paradoxical embolization”,
in appropriately selected younger patients with “atrial septal aneurysm”, and “right-to-left shunt”.
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State of the Art REVIEW
We reviewed medRxiv (https://www.medrxiv.org/)
for any RCTs or prospective observational studies
that were pending publication and examined
ClinicalTrials.gov (https://www.clinicaltrials.gov/)
to assess the state of ongoing prospective studies
on this topic. We then searched the reference lists
of clinical guidelines, meta-analyses, major clinical
trials, and relevant review articles in the area. We
included articles published outside of the above
specified date range when they were especially
informative and relevant to the subject matter. When
discussing treatment options, we mostly restricted
our consideration to adequately powered and
appropriately controlled clinical trials. We included
cohort studies and case-control studies where they
provided important detail on the epidemiology or
pathophysiology of PFO. We did not include case
reports. We included articles from peer reviewed
journals only, but we placed no restrictions on
language.
Prevalence
An autopsy study of 965 human hearts from people
without a history of cardiovascular disease, balanced
between the sexes and across the lifespan, described
a PFO in 27.3% of all participants, 34.3% of those
less than 30 years old, and 20.2% of those above 80.1
Although some studies did not find an association
between PFO and stroke,13-15 most suggest that
PFO is more common in patients with cryptogenic
stroke than in matched patients without cryptogenic
stroke.16 17 A meta-analysis of 23 case-control studies
of patients younger than 55 years old found a strong
association between the presence of a PFO and
cryptogenic stroke subtype compared with stroke
arising from a known etiology (pooled odds ratio 5.1,
95% confidence interval 3.3 to 7.8).18
Emerging evidence supports a link between
PFO and stroke in older adults. The magnitude of
the association between PFO and stroke should
be lower in older populations as the incidence of
stroke due to other causes increases. However, the
substrates for venous thromboembolism, including
immobility and malignancy, become more common
with age. A prospective study of 503 consecutive
patients with ischemic stroke compared 227 patients
with cryptogenic stroke and 276 patients with a
stroke of known cause on the basis of findings
from transesophageal echocardiography.19 Among
patients over 55 years old with cryptogenic stroke,
the prevalence of PFO was 28% compared with 12%
in patients with stroke of known cause, and the
association between PFO and stroke in older patients
remained significant after differences in age and
vascular risk factors were accounted for (adjusted
odds ratio 3.0, 1.7 to 5.2; P<0.001). In a population
based study from the Oxford Vascular Study,
transcranial Doppler ultrasonography (TCD-US) with
bubble studies was used to establish the presence of
a PFO in patients over 60. Among older patients with
cryptogenic stroke, 35.8% had a right-to-left shunt
(indicative of a PFO) compared with 21.3% of those
2
BMJ: first published as 10.1136/bmj-2020-063161 on 9 February 2022. Downloaded from http://www.bmj.com/ on 25 July 2022 at USP - Universidade de Sao Paulo. Protected by copyright.
with a stroke of known cause.20 This association is not
universally observed. A prospective, cross sectional
study of consecutive ischemic patients in Italy found
no difference in the proportion of patients with PFO
among those with cryptogenic stroke compared
with stroke of determined subtype.15 Furthermore,
no significant interaction was seen between stroke
subtype and age on PFO status.
PFO and embolic stroke of undetermined source
Cryptogenic stroke refers to a subclass of ischemic
stroke for which no cause can be identified and
comprises 25-33% of all ischemic strokes.21-24
The TOAST criteria formalized the classification
of cryptogenic stroke,25 with other causes of
stroke including large artery atherosclerosis,
cardioembolism, small vessel stroke, and other
determined causes. By this classification scheme,
the “cryptogenic” group is heterogeneous and
comprises any stroke without a defined cause. This
includes strokes with no candidate mechanism
identified despite thorough investigation, strokes
caused by more than one potential mechanism,
and cases in which the diagnostic investigation
remains incomplete. The heterogeneity of this
scheme was considered a disadvantage and led to
the more refined classification of embolic stroke of
undetermined source (ESUS).26 27 This classification
describes an embolic appearing stroke for which
thorough diagnostic investigation (cervical and
intracranial vessel imaging, transthoracic
echocardiography, electrocardiography, and ≥24
hours of cardiac monitoring with automatic rhythm
detection) has yielded no definitive cardioembolic
source or high grade arterial stenosis corresponding
to the affected brain region. The more sensitive
testing modalities such as transesophageal
echocardiography and TCD-US are not mandatory
as part of the diagnostic investigation of ESUS,
leading to likely under-identification of PFO within
this framework. Additional consideration should
be given to emerging non-cardiac causes of ESUS
including occult malignancy,28 the carotid web,29
aortic arch atherosclerosis, and substenotic carotid
atherosclerosis within the early phases of a patient’s
diagnostic investigation.
One challenge posed by the discovery of a PFO in
the context of stroke is to determine its likelihood
of causation. A related but separate question is
whether an intervention to close the PFO will
benefit the patient. Although the likelihood that
a PFO is pathogenic rather than incidental varies
depending on a patient’s age,30 in clinical practice
PFOs are usually detected in younger patients
without vascular risk factors.31 Thus, the presence
of a PFO paradoxically signifies a group of patients
at particularly low risk of recurrence.32 In general,
the risk of recurrent stroke in patients with a PFO
is approximately 2% per year,33 but most patients
with a PFO have more than one mild to moderate
risk embolic source,34 further complicating the
assignment of causality.
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Several strategies have been devised to assign
a likelihood that a PFO is causally related to an
ischemic stroke. The Risk of Paradoxical Embolism
(RoPE) score is a 10 item scale that is calculated on
the basis of a person’s age (18-29, 30-39, 40-49, 50-
59, 60-69, or ≥70 years), cortical infarct location,
and absence of vascular risk factors (hypertension,
diabetes, previous stroke, or smoking).35 36 In a
patient with a maximum RoPE score of 10, the tool
estimates an 88% probability of the stroke being
attributable to a PFO. By comparison, a RoPE score
of 0 would suggest a 0% probability of stroke being
attributable to a PFO. Although clinically useful,
this score does not account for characteristics of
the PFO itself (discussed below) or for the presence
of venous thromboembolism, which may increase
the probability that a PFO is a causative lesion.
Nevertheless, a RoPE score of 7-10 has been proposed
to be more likely to reflect a pathogenic PFO,37 and
the tool has been suggested for use in predicting the
presence of PFO in patients with stroke.38
The success of recent RCTs has led to calls to codify
PFO as a causative mechanism of stroke in patients
with ESUS.39 A recent consensus statement from the
PFO International Workup Group proposed to update
the nomenclature related to stroke risk and PFO,
coining the term “PFO-associated stroke.”12 This
diagnosis requires a superficial, large deep, or retinal
infarct in the presence of a medium to high risk PFO
and no other likely cause identified. Such cases are
then classified according to the probability of the PFO
being the causative mechanism (highly probable,
probable, possible, or unlikely), with this probability
being based on factors such as evidence of straddling
thrombus, atrial septal aneurysm (ASA), presence of
large shunt, presence of pulmonary embolism, or
deep venous thrombosis (DVT).
Pathophysiology of PFO associated stroke
Mechanisms of stroke in patients with PFO
Despite a consistent signal in the observational
literature linking PFO with cryptogenic stroke,16  17
the presence and risk profile of PFO depends on
the presence of other proposed mechanisms. For
instance, the presence of a pathogenic PFO is
inversely related to the presence of non-stenotic
ipsilateral carotid atherosclerosis in patients with
ESUS.40 Additionally, the prevalence of a likely
pathogenic PFO was found to be markedly lower in
ESUS patients with atrial cardiopathy compared with
those without atrial cardiopathy (3.3% v 23.7%;
adjusted odds ratio 0.2, 0.02 to 0.6).41
Paradoxical embolization refers to any passage
of material between the right and left sides of the
heart and can occur by way of a PFO, atrial septal
defect, ventricular septal defect, or pulmonary
arteriovenous fistula. This presumed mechanism of
stroke associated with PFO is supported by several
observations. Firstly, the frequency of concurrent
ischemic stroke among patients with pulmonary
embolism is higher among patients with than without
PFO.42 Secondly, strokes associated with PFO have a
the bmj | BMJ 2022;376:e063161 | doi: 10.1136/bmj-2020-063161
BMJ: first published as 10.1136/bmj-2020-063161 on 9 February 2022. Downloaded from http://www.bmj.com/ on 25 July 2022 at USP - Universidade de Sao Paulo. Protected by copyright.
State of the Art REVIEW
predilection for the cerebral or cerebellar cortices, a
