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The RESPECT trial came close to significance with a P-value of .08 [13]. The 10 year follow-up of the RESPECT trial
revealed a statistically significant P-value of .046, demonstrating that PFO-occluding devices reduce the risk of
stroke compared to medical therapy in patients with ischemic stroke of no other identifiable source [14].
Almost concomitantly, 3 other randomized trials were consistent in showing that percutaneous PFO closure was
superior to medical therapy in preventing recurrent stroke [15e17]. This chapter will review the findings of these
newer trials and discuss the results that have led to the identification of patients who benefit from percutaneous
PFO closure ( Table 7.1).
NEWER RANDOMIZED TRIALS OF PFO CLOSURE FOR STROKE
The CLOSE PFO Trial
CLOSE (PFO Closure or Ant icoagulants vs. Antiplatelet Therapy to Prevent Stroke Recurrence) was a multi-
center, randomized, open label trial conducted in France and Germany. A total of 663 patients aged 16e60 years
who had a rec ent stroke attributed to a PFO, with an associated atri al septal aneurysm or large interatrial shunt,
were randomiz ed in a 1:1:1 ratio to transcatheter PFO closure, antiplatelet therapy, or oral anticoagulation. PFO
closure using 1 of 11 devices was compared with antiplatelet therapy, and antiplatelet therapy was compared
with oral anticoagulation [15].
After a mean follow-up of 5.3 2.0 years, no patient in the PFO closure arm had suffered a stroke, whereas 14 pa-
tients in the antiplatelet therapy group had recurrent stroke (0% vs. 6.0%, HR: 0.03; 95% CI: 0 to 0.26; P < .001). The
secondary composite outcome of stroke, transient ischemic attack, or systemic embolism also occurred in significantly
fewer patients in the device arm (3.4% vs. 8.9%, HR: 0.39; 95% CI, 0.16 to 0.82; P ¼ .01). Fourteen patients (5.9%) had a
major procedural complication in the PFO closure arm. There was no statistical difference in major bleeding, death, or
all-cause serious adverse events when PFO closure was compared to medical therapy; however, atrial fibrillation/
flutter occurred at a higher rate in the device arm (4.6% vs. 0.9%; P ¼ .02). Of 11 cases of atrial fibrillation after device
implantation, 10 (91%) occurred within 1 month after the procedure with no recurrence during a median follow-up of
4.4 years. Oral anticoagulation was eventually discontinued in 70% (7/10) of these patients at a median of 6 months.
When oral anticoagulation was compared to antiplatelet therapy, the incidence of recurrent stroke was not signif-
icantly higher in the antiplatelet arm (1.6% vs. 4.0; HR; 0.44, 95% CI, 0.11 to 1.48), and the rate of major bleeding was
not significantly higher in the anticoagulant arm (5.3% vs. 2.3%, P ¼ .18). In comparison, the RESPECT trial showed
better protection with oral anticoagulation than with antiplatelets [13,14]. However, the CLOSE trial was underpow-
ered to make a definitive conclusion with regard to a preference of anticoagulation versus antiplatelet medical
therapy.
Results of the CLOSE trial also confirmed the long-term follow-up data from the RESPECT trial, where PFO
closure was fou nd to be superior to medical therapy for prevention of recurrent stroke, with greatest efficacy
observed in patients with an atrial septal ane urysm or large shunt. It should be emphasized that the CLOSE trial
FIGURE 7.1 Thrombus in Transit. Left: Transesophageal echocardiogram short axis view showing an oblong thrombus, with 2 distinct ex-
tensions trapped in a PFO (yellow arrow). Right: Superimposed illustration of a transesophageal echocardiogram short axis view showing the
thrombus in transit across the PFO flap. Adapted with permission from Ref. [8].
7. NEWER RANDOMIZED TRIALS OF PFO CLOSURE FOR STROKE (CLOSE, REDUCE AND DEFENSE-PFO)80
III. STROKE AND PFO
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TABLE 7.1 Summary of All Randomized Trials of PFO Closure for Stroke.
