Contemporary Reviews in Cardiovascular Medicine
Patent Foramen Ovale and Stroke
Shunichi Homma, MD; Ralph L. Sacco, MD
T his review summarizes the current state of knowledge
about the relationship of patent foramen ovale (PFO)
with ischemic stroke. Initial sections discuss the studies that
identified this association. Subsequent sections discuss the
detection techniques for PFO and other variables that may
cause a PFO to be a conduit of paradoxical embolization.
Finally, a section is devoted to summarizing the studies that
assessed the strategies for preventing recurrent ischemic
events in patients with PFO.
Cryptogenic Stroke and PFO
In ⬇40% of patients with acute ischemic stroke, the cause
remains undefined.1 PFO is a hemodynamically insignificant
interatrial communication present in ⬎25% of the adult
population. During fetal life, because the lungs do not receive
blood flow, blood returning to the right atrium is shunted
through a PFO to the left atrium. Postnatally, PFO closes
spontaneously in ⬇75% of the population. However, in a
portion of adults, by maintaining a direct communication
between the right- and left-sided circulation, PFO can serve
as a conduit for paradoxical embolization.
In 1877, Cohnheim2 described the association of PFO with
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stroke in a young woman with cerebral arterial embolism.
However, it has been difficult to diagnose PFO in vivo until
the development of echocardiography and its ability to image
the interatrial shunting with an injection of saline contrast.
With the use of contrast echocardiography, a strong associa-
tion of cryptogenic stroke with PFO has become evident in
patients ⬍55 years of age (Table 1).3– 8
Because stroke occurs more frequently in older population,
with only 3% of cerebral infarctions occurring in patients
⬍40 years of age, the number of stroke patients with PFO
ⱖ40 years of age is much larger than in the younger patients.9
Several studies reported the association of PFO with crypto-
genic stroke in older patient populations.6,7 However, this has
not been seen in other studies (Table 1).8,10 Therefore,
although the association between cryptogenic stroke and PFO
is established among the younger population, it is not clearly
established in the older population. This also has been
substantiated in a meta-analysis of studies relating to atrial
abnormalities and stroke.11
In support of PFO as a conduit for paradoxical emboliza-
tion, there are occasional case reports demonstrating venous
thrombi trapped in a PFO in patients with central or systemic
embolization.12–14 Nevertheless, other possible mechanisms
From the Division of Cardiology (S.H.) and Neurological Institute (R.L.S.), Columbia University, New York, NY.
Correspondence to Shunichi Homma, MD, Division of Cardiology, Columbia University, College of Physicians and Surgeons, 630 W 168th St, New
York, NY 10032. E-mail sh23@columbia.edu
(Circulation. 2005;112:1063-1072.)
© 2005 American Heart Association, Inc.
Circulation is available at http://www.circulationaha.org
1063
of stroke cannot be excluded. Given that a PFO can be a
tunnel-like structure with possibly a stagnant area of flow, in
situ thrombus fromation may occur. Also, patients with PFO
may be susceptible to atrial arrhythmias with possible intra-
atrial thrombus formation, leading to stroke.15
Detection of PFO
Contrast Echocardiography
Transthoracic (TT) echocardiography and transesophageal
(TE) echocardiography with saline contrast injection are
widely used to detect PFO. A PFO is judged to be present if
any microbubble is seen in the left-sided cardiac chambers
within 3 cardiac cycles from the maximum right atrial
opacification. Figure 1 demonstrates the appearance of mi-
crobubbles in the left-sided cardiac chambers after the venous
injection of contrast material in TT imaging. Injection is
performed with and without the Valsalva maneuver. Cough-
ing during injection may increase the sensitivity for detecting
PFO over that achieved by the Valsalva maneuver.16 Use of
harmonic imaging with TT echocardiography and contrast
injection may also increase the sensitivity of PFO detec-
tion.17,18 Saline contrast injection can be performed while
imaging the heart with a TE probe. Again, PFO is judged to
be present with the visualization of microbubbles in the left
atrium within 3 cardiac cycles from the right atrial opacifi-
cation. Figure 2 demonstrates the passage of microbubbles
from the right atrium into the left atrium through PFO as
demonstrated by TE echocardiography.
Location of the contrast material injection can influence
the chance of detecting a PFO. Contrast material injected into
the lower extremities has a higher chance of crossing a PFO
because the flow from the inferior vena cava is directed
toward the fossa ovalis as it enters the right atrium.19 Doppler
color-flow detection of a PFO is possible with TE; however,
this technique may not be as sensitive as contrast injection.20
Transcranial Doppler in PFO Detection
Paradoxical embolization through a PFO is considered to be
a mechanism for stroke associated with a PFO. In support,
direct demonstration of embolism through a PFO to the
cerebral circulation has been demonstrated. Figure 3 demon-
strates the baseline flow pattern obtained by transcranial
Doppler (TCD) in the middle cerebral artery and that seen
after saline contrast injection in a patient with a PFO.
However, detection of microbubbles in the cerebral circula-
DOI: 10.1161/CIRCULATIONAHA.104.524371
 1064 Circulation August 16, 2005

