Circulation Journal

Official Journal of the Japanese Circulation Society

REVIEW
http://www. j-circ.or.jp

Patent Foramen Ovale and Stroke

Yee-Ping Sun, MD; Shunichi Homma, MD

A patent foramen ovale (PFO) is common and found in nearly 25% of healthy individuals. The majority of patients
with PFO remain asymptomatic and they are not at increased risk for developing a stroke. The presence of PFO,
however, has been found to be higher in patients with cryptogenic stroke, suggesting there may be a subset of
patients with PFO who are indeed at risk for stroke. Paradoxical embolization of venous thrombi through the PFO,
which then enter the arterial circulation, is hypothesized to account for this relationship. Although aerated-saline
transesophageal echocardiography is the gold standard for diagnosis, aerated-saline transthoracic echocardiogra-
phy and transcranial Doppler are often used as the initial diagnostic tests for detecting PFO. Patients with cryptogenic
stroke and PFO are generally treated with antiplatelet therapy in the absence of another condition for which antico-
agulation is necessary. Based on the findings of 3 large randomized clinical trials, current consensus guidelines do
not recommend percutaneous closure, though this is an area of controversy. The following review discusses the
relationship of PFO and cryptogenic stroke, focusing on the epidemiology, pathophysiological mechanisms, diag-
nostic tools, associated clinical/anatomic factors and treatment. (Circ J2016; 80: 16651673)

Key Words: Paradoxical embolism; Patent foramen ovale (PFO); Stroke

T
he foramen ovale is an important fetal structure that
closes after birth in most individuals and remains open
as a patent foramen ovale (PFO) in approximately
25% of the healthy population.13 In these individuals, bypass
of the pulmonary circulation via shunting from the right-sided
venous circulation to the left-sided arterial circulation is pos-
sible. Although most patients with PFOs are completely
asymptomatic, reports from the late 1800s by Cohnheim and
Litten described cases of patients who were found to have the
triad of deep venous thrombosis (DVT), PFO and systemic
embolization. They hypothesized that the PFO enabled bypass
of a venous thrombosis to the systemic arterial circulation, a
process now termed paradoxical embolization.4,5 Since those
initial observations, additional studies have demonstrated a
strong association between the presence of PFO and crypto-
genic stroke in young patients.611 In addition to its association
with stroke, PFO has also been implicated in platypnea-
orthodeoxia,12 decompression illness,13 myocardial infarction,14
obstructive sleep apnea,15 and migraine headaches.16
This review will focus on the relationship between PFO and
stroke, discussing the embryology, epidemiology, association,
mechanisms, diagnostic methods, associated anatomic factors
and management strategies.
Embryology
The right and left atria begin as a single chamber and separa-
tion begins with growth of the septum primum from the roof
of the common atrium. As the septum primum grows downward,
fenestrations form in its superior portion. The fenestrations
coalesce into a single orifice that becomes the foramen secun-
dum. The septum secundum then forms via involution of the
ventrocranial wall and overlaps with the foramen secundum.
The septum secundum does not close fully and an oval-shaped
opening remains, which becomes the foramen ovale.17
Prior to birth, the fetus is dependent on the maternal circula-
tion for oxygenation, as the immature fetal lungs do not yet
participate in oxygen exchange. As such, the foramen ovale
(as well as the ductus arteriosus), enables shunting of blood
away from the pulmonary circulation. At birth, when the neo-
nates lungs begin to participate in oxygen exchange, there is
a precipitous drop in the pulmonary vascular resistance and
there is reversal of flow through both the foramen ovale and
ductus arteriosus.18 In approximately 75% of individuals, the
foramen ovale closes within a few years while in the remain-
ing others, it stays open permanently as a PFO.
Epidemiology
The prevalence of PFO in the healthy adult population ranges
from 15% to 25% on echocardiography and 1535% on autopsy
studies.1,2,19,20 Observational and autopsy studies have showed
that the prevalence of detected PFOs is lower in older patients
and that detected PFOs in older individuals tend to be larger.1,19,20
Those studies, however, may be confounded by selection and
detection bias because none of the longitudinal studies have
demonstrated that individual PFOs change in size. The preva-
lence of PFOs is equal among men and women, though there
may be race-ethnic differences.1,19,21

Received June 2, 2016; accepted June 2, 2016; released online June 22, 2016
Columbia University Medical Center, New York, NY, USA
Mailing address: Shunichi Homma, MD, Columbia University Medical Center, PH 3-342, 630 West 168th Street, New York, NY 10032,
USA.E-mail: sh23@cumc.columbia.edu
ISSN-1346-9843doi:10.1253/circj.CJ-16-0534
All rights are reserved to the Japanese Circulation Society. For permissions, please e-mail: cj@j-circ.or.jp