Trial N Device Medical Therapy Primary Outcome Age Event
Follow-up
(Years)
Post Device
Therapy
PFO
Anatomy Result
CLOSURE I
(2012)
909 STARFlex
device
- Warfarin (INR 2e3)
- Acetylsalicylic acid
325 mg
- Acetylsalicylic
acid þ warfarin
Composite of stroke or
TIA in 2 years, death
from any cause in first
30 days and death from
neuro cause from day
31 to 2 years
18e60 Stroke or TIA 2 Acetylsalicylic acid
81 mg-324 mg 2
years þ clopidogrel
75 mg 6 months
All PFO closure did not
significantly reduce
recurrent stroke or
TIA compared with
medical therapy
PC (2013) 414 Amplatzer
PFO Occluder
Antiplatelet
or OAC
Composite of death,
nonfatal stroke, TIA, or
peripheral embolism
60 Clinical
stroke þ radiology
evidence, clinical
TIA þ radiology
evidence,
clinical þ radiological
evidence of
extracranial
thromboembolism
4.1 Acetylsalicylic acid
100e324 mg 5/
6 months þ ticlopidine/
clopidogrel 1e6 months.
If acetylsalicylic acid
allergy, then only
ticlopidine or
clopidogrel
All PFO closure did not
significantly reduce
recurrent embolic
events or death
compared with
medical therapy
RESPECT
(extended
follow-up)
(2017)
980 Amplatzer PFO
Occluder
- Acetylsalicylic acid
- Warfarin
- Clopidogrel
- Acetylsalicylic
acid þ dipyridamole
Composite of recurrent
nonfatal ischemic stroke,
fatal ischemic stroke, or
early death
18e60 Ischemic stroke 5.9 Acetylsalicylic acid 81
e324 mg þ clopidogrel
75 mg 1 month
followed by
acetylsalicylic acid only
for 5 months
All PFO closure
reduced recurrent
stroke events
compared with
medical therapy
CLOSE (2017) 663 11 different
devices
- Acetylsalicylic acid
- Clopidogrel
- Acetylsalicylic
acid þ dipyridamole
- Warfarin (INR 2e3)
- DOAC
Fatal or nonfatal
stroke
16e60 Clinical ischemic
stroke þ radiology
evidence
5.3 Acetylsalicylic acid
75 mg þ clopidogrel
75 mg 3 months
- Atrial septal
aneurysm:
>10 mm
excursion of
septum
primum
- Large
interatrial
shunt: >30
microbubbles
in LA within 3
cardiac cycles
PFO closure
reduced recurrent
stroke events
compared with
medical therapy
Gore
REDUCE
(2017)
664 Gore Helex or
Gore Cardioform
Septal Occluder
- Acetylsalicylic acid 75
e325 mg
- Acetylsalicylic acid 50
e100 mg þ
dipyridamole 225
e400 mg
- Acetylsalicylic acid 50
e100 mg þ
clopidogrel 75 mg
Stroke 18e59 Ischemic stroke
(FND for >24 hours
or clinical evidence þ
imaging evidence
of infarction)
3.2 Clopidogrel
75 mg 3 days and
then chosen
antiplatelet therapy
All PFO closure
reduced recurrent
stroke events and
new brain infarcts
on MRI compared
with medical
therapy
Continued
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TABLE 7.1 Summary of All Randomized Trials of PFO Closure for Stroke.dcont’d
Trial N Device Medical Therapy Primary Outcome Age Event
Follow-up
(Years)
Post Device
Therapy
PFO
Anatomy Result
DEFENSE-PFO
(2018)
120 Amplatzer PFO
Occluder
- Acetylsalicylic acid
- Acetylsalicylic
acid þ clopidogrel
75 mg
- Acetylsalicylic acid þ
Cilostazol 200 mg
- Warfarin (INR 2e3)
Composite of stroke,
vascular death, or TIMI
major bleeding
No
limit
Clinical ischemic
stroke þ radiographic
evidence
2.8 Acetylsalicylic acid
100 mg þ clopidogrel
75 mg 6 months
- Atrial septal
aneurysm
(protrusion
of the
dilated
segment of
the septum
at least
15 mm
beyond
septum)d
hypermobility
(>10 mm
excursion)
- Large PFO
(>2mm
separation of
primum and
secundum
with Valsalva)
PFO closure
reduced composite
of stroke, vascular
death or TIMI major
bleeding and
recurrent stroke
events
compared with
medical therapy
DOAC, direct oral anticoagulant; FND, focal neurological deficits; INR, international normalized ratio; LA, left atrium; MG, milligram; MM, millimeters; MRI, magnetic resonance imaging; OAC, oral anticoagulant; PFO, patent foramen
ovale; TIA, transient ischemic attack; TIMI, thrombolysis in myocardial infarction.
https://t.me/med1917
observed zero recurrent strokes in 5 years among patients who had PFO with these echocardiographic features and
received a device.