pattern consistent with other cardioembolic disorders
(such as atrial fibrillation).43-45 Thirdly, material other
than thrombus may cross a PFO, as in the case of air
embolization in divers with PFO.46 Finally, many
cases of emboli being visualized straddling the right
and left atria through a PFO have been reported.47
Under normal physiology, microthrombi are forming
nearly continuously in the venous system and enter
the right side of the heart via the inferior or superior
vena cava before being filtered out in the pulmonary
circulation. In the presence of a right-to-left shunt,
these thrombi may pass directly from the right to the
left side of the heart and enter the arterial system.48
49
A large residual Eustachian valve may potentiate
paradoxical embolism by directing a jet of blood
toward the PFO, thereby increasing the likelihood of
right-to-left passage as opposed to filtration through
the pulmonary circulation.50 51
A potential alternative explanation to paradoxical
embolization as the causative mechanism of PFO
associated stroke is that intrinsic differences exist
in the bloodstream of people with right-to-left
shunting. In addition to oxygenating blood, the
pulmonary arterial circulation plays a crucial role in
filtering out waste products including prothrombotic
and vasoactive metabolites such as serotonin. This
property of the pulmonary arterial circulation is
partially neutralized in patients with PFO and may
also help to explain the association between PFO
and migraine.52 53 Exploratory work has identified
differing patterns of plasma protein expression
in patients before and after PFO closure,54 55 but
whether this mechanism is a contributor to risk of
stroke in patients with PFO remains to be seen.
For paradoxical embolization to arise, thrombus
formation must be present within the venous
system. Many aspects of normal life increase the
propensity to formation of a DVT in the extremities.
For instance, the risk of DVT in people not wearing
compression stockings after a long haul flight is
10.3%.56 Once a lower extremity DVT has developed,
ongoing embolization to the right side of the heart
ensues. In a prospective study of 60 patients with
a lower extremity DVT, 43% showed evidence of
active emboli detected at a rate of 5-800 per minute
when screened via ultrasonography at the proximal
femoral vein or above.57 Stroke in patients with PFO
may also be provoked by the Valsalva maneuver or
by pulmonary hypertension, which may increase
the tendency for right-to-left flow across the PFO (for
example, as occurs nightly in patients with sleep
apnea).58
Characteristics associated with increased risk of
stroke recurrence
Three overlapping, although distinct, reasons
exist to examine patient related or PFO related
characteristics in a person with a PFO associated
stroke: to determine the likelihood of a recurrent
event after an index stroke related to PFO; to
determine the likelihood that a stroke was caused
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State of the Art REVIEW
by a PFO compared with an alternative mechanism;
and to determine whether a person meets enrollment
criteria for any given clinical trial.
Factors that predict a higher likelihood of recurrence
(first point above) may also be associated with a
reduced likelihood that a PFO was causative (second
point) and vice versa. A PFO with no competing
cause of stroke is more likely to be pathogenic but,
paradoxically, denotes a population at particularly
low risk of recurrence. Furthermore, key morphologic
criteria such as a PFO size are important to consider
because they were enrollment criteria in two major
clinical trials (third point above) but are not clearly
associated with an increased likelihood of recurrent
stroke (first point). The risk of recurrence after stroke
associated with PFO is low (discussed in subsequent
sections). Thus, most analyses describing the
relation between patient or PFO related factors
and recurrent events are exploratory in nature.
Box 1 outlines patient and PFO related factors that
have been associated with an increased risk of
stroke recurrence.Figure 1 and figure 2 depict the
evaluation of key morphometric criteria associated
with PFO on transthoracic echocardiography and
transesophageal echocardiography respectively.
Two major structural features of PFO are
hypothesized to portend a higher risk of recurrent
stroke after an index PFO associated stroke. The first
is atrial septal aneurysm.59 68 An ASA describes the
impingement of the atrial septum into the left and
right atria according to the cardiac cycle. ASAs have
been associated with an increased risk of recurrent
stroke in patients with PFO (adjusted hazard ratio
3.3, 95% confidence interval 1.8 to 5.9, in a pooled
analysis of four prospective studies of patients with
PFO and cryptogenic stroke43) and represent an
independent predictor for cryptogenic stroke.68-70
However, the reason for this is not yet known. ASAs
may cause turbulent blood flow in the region of
the PFO, leading to direct thrombus formation, a
Box 1: Patient related and patent foramen ovale
(PFO) related factors with reported association with
subsequent stroke
Patient related factors
• Age59 60
• Hypertension59
• Diabetes mellitus61
• Active migraine62
• Prothrombotic mutations (eg, protein C deficiency,
protein S deficiency, factor V Leiden, and prothrombin
G20210A)63 64
• Risk of Paradoxical Embolism (RoPE) score <561
• Stroke in posterior cerebral artery territory62
• Post-procedure atrial fibrillation61
PFO related factors
• Interatrial septal aneurysm33
• Shunt size37 65 66
• Residual shunting after closure67
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mechanism separate from paradoxical embolization.
Of note, a synergistic effect has been described
between PFO and ASA, wherein the risk of subsequent
stroke associated with both in combination is greater
than the sum of their individual risks.68 Figure 1 (D)
shows an interatrial septal aneurysm in the absence
of a PFO.
The second feature hypothesized to portend
a higher risk of recurrent stroke after an index
PFO associated stroke is shunt size. Data on the
association between shunt size and recurrent stroke
are conflicting. Shunt size during life can be inferred
on the basis of the number of bubbles that cross the
interatrial septum with each cardiac cycle, the degree
of maximum separation of the septum primum and
septum secundum during a Valsalva maneuver, the
maximum number of bubbles observed in the left
atrium in a single frame, or whether shunting occurs
at rest or only in response to provocative maneuvers.
The optimal method of measurement is three
dimensional transesophageal echocardiography.71
A large shunt may be expected to increase the
propensity for paradoxical embolization, as a
great volume of blood is crossing the interatrial
septum. Several small, observational studies have
associated large shunt size with recurrence,65 66 72
although in each study the number of events was
low. For instance, in a single center, retrospective,
observational cohort study of consecutive patients
with cryptogenic ischemic stroke referred for
transesophageal echocardiography, 181 patients
were followed for a median of 3.5 years. Fourteen
(8%) patients had a recurrent stroke, and PFO size ≥3
mm was independently associated with recurrence
of stroke (hazard ratio 3.0, 1.96 to 4.69; P=0.003).65
In randomized trials, shunt size was associated
with higher magnitude of benefit of closure in
RESPECT (significant interaction between shunt
size and treatment effect; P=0.07 with threshold
for significance set at 0.10) but not in CLOSE or
DEFENSE-PFO.7 9 10 The caveat is that shunt size
may alter technical aspects of percutaneous closure,
which may mediate this difference, instead of
shunt size being itself a risk factor for recurrence.
By contrast, two large, observational studies and
two meta-analyses found no association between
shunt size and risk of recurrent stroke.33 59 62 73
Paradoxically, a study of 1324 patients from the
RoPE database found that in patients with a RoPE
score of >6 (that is, who had a higher likelihood that
the PFO was the causative mechanism), small shunt
size (maximum number of bubbles in the left atrium
observed in a single frame of ≤10) was associated
with an increased risk of subsequent stroke (hazard
ratio 3.26, 1.59 to 6.67).37 In patients with a RoPE
score of ≤6, no association was observed between
shunt size and recurrent stroke (hazard ratio 1.29,
0.82 to 2.03).
The relation between other morphologic features
(large residual Eustachian valve,51 biomarkers of left
atrial dysfunction74 75) and PFO pathogenicity or risk
of recurrence after PFO associated stroke is unclear.
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Fig 1 | Key morphometric features of patent foramen ovale (PFO) on transthoracic
echocardiography. A: Orientation of atria and ventricles on apical four chamber view. B:
Sonicated air bubbles visible during bubble study with Valsalva maneuver confirming
presence of right-to-left shunt. C: Doppler jet associated with PFO. D: Interatrial septal
aneurysm without PFO. Note sonicated bubbles present in right atrium and right
ventricle but not in left atrium. LA=left atrium; LV=left ventricle; RA=right atrium;
RV=right ventricle.
Diagnostic approaches
A PFO is usually identified during structured
diagnostic investigation for potential causes
of ischemic stroke.21 Diagnostic modalities to
specifically test for the presence of a PFO include
transthoracic echocardiography, transesophageal
echocardiography, and TCD-US. Cardiac computed
tomography does not have adequate sensitivity to