Circulation Journal Vol.80,August2016

1666
Cryptogenic Stroke and PFO
A stroke is considered cryptogenic when a cause has not been
identified. Depending on the classification system, cryptogenic
strokes account for almost 30% of cases and are more com-
mon in younger patients.22 Multiple studies have demonstrated
an association between PFO and cryptogenic stroke.611,23
Attributing an initial stroke to the presence of a PFO can be
challenging, given the multiple other causes of stroke com-
bined with the high prevalence of PFOs in the general popula-
tion. The Risk of Paradoxical Embolism (RoPE) study helped
address this issue.24 In this patient-level meta-analysis, nearly
3,000 patients from 12 independent studies were included and
the following factors were found to be associated with the
detection of a PFO: younger age, radiographic evidence of a
cortical infarct and absence of traditional vascular risk factors
(hypertension, diabetes, prior history of stroke/transient isch-
emic attack (TIA) and smoking). The data suggested that the
fewer traditional risk factors that were present, the more likely
that the stroke was caused by a PFO. Importantly, it also dem-
onstrated that the more likely the stroke was caused by the
PFO, the lower the risk for recurrent stroke.
Although it has been well established that a PFO is associ-
ated with cryptogenic stroke, it is important also to note that
studies following patients with PFO without stroke have not
shown them to be at an increased risk of developing an isch-
emic stroke.2,25,26 These observations suggest, therefore, that
the development of stroke in patients with PFO is likely mul-
tifactorial with contributions from other factors. Although the
main hypothesized pathophysiological explanation is that of
paradoxical embolism, the exact causative mechanism remains
controversial.27 Other possible mechanisms for the association
between PFO and stroke have been proposed. It is well estab-
lished that atrial fibrillation (AF) and atrial flutter are risk
factors for stroke and several studies have suggested that the
risk for recurrence in patients with PFO and cryptogenic
stroke may be related to the subsequent development of these
atrial arrhythmias.28 This mechanism, however, remains uncer-
tain as the results from the CRYSTAL AF study showed that
subsequent development of AF (at 3 years) in patients with
cryptogenic stroke was not related to the presence of PFO.29
In addition to a connection with atrial arrhythmias, recent
proteomic profiling studies have demonstrated differences in
protein expression in patients with PFOs with and without
Circulation Journal Vol.80,August2016
SUN YP et al.
Figure1. PFO as visualized on biplane
TEE. LA, left atrium; PFO, patent foramen
ovale; RA, right atrium; TEE, transesoph-
ageal echocardiography.
stroke and have also shown that PFO closure results in altera-
tions in cholesterol handling, thereby providing additional
alternative mechanisms.30,31
Detection
Although PFO was initially a diagnosis that was made at the
time of autopsy, it can now be detected non-invasively using
ultrasound. Contrast transthoracic echocardiography (TTE) and
transcranial Doppler (TCD) allow for the physiologic identi-
fication of PFOs through detection of microbubbles in the
left-sided circulation that in the absence of a PFO are filtered
out by the pulmonary circulation.32,33 Neither of these tech-
niques, however, are able to localize the level of shunting. The
third method, contrast transesophageal echocardiography (TEE),
allows for direct anatomic visualization of shunting across a
PFO and is considered the gold standard for diagnosis.3
Aerated-saline TTE is commonly used for initial evaluation
for PFO. In order to perform this test, intravenous access is
obtained and aerated saline is injected. While visualizing the
entire heart (either apical or subxiphoid view), aerated saline
(which appears echobright) is first seen filling the right atrium
(RA) and right ventricle. If microbubbles are seen on the left
side of the heart within 3 cardiac cycles, this is considered a
positive test for evidence of intracardiac shunting. Occasion-
ally in the presence of rapid pulmonary transit (as can be seen
with pulmonary arteriovenous malformations), microbubbles
can appear on the left side of the heart after 5 cardiac cycles.
In normal individuals without intracardiac shunting or rapid
pulmonary transit, microbubbles are filtered by the lungs and
are not seen on the left side. Given that the distinction between
intracardiac shunting and rapid pulmonary transit is made
based upon the time of microbubble appearance, distinguish-
ing between these entities can be challenging. If no shunting
is seen at rest, repeat injections are performed after release of
the strain phase of the Valsalva maneuver or coughing, and
imaging is again acquired. The purpose of these maneuvers is
to transiently increase right-sided filling pressures, which can
improve the ability to detect intracardiac shunting.34 Although
early studies demonstrated a sensitivity of close to 50%,35,36
more contemporary studies have indicated that it has increased
to 8090%, an improvement that is likely related to technical
improvements in imaging quality.37,38 Given the reduced sensi-
tivity, it is not surprising, therefore, that the estimated prevalence
PFO and Stroke 1667

Figure2.PFO as visualized on color

Doppler biplane TEE. Color flow demon-
strates left-to-right shunting through the
PFO. LA, left atrium; PFO, patent fora-
men ovale; RA, right atrium; TEE, trans-
esophageal echocardiography.

of PFOs in the general population when TTE is used is

approximately 15% as compared with 24% with TEE.2,26
TCD is a noninvasive and reproducible assessment of cere-
bral blood flow that when coupled with use of aerated-saline
injection is also often used in the initial evaluation for PFO.33
In this technique, the ultrasound probe is placed over the tem-
poral window and insonation of the middle cerebral artery is
performed. Aerated saline is then injected into a peripheral
vein. In the presence of a right-to-left shunt, microbubbles
bypass the pulmonary circulation and are detected on Doppler
assessment of the middle cerebral artery. Quantification of
shunting is possible through counting of the number of micro-
bubble signals.39 Detection of right-to-left shunting can be
improved through imaging in multiple positions and with
maneuvers that transiently increase right-sided pressures,
maneuvers that are more easily performed with TCD.40 Simi-
lar to TTE, the detection of microbubbles indicates only the
presence of right-to-left shunting. Although early detection Figure3. Aerated-saline contrast injection demonstrating the
and large quantity of microbubbles can be helpful in suggest- presence of PFO on TEE. Bubbles are seen traversing the
ing an intracardiac source of shunting,39 no consensus stan- PFO entering the left atrium (LA). PFO, patent foramen ovale;
RA, right atrium; TEE, transesophageal echocardiography.
dardization has been established and distinguishing between
intracardiac shunting and intrapulmonary shunting can still be
difficult. When comparing TCD with contrast-enhanced TTE
for detection of PFO, a recent meta-analysis suggested it to be
more sensitive but less specific.41 When compared with TEE, TEE allows for the direct visualization of the PFO opening
however, there remains controversy regarding which modality and measurement of the separation height between the septum
is most sensitive.35,42 The uncertainty is likely related to dif- primum and septum secundum (Figure1). The shunting of
ferences in what is used as the gold standard for the presence blood can sometimes be visualized directly by color Doppler
of a PFO.43 (Figure2). Oftentimes, however, diagnosis requires injection
Although both TCD and contrast-enhanced TTE enable of aerated saline via a peripheral vein. The interatrial septum
detection of PFOs in a noninvasive fashion, TEE provides is visualized in the mid-esophageal bicaval view. PFO is diag-
direct visual assessment of the PFO anatomy and further iden- nosed with the appearance of microbubbles in the left atrium
tification of other associated structures such as a prominent and they can often be seen traversing the PFO (Figure3). This
Eustachian valve, Chiari network and atrial septal aneurysm assessment is performed both at rest and with maneuvers that
(ASA). The sensitivity and specificity of contrast-enhanced result in increased right atrial pressure such as coughing or the
TEE is close to 100%,3 a finding that is supported by the fact Valsalva maneuver. If initially negative, this can be repeated
that the prevalence of PFO in the general population when with multiple injections, which has been shown to improve
diagnosed by TEE is 24.3%,2 which is very similar to that the sensitivity.44 In contrast to TTE and TCD, direct visual
reported in autopsy studies.1,20 assessment of the pulmonary veins can often be used to better

