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The subsequent American Heart Association/American Stroke Association (AHA/ASA) 2014 guidelines deter-
mined that there were insufficient data to establish whether oral anticoagulation was equivalent or superior to acetyl-
salicylic acid for secondary stroke prevention in patients with PFO (Class IIb; Level of Evidence B). For patients with an
ischemic stroke or transient ischemic attack (TIA) and a PFO, who do not take oral anticoagulation, antiplatelet therapy
was recommended (Class I; Level of Evidence B) [11]. However, for patients with an ischemic stroke or TIA and both a
PFO and a source of venous thrombosis, anticoagulation was recommended (Class I; Level of Evidence A).
Observational Studies of PFO Closure for Stroke
Percutaneous cardiac closure devices of different types have been commercially available in the United States for
over 16 years. The earliest implanted occluder device was the “Bard Clamshell double umbrella device,” first
described in 1992. The study to prove its safety and efficacy included 36 patients. Each patient had 1 or more events
(e.g., embolic stroke, transient focal neurological deficit, peripheral arterial embolism, or brain abscess) without a left
heart or carotid source, and each had an interatrial communication with intermittent or continuous right-to-left
shunting by echocardiography [12]. The study demonstrated that transcatheter closure of a PFO can be accom-
plished with little morbidity and may reduce the risk of stroke recurrence [12]. Of 34 patients who returned for
follow-up, 1 had a clinically significant residual interatrial shunt, 5 had trivial leaks, and 28 had complete PFO
closure. No strokes were observed during a mean follow-up of 8.4 months [12]. To date, there have been 6 random-
ized controlled trials that evaluated the efficacy and safety of PFO closure for secondary prevention of stroke (Chap-
ters 6 and 7); most of these studies were completed in the last 5 years. However, there is a large pool of observation al
data that led to the design and enrollment of these pivotal randomized trials. Several of these key observational
studies are discussed below.
Windecker et al. compared the risk of recurrent stroke in 308 patients with cryptogenic stroke and PFO who were
not randomized but treated either medically (158 patients) or with percutaneous PFO closure (150 patients), between
1994 and 2000 [13]. Compared to those treated with standard medical therapy, patients who underwent percuta-
neous PFO closure had a larger right-to-left shunt (P < .001; 95% confidence interval 1.38 to 3.07) and were more
likely to have suffered more than 1 cerebrovascular event (P ¼ .03; 95% CI 1.04 to 2.71). At a 4-year follow-up,
PFO closure resulted in a nonsignificant trend toward risk reduction of death, stroke, or TIA combined (8.5% vs.
24.3%; P ¼ .05; 95% CI 0.23 to 1.01), and of recurrent stroke or TIA (7.8% vs. 22.2%; P ¼ .08; 95% CI 0.23 to 1.11)
when compared with medical treatment. Individuals with more than 1 cerebrovascular event at baseline and those
with completely sealed PFO were at lower risk of recurrent stroke or TIA following PFO closure, when compared
with medical therapy (7.3% vs. 33.2%; P ¼ .01; 95% CI 0.08% to 0.81%, and 6.5% vs. 22.2%; P ¼ .04; 95% CI 0.14 to
0.99, respectively). This study showed that percutaneous PFO closure was at least as effective as medical treatment
for prevention of recurrent cerebrovascular events in stroke of no clear etiology other than PFO.
In 2006, Thanopoulos et al. evaluated the safety and efficacy of PFO device closure versus antiplatelet therapy in
patients with cryptogenic stroke [14]. This was a nonrandomized, prospective, patient-preference study comparing
the recurrence rate of stroke in 92 patients with PFO who were treated with antiplatelets (44 patients) or PFO closure
(48 patients) using the Amplatzer PFO Occluder (Abbott; Chicago, Illinois). All patients completed a 2-year follow-
up. In the PFO closure group, immediate complete closure was observed in 44/48 (91%) patients. Four (9%) patients
had a minimal residual shunt immediately after the procedure. One patient developed hemopericardium that was
successfully managed by pericardiocentesis. No other complication was observed. A 6-month follow up transtho-
racic echocardiogram with bubble study confirmed complete closure in all 48 patients. In the antiplatelet arm, 3
(6%) and 6 (13%) patients had a major and minor bleeding event, respectively. The average incidence of embolic
events/year was 0% for the PFO closure group and 15% for the antiplatelet therapy group (P < .001). The authors
concluded that PFO closure using the Amplatzer device is a reasonable alternative to standard medical therapy
in patients with an index stroke from no other identifiable cause.