exclude a PFO and will not be discussed further.76
Transthoracic echocardiography
Transthoracic echocardiography with an agitated
saline bubble study is generally the first test used
in clinical practice to examine for the presence of a
PFO (fig 1, A-C). In a bubble study, agitated saline
Fig 2 | Key morphometric features of patent foramen ovale (PFO) on transesophageal
echocardiography. A: Direct visualization of PFO on mid-esophageal short axis view.
B: Doppler jet associated with PFO. C: Bubbles (marked with *) traversing interatrial
septum during Valsalva maneuver. D: Well seated PFO closure device (marked with **).
AA=ascending aorta; AV=aortic valve; LA=left atrium; RA=right atrium.
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State of the Art REVIEW
is injected into a tributary of the superior vena
cava—typically the brachiocephalic vein—which
then flows to the right atrium. In the presence of
an interatrial septal defect, passage between the
right and left sides of the heart may be visualized
on echocardiography (a so-called “positive bubble
study”). A Valsalva maneuver is often used during
the test to increase intrathoracic pressure and thus
increase the likelihood that right-to-left passage of
bubbles will be visualized. However, detection of a
PFO via transthoracic echocardiography is user and
technique dependent. For example, the detection
of a PFO increases with an increasing number of
injections of agitated saline.77 78 Additionally, the
superior vena cava may not always orient toward the
PFO, in which case injection of agitated saline into the
femoral vein and inferior vena cava may be a superior
technique.79 In older studies, when compared with
transesophageal echocardiography, the overall
sensitivity of transthoracic echocardiography was
50% and specificity was 92%.80 However, with the
advent of more modern approaches including second
harmonic imaging (an echocardiographic technique
that reduces artifact from the chest wall and improves
the quality of the signal from deeper structures),
the sensitivity of transthoracic echocardiography
approaches 90%.81
Multiple potential causes of interatrial shunting can
be discriminated on the basis of echocardiography
according to the location, size, and stability of an
interatrial septal defect. These include a PFO, an
atrial septal defect, a pulmonary arteriovenous
fistula, an unroofed coronary sinus, and rarer
congenital cardiac defects. A PFO is a potential
defect in the interatrial septum and is visible only
when atrial hemodynamics promote shunting of
blood from one side to another. By contrast, an
atrial septal defect is a structural deficiency of the
septum that is visible regardless of atrial pressure
differentials. Pulmonary arteriovenous fistula
(pAVF) describes a connection between a pulmonary
artery and pulmonary vein without an intervening
capillary bed. The time elapsed between injection
and visualization of bubbles in the left atrium may
aid in discriminating between a PFO and a pAVF. An
“early positive” bubble study is indicative of a PFO,
whereas a “late positive” bubble study is suggestive
of a pAVF. An unroofed coronary sinus (coronary
sinus septal defect) describes a deficiency of the
wall of the coronary sinus permitting transmission
of blood from the right atrium to the left atrium via
this deficiency.
Transesophageal echocardiography
Transesophageal echocardiography permits more
direct visualization of relevant cardiac structures
than transthoracic echocardiography (fig 2).
Transesophageal echocardiography is performed by
inserting an ultrasonic probe into the esophagus and
bringing it in close proximity to the left side of the
heart, thus providing a superior acoustic window.
Thus, less artifact is imposed by skin, fat, muscle,
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State of the Art REVIEW
bone, and other chest wall structures. A postmortem
study of 35 patients who had transesophageal
echocardiography performed before death found
nine PFOs, of which all were diagnosed by color
Doppler transesophageal echocardiography and
eight were diagnosed by contrast transesophageal
echocardiography.82
When a PFO is already known, transesophageal
echocardiography is the gold standard to determine
its size and to further characterize the interatrial
septum. One measure of right-to-left shunt size
considers early microbubble appearance in the
left atrium, with the shunt classified as trace (0-5
microbubbles), moderate (6-25 microbubbles),
or large (>25 microbubbles). Transesophageal
echocardiography is also useful to examine for
competing structural causes of stroke that may not
be visualized on transthoracic echocardiography,
including right atrium appendage thrombus, atrial
myxoma, fibroelastoma, aortic arch atheroma,
or small aortic or mitral valvular vegetations.83 84
Transesophageal echocardiography is well tolerated
even in older patients.85
Absolute contraindications to transesophageal
echocardiography include active gastrointestinal
bleeding, recent gastroesophageal surgery, or
esophageal stricture, diverticulum, or neoplasm;
relative contraindications include recent
upper gastrointestinal bleeding, hiatal hernia,
coagulopathy, and cervical osteoarthritis.86 The risk
of esophageal perforation is less than 0.1%87 88; other
more common risks include transient bronchospasm,
cardiac arrythmias, minor pharyngeal bleeding, or
procedural failure due to intolerance of the probe.89
A judicious approach to the use of transesophageal
echocardiography is important because, although
a low risk procedure, it is resource intensive and
requires a large team to deploy. Furthermore, staff
members performing the procedure are exposed
to large volume aerosol because of coughing and
gagging during probe insertion, which magnifies the
risk of transmission of respiratory viruses including
SARS-CoV-2.90
Transcranial Doppler ultrasonography
TCD-US in tandem with an agitated saline bubble
study is a sensitive modality for detection of a PFO.91
Inference of a right-to-left shunt is possible when
bubbles are insonated in the cerebral circulation.
TCD-US also permits quantification of microemboli as
an indirect measure of the magnitude of right-to-left
shunting. The Spencer grading system considers five
levels of right-to-left shunt size: grade I (trace, 1-10
microemboli), grade II (small, 11-30 microemboli),
grade III (moderate, 30-100 microemboli), grade
IV (large, 101-300 microemboli), and grade V (very
large, >300 microemboli),92 although such fine
gradations between shunt size are unlikely to prove
useful in clinical practice
A bubble study is less reliable in transesophageal
echocardiography than in TCD-US because the
presence of the ultrasonic probe in the throat may
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render performance of the Valsalva maneuver more
difficult for the person under study and because
sedation may be needed for the procedure. One
head-to-head comparison of transesophageal
echocardiography and TCD-US found that the latter
had a sensitivity of 95% and specificity of 100%
for the detection of PFO relative to transesophageal
echocardiography. Provocative maneuvers such
as coughing or the Valsalva maneuver further
increase its sensitivity.93 In general, the concordance
between transesophageal echocardiography
and TCD-US is approximately 90%.94 However,
TCD-US is more sensitive than transesophageal
echocardiography for the presence of right-to-left
shunting in regular breathing,94 so it should be
strongly considered in patients who are unable to
perform a Valsalva maneuver. Although most studies
consider transesophageal echocardiography as the
reference standard, a proportion of patients have
small PFOs that are not visible on transesophageal
echocardiography but are identified via TCD-US.81
93  95
Thus, transesophageal echocardiography and
TCD-US should be considered complementary
studies, with both needed for confident exclusion of
a PFO.
TCD-US may also be used to examine for the
presence of spontaneous microembolism via high
intensity transient signals, screen for extracardiac
shunting, and assay for the presence of residual
shunting after percutaneous PFO closure.
Testing for venous thromboembolism
The role of testing for venous thromboembolism in
patients with a cryptogenic stroke, a PFO, and no signs
or symptoms suggestive of venous thromboembolism
is unclear. An assay of serum D-dimer is a highly
sensitive test and, when negative, is useful for
the exclusion of venous thromboembolism in
patients with a low pre-test probability of venous
thromboembolism.96 Further options for testing
including venous Doppler ultrasonography of the
upper and lower extremities, magnetic resonance
venography of the pelvis, and computed tomography
angiography of the chest. A retrospective, single
center study of 114 patients with cryptogenic
ischemic stroke and a PFO found that 9% also had a
DVT and 4% had a pulmonary embolism.97 Another
retrospective study found that 29% of patients with
cryptogenic stroke and a PFO had a concurrent DVT
and 7% had a pulmonary embolism.98 When present,
venous thromboembolism strongly implicates
the PFO as a mechanism for stroke and warrants
treatment with anticoagulation,99 although it does
not necessarily bolster the argument for pursuing
percutaneous PFO closure.
Hypercoagulability/thrombophilia testing
Testing for both arterial and venous
hypercoagulability disorders may be considered
as part of the investigation of diagnostic stroke in
younger patients. However, no evidence associates
hypercoagulablity with reduction of risk for
doi: 10.1136/bmj-2020-063161 | BMJ 2022;376:e063161 | the bmj