Circulation Journal Vol.80,August2016

1668
Figure4. Atrial septal aneurysm (ASA) as visualized on TEE.
ASA is defined as a hypermobile interatrial septum that devi-
ates >10mm from the plane of the septum or >15mm of total
excursion. LA, left atrium; RA, right atrium; TEE, transesopha-
geal echocardiography.
Figure5. Prominent Chiari network as visualized on TEE. The
Chiari network is a remnant of the right valve of the sinus
venosus. It typically extends from the junction of the inferior
vena cava to the upper wall of the right atrium (RA) or septum
(though it can be fenestrated). LA, left atrium; TEE, trans-
esophageal echocardiography.
distinguish between PFO and intrapulmonary shunting. It is
important to note that although TEE is considered the gold
standard for diagnosis, it is a semi-invasive test that is gener-
ally performed with conscious sedation. Because of this, it can
often be difficult for patients to perform the Valsalva maneu-
ver or to cough and as such, may lead to rare false-negative
results. Although multiple studies have demonstrated the safety
of aerated-saline injections, the rare development of transient
neurological symptoms has been reported.45
Factors Associated With PFO
and Cryptogenic Stroke
The main hypothesized pathophysiologic mechanism relating
PFO and cryptogenic stroke is that of paradoxical emboliza-
tion. Although there is a clear association between PFO and
Circulation Journal Vol.80,August2016
SUN YP et al.
Figure6.Eustachian valve as visualized on TEE. The
Eustachian valve is a remnant of the right valve sinus venosus
and extends anteriorly from the IVC-RA junction. EV,
Eustachian valve; IVC, inferior vena cava; LA, left atrium; RA,
right atrium; SVC, superior vena cava.
cryptogenic stroke,611 the observation that the rate of strokes
in asymptomatic individuals is no different than in patients
without PFOs2,25,26 means it is likely that a multifactorial
model exists whereby additional factors need to also be pres-
ent in order for paradoxical embolization to occur. This sec-
tion will discuss several factors that may be associated with
paradoxical embolization, including PFO size, and the pres-
ence of other anatomic features, including ASA, prominent
Eustachian valve, Chiari network and hypercoagulability.
PFOs have a wide variability in size and autopsy studies
have demonstrated that the mean diameter is 4.9mm and
ranges from 1 to 19mm.1 This differs from sizing defined by
TEE, which defines PFO size as the maximal height of separa-
tion between the septum primum and secundum.46 There are
conflicting reports regarding the relationship of PFO size and
the development of cryptogenic stroke, with early studies sug-
gesting that larger PFOs are associated with cryptogenic
stroke,47 but observations from the RoPE database showing no
relationship.48 Along these same lines, other characteristics,
including the physiologic shunt size (determined by the quan-
tity of bubbles that cross the PFO) and the presence of shunt-
ing at rest, have also been inconclusive, with some showing
an increased risk of stroke and stroke recurrence,49,50 and
others showing no relationship.48,51
ASA is a redundancy of the atrial septum that results in
significant movement (>10mm from the plane of the septum
or 15mm of total excursion) (Figure4).52 ASAs are more
commonly observed in patients with stroke than in the general
population.6,53 PFOs are found in approximately 60% of patients
with cryptogenic stroke and ASA as compared with approxi-
mately 30% of patients with cryptogenic stroke but no ASA.53
In the same study, larger PFOs were more commonly seen in
those with ASA as compared with those without ASA.53 In
addition to the hypothesis that the presence of ASA may help
facilitate paradoxical embolization through a PFO, it has also
been shown that the presence of ASA alone is associated with
left atrial dysfunction and may serve as another mechanism by
which ASA may be related to stroke. It is not yet clear how the
presence of ASA affects the risk of cryptogenic stroke in the
setting of PFO, if at all,48 and further studies are required.
A prominent Chiari network and Eustachian valve are com-
monly seen in patients with PFO and stroke.53,54 Both structures
PFO and Stroke
Table1. Summary of the Randomized Controlled Trials Evaluating Percutaneous Closure of Patent Foramen Ovale
Closure 1
Device STARFlex
Design 909 patients randomized to medical
therapy (aspirin, warfarin or both at
physician discretion) vs. closure
Follow-up 2 years
Primary Composite of stroke/TIA at 2 years, death
endpoint from any cause in the first 30 days or
death from neurologic causes between 31
days and 2 years
Results No differences in closure vs. medical
therapy:
Primary endpoint (5.5% vs. 6.8%) Primary endpoint (5.2% vs. 3.4%)
Recurrent stroke (2.9% vs. 3.1%) Recurrent stroke (2.4% vs. 0.4%)
No procedural deaths
Increased risk of atrial fibrillation in the
closure group over the medical therapy
group (5.7% vs. 0.7%, P<0.001)
HR, hazard ratio; TIA, transient ischemic attack.
are remnants of the embryologic right valve of the sinus veno-
sus that directs blood preferentially through the foramen ovale
in utero. The Chiari network is a mobile web-like structure
that typically extends from the junction of the inferior vena
cava (IVC) and RA and attaches to the upper wall of the RA
or the septum (though it can also be fenestrated) (Figure5).
The Eustachian valve extends anteriorly from the IVC-RA
junction and unlike the Chiari network typically does not
attach at other sites (Figure6). Although the mechanism for
the association between these structures, PFO and stroke is not
clear, they have been shown to direct blood flow from the IVC
towards the PFO, which, in the setting of a lower extremity
DVT, may help facilitate paradoxical embolization.55
In order for paradoxical embolism to occur, there must be a
source of thrombus in addition to a PFO. Both lower extremity
and pelvic DVT have been reported in patients with crypto-
genic stroke and PFO.56,57 In 1 study, when compared with
patients with known etiology for stroke, the rates of pelvic
DVT in cryptogenic stroke were higher (20% vs. 4%),58 though
another more recent study showed no differences in the rates
of DVT.59 In addition, studies have shown that the prevalence
of the otherwise rare May-Thurner syndrome (an anatomic
vascular variant that predisposes towards development of
DVT) in patients with cryptogenic stroke and PFO is approx-
imately 68%.60,61 Despite these conflicting results, pelvic
vein thrombosis may still be an important source of thrombi
in patients with cryptogenic stroke and DVT.
Hypercoagulable states have been implicated as additional
risk factors for cryptogenic stroke in patients with PFO. Two
of these, the prothrombin G20210A mutation and Factor V
Leiden, have been most strongly linked to the development of
cryptogenic stroke in the setting of a PFO.62,63 though results
are inconsistent.64 Polymorphisms in APOCIII, a lipoprotein
that is critical in triglyceride metabolism and is associated
with increased cardiovascular risk,65 have been reported in
patients with cryptogenic stroke and PFO as well.62 Antiphos-
pholipid antibodies were not found to be a risk factor how-
ever.66 Although not specifically linked with cryptogenic
stroke, traditional risk factors for DVT, including prolonged
immobility, malignancy and use of oral contraceptives, to name
only a few,67 are likely to also be potential risk factors for
paradoxical embolization in the setting of a PFO.
Circulation Journal Vol.80,August2016
1669
PC Trial RESPECT
Amplatzer PFO Occluder Amplatzer PFO Occluder
414 patients randomized to medical 980 patients randomized to medical
therapy (70% antiplatelet, 30% anti- therapy (antiplatelet 75%, anticoagulation
coagulation) vs. closure 25%) vs. closure
Follow-up 4 years Follow-up 2.5 years
Composite of death, nonfatal stroke, Recurrent stroke or death
TIA, embolism
No difference in closure vs. medical Total 25 primary endpoints occurred, all
therapy: nonfatal strokes
Intention-to-treat analysis showed no
difference between closure vs. medical
No differences in bleeding or atrial therapy (0.66 events per 100 patient-years
fibrillation vs. 1.38 events per 100 patients-years,
HR=0.49, P=0.08)
As-treated analysis showed benefit of
closure (HR=0.27, P=0.007)
No difference in atrial fibrillation
Medical Therapy
Currently, it is recommended that patients with cryptogenic
stroke and PFO be treated with antiplatelet therapy (in the
absence of another indication for anticoagulation).68 Because
it is hypothesized that these strokes are caused either by para-
doxical embolism or embolism of in situ atrial thrombi, it
seems logical that some type of antithrombotic therapy would
be of benefit. Although there is no direct evidence supporting
use of antiplatelet therapy in patients with PFO and stroke
over no therapy, given the safety and well-demonstrated ben-
efit of these agents in the treatment of stroke in general, it
remains the standard of care for the subset of patients with
stroke and PFO.68
Because of the role that paradoxical embolization may play
in the pathogenesis of stroke in patients with PFO, it has been
hypothesized that anticoagulation may be of benefit in these
patients. There is, however, limited data comparing antiplate-
let therapy with anticoagulation in these patients. PICSS (PFO
in Cryptogenic Stroke Study) was a substudy of a large, ran-
domized control trial of warfarin vs. aspirin for secondary
stroke prevention.69 The study compared dose-adjusted warfa-
rin (targeting an internal normalized ratio of 23) with aspirin
325mg daily in those with cryptogenic stroke and PFO. Of the
630 stroke patients included in the original trial, 98 had both
cryptogenic stroke and PFO; 42 of the 98 patients were treated
with warfarin and the remaining 56 were treated with aspirin.
There was no difference in the primary endpoint (recurrent
stroke or death) at 2 years between the 2 groups.
A very small (44 patients), single-center randomized con-
trolled trial compared dose-adjusted warfarin (targeting an
international normalized ratio of 23) with aspirin (240mg
daily) in patients with PFO and cryptogenic stroke. There were
no significant differences between the 2 groups in the primary
endpoint (ischemic stroke, TIA or death), though the study was
underpowered to fully detect such a difference.
Given the small numbers in the previously discussed studies
(in addition to others), meta-analyses have been performed,
with some favoring warfarin therapy70 and others demonstrat-
ing no benefit of anticoagulation over antiplatelet therapy.71
Although there is currently no evidence to suggest a benefit of
warfarin over aspirin, the lack of adequately powered studies
1670 SUN YP et al.