Long-term data on the efficacy of percutaneous device closure were provided by Wahl et al. in an observational
study of propensity scoreematched groups [15]. Between 1994 and 2000, 308 consecutive patients with cerebrovas-
cular events, presumably related to PFO, underwent PFO closure (150 patients) or medical treatment (158 patients).
These patients were followed prospectively for up to 15 years. Patients were treated with 6 different devices (36%
with Amplatzer PFO Occluder, 28% with PFO STAR [Cardia, Burnsville, Minnesota], 17% with Sideris Buttoned
[Custom Medical Devices, Amarillo, Texas], 7% with Angel Wing [Microvena Corporation, White Bear Lake, Min-
nesota], 6% with Amplatzer ASD, and 5% with CardioSEAL [NMT Medical, Boston, Massachusetts]) closure de-
vices. Transthoracic contrast echocardiography was performed within 24 hours of percutaneous PFO closure to
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document device positioning. Stroke patients who were medically managed were treated with warfarin or antiplate-
let therapy. Warfarin was prescribed with a target international normalization ratio of 2.0e3.0, acetylsalicylic acid at
a dose of 100e300 mg, and clopidogrel at a dose of 75 mg once daily. The primary outcome was a composite of
stroke, TIA, or peripheral embolism. An analysis was perform ed of 103 propensity score-matched patients who un-
derwent PFO closure or medical treatment. At a median long-term follow-up of 9 years, the primary composite
outcome occurred in 11 patients (11%) in the device arm and 22 patients (21%) in the medical therapy arm (hazard
ratio 0.43; 95% confidence interval 0.20e0.94; P ¼ .033). The treatment effect was predominantly driven by a decrease
in the risk of TIA with PFO closure (5% vs. 14%, hazard ratio 0.31, 95% confidence interval 0.10e0.94; P ¼ .039). The
risk of all-cause mortality (6% in both groups) and cardiovascular mortality (3% in both groups) was identical, indi-
cating that device closure was equally safe as medical therapy, but percutaneous PFO closure was more effective
than medical treatment for the secondary prevention of recurrent cerebrovascular events among patients with
PFO-associated TIA or stroke. Interestingly, yearly mortality was significantly lower when comparing patient-years
with device closure (0.4%) verses without closure (1.1%, P ¼ .03) [15]. One difficulty with all studies that include TIA
as an endpoint, is that it is close to impossible to distinguish a TIA, which is presumed to be due to an embolus, from
a complex migraine. Both produce a transient neurologic deficit and have a normal brain MRI. Since a PFO is asso-
ciated with migraine and aura, in those subjects who do not get their PFO closed, they could have more migraine,
which is incorrectly adjudicated as an embolic endpoint.
An observational multicenter study from Italy by Paciaroni et al. evaluated the risk of recurrent cerebrovascular
events among patients with a PFO, in addition to comparing medical therapy versus transcatheter device closure
[16]. Consecutive patien ts (aged 55 years) with first-ever cryptogenic stroke or TIA and PFO were recruited in
13 Italian hospitals between January 2006 and September 2007; patients were followed for 2 years. A total of 238 pa-
tients were included in the study (mean age 42.2 10.0 years; 118 males); 117 (49.2%) received antithrombotic ther-
apy while 121 (50.8%) underwent PFO closure. The presence of atrial septal aneurysm and evidence of 20 bubbles or
more on transcranial Doppler were more common at baseline in the PFO closure group (P ¼ .002 and P ¼ .02, respec-
tively). Eight patients (6.6%) experienced a nonfatal complication during PFO closure. At the 2-year follow-up, 17
recurrent neurological events (3.6% per year) were observed; of these, 7 (2.9% per year) occurred in the percutaneous
PFO closure group and 10 (4.2% per year) in the medical therapy group. The rate of recurrent stroke was 0.4% per
year in patients who underwent device closure (1 event) and 3.4% per year in patients who received medical treat-
ment (8 events). However, the results did not reach statistical significance with multivariate analysis. The results of
this observational, nonrandomized study suggested that PFO closure may be superior to medical therapy for the
prevention of recurrent stroke.