One strength of the CLOSE trial was the inclusion of a subset of patients (i.e., patients with an atrial septal aneu-
rysm or large shunt) who may be at higher risk of recurrent stroke. A major limitation of CLOSE was slow patient
recruitment resulting in premature termination of the study; the trial enrolled 663 patients compared to a 900-patient
target. This may at least partly be explained by the availability of off-label septal occluder devices, with clinicians
referring higher-risk patients for off-label PFO closure as opposed to a 2/3 chance of randomization to anticoagu-
lation or antiplatelets. In hindsight, these patients were well served. Additionally, there was no prolonged electro-
cardiographic monitoring to detect occult atrial fibrillation as a potential cause of the index stroke; however, the yield
of prolonged monitoring in young cryptogenic stroke patients remains controversial.
The Gore REDUCE Trial
Gore REDUCE (Gore Helex Septal Occluder/Gore C ardioform Septal Occluder and Antiplatelet Medical Man-
agement for Reduction of Recurrent Stroke or Imaging-Confirmed Transient Ischemic Attack in Patients with
PFO) [16] was a randomized, multicenter, open-label trial enrolling 664 patients, aged 18e59 years with a recent
cryptogenic ischemic stroke and a TEE-confirmed PFO. Alternative etiologies of stroke including large-artery
atherosclerosis, small vessel disease (lacunar infarct), atrial fibrillati on/flutter (via longer inpatient monitoring),
hypercoagulable disorder, or arterial dissection were excluded from the study. In addition, patients with strong
risk factors like uncontrolled hypertension, uncontrolled diabetes, autoimmune disease, or recent drug or
alcohol abuse were excluded. Patients underwent 2:1 randomization to device closure with the Gore Helex or
Cardioform Septal Occluder (W.L. Gore and Associates; Flagstaff, Arizona) p lus antiplatelets or antiplatelet
therapy alone.
At a median follow-up of 3.2 years, recurrent ischemic stroke occurred less frequently in the device arm
compared to medical therapy (1.4% vs. 5.4%, HR: 0.23; 95% CI: 0.09 to 0.62; P ¼ .002) . The rate of new imaging-
confirmed brain infarctions was also lower with PFO closure (5.7% vs. 11.3%, RR: 0.51; 95% CI; 0.29 to 0.91;
P ¼ .04). The number needed to treat to prevent 1 stroke in 2 4 months was 2 8 patients. Exploratory analyses to eval-
uate heterogeneity in relation to baselin e covariates indicated no interactions with age, sex, shunt size, or
geographic region.
There was no difference in serious adverse events between device closure and medical therapy (23.1% vs. 27.8%,
P ¼ .22). In the device arm, procedure-related serious events occurred in 2.5% of patients and device-related serious
adverse events in 1.4%. The risks of major bleed ing, deep vein thrombosis, and pulmonary embolism were also
similar between the 2 groups (P > .05 for all). Patients in the device arm had a significantly higher rate of
new-onset atrial fibrillation/flutter compared to medical therapy (6.6% vs. 0.4%, P < .001). Most cases of post device
atrial arrhythmias (83%) occurred within the first 45 days after closure, with the majority (59%) resolving within
2 weeks. Of 29 atrial arrhythmias post-PFO closure, 1 had a recurrent stroke.
Similar to the CLOSE trial, Gore REDUCE showed that with good patient selection, it can be demonstrated that
PFO closure reduces the risk of recurrent stroke compared to medical therapy in patients with ischemic stroke of no
other identifiable source. Lack of blinding and the availability of off-label septal occluder devices resulted in 14
patients in the antiplatelet arm undergoing PFO closure outside of the trial. Furthermore, the differential dropout
rate between the 2 study groups (8.8% in device arm vs. 14.8% in antiplatelet arm) may have led to misclassification
bias. Lastly, the relatively low number of total events made the subgroup analyses less conclusive.