Table2. Summary of Meta-Analyses Evaluating Percutaneous Closure of Patent Foramen Ovale

Studies favoring PFO closure
Khan et al, 201378 Pooled results showed benefit of PFO closure over medical therapy for intention-to-treat (HR 0.67, P=0.05),
per-protocol (HR=0.62, P=0.03) and as-treated (HR=0.61, P=0.03) cohorts
Rengifo-Moreno et al, Significant reduction in stroke and/or TIA in intention-to-treat analysis (HR=0.59, P=0.04)
201379 Borderline significant reduction in combined outcome of death and vascular events (HR=0.67, P=0.05)
Kent et al, 201685 No difference in unadjusted primary outcome (stroke, TIA, death)
Closure favored over medical therapy in covariate-adjusted primary outcome (HR=0.68, P=0.049)
Closure favored over medical therapy for recurrent stroke, both unadjusted (HR=0.58, P=0.043) and adjusted
(HR=0.58, P=0.044)
Closure with the Amplatzer PFO Occluder favored over medical therapy for recurrent stroke (HR=0.39,
P=0.013)
Number needed to treat to prevent 1 stroke over 2.5 years=65 patients
Equivocal studies regarding PFO closure
Pineda et al, 201382 No significant reduction in composite outcome (stroke and TIA) in intention-to-treat analysis (OR=0.700,
P=0.08)
Significant reduction in composite outcome in as-treated analysis (OR=0.62, P=0.02)
Stortecky et al, 201580 Network meta-analysis showed that PFO closure with the Amplatzer PFO Occluder resulted in fewer strokes
over medical therapy (RR=0.39, 95% CI=0.170.84)
Closure with Amplatzer PFO Occluder showed no benefit over medical therapy with respect to TIA or death
No differences between closure with StarFlex or Helex device closure over medical therapy
Studies against PFO closure
Kitsios et al, 201383 No significant reduction in recurrent stroke with PFO closure (StarFlex+Amplatzer PFO Occluder combined
AND Amplatzer PFO Ocluder alone) over medical therapy
Udell et al, 201481 PFO closure did not result in a significant reduction in recurrent stroke over medical therapy (3.7% vs. 5.2%,
RR=0.73, P=0.10)
PFO Closure lead to an increased risk of atrial fibrillation/flutter over medical therapy (3.8% vs. 1%, RR=3.67,
P<0.0001)
Spencer et al, 201484 No significant reduction in recurrent stroke with PFO closure over medical therapy (2.1% vs. 3.6%, RR=0.61,
P=0.34)
CI, confidence interval; OR, odds ratio; RR, relative risk; TIA, transient ischemic attack.

leaves this as an area of uncertainty. However, given the low
risk of stroke recurrence and the well-established increased
bleeding risk of warfarin over aspirin, antiplatelet therapy is
likely to be favored in most patients with PFO and cryptogenic
stroke. Treatment with novel oral anticoagulants (NOACs) in
this population is intriguing, given their lower bleeding risk
when compared with warfarin.72 Studies evaluating their use
in the cryptogenic stroke population are underway and may
provide additional insight into the optimal medical therapy for
these patients.73,74
Advances in catheter-based techniques have made PFO
closure an attractive treatment option. Percutaneous closure is
highly effective, with >90% success rate and a low rate of
adverse events (<5%).75,76 It can often be performed as a same-
day procedure and patients are generally maintained on anti-
platelet therapy for at last 6 months (and often indefinitely).
Three randomized clinical trials comparing percutaneous
PFO closure vs. medical therapy have been performed
(Table1). The first was CLOSURE I, which was a multi-
center trial that randomized 909 patients to percutaneous clo-
sure with the STARFlex device (NMT Medical) or medical
therapy (specific treatments were left to the discretion of the
treating provider).77 The primary endpoint was a composite of
stroke or TIA during 2 years of follow-up, death from any
cause during the first 30 days or death from neurologic causes
between 31 days and 2 years. There were no significant differ-
ences in the primary endpoint, recurrent stroke or TIA. The
majority of recurrent strokes in both groups were caused by
mechanisms unrelated to the PFO (87% in the closure group
and 76% in the medical group). Although there were no pro-
cedural deaths in the closure group, there was a 3% risk of
major vascular procedural complication. In addition, the rate
of AF in the closure group was significantly higher (5.7% in
the closure group vs. 0.7%, P<0.001).
The other 2 randomized clinical trials of percutaneous PFO
closure were the PC Trial and the Randomized Evaluation of
Recurrent Stroke Comparing PFO Closure to Established Cur-
rent Standard of Care Treatment (RESPECT) trial, both of
which used the Amplatzer PFO Occluder (St. Jude Medical
Inc).75,76 The PC trial randomized 414 patients with crypto-
genic stroke, TIA or peripheral thromboembolism to PFO
closure or medical therapy.76 The choice of medical therapy
was left to the discretion of the treating provider, though it was
specified that patients must be on at least 1 antithrombotic
agent. The primary endpoint was a composite of death, nonfa-
tal stroke, TIA or peripheral embolism. The mean follow-up
was similar (4.1 years in the closure group, 4 years in the
medical therapy group). There were no differences in the pri-
mary outcome, or TIA.
The RESPECT trial was a multicenter study that random-
ized 980 patients to PFO closure or medical therapy.75 Specific
medical therapy was, again, left to the discretion of the treat-
ing provider, but 75% of the patients received 1 antiplatelet
medication and the remaining 25% received warfarin. The
primary endpoint was a composite of recurrent nonfatal isch-
emic stroke, fatal ischemic stroke or early death after ran-
domization. In the intention-to-treat analysis, there was a
non-statistically significant trend towards a reduction in the
primary outcome with closure (9 events in the closure group
vs. 16 in the medical therapy group, hazard ratio 0.49, 95%
confidence interval (CI) 0.221.11, P=0.08). There were
higher rates of dropout in the medical therapy group vs. the
closure group, resulting in a significant difference in follow-up
observation (1,375 years in the closure group vs. 1,184 years
in the medical therapy group, P=0.009). In a prespecified as-
treated analysis, however, there was a reduction in the primary