The occurrence of ischemic stroke in a young person, without clinically relevant risk factors for atherosclerosis,
raises the possibility of paradoxical embolism. A strong association has been demonstrated between cryptogenic
stroke and PFO in patients <55 years of age [17]. Due to the increased prevalence of cardiovascular risk factors in
the elderly, the relationship between stroke and PFO is harder to prove in older patients [18] . Spies et al. evaluated
recurrent thromboembolic events after PFO closure in patients >55 years of age who had presumed paradoxical em-
bolism [19]. PFO closure was performed in 1055 patients, 423 of whom were above 55 years of age. A PFO occluding
device was implanted successfully in all patients. Other identifiable causes of thromboembolism had to be excluded
with vascular ultrasound, computed tomography, or magnetic resonance imaging of the cerebral vessels and aorta; a
24-hour ambulatory cardiac monitor was used to rule out atrial arrhythmias, and transesophageal echocardiogram
(TEE) was used to exclude intracardiac sources of embolism and to document a PFO. If a right-to-left shunt was
clearly visible with transthoracic echocardiography (TTE), TEE was not mandated. The majority of patients under-
went PFO closure with a Cardia PFO Occluder or Intrasept (both Cardia, Eagan, Minnesota), Amplatzer Septal
Occluder or Amplatzer PFO Occ luder. Residual shunting was documented in 10% of patients above 55 years of
age and in 8.4% of patients aged 55 years (P ¼ .325). During a median follow-up of 18 months, the annual incidence
of recurrent thromboembolic events was 1.8% in patients aged >55 years and 1.3% in patients aged 55. The authors
concluded that PFO closure was equally efficacious in the young and elderly. These observational data suggest that,
although traditional cardiovascular risk factors may occur more frequently in the older age group, PFO closure
should not be withheld as a potential therapeutic option in this age group, when clinically indicated.
These data were corroborated by a large meta-analysis of observational studies [10], where a higher rate of recur-
rent neurological events was observed in the medically treated elderly group compared to younger patients who
received medical therapy alone. However, the rate of recurrent neurological events was similar between the elderly
and younger age groups who underwent percutaneous PFO closure, implying that elderly individuals with crypto-
genic stroke or TIA may derive a benefit of a lower rate of recurrent neurological events by having their PFOs closed.
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Currently, the Amplatzer PFO Occluder and Gore Cardioform Septal Occluder (W.L. Gore and Associates; Flag-
staff, Arizona) are the only devices approved by the Food and Drug Administration for percutaneous PFO closure in
the United States. However, many different devices have been used in the past. Taafee et al. compared the peripro-
cedural complications and 30-day clinical outcomes of 3 PFO-occluding devices [20] . The devices compared were
Amplatzer, CardioSEAL-STARFlex (NMT Medical Inc; Boston, Massachusetts), and Helex Septal Occluder (W.L.
Gore and Associates; Flagstaff, Arizona). The study enrolled 660 patients (361 men, 299 women, mean age
49.3 1.9 years), with 220 patients in each group. They fulfilled the criteria for a PFO closure through having a his-
tory of stroke or a TIA and coincidental migraine (n ¼ 50) and/or decompression illness (n ¼ 3). Other causes of
stroke or embolism were ruled out before the procedure. Procedural success was reported in 100% of the patients.
Complete PFO closure, assessed using TEE at 30 days post-procedure, was achieved in 143 of 220 patients (65%) in
the Amplatzer group, 116 of 220 patients (52.7%) in the Helex group, and 137 of 220 patients (62.3%) in the Cardi-
oSEAL-STARFlex group at 30 days. There were significant differences between the devices. The Helex Occluder had
more frequent device embolization (0.9%). Thrombus formation on the device and paroxysmal atrial fibrillation
were more common with the CardioSEAL-STARFlex Occluder. Long-term data from this study were subsequently
published in 2013, which looked at the extended 5-year outcomes [21]. Thrombus formation was now detected in 12
cases (11 CardioSEAL-STARFlex, 1 Helex, 0 Amplatzer; P < .0001), of which 2 required surgery. Complete closure
after a single device implant was more common with the Amplatzer and CardioSEAL-STARFlex devices than
with the Helex Occluder (98.6% with Amplatzer vs. 96.8% with CardioSEAL-STARFlex vs. 91.8% with Helex
[P ¼ .0012]). Within 5 years, the primary endpoint occurred in 25 (3.8%) patients (10 TIAs, 12 strokes, and 3 cerebral
deaths). There were significantly more events that occurred with the CardioSEAL-STARFlex (6%; 6 TIAs, 6
strokes, 1 cerebral death) and Helex groups (4%; 4 TIAs, 4 strokes, 1 cerebral death) when compared with the
Amplatzer group (1.4%; 2 strokes, 1 cerebral death) (P ¼ .04). The authors concluded that although procedural com-
plications and long-term neurological event rates are low regardless of the device used, the recurrent neurological
event rate was significantly lower when the Amplatzer device is used over the CardioSEAL-STARFlex or Helex de-
vices. These observations indicate that not all PFO closure devices function equally, and it is important to know the
risks of each device when interpreting clinical trials comparing PFO device closure with medical management.