The DEFENSE-PFO PFO Trial
DEFENSE-PFO (Device Closure versus Medical Therapy for Cryptogenic Stroke Patients With High-Risk PFO)
[17] was a multicenter, open-label trial, enrolling 120 patients with cryptogenic stroke and high-risk PFO (atrial
septal aneurysm, septal hypermobility, or large PFO 2 mm); patients were randomized in a 1:1 manner to percu-
taneous PFO closure with the Amplatzer PFO Occluder (Abbott; Chicago, Illinois) or medical therapy (acetylsalicylic
acid, acetylsalicylic acid plus clopidogrel, acetylsalicylic acid plus cilostazol, or warfarin). Patients underwent exten-
sive evaluation to exclude stroke from large-artery atherosclerosis, cardioembolism, hypercoagulable disorder, arte-
rial dissection, and atrial fibrillation/flutter with a 24-h our or prolonged cardiac monitor.
III. STROKE AND PFO
NEWER RANDOMIZED TRIALS OF PFO CLOSURE FOR STROKE 83
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At a median follow-up of 2.8 years, the primary composite outcome of stroke, vascular death, or TIMI
(thrombolysis in myocardial infarction) major bleeding occurred in zero patients in the device arm and 6 patients
in the medical therapy arm (0% vs. 12.9%, 95% CI 3.2 to 22.6; P ¼ .013). The rate of recurrent ischemic stroke was
significantly lower with PFO closure compared to medical therapy (0% vs. 10.5%; 95% CI 1.68 to 19.32; P ¼ .023);
the trial suggested a number needed to treat of 10 to avoid 1 stroke within 2 years. The incidence of silent brain in-
farctions was not different between the groups (8.8% in device group vs. 18.4% in medical therapy group; P ¼ .24).
The rate of major procedural complications was low with only 2 events, with 1 patient developing pericardial effu-
sion and 1 developing pseudoaneurysm at the puncture site. Of 60 patients in the device arm, 2 (3.3%) developed
post-implant atrial fibrillation.
Results of DEFENSE-PFO confirmed data from the CLOSE trial, where zero recurrent strokes were again
observed for patients with high-risk echocardiographic features (i.e., atrial septal aneurysm/hypermobility or large
PFO/shunt) who had their PFO closed. A major limitation of this study was that it was terminated early and thus,
likely underpowered. Hence, the number needed to treat of 10 at 2 years is likely an overestimation of the true ef-
ficacy of PFO closure for stroke prevention; this contrasts with CLOSE and Gore REDUCE, which had a number
needed to treat of 20 and 28 over 5 and 2 years, respectively (Table 7.2). Additionally, early termination and involve-
ment of only 2 centers potentiates selection bias, which may have affected the results.
META-ANALYSES OF PFO CLOSURE
TRIALS FOR STROKE PREVENTION
A number of meta-analyses have combined the cryptogenic stroke trials to increase the sample size and reduce
type II error. All of the published meta-analyses confirmed that percutaneous PFO closure reduces risk of recurrent
stroke compared to medical therapy, with no increased risk of serious adverse events or influence on major bleeding
[18e23]. The risk of new-onset atrial fibrillation/flutter was increased by fourfold with device closure compared to
medical therapy (Fig. 7.2) [24].
Nearly two-thirds of atrial fibrillation/flutter episodes occurred early within the first 30 days after implantation;
two-thirds of the atrial arrhythmias were characterized by a single paroxysmal episode that resolved spontaneously,
medically, or with cardioversion. The majority of patients with device-associated atrial fibrillation did not receive
long-term anticoagulation (e.g., anticoagulation was discontinued in 70% of patients in the CLOSE trial in
whom it was started) [25]. In the randomized trials, only 5 patients (3 in CLOSURE I, 1 in RESPECT, and 1 in
Gore REDUCE) with presumed device-associated new-onset atrial fibrillation had a recurrent stroke during
follow-up (i.e., w0.1% of patients randomized to a device). Observational studies suggest that only 3.8% of post-PFO
closure atrial arrhythmias progress to permanent atrial fibrillation [26].
There is some suggestion that the PFO size and type of device used may affect outcomes. A number of different
devices were utilized in the PFO closure trials (Fig. 7.3).
Several meta-analyses [19e21] excluded the CLOSURE I trial, since the trial’s STARFlex device (NMT Medical;
Boston, Massachusetts) is no longer manufactured; this device had previously been associated with more throm-
bosis, atrial fibrillation, and residual shunting postclosure [27e29]. With exclusion of the CLOSURE I trial, the
odds ratio for recurrent stroke with PFO closure improved from 0.42 to 0.30, and new-onset atrial fibrillation
decreased from 6.63 to 5.89 [21].
TABLE 7.2 Number Needed to Treat of All Positive Randomized Trials of PFO Closure for Stroke.