TABLE 1. Relationship of Cryptogenic Stroke With PFO in Younger and Older Patients
PFO

Study Patients, n Age, y Cryptogenic, % (n/total) Control, % (n/total) P

Younger patients
Lechat et al3 26 ⬍55 54 (14/26) 10 (10/100) ⬍0.001
Webster et al4 34 ⬍40 56 (19/34) 15 (6/40) ⬍0.001
Cabanes et al5 64 ⬍55 56 (36/64) 18 (9/50) ⬍0.0001
De Belder et al6* 39 ⬍55 13 (5/39) 3 (1/39) 䡠䡠䡠
Di Tullio et al7 21 ⬍55 47 (10/21) 4 (1/24) ⬍0.001
Hausmann et al8 18 ⬍40 50 (9/18) 11 (2/18) ⬍0.05
Total 䡠䡠䡠 䡠䡠䡠 46 (93/202) 11 (29/271)
Older patients
De Belder et al6* 64 ⬎55 20 (13/64) 5 (3/56) ⬍0.001
Di Tullio et al7 24 ⬎55 38 (9/24) 8 (6/77) ⬍0.001
Hausmann et al8 20 ⬎40 15 (3/20) 23 (23/98) NS
Jones et al10 57 ⬎50 18 (10/57) 16 (29/183) NS
Total 䡠䡠䡠 䡠䡠䡠 21 (35/165) 15 (61/414)
*Includes different stroke subtypes.

tion by TCD does not necessarily imply the presence of a
PFO. Any right-to-left shunt such as that resulting from
ventricular septal defect or intrapulmonary shunt may result
in the detection of microbubbles in the cerebral circulation by
TCD. As a result, TCD cannot identify the site of right-to-left
shunt, whereas TT or TE studies provide this information.21,22
Several studies performed contrast TT, TE, and TCD imaging
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ography.4 The Doppler signal across the mitral valve can also
be quantified.31 Similarly, the number of microbubbles can be
counted with TE studies.32,33 With TCD, high-intensity tran-
sient signals also can be quantified.34,35 However, any of
these methods will be variable because of differences in the
amount of bubbles injected, speed with which they are
injected, and variations in blood flow pattern in cardiac

in the same patient group to compare the sensitivity of the
techniques (Table 2).23–30 The TE contrast study is the most
sensitive diagnostic test available for detecting a PFO, fol-
lowed by TCD and TT contrast studies (P⬍0.001 for TE
versus TT and for TCD versus TT contrast studies).
Quantification of Size and Shunt
There are several methods to quantify the size of a shunt. The
number of microbubbles can be counted with TT echocardi-
chambers.36 –38 Alternatively, anatomic size of a PFO can be
measured by TE echocardiography (Figure 2). Measurement
from a vertical plane view in TE studies correlates well with
that by the invasive balloon method,39 which in general
relates to the amount of shunt.32 However, a PFO is inher-
ently a 3D structure with dynamic opening and closing, as
well as a channel-like structure in some patients that makes it
difficult to describe the size in 1 dimension.