Between June 1999 and June 2002, Onarato et al. performed transcatheter closure of PFO in 256 consecutive pa-
tients (female/male ¼ 1.45; mean age 48 16 years; range 14e75) with ischemic stroke (n ¼ 101), TIA (n ¼ 144), pe-
ripheral and coronary arterial embolism (n ¼ 17), multiple events (n ¼ 23), platypnea-orthodeoxia syndrome
(n ¼ 2), refractory hypoxemia (n ¼ 1), and migraine with aura (n ¼ 27) [22]. Devices used were the Amplatzer
PFO Occluder (n ¼ 248), Gore Helex Septal Occluder (n ¼ 4), and PFO STAR (n ¼ 4). Total occlusion rate at a
mean follow-up of 19 months was 98.1%. No significant recurrent neurological events were observed. Transcatheter
closure of PFO, with or without atrial septal aneurysm, was found to be a safe and effective minimally invasive pro-
cedure that ensured high long-term closure rates and avoided life-long oral anticoagulation.
Many of the individual observational studies could not statistically prove that percutaneous PFO closure was
preferable to standard medical therapy, but the high efficacy of closure and relatively low complication rate sug-
gested that device closure should be tested in a randomized controlled trial. The significant mortality benefit
observed with one large 10-year study [15], the findings of noninferiority of PFO closure compared with medical
therapy, along with an excellent safety profile and less bleeding risk with device closure, made enrollment in ran-
domized trials unethical for some PFO closure advocates [17,23,24,25,26,27].
Meta-Analysis of Observational Studies of PFO Closure for Stroke
In a meta-analysis of 39 observational studies (8185 patients with index neurological events) treated with percu-
taneous PFO closure using different devices versus medical therapy, the pooled incidence of recurrent neurological
events in the closure group was significantly lower and estimated at 0.76 events (95% CI: 0.48 to 1.05) as compared
with 4.39 events (95% CI: 3.20 to 5.59) in the medical therapy group [10]. A direct comparison of PFO closure versus
medical therapy was made in 10 of these studies. This involved 1886 patients and showed a significantly reduced
number of recurrent neurological events among patients who underwent PFO closure compared with medical ther-
apy alone (RR: 0.25 [95% CI: 0.11 to 0.58]) (Fig. 5.2).
With respect to device-related complications, transcatheter PFO closure is considered a safe procedure. The rein-
tervention rate in the follow-up period has been estimated as 0.9% (0.2%e1.6%). The most frequent complication
after device closure was reported to be atrial arrhythmias in 3.9% of cases. The incidence of device related
III. STROKE AND PFO
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thrombosis has been estimated as 0.6%. Procedural complications requiring surgical intervention was 0.3%. The rate
of bleeding complications in the transcathete r closure arm was 1.7% (Table 5.1) [10].
Table 5.2 [10] demonstrates the rates of recurrent neurological events and major complications across the most
common devices utilized in the included studies. The Amplatzer PFO Occluder has been the most common device
used (38.5%), followed by the CardioSEAL device (18.6%). The rates of recurrent neurological events ranged from 0.1
to 1.7 events per 100 patient-years (PY) across the various device types. Atrial arrhythmias were mos t frequently
encountered with CardioSEAL (10.2 per 100 PY) and STARFlex devices (9.0 per 100 PY) and least commonly with
Amplatzer and Helex devices. Among all the devices utilized, device-related thrombosis was most commonly
encountered with the STARFlex (3.3 per 100 PY) and PFO Star device (2.8 per 100 PY). Helex devices appeared to
FIGURE 5.2 Incidence of recurrent neurological events in the 2 study groups. (A) Incidence (per 100 patient-years) of recurrent neurological
events in the medical management arm and transcatheter closure arm stratified by year of publication. (B) Forest plot comparing the risk of
recurrent neurological events between the transcatheter closure and medical management arms in comparative studies. CI ¼ confidence interval;
RR ¼ relative risk. Adapted with permission from Ref. [10].
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have the highest rates of medium- to long-term (14.8%) residual shunting and a slightly higher risk of device embo-
lization or malposition (1.4 per 100 PY) when compared to other device types. This study, however, did not stratify
for device size, which may have been a confounder, especially when comparing residual shunting between different
devices [12].
It has been argued that the benefit of closure may be attenuated in patients with incomplete PFO closure because
residual shunting may put them at risk for recurrent events despite antithrombotic therapy. Complete closure of the
right-to-left shunt likely occurs after endocardialization of the device. Studies have shown that a PFO associated
TABLE 5.1 Device-Related Complications Stratified by Treatment Arm.