Trial Only High-Risk PFOs Number Needed to Treat Duration
RESPECT No 42 5 years
CLOSE Yes
a
20 5 years
REDUCE No 28 2 years
DEFENSE-PFO Yes
b
10 2 years
a
Atrial septal aneurysm or large shunt.
b
Atrial septal aneurysm or septal hypermobility or PFO size 2 mm.
III. STROKE AND PFO
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Ntaios et al. [22] performed subgroup analyses stratifying for device type and high- versus low-risk PFO.
High-risk PFO was defined as the presence of a moderate to large shunt or an atrial septal aneurysm. Subgroup
analysis of outcomes by high-/low-risk PFO anatomy showed that percutaneous closure for high-risk PFOs was
an effect modifier (OR 0.39; 95% CI 0.16 to 0.96, P ¼ .04). Subgroup analyses in several prior meta-analyses have
also shown greater stroke reduction with device closure of a high-risk PFO [21,30e32]. Ntaios et al. also demon-
strated that recurrent stroke was reduced with the Gore devices (OR 0.24; 95% CI 0.09 to 0.66, P ¼ .005) and the
(A) (C) (D)
(B)
FIGURE 7.3 PFO-Occluding Devices Used in the Randomized Trials. (A) The STARFlex device was used in the CLOSURE I trial. (B) The
Amplatzer PFO Occluder was used in the PC, RESPECT, and DEFENSE-PFO trials. (C) The Gore Cardioform Septal Occluder was 1 of 2 devices
used in the Gore REDUCE trial. (D) The Gore Helex Septal Occluder was 1 of 2 devices used in Gore REDUCE trial. *The CLOSE trial utilized 11
different devices. PFO, patent foramen ovale.
FIGURE 7.2 Recurrent Stroke and Atrial Fibrillation/Flutter in Cryptogenic Stroke Patients Randomized to PFO Closure or Medical Therapy.
Summary plot for primary efficacy (recurrent stroke) and primary safety (atrial fibrillation/flutter) endpoints. Relative size of data markers in-
dicates weight of sample size. CI ¼ confidence interval; PFO ¼ patent foramen ovale; RR ¼ risk ratio. Adapted from Ref. [24].
III. STROKE AND PFO
META-ANALYSES OF PFO CLOSURE TRIALS FOR STROKE PREVENTION 85
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Amplatzer PFO Occluder (OR 0.56; 95% CI 0.31 to 1.00, P ¼ .05) but not with the STARFlex device (OR 0.95; 95% CI
0.43 to 2.11). The incidence of atrial fibrillation was also found to be device dependent, being more common with
Gore devices (6.6%), which was higher than expected when compared to previous observation studies [26], followed
by the STARFlex device (5.7%), and the Amplatzer PFO occluder used in PC, RESPECT, and DEFENSE-PFO (2.0%).
LESSONS LEARNED FROM PFO CLOSURE
TRIALS FOR STROKE PREVENTION
The reason for success of the more recently published trials (long-term RESPECT, CLOSE, Gore REDUCE,
DEFENSE-PFO) compared to the earlier statistically nonsignificant studies (CLOSURE I, PC) may be a result of
stricter patient selection, with inclusion of index strokes more likely attributable to PFO-mediated paradoxical em-
bolism. While a thorough workup was perform ed to rule out alternative etiologies of stroke in the recently published
trials, the CLOSE and DEFENSE-PFO trials only included patients with echocardiographic features suggestive of a
high-risk PFO (atrial septal aneurysm with a hypermobile septum, a large shunt, or large PFO). Gore REDUCE had
very strict exclusion criteria to omit patients with alternative etiologies of stroke via extensive cerebrovascular im-
aging, and the trial excluded patients with uncontrolled risk factors.
Although there was no difference in serious adverse events or influence on major bleeding when PFO closure was
compared to medical therapy (P > .05 in all trials), device closure was associated with a fourfold increased risk of
new-onset atrial fibrillation/flutter [18]. These episodes usually occurred early (<30 days), were transient (a single
episode), and rarely were associated with recurrent stroke (w0.1% of patients randomized to a device). Given the
concern for occult atrial fibrillation as a missed cause of the index stroke and risk of atrial arrhythmias post-device
closure, prolonged (30 days) cardiac monitoring may be considered before PFO closure. ECG monitoring may be
appropriate for some individuals after device closure [24,33,34]. There are “smartphone” applications that patients
can download to self-monitor their rhythm and forward the ECG strips to their physician for review.