recurrent stroke, so appropriate patients must be
carefully selected. Most hypercoagulability panels
contain at least 10 individual tests, so the cost of
testing and the probability of obtaining at least one
value outside the reference range are both high.100
Nevertheless, disorders of hypercoagulability
become more prevalent with age,101 and they
should still be considered even in older patients
when clinical suspicion is high and traditional
vascular risk factors are absent. For definitive
results, testing must be repeated at an interval of 12
weeks,102 as many individual tests may be spuriously
elevated in the presence of acute thrombosis. Of
note, both arterial and venous hypercoagulability
disorders may predispose to stroke in the presence
of a PFO.103 A retrospective, observational cohort
study conducted at a tertiary referral center found
that laboratory testing for hypercoagulability in
patients below the age of 65 resulted in a change in
management (defined for the purposes of the study
as starting anticoagulation or PFO closure) in one in
12 patients.104
Common disorders tested for across most
hypercoagulable panels include those causing
venous hypercoagulability (for example, protein
C and S deficiency, factor V Leiden, prothrombin
gene mutation, and anti-thrombin III deficiency105),
arterial hypercoagulability (for example,
hyperhomocysteinemia106), and mixed arterial
and venous hypercoagulability (for example,
antiphospholipid antibody syndrome107). Cancer
increases the tendency to both arterial and venous
hypercoagulability and should be suspected in
people with indicative physical examination findings
(such as lymphadenopathy), unexplained weight
loss, other B symptoms (fever or night sweats), toxin
exposure, or a family history of cancer at an early
age and in those who have not had age appropriate
cancer screening. Other hypercoagulable states such
as exposure to hormonal contraception, hormone
replacement therapy, or tobacco should also be
considered.
Importantly, all clinical trials of percutaneous PFO
closure have excluded patients with hypercoagulable
disorders. However, several observational studies
have shown that concurrent hypercoagulability in
patients with stroke and a PFO is associated with
a higher risk of recurrent stroke. These findings
suggest that the benefit of closure may therefore
be even further magnified in this population,63 108
but additional prospective studies are needed to
definitively answer this question.
Long term cardiac monitoring
Two recent studies explored the diagnostic yield
of extended cardiac monitoring after a stroke or
transient ischemic attack. EMBRACE was an RCT in
which 572 patients were randomized to 30 days of
ambulatory cardiac monitoring or standard medical
therapy.109 The primary endpoint (newly detected
atrial fibrillation of ≥30 seconds within 90 days of
randomization) was attained by 16.1% of patients
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State of the Art REVIEW
assigned to cardiac monitoring and 3.2% of control
patients (an absolute difference of 12.9%, 95%
confidence interval 8.0% to 17.6%). CRYSTAL-AF
was an RCT in which 441 patients were randomized
to insertion of an insertable cardiac monitor (ICM) or
standard medical therapy.110 The primary endpoint
was time to detection of new atrial fibrillation of ≥30
seconds. By six months, this endpoint was reached
by 8.9% of patients in the ICM group compared with
1.4% of controls (hazard ratio 6.4, 1.9 to 21.7), with
a sustained, incremental improvement in detection
rates of paroxysmal atrial fibrillation up to three
years post-implantation. Such monitoring has also
been shown to increase anticoagulant use and is
associated with the risk of subsequent stroke.111
However, patients enrolled in these trials were
markedly older and had a high burden of vascular risk
factors relative to patients enrolled in the major trials
of percutaneous PFO closure, which mostly consisted
of young patients without vascular risk factors. Age is
the strongest predictor for the development of atrial
fibrillation,112 with fivefold higher rates of detection
of atrial fibrillation described in patients older than
65 compared with those younger than 65.110
Importantly, none of the PFO closure trials
mandated cardiac monitoring before enrollment. Two
small studies have subsequently examined the yield
of cardiac monitoring in patients eligible for both PFO
closure and enrollment in CRYSTAL-AF or EMBRACE.
One such study documented a yield of 27% for the
detection of new atrial fibrillation after three years of
recording via an ICM,113 and another used external
cardiac monitoring and reported a diagnostic yield
of 9.5% for new atrial fibrillation at three weeks.114
As a result, a reasonable approach may be to pursue
short term cardiac monitoring before PFO closure,
reserving longer term monitoring for patients with
risk factors for atrial fibrillation or biomarkers of left
atrial dysfunction,115 which increase the likelihood
of detection of atrial fibrillation in patients with
ESUS.116-118
Using long term cardiac monitoring in all patients
under consideration for PFO closure may not be
reasonable, as the trials of PFO closure all mandated
enrollment within six months of the index event
(with the exception of RESPECT8). Whether their
findings may be similarly applied beyond this time
frame is therefore uncertain. Long term cardiac
monitoring is also costly and associated with a risk
of detecting brief, transient, incidental runs of atrial
fibrillation (which can itself be provoked by ischemic
stroke119 120).
Medical treatment after PFO associated stroke
Pharmacologic secondary prevention is generally
recommended after stroke associated with PFO,
with options including antiplatelet therapy and
anticoagulation. Of the two, anticoagulation
has been posited to be more effective, as stroke
attributable to PFO is hypothesized to arise from
thrombi originating in the venous blood supply.
However, this position has not been conclusively
7
 BMJ: first published as 10.1136/bmj-2020-063161 on 9 February 2022. Downloaded from http://www.bmj.com/ on 25 July 2022 at USP - Universidade de Sao Paulo. Protected by copyright.
State of the Art REVIEW