Arrhythmia 3.9%
Atrial fibrillation 1.2%
Atrial flutter 0.9%
Bleeding complication 1.7%
Minor hematoma 0.8%
Major hematoma 0.1%
Arteriovenous fistula 0.2%
Pseudoaneurysm 0.6%
Reintervention 0.9%
Pericardial bleeding 0.3%
Pericardial effusion 0.1%
Tamponade 0.2%
Embolization/malposition of device 0.4%
Death 0.4%
TABLE 5.2 Recurrent Neurological Events and Major Complications Stratified by Device Type.
Amplatzer CardioSEAL PFO Star StarFlex Helex
Proportion of total procedure 38.5% 18.6% 11.0% 9.3% 8.9%
Stroke or TIA 0.6 (0.3e0.8) 1.7 (0.1e3.2) 1.6 (0e3.3) 0.9 (0e2.0) 0.1 (0e0.5)
Effusion or tamponade 0.2 (0e0.8) 0.1 (0e2.8) 0.1 (0e1.1) 0.1 (0e0.8) 0.5 (0e1.7)
Embolization/malposition 0.1 (0e0.5) 0.3 (0e0.9) 0.7 (0e1.7) 0.6 (0e2.0) 1.4 (0e3.0)
Thrombus 0.1 (0e0.5) 0.6 (0e1.5) 2.8 (1.0e4.7) 3.3 (1.5e5.1) 0 (0e0.7)
Atrial arrhythmia 1.8 (0.8e2.7) 9.0 (0.2e17.9) 6.9 (0e18.7) 10.2 (4.9e15.4) 0.1 (0e8.0)
Bleeding complications 1.6 (0.1e3.1) 2.6 (0.6e3.4) 4.7 (1.0e13.7) 0.2 (0e1.0) 2.0 (0e6.1)
Reintervention 0.8 (0e1.8) 0 (0e3.2) 0 (0e2.9) 1.8 (0e7.2) 2.1 (0e4.6)
Surgical intervention 0.2 (0e0.8) 0.4 (0e1.0) 0.8 (0e2.0) 2.2 (0e4.5) 0 (0e1.7)
Related death 0 (0e0.3) 0 (0e0.4) 0 (0e1.0) 0 (0e1.1) 0 (0e1.4)
RESIDUAL SHUNT
Postprocedure 17.3 (8.4e26.3) 13.6 (5.4e21.8) 46.9 (36.5e57.3) 33.6 (19.1e48.1) 46.1(23.7e68.5)
12 months or less 6.3 (2.5e10.2) 6.2 (0e12.4) 11.8 (2.4e21.2) 8.8 (4.8e12.9) 21.3 (1.0e51.7)
More than 12 months 1.8 (0e5.2) 1.5 (0e4.9) e 1.8 (0e3.6) 14.8 (0e48.5)
Values are incidence (95% confidence interval)/100 person years. All major device types have been represented in this table. TIA ¼ transient ischemic attack.
Adapted with permission from Ref. [10].
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with atrial septal aneurysm and related anatomical variants were independent predictors of embolic events in a
multivariate analysis [28]. This theory was further analyzed by pooling the data from the observational studies
[12]. In the medical management group, the incidence of recurrent neurological events was significantly lower
among patients with a PFO only (2.4 events per 100 PY, 95% CI: 0.9 to 4.0) compared to those with PFO and atrial
septal aneurysm (6.2 events per 100 PY, 95% CI: 2.8 to 9.6 events) (P ¼ .03). In the transcatheter closure arm, the inci-
dence of recurrent neurological events among patients with PFO alone versus PFO and atrial septal aneurysm was
estimated as 0 .3 events (95% CI: 0.1 to 0.6) and 0.4 events (95% CI: 0.1 to 1.0), respectively (P ¼ NS). Interestingly, in
the transcatheter closure arm, there was no significant difference in the incidence of recurrent neurological events
observed between the 2 morphological groups. However, in the medical management arm, there was an increased
incidence of recurrent neurological events in patients with PFO and atrial septal aneurysm when compared to pa-
tients with PFO alone (Fig. 5.3). It has also been sugge sted that closure of a PFO may be most beneficial in patients
who have had greater than 1 previous neurological event [13].
The current AHA/ASA guidelines (2014) state that in patients with a cryptogenic stroke or TIA who have a PFO
without evidence for deep venous thrombosis, the available data do not support PFO closure (Class III; Level of Ev-
idence A) (Revised recommendation). However, in the setting of PFO and deep vein thrombosis, PFO closure by a
transcatheter device may be considered, depending on the risk of recurrent venous thromboembolism (Class IIb;
Level of Evidence C) (New recommendation) [13]. These guidelines preceded the publication of the seminal
2017e18 clinical trials and will likely be updated to reflect the most recent evidence-based randomized data, which
are discussed in Chapters 6 and 7.