EVOLUTION OF GUIDELINES
Following the long-term RESPECT trial results, and positive meta-analyses of the early randomized trials [35], the
FDA approved the Amplatzer PFO occluder on October 28, 2016 for patients aged 18e60 years who have crypto-
genic stroke presumed to be from PFO-mediated paradoxical embolism, as determined by a neurologist and cardi-
ologist [36]. More recently, the Gore Cardioform Septal Occluder was approved by the FDA on March 30, 2018 for the
same indication [37]. A timeline showing the important mi lestones in the PFO closure trials and FDA approval of
devices are illustrated in Fig. 7.4 [38].
The professional society stroke guidelines within the United States were published prior to publication of the
newer trials, and they do not currently support routine PFO closure as first-line therapy for ischemic stroke of un-
known etiology [39]. A recent update in the Canadian [40] and German [41] guidelines now recommend device
closure plus antiplatelet therapy over antithrombotic therapy for ischemic stroke of undetermined etiology with
an associated PFO (limited to 16 e 60 years in the German version and 18e60 years in the Can adian version). With
the exception of the United Kingdom, the European stanc e [42] on device closure has been more liberal for decades;
it was felt that an update in recommendations on device closure was not necessary in many countries (Table 7.3).
PATIENT SELECTION FOR PFO CLOSURE FOR STROKE
A PFO is present in 40%e60% of patients with cryptogenic stroke [4e6], but not all of these patients have para-
doxical embolism as the culprit of their stroke. To assess if a detected PFO is the likely culprit of stroke versus just an
“innocent bystander,” the RoPE (Risk of Paradoxical Embolus) score [43] was developed in an effort to determine
which PFO should be closed (Chapter 4). The RoPE score considers a patient’s age, cerebral infarct pattern, smoking
status, and other comorbidities. However, a major limitation of the RoPE score is that it does not factor in that the
absolute risk of paradoxical embolism increases with age and other clinical features such as coexisting venous
thromboembolism, straining prior to stroke, and echocardiographic features of the PFO anatomy (atrial septal aneu-
rysm or large shunt), all of which may suggest stroke from paradoxical embolism.
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TABLE 7.3 Summary of Current Guideline Recommendations in North America and Europe of PFO Closure for Secondary Prevention of
Stroke.
Region Year Recommendation
USA 2014 1. For patients with an ischemic stroke or TIA and a PFO who are not undergoing anticoagulation therapy,
antiplatelet therapy is recommended (Class I; Level of Evidence B)
2. For patients with an ischemic stroke or TIA and both a PFO and a venous source of embolism, anticoagulation is
indicated, depending on stroke characteristics (Class I; Level of Evidence A). When anticoagulation is
contraindicated, an inferior vena cava filter is reasonable (Class IIa; Level of Evidence C)
3. For patients with a cryptogenic ischemic stroke or TIA and a PFO without evidence for DVT, available data do
not support a benefit for PFO closure (Class III; Level of Evidence A)
4. In the setting of PFO and DVT, PFO closure by a transcatheter device might be considered, depending on the risk
of recurrent DVT (Class IIb; Level of evidence C)
Canada 2017 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):
A. Age 18e60 years;
B. 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;
C. 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.
Germany 2018 1. In patients 16e60 years with cryptogenic stroke (according to neurologic and cardiologic workup) and a PFO
with moderate to severe right-to-left shunt, percutaneous PFO closure should be done (recommendation Grade
A, evidence level I)
2. In patients with cryptogenic ischemic cerebral insult and a PFO, who refuse PFO closure, there are no hints of
superiority of oral anticoagulation over antiplatelet therapy. Hence, acetylsalicylic acid or clopidogrel should be
used for secondary prevention (Recommendation Grade B, Evidence level II)
Europe (except UK) 2008 It is recommended that endovascular closure of PFO be considered in patients with cryptogenic stroke and
high-risk PFO (PFO associated with ASA, Eustachian valve, Chiari network, or >1 stroke) (Class IV)
ASA, atrial septal aneurysm; DVT, deep venous thrombosis; PFO, patent foramen ovale; TIA, transient ischemic attack; UK, United Kingdom; USA, United Stated
of America.
Class IV, Evidence from uncontrolled studies, case series, case reports, or expert opinion.
FIGURE 7.4 Timeline Showing Important Dates of PFO Closure Trials and Food and Drug Administration Milestones in the United States.