Circulation Journal Vol.80,August2016

PFO and Stroke
outcome in the closure group (5 events in the closure group vs.
14 events in the medical therapy group, hazard ratio 0.27, 95%
CI 0.10.75, P=0.007). The difference between these 2 analy-
ses was a result of non-adherence to the protocol in each
group. It is possible that confounding factors could have intro-
duced bias into this analysis; however, it is important to note
that 3 of the 9 events in the closure group occurred in patients
who did not actually receive a device. One event occurred
after randomization but prior to PFO closure, the second event
occurred in a patient who decided not to undergo PFO closure
and the third event occurred in a patient who underwent unan-
ticipated coronary artery bypass surgery and surgical PFO
closure. The rate of serious adverse events was similar in both
groups (23% in the closure group vs. 21.6% in the medical
therapy group, P=0.65). Procedure or device-related serious
adverse events occurred in 21 patients (4.2%) in the closure
group and the rates of AF were not significantly different (3%
in the closure group, 1.5% medical therapy group, P=0.13).
One of the challenges in evaluating therapies for crypto-
genic stroke and PFO is that the risk of recurrent stroke/TIA
is quite low in this population. Although these 3 randomized
controlled trials failed to demonstrate stroke reduction with
PFO closure in the intention-to-treat analyses, it has been
hypothesized that larger trials may have been necessary in
order to fully detect the benefit of PFO closure. Addressing
this, the multiple meta-analyses using published aggregate data
have been conflicting (Table2).7884 Recently, a meta-analysis
was performed using individual patient-level data that enabled
standardization across all 3 studies, as well as more detailed
statistical assessment.85 The primary endpoint was the com-
posite of stroke, TIA or death and the secondary endpoint was
recurrent stroke. There was no statistical difference between
the closure group and the medical therapy group in the pri-
mary endpoint (1.5% vs. 2.3%, P=0.517); however, the differ-
ence became significant after adjusting for covariates (P=0.0491).
There was a significant difference in the secondary endpoint
of recurrent stroke (0.7% in the closure group vs. 1.3% in the
medical therapy arm) in both the unadjusted analysis (P=0.04)
and the covariate-adjusted analysis (P=0.04). The number
needed to prevent 1 ischemic stroke over 2.5 years was 67.
Given that the average age of the patients in these trials was
45, it has been argued that the most appropriate time frame is
1520 years, and based on this data would reduce the number
needed to treat to 11 and 8, respectively, a number that is
comparable to other currently recommended invasive proce-
dures.86 There was no difference in bleeding between the
closure group and the medical therapy group. Although there
was significantly more AF in the closure group over the med-
ical therapy group (1.44% vs. 0.48%, P=0.0002), this was
driven by those patients who received the STARFlex device.
In comparisons of the Amplatzer PFO Occluder, there was no
statistical difference in AF (0.87% in the Amplatzer PFO
Occluder group vs. 0.47% in the medical therapy group, P=0.12).
Based on the 3 randomized clinical trials, the 2014
American Heart Association and American Stroke Associa-
tion guidelines recommend against closure of PFO in crypto-
genic stroke.68 The most recent patient-level meta-analysis
attempted to address the main criticism of the randomized
trials (mainly, the low event rate) while providing a rigorous
standardized approach to handling data from the 3 separate
trials and provides possible evidence in favor of PFO closure.85
The last remaining randomized trial evaluating PFO closure in
patients with cryptogenic stroke has recently completed enroll-
ment but the results have not yet been published.87 Of note for
all these trials, long-term monitoring for AF was not performed
Circulation Journal Vol.80,August2016
1671
and NOACs were not yet available. Newer trials addressing
these 2 issues are needed to fully assess efficacy of percutane-
ous closure over medical therapy.
Conclusions
PFO is more commonly found in patients with cryptogenic
stroke than in the normal population. The mechanism of stroke
in this setting is thought to be paradoxical embolization.
Although it can be challenging to attribute a stroke to a PFO,
the RoPE score can be helpful in making this distinction. Given
that the rate of stroke in asymptomatic patients with PFO is no
different than in those without stroke, it is likely that other risk
factors (eg, ASA, Chiari network, prominent Eustachian valve,
anatomic and physiologic PFO size and hypercoagulable states)
need to be present in order for stroke to occur. Current guide-
lines recommend use of antiplatelet medications in all patients
with cryptogenic stroke and PFO and, based on the 3 random-
ized clinical trials, against PFO closure. Despite these recom-
mendations, however, there is likely a subset of patients who
would benefit from anticoagulation and/or percutaneous clo-
sure. Given that the majority of patients with cryptogenic
stroke caused by a PFO are young and otherwise healthy with
significant remaining expected life years, a recurrent stroke
has the potential to be a particularly life-changing event. It is
imperative to take into account the relative effect of a recur-
rent event for that particular patient and balance that with the
potential benefits and risks of the intervention (both in the
selection of pharmacologic therapy and the decision of whether
or not to pursue percutaneous closure). Further studies clarify-
ing patient groups for whom device closure is beneficial need
to be performed.
References
1. Hagen PT, Scholz DG, Edwards WD. Incidence and size of patent
foramen ovale during the first 10 decades of life: An autopsy study
of 965 normal hearts. Mayo Clin Proc 1984; 59: 1720.