CONCLUSIONS
Numerous observational studies and meta-analyses have demonstrated that transcatheter PFO closure is associ-
ated with a significant reduction in the rate of recurrent neurological events when compared with standard medical
FIGURE 5.3 Comparison of recurrent neurological events between PFO with or without atrial septal aneurysm. Forest plot comparing the risk
of recurrent neurological events between the patients with PFO only versus patients with PFO and atrial septal aneurysm, stratified by the
treatment arm. RD ¼ risk difference. Adapted with permission from Ref. [10].
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management, among patients with an index stroke of no other determined source [10]. When medical therapy alone
was investigated, meta-analyses showed a significantly lower risk of recurrent neurological even ts when crypto-
genic stroke patients were treated with oral anticoagulation compared to medical therapy, albeit with a concomitant
increased incidence of bleeding. Observational studies showed that transient atrial fibrillation or flutter was the most
frequent complication associated with transcatheter PFO device closure.
The consistent results from the observational studies of PFO closure for stroke showed a significantly lower inci-
dence of recurrent neurological events with PFO closure over medical therapy. These observations have now been
corroborated by randomized trials. Only randomized clinical trials can accurately demonstrate the efficacy and
safety of percutaneous PFO closure over standard of care medical therapy for the treatment of PFO-associated stroke
(Chapters 6 and 7).
The prior observational data sought to identify those aspects of PFO anatomy or clinical presentations that might
indicate whether PFO closure would be preferable to medical therapy. They led to the hypothesis that percutaneous
PFO closure would prove to be superior to medical therapy in preventing recurrent stroke in young
subjects 60 years old who presented with stroke of no other identifiable etiology. Subsequently, several ran domized
trials sought to answer this question. An important concern regarding recruitment in randomized trials was selec-
tion of the “ideal population” of patients. The observational studies helped to formulate the correct target cohort.
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[16] Paciaroni M, Agnelli G, Bertolini A, Pezzini A, Padovani A, Caso V, et al. Risk of recurrent cerebrovascular events in patients with cryptogenic
stroke or transient ischemic attack and patent foramen ovale: the FORI (Foramen Ovale Registro Italiano) study. Cerebrovasc Dis 2011;31(2):
109e16.
[17] Overell JR, Bone I, Lees KR. Interatrial septal abnormalities and stroke: a meta-analysis of case-control studies. Neurology 2000;55(8):1172e9.
[18] Handke M, Harloff A, Bode C, Geibel A. Patent foramen ovale and cryptogenic stroke: a matter of age? Semin Thromb Hemost 2009;35(5):
505e14.
[19] Spies C, Khandelwal A, Timmemanns I, Kavinsky CJ, Schrader R, Hijazi ZM. Recurrent events following patent foramen ovale closure in
patients above 55 years of age with presumed paradoxical embolism. Cathet Cardiovasc Interv 2008;72(7):966e70.
[20] Taaffe M, Fischer E, Baranowski A, Majunke N, Heinisch C, Leetz M, et al. Comparison of three patent foramen ovale closure devices in a
randomized trial (Amplatzer versus CardioSEAL-STARflex versus Helex occluder). Am J Cardiol 2008;101(9):1353e8.
[21] Hornung M, Bertog SC, Franke J, Id D, Taaffe M, Wunderlich N, et al. Long-term results of a randomized trial comparing three different de-
vices for percutaneous closure of a patent foramen ovale. Eur Heart J 2013;34(43):3362e9.
[22] Onorato E, Melzi G, Casilli F, Pedon L, Rigatelli G, Carrozza A, et al. Patent foramen ovale with paradoxical embolism: mid-term results of
transcatheter closure in 256 patients. J Interv Cardiol 2003;16(1):43e50.
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[23] Ford MA, Reeder GS, Lennon RJ, Brown RD, Petty GW, Cabalka AK, et al. Percutaneous device closure of patent foramen ovale in patients
with presumed cryptogenic stroke or transient ischemic attack: the Mayo Clinic experience. JACC Cardiovasc Interv 2009;2(5):404e11.
[24] Mirzaali M, Dooley M, Wynne D, Cooter N, Lee L, Haworth P, et al. Patent foramen ovale closure following cryptogenic stroke or transient
ischaemic attack: long-term follow-up of 301 cases. Cathet Cardiovasc Interv 2015;86(6):1078e84.