tested in head-to-head comparisons with antiplatelet

2:1 randomization

1:1 randomization
medical treatment

medical treatment

medical treatment

medical treatment

medical treatment
1:1:1 PFO closure
1:1 PFO closure v

1:1 PFO closure v

1:1 PFO closure v

therapy, and the increased bleeding risk associated
Randomization

to PFO closure v
v antiplatelets v
anticoagulation

PFO closure v
with anticoagulation may eclipse any benefit with
respect to reduction of stroke risk.
The PFO Cryptogenic Stroke Study (PICSS)121
only

only

only

only

only
enrolled 630 patients with cryptogenic stroke nested

ASA=atrial septal aneurysm; ; DAPT=dual antiplatelet therapy; DOAC=direct oral anticoagulant; SAPT=single antiplatelet therapy; TIA=transient ischemic attack; TOE=transesophageal echocardiogram; TTE=transthoracic echocardiogram.
Aspirin, clopidogrel, or

Aspirin, clopidogrel, or
within the Warfarin-Aspirin Recurrent Stroke Study
Antiplatelet therapy or

DAPT for 3 months then SAPT aspirin+dipyridamole;

aspirin+dipyridamole

aspirin+dipyridamole

aspirin+cilostazol, or
oral anticoagulation

aspirin+clopidogrel,
Warfarin, aspirin, or
Medical treatment

(WARSS),122 of whom 33.8% had a PFO. This PFO

warfarin or DOAC
Aspirin, warfarin, substudy was underpowered to detect a difference
clopidogrel, or
in rates of recurrent stroke between patients treated

warfarin
with warfarin and those treated with aspirin (hazard

Aspirin,
both
arm

ratio 0.52, 0.16 to 1.67; P=0.28). The PFO Closure

or Anticoagulants versus Antiplatelet Therapy to
Clopidogrel 300 mg before or

recommendation for DAPT for

days post-procedure; aspirin,
clopidogrel 75 mg daily for 3
immediately post-procedure;

clopidogrel monotherapy for

At discretion of investigator;
Prevent Stroke Recurrence (CLOSE) study was also
after conclusion of DAPT for
DAPT for 1-6 months; SAPT

5 months; at investigator’s
Anti-thrombotic therapy

discretion from 6 months

DAPT for 6 months; SAPT

after conclusion of DAPT

underpowered to find a significant difference in rates

from 6 months onwards

DAPT for 1 month; SAPT

aspirin/dipyrimadole or
of subsequent stroke between its anticoagulation

remainder of trial
and antiplatelet therapy medical treatment arms
post-procedure
post‑closure

(hazard ratio 0.44, 0.11 to 1.48; P=0.18).7 Even

6 months
after an individual participant meta-analysis of
prospective observational cohort studies and the
Table 1 | Overview of study design for randomized controlled trials comparing patent foramen ovale (PFO) closure with medical therapy

medical arms of three RCTs,123 conclusive evidence

to compare anticoagulation treated patients and
Septal Occluder
Closure device

Amplatzer PFO

Amplatzer PFO

Amplatzer PFO
Any approved

antiplatelet therapy treated patients with respect to

Cardioform
STARFlex

Occluder

Occluder

Occluder

stroke recurrence rates is still not available (adjusted

Helex or
device

hazard ratio 0.75, 0.44 to 1.27).

No dedicated trials have specifically compared
peripheral embolism without Canada, Brazil,

the direct oral anticoagulants (DOACs) apixaban,

South Korea
US, Canada,
US, Canada

US, Canada

rivaroxaban, edoxaban, or dabigatran with

Locations

Germany
Australia
Europe,

France,

Europe

antiplatelet therapy in patients with PFO and stroke,

although subgroup analyses have been done using
data from recent trials in patients with ESUS. A
without competing etiology

pre-specified post hoc analysis of the NAVIGATE-

atrial shunt within 3 cardiac cycles, cryptogenic stroke without

microbubbles) or ASA on TOE (base cryptogenic stroke without

atrial shunt within 3 cardiac cycles, cryptogenic stroke without

PFO+ASA (with protrusion ≥15 mm cryptogenic stroke without

Any cryptogenic stroke or
Other selection criteria

ESUS trial was not powered to examine recurrent

Within 6 months of any

Within 9 months of any

Within 6 months of any

Within 6 months of any

Within 6 months of any

cryptogenic stroke/TIA

stroke rates in patients treated with rivaroxaban

competing etiology

competing etiology

competing etiology

competing etiology

competing etiology

compared with those treated with aspirin (hazard

ratio 0.54, 0.22 to 1.36).124 125 However, the
addition of data from the PICCS and CLOSE trials
in a subsequent meta-analysis resulted in a net
benefit of anticoagulation over antiplatelet therapy
(odds ratio 0.48, 0.24 to 0.96; P=0.04). A similar
TOE with bubble study showing

TOE with bubble study showing

TOE with bubble study showing

TOE with bubble study or color

subgroup analysis of the RESPECT ESUS trial

Doppler flow imaging showing

TTE/TOE with large shunt (>30

≥15 mm, excursion >10 mm)

atrial shunt at rest or during

TOE showing PFO ≥2 mm or

atrial shunt during Valsalva

included 680 patients with a PFO, for whom the risk

at rest or during Valsalva

at rest or during Valsalva

of recurrent stroke in those treated with dabigatran

or excursion ≥10 mm)

was 2.9% compared with 3.2% in patients treated

with aspirin.126 127 A meta-analysis combining
PFO criteria

participants with PFO from all four of these trials did

Valsalva

not find a significantly lower likelihood of recurrent

stroke in DOAC treated patients (odds ratio 0.70, 0.43
to 1.14).127 Two major limitations are inherent in this
18-60

18-60

16-60

18-59

18-80

analysis: morphometric properties of the PFO were

Age

<60

not considered in this analysis as transesophageal

echocardiography was not an enrollment criterion
patients

for NAVIGATE-ESUS or RESPECT, and, even in

No of

909

414

980

663

664

120

combination, these data lack statistical power to

conclusively establish which treatment, if either, is
2013, 2017

2018, 2021
publication

better.
(extended

Gore REDUCE (extended

follow‑up)

follow‑up)
Year of

2012

2013

2017

DEFENSE PFO 2018

Percutaneous PFO closure

Percutaneous PFO closure was first proposed
almost 30 years ago.128 The underlying rationale
CLOSURE I