2. Meissner I, Khandheria BK, Heit JA, Petty GW, Sheps SG, Schwartz
GL, et al. Patent foramen ovale: Innocent or guilty?: Evidence from
a prospective population-based study. J Am Coll Cardiol 2006; 47:
440445.
3. Schneider B, Zienkiewicz T, Jansen V, Hofmann T, Noltenius H,
Meinertz T. Diagnosis of patent foramen ovale by transesophageal
echocardiography and correlation with autopsy findings. Am J Car-
diol 1996; 77: 12021209.
4. Cohnheim J. Vorlesungen uber allgemenie pathologie. J Thromb
Emboli 1877; 1: 134 (in German).
5. Litten M. Pathologisch-anatomisch Beobachtungen I, Ueber einen
Fall von infiltriertem Leberkrebs, nebst epikritischen Bemerkungen.
II: Ueber embolische Muskelveranderung und die Resorption todter
Muskelfasern. Virch Archiv 1880; 80: 269295 (in German).
6. Cabanes L, Mas JL, Cohen A, Amarenco P, Cabanes PA, Oubary P,
et al. Atrial septal aneurysm and patent foramen ovale as risk factors
for cryptogenic stroke in patients less than 55 years of age: A study
using transesophageal echocardiography. Stroke 1993; 24: 1865
1873.
7. Di Tullio M, Sacco RL, Gopal A, Mohr JP, Homma S. Patent fora-
men ovale as a risk factor for cryptogenic stroke. Ann Intern Med
1992; 117: 461465.
8. Lechat P, Mas JL, Lascault G, Loron P, Theard M, Klimczac M, et
al. Prevalence of patent foramen ovale in patients with stroke. N Engl
J Med 1988; 318: 11481152.
9. Webster MW, Chancellor AM, Smith HJ, Swift DL, Sharpe DN,
Bass NM, et al. Patent foramen ovale in young stroke patients. Lan-
cet 1988; 2: 1112.
10. de Belder MA, Tourikis L, Leech G, Camm AJ. Risk of patent fora-
men ovale for thromboembolic events in all age groups. Am J Car-
diol 1992; 69: 13161320.
11. Hausmann D, Mugge A, Becht I, Daniel WG. Diagnosis of patent
foramen ovale by transesophageal echocardiography and association
with cerebral and peripheral embolic events. Am J Cardiol 1992; 70:
668672.
1672
12. Rigatelli G, Ronco F. Patent foramen ovale: A comprehensive review
for pulmonologists. Curr Opin Pulm Med 2010; 16: 442447.
13. Billinge M, Zbinden R, Mordasini R, Windecker S, Schwerzmann
M, Meier B, et al. Patent foramen ovale closure in recreational div-
ers: Effect on decompression illness and ischaemic brain lesions
during long-term follow-up. Heart 2011; 97: 19321937.
14. Wohrle J, Kochs M, Hombach V, Merkle N. Prevalence of myocar-
dial scar in patients with cryptogenic cerebral ischemic events and
patent foramen ovale. JACC Cardiovasc Imaging 2010; 3: 833839.
15. Lau EM, Yee BJ, Grunstein RR, Celermajer DS. Patent foramen
ovale and obstructive sleep apnea: A new association? Sleep Med
Rev 2010; 14: 391395.
16. Rundek T, Elkind MS, Di Tullio MR, Carrera E, Jin Z, Sacco RL, et
al. Patent foramen ovale and migraine: A cross-sectional study from
the Northern Manhattan Study (NOMAS). Circulation 2008; 118:
14191424.
17. Calvert PA, Rana BS, Kydd AC, Shapiro LM. Patent foramen ovale:
Anatomy, outcomes, and closure. Nat Rev Cardiol 2011; 8: 148
160.
18. van Vonderen JJ, Roest AA, Siew ML, Walther FJ, Hooper SB, te
Pas AB. Measuring physiological changes during the transition to
life after birth. Neonatology 2014; 105: 230242.
19. Di Tullio MR. Patent foramen ovale: Echocardiographic detection
and clinical relevance in stroke. J Am Soc Echocardiogr 2010; 23:
144155; quiz 220.
20. Penther P. Patent foramen ovale: An anatomical study: Apropos of
500 consecutive autopsies. Arch Mal Coeur Vaiss 1994; 87: 1521
(in French).
21. Rodriguez CJ, Homma S, Sacco RL, Di Tullio MR, Sciacca RR,
Mohr JP, et al. Race-ethnic differences in patent foramen ovale, atrial
septal aneurysm, and right atrial anatomy among ischemic stroke
patients. Stroke 2003; 34: 20972102.
22. Putaala J, Metso AJ, Metso TM, Konkola N, Kraemer Y, Haapaniemi
E, et al. Analysis of 1008 consecutive patients aged 15 to 49 with
first-ever ischemic stroke: The Helsinki young stroke registry. Stroke
2009; 40: 11951203.
23. Handke M, Harloff A, Olschewski M, Hetzel A, Geibel A. Patent
foramen ovale and cryptogenic stroke in older patients. N Engl J Med
2007; 357: 22622268.
24. Kent DM, Ruthazer R, Weimar C, Mas JL, Serena J, Homma S, et
al. An index to identify stroke-related vs incidental patent foramen
ovale in cryptogenic stroke. Neurology 2013; 81: 619625.
25. Di Tullio MR, Jin Z, Russo C, Elkind MS, Rundek T, Yoshita M, et
al. Patent foramen ovale, subclinical cerebrovascular disease, and
ischemic stroke in a population-based cohort. J Am Coll Cardiol
2013; 62: 3541.
26. Di Tullio MR, Sacco RL, Sciacca RR, Jin Z, Homma S. Patent fora-
men ovale and the risk of ischemic stroke in a multiethnic popula-
tion. J Am Coll Cardiol 2007; 49: 797802.
27. Rundek T. PFO in stroke: A direct association or coincidence? Eur
J Neurol 2008; 15: 887888.
28. Sanna T, Diener HC, Passman RS, Di Lazzaro V, Bernstein RA,
Morillo CA, et al. Cryptogenic stroke and underlying atrial fibrilla-
tion. N Engl J Med 2014; 370: 24782486.
29. Thijs VN, Brachmann J, Morillo CA, Passman RS, Sanna T,
Bernstein RA, et al. Predictors for atrial fibrillation detection after
cryptogenic stroke: Results from CRYSTAL AF. Neurology 2016;
86: 261269.
30. Lopez MF, Krastins B, Sarracino DA, Byram G, Vogelsang MS,
Prakash A, et al. Proteomic signatures of serum albumin-bound
proteins from stroke patients with and without endovascular closure
of PFO are significantly different and suggest a novel mechanism for
cholesterol efflux. Clin Proteomics 2015; 12: 2.
31. Lopez MF, Sarracino DA, Vogelsang M, Sutton JN, Athanas M,
Krastins B, et al. Heart-brain signaling in patent foramen ovale-related
stroke: Differential plasma proteomic expression patterns revealed
with a 2-pass liquid chromatography-tandem mass spectrometry
discovery workflow. J Invest Med 2012; 60: 11221130.
32. Kronik G, Mosslacher H. Positive contrast echocardiography in
patients with patent foramen ovale and normal right heart hemody-
namics. Am J Cardiol 1982; 49: 18061809.
33. Sharma VK, Tsivgoulis G, Lao AY, Alexandrov AV. Role of tran-
scranial Doppler ultrasonography in evaluation of patients with cere-