[25] Moon J, Kang WC, Kim S, Oh PC, Park YM, Chung WJ, et al. Comparison of outcomes after device closure and medication alone in patients
with patent foramen ovale and cryptogenic stroke in Korean population. Yonsei Med J 2016;57(3):621e5.
[26] Siddiqui IF, Michaels AD. Percutaneous patent foramen ovale closure using Helex and Amplatzer devices without intraprocedural echocar-
diographic guidance. J Interv Cardiol 2011;24(3):271e7.
[27] Stanczak LJ, Bertog SC, Wunderlich N, Franke J, Sievert H. PFO closure with the Premere PFO closure device: acute results and follow-up of
263 patients. EuroIntervention 2012;8(3):345e51.
[28] Mattioli AV, Aquilina M, Oldani A, Longhini C, Mattioli G. Atrial septal aneurysm as a cardioembolic source in adult patients with stroke and
normal carotid arteries. A multicentre study. Eur Heart J 2001;22(3):261e8.
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5. OBSERVATIONAL STUDIES OF PFO CLOSURE FOR STROKE66
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CHAPTER
6
Early Randomized Trials of PFO Closure for
Stroke (CLOSURE I, PC and RESPECT)
Preetham Kumar
1
, M. Khalid Mojadidi
2
, Jonathan M. Tobis
1
, Bernhard Meier
3
1
University of California, Los Angeles, Los Angeles, CA, United States;
2
Virginia Commonwealth University, Richmond,
VA, United States;
3
University Hospital Bern, Bern, Switzerland
OUTLINE
Introduction 67
The CLOSURE I PFO Trial 68
The PC Trial 69
The RESPECT Trial 70
Early Follow-Up of the RESPECT Trial 70
Long-Term Follow-up of the RESPECT Trial 72
A Common Limitation of All the Early
Randomized Trials 72
Meta-analyses of the Early Trials of PFO
Closure for Stroke
73
FDA Approval of Percutaneous PFO
Closure for Stroke
75
Conclusion
75
References
76
INTRODUCTION
Whereas the prevalence of a patent foramen ovale (PFO) in the adult population is approximately 25%, the fre-
quency of PFO in patients who suffer a cryptogenic stroke is 40%e60% [1,2]. This observation of an increased fre-
quency of PFO in cryptogenic stroke patients and respective case desc riptions led to the theory that the passage of a
venous clot across a PFO can result in systemic embolic events such as ischemic stroke or transient ischemia attack
(Chapters 4e7), myocardial infarction (Chapter 8), or peripheral ischemia (Chapter 9) [3e7]. In addition, the results
of the PFO-ASA trial (Clinical and Imaging Findings in Cryptogenic Stroke Patients with and without PFO) led to the
development of the hypothesis that PFO closure in patients with ischemic stroke of unknown etiology but associated
with a PFO may reduce the risk of recurrent stroke [8]. However, findings from PICSS (Effect of Medical Treatment in
Stroke Patients with PFO) [9] and the uncertain effectiveness of PFO closure [10] convinced many neurologists that
medical therapy was the preferred treatment.
The PFO-ASA trial was a prospective multicenter study involving 30 European neurology departments that eval-
uated differences in (cryptogenic) stroke risk factors and patterns among patients, with and without PFO, presenting
with an otherwise unexplained ischemic stroke [8]. Of 581 stroke patients enrolled, 267 (46%) had PFO and 314 (54%)
had no PFO as determined by transesophageal echocardiography (TEE) with a contrast bubble study performed at
rest and during provocative maneuvers (Valsalva maneuver and cough). Patients with PFO were younger (40.1 vs.
44.5 years, P < .0001) and less likely to have traditional risk factors, such as hypertension (8.6% vs. 21.3%, P < .0001),
hypercholesterolemia (10.9% vs. 23.2%, P < .0001), tobacco use (43.4% vs. 51.6%, P ¼ .05), and alcohol use (13.1% vs.
67
PFO Closure for Stroke, Myocardial Infarction, Peripheral Embolism, Migraine, and Hypoxemia
Copyright © 2020 Elsevier Inc. All rights reserved.https://doi.org/10.1016/B978-0-12-816966-7.00006-3
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21.3%, P ¼ .01). These findings suggested that the mechanism of stroke in patients with and without PFO were
different, supporting the need for randomized trials to evaluate the efficacy of PFO device closure in patients
with PFO-associated stroke.