HDE, humanitarian device exemption, FDA, Food and Drug Administration, PFO, patent foramen ovale. Adapted from Ref. [38].
PATIENT SELECTION FOR PFO CLOSURE FOR STROKE 87
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The clinical trials varied in their patient enrollment criteria. Although the RESPECT, CLOSE, Gore RED UCE,
and DEFENSE-PFO studies only included patients with cryptogenic ischemic stroke, CLOSURE I enrolled patients
with both ischemic stroke and transient ischemic attack; the PC trial included ischemic stroke, extracerebral
thromboembolism, or transient ischemic attack with positive cerebrovascular imaging. While a protocol-
mandated evaluation was performed for the etiology of the index ischemic stroke, diagnostic cerebrovascular imag -
ing has evolved with higher magnetic resonance imaging field strength, multiple acquisition sequences, and newer
criteria with respect to size and location of ischemic lesions [44,45] since the initial cryptogenic stroke trials. None of
the 6 trials used prolonged 30-day cardiac event monitoring as a strict inclusion criterion to rule out occult atrial
fibrillation/flutter; prolonged cardiac monitoring has been found to detect undiagnosed paroxysmal atrial fibrilla-
tion at a higher frequency than standard 24-hour cardiac monitoring, in strokes initially thought to be cryptogenic
[33,34]. Other notable differences were that the DEFENSE-PFO and CLOSE trials only included patients with a high-
risk PFO, and the Gore REDUCE trial additionally excluded patients with uncontrolled vascular risk factors.
Based on lessons learned from these trials, a multidisciplinary team is recommended inclusive of a neurologist,
cardiologist, and other healthcare professionals trained in stroke management [46]. Neurologists should diagnose
the cryptogenic stroke while cardiologists would facilitate in the detection of PFO and high-risk anatomical features
and rule out other cardiovascular culprits, to ensure that PFO closure is performed for all strokes caused by para-
doxical embolism (Fig. 7.5) [47].
UNANSWERED QUESTIONS
Although the benefit of device closure in young patients with PFO-associated stroke has now been established by
4 randomized clinical trials, a number of unanswered questions remain:
1. What is the best treatment modality for cryptogenic stroke patients aged >60 years who have a PFO [48]?Ina
recent observational study, Mazzucco et al. [49] demonstrated that even at an advanced age, there was
significantly increased incidence of right-to-left shunting among patients with cryptogenic ischemic stroke.
FIGURE 7.5 Evidence-Based Algorithm for PFO Closure in Ischemic Stroke Patients for Highest Clinical Yield Based on Randomized Trials.
Patients can expect the greatest benefit from percutaneous PFO closure if they have no other cause of cardiovascular stroke on imaging/laboratory
analyses, no uncontrolled risk factors, no atrial fibrillation or flutter, and no poor prognostic markers. However, there are situations where it is
impossible to prove the precise etiology of the stroke. In those cases, because the risk of PFO closure is very low, it may be prudent to treat
whatever is possible, such as lowering cholesterol, but also closing a PFO. PFO, patent foramen ovale. Adapted with permission from Ref. [47].
III. STROKE AND PFO
7. NEWER RANDOMIZED TRIALS OF PFO CLOSURE FOR STROKE (CLOSE, REDUCE AND DEFENSE-PFO)88
https://t.me/med1917
Given that PFO closure is a low-risk procedure, device closure may be considered in patients aged >60 years,
particularly but not exclusively if they have no evidence of atherosclerosis, occult atrial fibrillation, or other stroke
etiologies; the presence of a multidisciplinary team including involvement of neurology is essential prior to PFO
closure. Future randomized trials may better address outcomes of PFO closure in older patients.
2. Trials that only enrolled a high-risk PFO (i.e., DEFENSE-PFO and CLOSE) demonstrated zero recurrent strokes on
follow-up with a number needed to treat of 10e20 in 2e5 years, respectively. This highlights the increased
propensity of a high-risk PFO to cause stroke. With this in mind, there are insufficient data on PFO closure in
young stroke patients with a high-risk PFO (i.e., large PFO/shunt or atrial septal aneurysm/hypermobility) who
are also found to have another cause of stroke such as atrial fibrillation or carotid disease. Considering the low
number needed to treat to prevent a stroke as reported by trials of percutaneous closure of a high-risk PFO, the
relative safety associated with PFO closure, the ever-accruing bleeding rate under oral anticoagulation, and the
compliance issue with medical therapy but not with PFO closure, percutaneous device closure should be
considered in these patients in addition to treatment of the other stroke risk factors. Beyond that, PFO closure has
the potential to prevent further paradoxical embolism also in patients whose index even t may have been caused
by another reason, and this at a very low price of risk.