RESPECT

is that preventing transmission of a thrombus

PC Trial
Study

CLOSE

across the interatrial septum would reduce the risk

8 doi: 10.1136/bmj-2020-063161 | BMJ 2022;376:e063161 | the bmj

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State of the Art REVIEW

Table 2 | Overview of outcomes for randomized controlled trials comparing patent foramen ovale (PFO) closure with medical therapy
Study Primary endpoints
Composite of stroke
or TIA, death (within
CLOSURE I 30 days), death from
neurologic causes (>30
days)
Composite of death,
PC Trial non-fatal stroke, TIA, or
peripheral embolism
Composite of stroke
RESPECT or early death after
randomization
CLOSE Fatal or non-fatal stroke
Clinical stroke or silent
Gore REDUCE infarct detected on
imaging
Composite of stroke,
DEFENSE PFO vascular death, or major
bleeding
AF=atrial fibrillation; CI= confidence interval; HR= hazard ratio; ITT=intention to treat; RR=relative risk; SAE=serious adverse event; TIA=transient ischemic attack.
Follow-up Findings
Non-significant difference in primary endpoint:
2 years (mean 5.5% event rate in closure group v 6.8% in medical
1.7 years) treatment group (HR 0.78, 95% CI 0.45 to 1.35;
P=0.37)
Non-significant difference in primary endpoint:
5 years (mean 3.4% event rate in closure group v 5.2% in medical
4.1 years) treatment group (HR 0.63, 95% CI 0.25 to 1.62;
P=0.34)
Extended follow-up: significant reduction in primary
Median 5.9 endpoint with PFO closure in ITT cohort: 0.58 events
years (extended per 100 patient years in closure group v 1.07 in
follow-up) medical therapy group (HR 0.55, 95% CI 0.31 to
0.999; P=0.046)
Significant reduction in primary endpoint: no events in
closure group v 4.9% cumulative estimated probability
Mean 5.3 years
in antiplatelet only group (HR 0.03, 95% CI 0 to 0.26;
P<0.001)
Significant reduction in clinical stroke (extended
follow-up): 1.8% in closure group v 5.4% in medical
treatment group (HR 0.31, 95% CI 0.13 to 0.76;
Median 5.0 years P=0.007). Significant reduction in any new brain infarct group v 0.4% in medical treatment group (P<0.001);
(initial follow-up): 4.7% in closure group v 10.7% in
medical treatment group (RR 0.51, 95% CI 0.29 to
0.91; P=0.04)
Significant reduction in primary endpoint with PFO
Median 2.8 years closure: no events in closure group v 12.9% event rate SAEs; AF: 3.3% in closure group; inadequate closure:
in medical treatment group (P=0.013)
Complication rates
Overall SAEs: 16.9% in closure group v 16.6% in
medical treatment group (P=0.90); AF: 5.7% in closure
group v 0.7% in medical treatment group (P<0.001);
3.2% with procedure related SAEs, 13.3% with
inadequate closure
Overall SAEs: 21.1% in closure group v 17.6% in
medical treatment group (P=0.37); AF: 2.9% in closure
group v 1.0% in medical treatment group (P=0.17);
1.5% procedure related SAEs, 4.1% with inadequate
closure
Overall SAEs: 40.3% in closure group v 36.0% in
medical treatment group (P=0.17); AF: 1.2% in closure
group v 0.8% in medical treatment group (P=0.75);
5.0% procedure or device related SAEs, 6.5% with
inadequate closure
Overall SAEs: 35.7% in closure group v 33.2% in
medical treatment group (P=0.56); AF: 4.6% in closure
group v 0.9% in medical treatment group (P=0.02);
5.9% procedure related SAEs, 7.0% with inadequate
closure
Overall SAEs: 28.6% in closure group v 30.9% in
medical treatment group (P=0.53); AF: 6.8% in closure
3.9% procedure or device related SAEs, 24.4% with
incomplete closure
Overall SAEs: Not reported; 3.3% procedure related
not reported

of subsequent stroke and that the magnitude of
treatment benefit would overcome any procedural
complications or long term negative effects of device
insertion. However, percutaneous closure has been
a controversial therapy for most of the past three
decades.129
A low risk of recurrent events exists in patients
with PFO associated stroke whether or not closure
is pursued. This, along with the relatively small
absolute benefit expected with treatment, has
rendered conducting a definitive and adequately
powered clinical trial difficult. Nevertheless, six
recent RCTs have provided compelling evidence
that percutaneous PFO closure is associated with
a reduced risk of recurrent events and is cost
effective.4-11 130 This conclusion was supported by
a study level meta-analysis,131 with an individual
participant level meta-analysis under way.132 All
six recent RCTs were open label with no sham
procedure but used blinded endpoint adjudication.
Five trials enrolled patients within six months of
their qualifying event, and one trial enrolled patients
up to nine months (RESPECT). Of these trials, five
were restricted to patients younger than 60, and
one enrolled patients up to age 80 (DEFENSE-PFO).
This trial was noteworthy as the only one to include
patients aged between 60 and 80; however, the
mean age was 49 (standard deviation 15) in the
percutaneous closure arm and 52 (12) in the medical
treatment arm, meaning that no conclusions about
patients between 60 and 80 can be definitively
drawn. Table 1 and table 2 outline key aspects of
each trial, including patients’ characteristics, key
enrollment criteria, device type, study endpoints,
and adverse outcomes.
Technical aspects of percutaneous PFO closure
Morphological PFO features such as size and presence
of an ASA influence the complexity of percutaneous
closure.133 The six key clinical trials used two
major classes of closure device: an older, umbrella-
clamshell design (CLOSURE) and a more modern
“double disc” device (PC, RESPECT, CLOSE, REDUCE,
DEFENSE-PFO). Figure 3 depicts placement of a
double disc device across the interatrial septum. With
both device classes, the objective is to permanently
close the PFO and prevent transmission of thrombus
from the right atrium to the left atrium while
minimizing the risk of complications. Technically
successful closure occurred in 93-96% of patients
in the double disc trials and 87% in the umbrella-
clamshell trials.30 One study level meta-analysis
of these RCTs suggested a significant reduction in
recurrent stroke with double disc devices but not with
umbrella-clamshell devices.30 The primary goal of
these interventions is the attainment of satisfactory
closure measured via degree of residual shunting, as
the presence of residual shunting is associated with
increased rates of recurrent stroke (hazard ratio 3.1
(1.7 to 5.6) for any residual shunt and 4.5 (2.2 to 9.2)
for a moderate to large residual shunt).67 134
Procedural complications of percutaneous
closure include procedural failure (that is,
substantial residual right-to-left shunting after
deployment), post-procedural atrial fibrillation,
cardiac tamponade, pneumothorax, hemothorax,

the bmj | BMJ 2022;376:e063161 | doi: 10.1136/bmj-2020-063161 9


State of the Art REVIEW
Fig 3 | Deployment of double disc closure device. A. Orientation of interatrial septum
compared with rest of adult heart. After cannulation of femoral vein, catheter is
introduced into right atrium (RA). B. Patent foramen ovale (PFO) is traversed with
catheter and distal-most disc is expanded in left atrium (LA). Catheter is retracted
to generate snug seal between interatrial septum and disc. As catheter is further
retracted, right atrial disc self-expands. C. Oppositional forces created by two discs
seal PFO
and aortic dissection; device complications include
device migration or thrombosis. Given these risks,
the performance of individual centers should
be assessed by key benchmarks, including the
proportion of PFO closure procedures that result
in a technically successful result and the rate of
procedural complications. A retrospective study
based on administrative claims data suggested that,
in real world practice, the rate of any adverse event
was 10.9% in patients over the age of 60 and 4.9%
in patients younger than 60.135 These complications
included atrial fibrillation or atrial flutter (3.7%),
vascular complications requiring surgical repair
(3.0%), surgical site hematomas (2.7%), cardiac
tamponade (0.5%), pneumothorax or hemothorax
(0.1%), and death (0.3%). Post-procedural atrial
fibrillation is associated with an increased risk
of recurrent events61; it may be a complication of
the procedure itself or an independent event and
an indicator of left atrial dysfunction that may
have predated the stroke. A meta-analysis of RCTs
suggested that the weighted mean incidence of
atrial fibrillation after PFO closure was 3.2% (95%
confidence interval 1.8% to 5.0%) over a mean
follow-up of 2.8 years, compared with 0.47% (0.15%
to 0.91%) in patients managed medically.136 In a
retrospective, observational cohort study including
1349 patients who underwent PFO closure, 53 (3.9%)
patients developed new atrial fibrillation or atrial
flutter.137 Of those 53 patients, 33 (62%) developed
atrial fibrillation within four weeks of the procedure
and 23 (43%) had only one documented episode
of <48 hours throughout study follow-up. Data
on the management of atrial fibrillation after PFO
closure are lacking. One reasonable approach may
include temporary anticoagulation with a vitamin
K antagonist or DOAC in tandem with placement of
an implantable loop recorder, which would permit
calculation of the overall atrial fibrillation burden
to determine whether lifelong anticoagulation is
warranted.
Options for medical treatment after percutaneous
closure include single antiplatelet therapy with either
aspirin or clopidogrel, dual antiplatelet therapy, or
anticoagulation. Most trials comparing percutaneous
closure with medical treatment mandated some
10
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duration of post-procedure dual antiplatelet therapy,
typically for at least one month. Table 1 outlines
antithrombotic therapy after percutaneous closure
for each of the major percutaneous closure trials.
Single antiplatelet therapy should be continued
indefinitely in all patients for secondary prevention
of stroke (even with a technically successful PFO
closure), given that one can never be absolutely
certain that the PFO was the causative lesion.
Consideration for percutaneous PFO closure
A discussion between a neurologist and a
cardiologist is necessary for all patients referred for
percutaneous closure according to US Food and Drug
Administration mandates for the Amplatzer and
Gore Septal Occluder devices.138 139 Input from other
specialties (for example, internal medicine/primary
care, hematology, rheumatology) should also be
sought when some ambiguity surrounds the results
of diagnostic testing or a patient’s unique medical
history. A multidisciplinary clinic or case conference
is a practical framework allowing a forum for such
discussion, with simultaneous opinions from a
neurologist and structural cardiologist. This dialog
should include the results of all relevant diagnostic
testing as discussed above, including an evaluation
of PFO specific and patient specific factors (fig 4).
An age cutoff of 60 is proposed on the basis of the
enrollment criteria for most of the clinical trials
(detailed in table 1); however, this should not be
considered absolute. For instance, a patient of 55-
60 with more than one vascular risk factor and
an enlarged left atrium might meet enrollment
criteria for the recent randomized trials but may
benefit from antiplatelet therapy, long term cardiac
monitoring, and risk factor modification as opposed
to percutaneous closure.
Patients should be counseled that the decision
to pursue PFO closure is rarely a straightforward
one and that other options including medical
management and surgical closure may be reasonable
depending on an individual’s preferences and
tolerance of risk. Patients should be counseled that
up to a third of PFOs are incidental, even in cases of
cryptogenic stroke, meaning that PFO closure might
be futile or potentially harmful,18 aside from the
small, theoretical benefit of primary prevention of
PFO associated stroke.
Although the number needed to treat to prevent
one ischemic stroke over five years is 24 across all
patients receiving PFO closure (and 13 in patients
with PFO and ASA),30 consideration should be given
to the risk of subsequent stroke even if the procedure
is performed. Closure reduces the risk of recurrent
cryptogenic stroke but not other stroke subtypes.140
Stroke recurrence may result from technical failure of
the procedure, device complications including atrial
fibrillation, the emergence of new stroke substrates
over time (carotid stenosis, atrial fibrillation, small
vessel disease), or covert mechanisms that were
overlooked at the time of the initial evaluation. Long
term follow-up from the RESPECT trial found that
doi: 10.1136/bmj-2020-063161 | BMJ 2022;376:e063161 | the bmj
 BMJ: first published as 10.1136/bmj-2020-063161 on 9 February 2022. Downloaded from http://www.bmj.com/ on 25 July 2022 at USP - Universidade de Sao Paulo. Protected by copyright.
State of the Art REVIEW