brovascular disease. Curr Neurol Neurosci Rep 2007; 7: 820.
34. Porter TR, Abdelmoneim S, Belcik JT, McCulloch ML, Mulvagh
SL, Olson JJ, et al. Guidelines for the cardiac sonographer in the
performance of contrast echocardiography: A focused update from
the American Society of Echocardiography. J Am Soc Echocardiogr
2014; 27: 797810.
35. Di Tullio M, Sacco RL, Massaro A, Venketasubramanian N,
Circulation Journal Vol.80,August2016
SUN YP et al.
Sherman D, Hoffmann M, et al. Transcranial Doppler with contrast
injection for the detection of patent foramen ovale in stroke patients.
Int J Card Imaging 1993; 9: 15.
36. Di Tullio M, Sacco RL, Venketasubramanian N, Sherman D, Mohr
JP, Homma S. Comparison of diagnostic techniques for the detection
of a patent foramen ovale in stroke patients. Stroke 1993; 24: 1020
1024.
37. Clarke NR, Timperley J, Kelion AD, Banning AP. Transthoracic
echocardiography using second harmonic imaging with Valsalva
manoeuvre for the detection of right to left shunts. Eur J Echocar-
diogr 2004; 5: 176181.
38. Daniels C, Weytjens C, Cosyns B, Schoors D, De Sutter J, Paelinck
B, et al. Second harmonic transthoracic echocardiography: The new
reference screening method for the detection of patent foramen ovale.
Eur J Echocardiogr 2004; 5: 449452.
39. Serena J, Segura T, Perez-Ayuso MJ, Bassaganyas J, Molins A,
Davalos A. The need to quantify right-to-left shunt in acute ischemic
stroke: A case-control study. Stroke 1998; 29: 13221328.
40. Droste DW, Lakemeier S, Wichter T, Stypmann J, Dittrich R, Ritter
M, et al. Optimizing the technique of contrast transcranial Doppler
ultrasound in the detection of right-to-left shunts. Stroke 2002; 33:
22112216.
41. Katsanos AH, Psaltopoulou T, Sergentanis TN, Frogoudaki A,
Vrettou AR, Ikonomidis I, et al. Transcranial Doppler versus trans-
thoracic echocardiography for the detection of patent foramen ovale
in patients with cryptogenic cerebral ischemia: A systematic review
and diagnostic test accuracy meta-analysis. Ann Neurol 2016; 79:
625635.
42. Droste DW, Schmidt-Rimpler C, Wichter T, Dittrich R, Ritter M,
Stypmann J, et al. Right-to-left-shunts detected by transesophageal
echocardiography and transcranial Doppler sonography. Cerebrovasc
Dis 2004; 17: 191196.
43. Zoghbi WA. Patent foramen ovale: Going beyond the bubbles. JACC
Cardiovasc Imaging 2014; 7: 251253.
44. Johansson MC, Helgason H, Dellborg M, Eriksson P. Sensitivity for
detection of patent foramen ovale increased with increasing number
of contrast injections: A descriptive study with contrast transesopha-
geal echocardiography. J Am Soc Echocardiogr 2008; 21: 419424.
45. Romero JR, Frey JL, Schwamm LH, Demaerschalk BM, Chaliki HP,
Parikh G, et al. Cerebral ischemic events associated with bubble
study for identification of right to left shunts. Stroke 2009; 40:
23432348.
46. Akhondi A, Gevorgyan R, Tseng CH, Slavin L, Dao C, Liebeskind
DS, et al. The association of patent foramen ovale morphology and
stroke size in patients with paradoxical embolism. Circ Cardiovasc
Interv 2010; 3: 506510.
47. Goel SS, Tuzcu EM, Shishehbor MH, de Oliveira EI, Borek PP,
Krasuski RA, et al. Morphology of the patent foramen ovale in
asymptomatic versus symptomatic (stroke or transient ischemic
attack) patients. Am J Cardiol 2009; 103: 124129.
48. Wessle BS, Thaler DE, Ruthazer R, Weimar C, Di Tullio MR,
Elkind MS, et al. Transesophageal echocardiography in cryptogenic
stroke and patent foramen ovale: Analysis of putative high-risk fea-
tures from the risk of paradoxical embolism database. Circ Cardio-
vasc Imaging 2014; 7: 125131.
49. Rigatelli G, DellAvvocata F, Cardaioli P, Giordan M, Braggion G,
Aggio S, et al. Permanent right-to-left shunt is the key factor in
managing patent foramen ovale. J Am Coll Cardiol 2011; 58: 2257
2261.
50. Rigatelli G, Dellavvocata F, Vassiliev D, Daggubati R, Buch A,
Nanjiundappa A, et al. ICE-classification of interatrial septum anat-
omy in patients with RL shunt. JACC Cardiovasc Imaging 2014;
7: 205206.
51. Serena J, Marti-Fabregas J, Santamarina E, Rodriguez JJ, Perez-
Ayuso MJ, Masjuan J, et al. Recurrent stroke and massive right-
to-left shunt: Results from the prospective Spanish multicenter
(CODICIA) study. Stroke 2008; 39: 31313136.
52. Silvestry FE, Cohen MS, Armsby LB, Burkule NJ, Fleishman CE,
Hijazi ZM, et al. Guidelines for the echocardiographic assessment of
atrial septal defect and patent foramen ovale: From the American
Society of Echocardiography and Society for Cardiac Angiography
and Interventions. J Am Soc Echocardiogr 2015; 28: 910958.
53. Homma S, Sacco RL, Di Tullio MR, Sciacca RR, Mohr JP. Atrial
anatomy in non-cardioembolic stroke patients: Effect of medical
therapy. J Am Coll Cardiol 2003; 42: 10661072.
54. Schneider B, Hofmann T, Justen MH, Meinertz T. Chiaris network:
Normal anatomic variant or risk factor for arterial embolic events? J
Am Coll Cardiol 1995; 26: 203210.
55. Kato Y, Dembo T, Takeda H, Fukuoka T, Tanahashi N. Prominent
persisting Eustachian valve initiates spontaneous right-to-left shunt
PFO and Stroke
and paradoxical embolism in a patient with patent foramen ovale.
Neurol Sci 2011; 32: 925926.
56. Cramer SC, Rordorf G, Kaufman JA, Buonanno F, Koroshetz WJ,
Schwamm L. Clinically occult pelvic-vein thrombosis in cryptogenic
stroke. Lancet 1998; 351: 19271928.
57. Lethen H, Flachskampf FA, Schneider R, Sliwka U, Kohn G, Noth
J, et al. Frequency of deep vein thrombosis in patients with patent
foramen ovale and ischemic stroke or transient ischemic attack. Am
J Cardiol 1997; 80: 10661069.
58. Cramer SC, Rordorf G, Maki JH, Kramer LA, Grotta JC, Burgin
WS, et al. Increased pelvic vein thrombi in cryptogenic stroke:
Results of the Paradoxical Emboli from Large Veins in Ischemic
Stroke (PELVIS) study. Stroke 2004; 35: 4650.
59. Liberman AL, Daruwalla VJ, Collins JD, Maas MB, Botelho MP,
Ayache JB, et al. Diagnostic yield of pelvic magnetic resonance
venography in patients with cryptogenic stroke and patent foramen
ovale. Stroke 2014; 45: 23242329.