PICSS, a subset analysis of the Warfarin-Aspirin Recurrent Stroke Study (WARSS) (n ¼ 2206), included any stroke
patient from WARSS who underwent TEE for clinical purposes (n ¼ 630), including assessment for a diagnosis of
cryptogenic stroke. PICSS was a double-blind 42-center study evaluating the rate of recurrent ischemic stroke or
death from any cause in patients with or without PFO who were originally randomized to either warfarin adjusted
to international normalized ratio 1.4 to 2.8 or acetylsalicylic acid 325 mg daily [9]. A total of 601 patients were
included in the final analysis. Within the cryptogenic stroke cohort (250 of the total 601 subjects), 39% (98/250)
had a PFO and 61% (152/250) did not have a PFO by TEE. The primary efficacy endpoint, defined as recurrent
ischemic stroke or death from any cause, occurred in 9.5% of the patients in the warfarin group and 17.9% of the
patients in the acetylsalicylic acid group (HR 0.52, 95% CI 0.16e1.67, P ¼ .28) at a mean follow-up of
13.2 10.5 months. Although this did not reach statistical significance, the risk of recurrent stroke with antiplatelet
therapy was nearly twice that of oral anticoagulation and presumably would have become statistically significant
with a larger sample size. Nonetheless, PICSS was interpreted as demonstrating that warfarin was no better than
acetylsalicylic acid in reducing the risk of a recurrent stroke in cryptogenic stroke patients found to have a PFO.
One must be cautious when interpreting the results of some of the early PFO studies because the diagnosis of
PFO was often determined by TEE or even just transthoracic echocardiography, techniques which are not as
sensitive as transcranial Doppler (Chapter 2) [11e14]. Thus, the presence of a PFO may have been missed in the
“non-PFO” group, potentially confounding the results and decreasing the accuracy of the conclusions.
Whether to close a PFO to reduce the risk of recurrent stroke remained a matter of debate. With the advent of
catheter-based percutaneous PFO closure, investigators speculated that the bene fits of PFO closure may outweigh
the procedural risks among individuals with PFO-associated stroke. In parallel to observational studies (Chapter
5), randomized clinical trials were designed to determine if percutaneous PFO closure was superior to medical
therapy for secondary prevention of stroke in patients who did not have another identifiable etiology for their
stroke other than PFO. The 3 early randomized trials of PFO closure for cryptogenic stroke are summarized in Ta-
ble 6.1 [15,16,18].
THE CLOSURE I PFO TRIAL
CLOSURE I (Evaluation of the STARFlex Septal Closure System in Patients with a Stroke and/or Transient
Ischemic Attack due to Presumed Paradoxical Embolism through a PFO) was the first randomized, multicenter,
open-label study to evaluate the efficacy and safety of percutaneous PFO closure plus medical therapy versus med-
ical therapy alone for secondary prevention of stroke or transient ischemic attack (TIA) [15]. A total of 909 patients,
aged 18e60 years, with cryptogenic stroke or TIA, who had a TEE-confirmed PFO were included. Patients random-
ized to the PFO closure group underw ent device closure with the STARFlex septal closure system (NMT Medical;
Boston, Massachusetts) and subsequently received acetylsalicylic acid 81 or 325 mg for 2 years and clopidogrel
75 mg for 6 months. Individuals randomized to the medical therapy group received either warfarin with a target
international norm alized ratio of 2.0e3.0, acetylsalicylic acid 325 mg daily, or acetylsalicylic acid 81 mg daily plus
warfarin. The cumulative incidence (KaplaneMeier estimate) of the primary composite endpoint, defined as 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, occurred in 5.5% (23/447) of patients in the device arm and 6.8% (29/462) of patients in
the medical therapy arm (HR 0.78, 95% CI 0.45e1.35, P ¼ .37). The rates of recurrent stroke were similar when PFO
closure was compared to medical therapy (2.9% vs. 3.1%, P ¼ .79). In addition, the rates of recurrent TIA were similar
between PFO closure and medical therapy (3.1% vs. 4.1%, P ¼ .44). Neither the device arm nor the medical therapy
arm had deaths from any cause within the first 30 days or from neurologic causes between 31 days and 2 years. In
regard to safety, episodes of device closure demonstrated a significantly higher rate of major vascular complications
(3.2% vs. 0%, P < .001) and atrial fibrillation (5.7% vs. 0.7%, P < .001) at 2 years.
Inconsistencies between CLOSURE I and previous observational studies have been attributed to problems with
the STARFlex septal closure device itself. Backed by prior observational studies [19,20], it was postulated that the
STARFlex device was likely more prone to thrombus formation, atrial fibrillation, and residual shunting when
compared to other PFO-occluding devices, resulting in a higher risk of recurrent stroke or TIA. For example, 14%
6. EARLY RANDOMIZED TRIALS OF PFO CLOSURE FOR STROKE (CLOSURE I, PC AND RESPECT)68
III. STROKE AND PFO
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