Figure 1. In this TT echocardiographic view, appearance of
microbubbles in left atrium (LA) and left ventricle (LV) is demon-
strated after saline contrast injection in patient with PFO. Arrows
point to microbubbles. RA indicates right atrium; RV, right
ventricle.
Figure 2. Vertical TE echocardiographic view of fossa ovalis
area demonstrating passage of microbubbles through PFO
(arrow) from right atrium (RA) into left atrium (LA). Separation of
septum primum (SP) from septum secundum (SS) is visualized
and can be measured.
 Homma and Sacco Relationship of PFO With Stroke 1065

TABLE 3. Autopsy Prevalence of PFO

Study n Prevalence, %
Parsons and Keith40 399 26
Fawcett and Blanchford41 306 32
42
Scammon et al 809 29
Patten43 4083 25
Figure 3. Baseline TCD pattern of middle cerebral artery, fol- Seib44 500 17
lowed by signals detected after microbubbles reach cerebral
circulation in patient with PFO (segment indicated by arrows). Wright et al45 492 23
46
Schroeckenstein et al 144 35
Sweeney and Rosenquist47 64 31
Factors Associated With Paradoxical
Hagen48 965 27
Embolization
Thompson and Evans49 1000 29
Atrial Anatomy
Penther50 500 15
Size of a PFO Total 9262 26
As shown in Table 3, the prevalence of a PFO in autopsy
studies is ⬇26%.40 –50 PFO frequency and size may vary by
age.48,49 Given the high prevalence of PFO in the general septal area and the selection bias for patients referred for TE
population and the variability in PFO size, its size may be an echocardiography (Table 4).69 –73
important factor in determining the importance of an individ- The prevalence of ASA is greater among patients with
ual PFO to act as a conduit for paradoxical embolization. embolic events.7,71,73–75 It is also well known that ASA is
With contrast TT echocardiography,4 TE echocardiogra- associated with PFO, with ⬇60% of patients with ASA
phy,32,33,51 or TCD25,52 or during cardiac catheterization,53 having a PFO (Table 4).57,59,69,71,72,76 –79 Additionally, the
patients with presumed paradoxical embolization appear to PFOs seen in the presence of ASA tend to be large compared
have larger PFOs compared with those in control groups. In with those seen without associated ASA.79,80 Thus, the
the recent PFO in Cryptogenic Stroke Study (PICSS), it also association of ASA with embolic events is likely based on the
has been shown that large PFOs were significantly more high prevalence of large PFOs. Because an ASA is usually
prevalent among cryptogenic stroke patients compared with highly mobile, protruding from right to left atrium, it is
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those with known cause of stroke.54 Additionally, stroke
patients with larger PFOs have brain imaging findings sug-
gestive of an embolic mechanism,55 and PFO size may be an
independent risk factor for recurrent cerebrovascular events.56
Atrial Septal Aneurysm
Atrial septal aneurysm (ASA) is a redundancy of the inter-
atrial septum detected most commonly by TT or TE studies.
On TE study, it is typically defined as ⬎10-mm protrusion
beyond the plane of the septum into the left or right
atrium.57,58 Although the definition varies somewhat in dif-
ferent series, the prevalence in the general population is
estimated with TT imaging to be only 0.23% (Table 4).59 – 69
A considerably higher prevalence of 4.6% is noted among
those referred for TE echocardiography, most likely because
of the higher sensitivity of the TE technique for imaging the
unlikely that a thrombus forms in the ASA itself. This is
corroborated by a rare finding of thrombus associated with
ASA in a large series of patients.57
Eustachian Valve and Chiari’s Network
The eustachian valve is a membrane-like structure in the right
atrium, a remnant of the right valve of the sinus venosus that
directs blood flow from the inferior vena cava to the fossa
ovalis area in the fetus.81 Among adults, a eustachian valve
can cause a significant right-to-left shunt in the presence of an
interatrial communication by altering the blood flow pat-
tern.82,83 Prominent eustachian valve is also more commonly
found among patients with presumed paradoxical embolism
than in control patients.84 The presence of Chiari’s network
and filamentous strands in the right atrium is also associated
with the presence of PFO.79,85 Therefore, the presence of