60. Kiernan TJ, Yan BP, Cubeddu RJ, Rengifo-Moreno P, Gupta V,
Inglessis I, et al. May-Thurner syndrome in patients with cryptogenic
stroke and patent foramen ovale: An important clinical association.
Stroke 2009; 40: 15021504.
61. Osgood M, Budman E, Carandang R, Goddeau RP Jr, Henninger N.
Prevalence of pelvic vein pathology in patients with cryptogenic
stroke and patent foramen ovale undergoing MRV pelvis. Cerebro-
vasc Dis 2015; 39: 216223.
62. Lantz M, Sjostrand C, Kostulas K. Ischemic stroke and patent fora-
men ovale: Risk factors and genetic profile. J Stroke Cerebrovasc
Dis 2013; 22: 841845.
63. Pezzini A, Grassi M, Zotto ED, Giossi A, Volonghi I, Costa P, et al.
Do common prothrombotic mutations influence the risk of cerebral
ischaemia in patients with patent foramen ovale?: Systematic review
and meta-analysis. Thromb Haemost 2009; 101: 813817.
64. Favaretto E, Sartori M, Conti E, Legnani C, Palareti G. G1691A
factor V and G20210A FII mutations, acute ischemic stroke of
unknown cause, and patent foramen ovale. Thromb Res 2012; 130:
720724.
65. Norata GD, Tsimikas S, Pirillo A, Catapano AL. Apolipoprotein
C-III: From pathophysiology to pharmacology. Trends Pharmacol
Sci 2015; 36: 675687.
66. Rajamani K, Chaturvedi S, Jin Z, Homma S, Brey RL, Tilley BC, et
al. Patent foramen ovale, cardiac valve thickening, and antiphospho-
lipid antibodies as risk factors for subsequent vascular events: The
PICSS-APASS study. Stroke 2009; 40: 23372342.
67. Goldhaber SZ. Risk factors for venous thromboembolism. J Am Coll
Cardiol 2010; 56: 17.
68. Kernan WN, Ovbiagele B, Black HR, Bravata DM, Chimowitz MI,
Ezekowitz MD, et al. Guidelines for the prevention of stroke in
patients with stroke and transient ischemic attack: A guideline for
healthcare professionals from the American Heart Association/
American Stroke Association. Stroke 2014; 45: 21602236.
69. Homma S, Sacco RL, Di Tullio MR, Sciacca RR, Mohr JP. Effect of
medical treatment in stroke patients with patent foramen ovale: Pat-
ent foramen ovale in Cryptogenic Stroke Study. Circulation 2002;
105: 26252631.
70. Almekhlafi MA, Wilton SB, Rabi DM, Ghali WA, Lorenzetti DL,
Hill MD. Recurrent cerebral ischemia in medically treated patent
foramen ovale: A meta-analysis. Neurology 2009; 73: 8997.
71. Kent DM, Dahabreh IJ, Ruthazer R, Furlan AJ, Weimar C, Serena J,
et al. Anticoagulant vs. antiplatelet therapy in patients with crypto-
genic stroke and patent foramen ovale: An individual participant data
Circulation Journal Vol.80,August2016
1673
meta-analysis. Eur Heart J 2015; 36: 23812389.
72. Lip GY, Lane DA. Stroke prevention in atrial fibrillation: A system-
atic review. JAMA 2015; 313: 19501962.
73. Bayer. Rivaroxaban versus aspirin in secondary prevention of stroke
and prevention of systemic embolism in patients with recent embolic
stroke of undetermined source (ESUS). 2018. https://ClinicalTrials.
gov/show/NCT02313909 (acessed May 30, 2016).
74. Boehringer-Ingelheim. Dabigatran etexilate for secondary stroke pre-
vention in patients with embolic stroke of undetermined source (RE-
SPECT ESUS). 2017. https://ClinicalTrials.gov/show/NCT02239120
(acessed May 30, 2016).
75. Carroll JD, Saver JL, Thaler DE, Smalling RW, Berry S, MacDonald
LA, et al. Closure of patent foramen ovale versus medical therapy
after cryptogenic stroke. N Engl J Med 2013; 368: 10921100.
76. Meier B, Kalesan B, Mattle HP, Khattab AA, Hildick-Smith D,
Dudek D, et al. Percutaneous closure of patent foramen ovale in
cryptogenic embolism. N Engl J Med 2013; 368: 10831091.
77. Furlan AJ, Reisman M, Massaro J, Mauri L, Adams H, Albers GW,
et al. Closure or medical therapy for cryptogenic stroke with patent
foramen ovale. N Engl J Med 2012; 366: 991999.
78. Khan AR, Bin Abdulhak AA, Sheikh MA, Khan S, Erwin PJ,
Tleyjeh I, et al. Device closure of patent foramen ovale versus
medical therapy in cryptogenic stroke: A systematic review and
meta-analysis. JACC Cardiovasc Interv 2013; 6: 13161323.
79. Rengifo-Moreno P, Palacios IF, Junpaparp P, Witzke CF, Morris
DL, Romero-Corral A. Patent foramen ovale transcatheter closure
vs. medical therapy on recurrent vascular events: A systematic
review and meta-analysis of randomized controlled trials. Eur Heart
J 2013; 34: 33423352.
80. Stortecky S, da Costa BR, Mattle HP, Carroll J, Hornung M, Sievert
H, et al. Percutaneous closure of patent foramen ovale in patients
with cryptogenic embolism: A network meta-analysis. Eur Heart J
2015; 36: 120128.
81. Udell JA, Opotowsky AR, Khairy P, Silversides CK, Gladstone DJ,
OGara PT, et al. Patent foramen ovale closure vs medical therapy
for stroke prevention: Meta-analysis of randomized trials and review
of heterogeneity in meta-analyses. Can J Cardiol 2014; 30: 1216
1224.
82. Pineda AM, Nascimento FO, Yang SC, Kirtane AJ, Sommer RJ,
Beohar N. A meta-analysis of transcatheter closure of patent foramen
ovale versus medical therapy for prevention of recurrent thrombo-
embolic events in patients with cryptogenic cerebrovascular events.
Catheter Cardiovasc Interv 2013; 82: 968975.
83. Kitsios GD, Thaler DE, Kent DM. Potentially large yet uncertain
benefits: A meta-analysis of patent foramen ovale closure trials.
Stroke 2013; 44: 26402643.
84. Spencer FA, Lopes LC, Kennedy SA, Guyatt G. Systematic review
of percutaneous closure versus medical therapy in patients with
cryptogenic stroke and patent foramen ovale. BMJ Open 2014; 4:
e004282, doi:10.1136/bmjopen-2013-004282.
85. Kent DM, Dahabreh IJ, Ruthazer R, Furlan AJ, Reisman M, Carroll
JD, et al. Device closure of patent foramen ovale after stroke: Pooled
analysis of completed randomized trials. J Am Coll Cardiol 2016;
67: 907917.
86. Love BA, Diener HC. PFO: Please figure out, or now Potentially
figured out? J Am Coll Cardiol 2016; 67: 918920.
87. WL Gore and Associates. GORE HELEX septal occluder GORE
septal occluder for patent foramen ovale (PFO) closure in stroke
patients: The Gore REDUCE Clinical Study. 2017. https://ClinicalTrials.
gov/show/NCT00738894 (acessed May 30, 2016).