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Fig 4 | Clinical decision making algorithm for management of patent foramen ovale (PFO) associated stroke. *In certain cases, other mechanisms
causing interatrial shunting may require targeted medical or surgical therapy—for example, an atrial septal defect or very large pulmonary
arteriovenous fistula. ARCADIA=AtRial Cardiopathy and Antithrombotic Drugs in Prevention After Cryptogenic Stroke; MRI=magnetic resonance
imaging; RCT=randomized clinical trial

the bmj | BMJ 2022;376:e063161 | doi: 10.1136/bmj-2020-063161 11


State of the Art REVIEW
28.3% of recurrences arose owing to a mechanism
unrelated to the PFO or its closure.10 A thoughtful
decision to refer a patient for percutaneous closure
depends on the following steps:
1. Making the diagnosis of PFO definitively
(including ruling out other potential causes of
interatrial shunting)
2. Careful history taking to elicit any provoking
maneuvers at onset
3. Assessing a patient’s overall vascular health
(including calculating their RoPE score);
4. Consideration of a potential concurrent venous
thromboembolism
5. Examining the characteristics of the PFO,
including its size and the presence of an ASA
6. Examining characteristics of the stroke itself (for
example, small, deep strokes are unlikely to be
associated with a PFO)
7. Completing a thorough investigation for
competing mechanisms including paroxysmal
atrial fibrillation, structural cardiac lesions, and
non-atherosclerotic vasculopathies.
Surgical closure
Open surgical closure of a PFO is sometimes done
at the same time as open heart surgery for other
indications and involves direct oversewing of the PFO.
A small study of 11 patients who underwent surgical
closure of a PFO (six of whom had concomitant open
valve replacement) examined technical success rates
via transesophageal echocardiography.141 Residual
shunting remained present in eight patients, of whom
six had incomplete sealing of the septum primum
and septum secundum and two had complete closure
of the original PFO but a new iatrogenic septal defect
in the middle or inferior part of the fossa ovalis. This
high rate of technical failure may explain why open
surgical PFO closure is associated with a higher risk
of subsequent stroke,142 and its use should therefore
be avoided.
Guidelines
Although some existing guidelines published before
2018 are agnostic to the benefits of percutaneous
closure,143-145 several major statements have come
from major professional organizations,146-149
as well as position papers and conference
proceedings,150-152 that are now endorsing its use
in appropriately selected patients. The American
Heart Association/American Stroke Association
(AHA/ASA) Guidelines for the Prevention of Stroke in
Patients With Stroke and Transient Ischemic Attack
advocate consideration of targeted investigation
for PFO in patients for whom a cause of stroke
is not identified after electrocardiography, basic
laboratory testing, echocardiography (either
transthoracic echocardiography or transesophageal
echocardiography) and non-invasive cervical
vessel imaging based on individual patient related
factors.146 The same guidelines state that choosing
percutaneous closure over antiplatelet therapy in
12
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patients aged 18-60 with a non-lacunar ischemic
stroke of undetermined cause (after thorough
investigation) and when the PFO has high risk
features is reasonable. The American Academy
of Neurology (AAN) states that percutaneous
closure may be recommended in patients <60 years
old with an embolic stroke for which no other
cause can be found.147 153 Whereas the AHA/ASA
guidelines recommend considering “prolonged
cardiac monitoring to screen for intermittent atrial
fibrillation,” the AAN recommends monitoring
for four weeks in patients older than 40 and one
to two weeks in those under 40 before referring
for percutaneous closure.153 All statements stress
the importance of a multidisciplinary approach
to management decisions and detailed diagnostic
investigation before intervention. Box 2 summarizes
guidelines and position papers from major
professional organizations.
Emerging treatments
As percutaneous PFO closure has been shown to
be effective within narrowly defined clinical trial
populations, opportunities remain to establish
the utility of this therapy in other populations.
In particular, the management of PFO in older
people remains controversial. Older patients are
more likely to harbor occult mechanisms of stroke
such as paroxysmal atrial fibrillation, non-stenotic
atherosclerotic carotid lesions, and aortic arch
atherosclerosis. Concurrently, the incidence of venous
thromboembolism also increases with advancing
age,154-157 which represents an increasingly likely
substrate for paradoxical embolization. High quality
observational evidence now links PFO with ESUS in
older people,19 20 and studies of stroke recurrence in
older patients with ESUS and a PFO suggest that PFOs
are associated with a meaningfully increased risk of
stroke.158 Further observational work suggests that
PFO closure is feasible in patients above the age of 60
in real world clinical practice.159 A trial comparing
percutaneous closure with medical treatment is
therefore rational in this patient population,60
especially in those without traditional vascular risk
factors. Two observational studies are under way to
assess the role of PFOs in older patients with a stroke
or transient ischemic attack (NCT00859885) and the
interrelation of PFOs and atrial fibrillation in older
people (DefenseElderly; NCT04285918).
Further studies are also needed to determine
which patients are most likely to benefit from PFO
closure on the basis of individual patient level
biomarkers. For instance, exploratory analyses of
existing trial data suggest that PFO closure may not
be efficacious in patients with very small shunts,160
and whether features of the eustachian valve can be
used to inform clinical decision making and the risk
of future stroke remains unknown.51 An individual
participant meta-analysis of the recent major RCTs
is under way and will examine associations between
morphological PFO biomarkers (including shunt size
and presence of an ASA) and benefit of treatment.132
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State of the Art REVIEW