3. Although thromboembolism is considered the mechanism of PFO-associated stroke, there is a paucity of data
comparing oral anticoagulants with PFO closure or antiplatelet agents [50,51]. As the only randomized study with
a device closure, antiplatelet, and oral anticoagulant arm, the CLOSE trial attempted a comparison of oral
anticoagulants versus antiplatelet agents. The study showed a nonsignificant 56% reduction in recurrent stroke
with anticoagulants; however, it was underpowered for this comparison [15]. The current randomized data have
not yet statistically proven superiority of warfarin or novel oral anticoagulants over antiplatelet therapy for
secondary prevention of embolic stroke of undetermined source [52e54], even in the subset of those who have
PFO [55,56]. Until a trial is performed that compares the efficacy and safety of percutaneous PFO closure versus
oral anticoagulation for secondary prevention of PFO-associated stroke, device closure should be considered the
most effective therapy based on the currently available randomized data. A recent network meta-analysis
suggested that patients receiving oral anticoagulation may have similar long-term stroke risk reduction compared
to PFO closure [57]; however, most experts give preference to PFO closure over oral anticoagulation due to a better
safety profile with device closure including less major bleeding risk, especially with a survival over decades,
typical for these younger patients [58].
References
[1] Benjamin EJ, Blaha MJ, Chiuve SE, et al. Heart disease and stroke statistics-2017 update: a report from the American heart association.
Circulation 2017;135:e146e603.
[2] Heidenreich PA, Trogdon JG, Khavjou OA, et al. Forecasting the future of cardiovascular disease in the United States: a policy statement from
the American Heart Association. Circulation 2011;123:933e44.
[3] 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;59:17e20.
[4] Lechat P, Mas JL, Lascault G, et al. Prevalence of patent foramen ovale in patients with stroke. N Engl J Med 1988;318:1148e52.
[5] Webster MW, Chancellor AM, Smith HJ, et al. Patent foramen ovale in young stroke patients. Lancet 1988;2:11e2.
[6] West BH, Noureddin N, Mamzhi Y, et al. Frequency of patent foramen ovale and migraine in patients with cryptogenic stroke. Stroke 2018;49:
1123e8.
[7] Mas JL. Patent foramen ovale, atrial septal aneurysm and ischaemic stroke in young adults. Eur Heart J 1994;15:446e9.
[8] Doufekias E, Segal AZ, Kizer JR. Cardiogenic and aortogenic brain embolism. J Am Coll Cardiol 2008;51:1049e59.
[9] Bridges ND, Hellenbrand W, Latson L, Filiano J, Newburger JW, Lock JE. Transcatheter closure of patent foramen ovale after presumed
paradoxical embolism. Circulation 1992;86:1902e8.
[10] Moses JW, Leon MB, Popma JJ, et al. Sirolimus-eluting stents versus standard stents in patients with stenosis in a native coronary artery.
N Engl J Med 2003;349:1315e23.
[11] Furlan AJ, Reisman M, Massaro J, et al. Closure or medical therapy for cryptogenic stroke with patent foramen ovale. N Engl J Med 2012;366:
991e9.
[12] Meier B, Kalesan B, Mattle HP, et al. Percutaneous closure of patent foramen ovale in cryptogenic embolism. N Engl J Med 2013;368:1083e91.
[13] Carroll JD, Saver JL, Thaler DE, et al. Closure of patent foramen ovale versus medical therapy after cryptogenic stroke. N Engl J Med 2013;368:
1092e100.
[14] Saver JL, Carroll JD, Thaler DE, et al. Long-term outcomes of patent foramen ovale closure or medical therapy after stroke. N Engl J Med 2017;
377:1022e32.
[15] Mas JL, Derumeaux G, Guillon B, et al. Patent foramen ovale closure or anticoagulation vs. Antiplatelets after stroke. N Engl J Med 2017;377:
1011e21.
[16] Sondergaard L, Kasner SE, Rhodes JF, et al. Patent foramen ovale closure or antiplatelet therapy for cryptogenic stroke. N Engl J Med 2017;
377:1033e42.
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