Box 2: Recommendations from professional societies on patent foramen ovale (PFO) closure for secondary
stroke prevention
American Heart Association/American Stroke Association secondary stroke prevention guideline 2021146
• “In patients with a nonlacunar ischemic stroke of undetermined cause and a PFO, recommendations for PFO closure
versus medical management should be made jointly by the patient, a cardiologist, and a neurologist, taking into
account the probability of a causal role for the PFO (level C-EO)”
• “In patients 18 to 60 years of age with a nonlacunar ischemic stroke of undetermined cause despite a thorough
evaluation and a PFO with high-risk anatomic features, it is reasonable to choose closure with a transcatheter device
and long-term antiplatelet therapy over antiplatelet therapy alone for preventing recurrent stroke (level B-R)”
American Academy of Neurology Practice Advisory Update 2020147
• “If a higher risk alternative mechanism of stroke is identified, clinicians should not routinely recommend PFO
closure (level B)”
• “In patients younger than 60 years with a PFO and an embolic appearing infarct and no other mechanism of stroke
identified, clinicians may recommend closure following a discussion of potential benefits (reduction of stroke
recurrence) and risks (procedural complication and atrial fibrillation) (level C)”
• “PFO closure may be offered to younger patients (e.g., <30 years) with a single, small, deep stroke (<1.5 cm), a
large shunt, and absence of any vascular risk factors that would lead to intrinsic small-vessel disease such as
hypertension, diabetes, or hyperlipidemia (level C)”
Society for Cardiovascular Angiography and Interventions Expert Consensus Statement 2019148
• “A successful PFO program must have a rigorous process for selection in order to offer the procedure to only
the patients with unexplained stroke who will benefit the most in order to mitigate risk and avoid unnecessary
procedures”
• “Patient selection should involve close collaboration between the PFO proceduralist and a neurologist (preferably a
stroke neurologist)”
• “Prior to considering PFO closure, a careful evaluation should be done to rule out other causes of stroke”
Canadian Best Stroke Practice Recommendation 2018149
• “For patients requiring long-term anticoagulation, the decision regarding PFO closure remains unclear, and
decisions should be based on individual patient characteristics and risk versus benefit profile [Evidence C]”
• “There is insufficient evidence to make a recommendation regarding the comparative effectiveness of PFO closure
vs. anticoagulant therapy”
• “For carefully-selected patients with a recent ischemic stroke or TIA attributed to a PFO, PFO device closure plus long-
term antiplatelet therapy is recommended over long-term antithrombotic therapy alone provided all the following
criteria are met [Evidence Level A]: (i) age 18–60 years; (ii) The diagnosis of the index stroke event is confirmed by
imaging as a nonlacunar embolic ischemic stroke or a TIA with positive neuroimaging or cortical symptoms; (iii) The
patient has been evaluated by a neurologist or clinician with stroke expertise, and the PFO is felt to be the most likely
cause for the index stroke event following a thorough etiological evaluation to exclude alternate etiologies”
European Stroke Organization Consensus Statement 2017145
• “In patients aged 18–60 years old with cryptogenic stroke/TIA and with high risk PFO features (moderate or severe
shunt, atrial septal aneurysm (ASA), atrial septal hypermobility) we recommend percutaneous closure plus medical
therapy instead of antiplatelet therapy alone (Grade A)”
• “In patients between 60 and 65 years, percutaneous closure plus medical therapy instead of antiplatelet
therapy alone can be offered (Grade B). Percutaneous closure plus medical therapy can be considered in place of
antiplatelet therapy alone also for patients aged <18 and >65 years old on an individual basis (Grade C)”
• “Based on the few available data, percutaneous closure and oral anticoagulation (OAC) therapy seem to perform
equally (Grade C). Therefore, while waiting for further evidence and based on the superiority of percutaneous
closure over medical therapy as a whole, patient engagement in the choice is pivotal”
TIA=transient ischemic attack

Additionally, as PFO closure is a relatively modern
therapy, the very long term stability of PFO closure
devices remains unknown. Several registries are
actively enrolling patients to determine the ongoing
stability of these devices, including the REDUCE Post-
Approval Study (NCT03821129), the Trevisio Post-
Approval Study (NCT04433520), and the Amplatzer
PFO Occluder Post-Approval Study (NCT03309332).
From the standpoint of medical treatment of PFO,
although previous studies did not find a significant
net benefit of anticoagulation over antiplatelet
therapy with respect to secondary prevention of
stroke in patients with PFO, such studies were
collectively underpowered and the use of DOACs
has not been tested in a randomized clinical trial.
These drugs are associated with fewer drug-drug
interactions than warfarin and confer a lower risk
of hemorrhagic complications.64 161 They may thus
be compelling targets for further study in patients
with cryptogenic stroke and PFO who do not undergo
PFO closure, especially in those over the age of 60.
Several observational studies suggest that the use

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State of the Art REVIEW
of DOACs is feasible in patients with PFO associated
stroke.159 161
Conclusion
PFOs are common structural cardiac lesions that
have been associated with cardioembolic stroke,
particularly in young patients without other vascular
risk factors. Options for secondary prevention after
PFO associated stroke include medical management
(with antiplatelet therapy or anticoagulation) or
percutaneous device closure in selected patients.
Percutaneous PFO closure is associated with a
high relative risk reduction but a low absolute risk
reduction for recurrent stroke. Before proceeding
with PFO closure, other known causes of ischemic
stroke should be definitively excluded, relevant
morphological features of the PFO should be fully
characterized, and each available treatment option
corresponding to patients’ individual preferences
should be considered as part of a multidisciplinary,
structured decision making process.
Glossary of abbreviations
• AAN—American Academy of Neurology
• AHA/ASA—American Heart Association/American
Stroke Association
• ASA—atrial septal aneurysm
• DOAC—direct oral anticoagulant
• DVT—deep venous thrombosis
• ESUS—embolic stroke of undetermined source
• ICM—insertable cardiac monitor
• pAVF—pulmonary arteriovenous fistula
• PFO—patent foramen ovale
• RCT—randomized controlled trial
• RoPE—Risk of Paradoxical Embolism
• TCD-US—transcranial Doppler ultrasonography
Research questions
• Is percutaneous patent foramen ovale (PFO) closure
of benefit in older patients?
• Can morphological features of PFOs identify patients
poised to benefit most from PFO closure?
• What is the role of novel oral anticoagulants in the
prevention of future stroke in patients with PFO?
• Is there a subset of patients with migraine who may
benefit from PFO closure?
We thank Franklin Schneider (Warren Alpert Medical School of Brown
University) for echocardiographic images used in figure 2, Eric Feng
for the creation of figure 3, and Vinald Francis for the creation of the
supplementary figure.
Contributors: All listed authors satisfy all four ICMJE authorship
criteria. BMG conceived and designed the work, drafted the
manuscript, and revised it for critically important intellectual content.
EMO, WF, YX, SY, and HK made substantial contributions to the design
of the work and revised it for critically important intellectual content.
MER conceived and designed the work and revised it for critically
important intellectual content. BMG, EMO, WF, YX, SY, HK, and MER
provided final approval of the version to be published and agreed to
be accountable for all aspects of the work in ensuring that questions
related to the accuracy or integrity of any part of the work are
appropriately investigated and resolved. BMG is the guarantor.
14
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Patient involvement
A patient of BMG’s who had had an embolic stroke of
undetermined source and subsequently underwent
percutaneous closure of a high risk patent foramen
ovale (PFO) contributed to the drafting of this
manuscript. This man and his wife (who had been
extensively involved at all stages of the decision
making process) reviewed an early draft of the
manuscript and provided extensive comments and
suggestions on its content and style. They emphasized
in particular the need to promote awareness of the
risk of PFO associated stroke in young patients. They
also wished to highlight that cryptogenic strokes may
present with mild symptoms at their first iteration and
therefore can easily be misdiagnosed.
Competing interests: We have read and understood the BMJ policy
on declaration of interests and declare the following interests: none.
Provenance and peer review: Commissioned; externally peer
reviewed.
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