TABLE 2. Comparison of Techniques for PFO Detection

Study Patients, n TT Echo, % (n/total) TCD, % (n/total) TE Echo, % (n/total)
23
Teague and Sharma 46 26 (12/46) 41 (19/46) 䡠䡠䡠
Di Tullio et al24 80 18 (14/80) 26 (21/80) 䡠䡠䡠
Jauss et al25 50 䡠䡠䡠 28 (14/50) 30 (15/50)
Karnik et al26 36 䡠䡠䡠 36 (13/36) 42 (15/36)
27
Job et al 137 䡠䡠䡠 42 (58/137) 47 (65/137)
Klötzsch et al28 111 䡠䡠䡠 38 (42/111) 41 (46/111)
Nemec et al29 32 23 (7/32) 41 (13/32) 41 (13/32)
Di Tullio et al30 49 18 (9/49) 27 (13/49) 38 (19/49)
Total 䡠䡠䡠 20 (42/207) 36 (193/541) 42 (173/415)
 1066 Circulation August 16, 2005

TABLE 4. Prevalence Studies Venous Thrombus and Hypercoagulable State

Study ASA Patients Prevalence, %
For paradoxical embolization to occur, a source of thrombus
is needed. A significant stroke can result from an arterial
Prevalence of ASA by TT study
occlusion by an embolus as small as 1 mm in diameter.93 A
Hanley et al59 80/36 200 0.22 greater prevalence of deep venous thrombus is observed in
60
Gallet et al 10/4840 0.21 one study in patients with cryptogenic stroke compared with
Longhini et al61 23/4000 0.57 a control group.94 However, several other studies do not
Bewick and Montague62 6/4700 0.12 corroborate this finding.95–97 More recently, pelvic vein
Wolf et al63 12/724 1.7 thrombi are reported to be found more frequently in young
Belkin et al 64
36/6979 0.5
patients with cryptogenic stroke compared with those with
more defined causes of stroke.98 Pelvic veins and abdominal
Brand et al65 35/3500 1.0
veins are not studied routinely in patients with cryptogenic
Roudant et al66 44/62 540 0.08
stroke and PFO, and these areas may harbor thrombus.
Katayama et al67 26/2074 1.2 Finding of a venous thrombus strengthens the possible role of
68
Oneglia et al 38/4031 0.94 PFO as a conduit for paradoxical embolization and will affect
Schneider et al69 20/12 137 0.16 treatment strategy. Patients with a tendency toward venous
Total 330/141 725 0.23 thrombus formation may be exposed to a higher chance of
Prevalence of ASA by TE Study paradoxical embolization in the presence of PFO. Several
Schneider et al69 23/765 3.0
studies report a higher frequency of prothrombotic states such
as G20210A and factor V Leiden mutations in patients with
Schreiner et al70 7/340 2.1
cryptogenic stroke and PFO.99 –102 A recent study demon-
Zabalgoitia et al71 20/199 10
strates a higher recurrent event rate in older cryptogenic
Pearson et al72 32/410 7.8 stroke patients with PFO compared with similarly aged
73
Mirode et al 32/751 4.2 cryptogenic stroke patients without PFO.103 This may be due
Total 114/2465 4.6 in part to the presence of occult thrombi in older patients
PFO prevalence among patients compared with the younger patients.
with ASA In summary, variation in PFO size, right atrial anatomy,
Mügge et al57 (TE echo) 106/195 54 hemodynamic conditions, and potential source of an available
Hanley et al59 (TE echo) 24/49 49 thrombus all play a part in influencing the chances of
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Schneider et al69 (TE echo) 17/22 77

paradoxical embolization.
Zabalgoitia-Reyes et al71 (TE echo) 17/20 85
Recurrent Stroke Prevention
Pearson et al72 (TE echo) 20/29 69
Possible treatment modalities to prevent recurrent events
Silver et al76 (autopsy) 8/16 50 among stroke patients with a PFO include medical treatment
Mattioli et al77 (TE echo) 39/44 89 with warfarin or antiplatelet agents, percutaneous PFO clo-
78
Burger et al (TE echo) 18/32 56 sure, and surgical PFO closure. In this section, recurrent event
Homma et al79 (TE echo) 44/69 64 rates from the available outcome studies are summarized.
Total 293/476 62 Recurrent event rates are estimated from published studies in
MedLine since 1990. The number of subjects, mean age, and
follow-up time are obtained for each publication. If there are
atrial anatomic variants that can promote flow from the duplications of patient population in studies, only one is
inferior vena cava toward the PFO may increase the chance of included or, to the extent possible, correction in numbers is
paradoxical embolization beyond that associated with PFO made. Inclusion criteria are (1) presumed paradoxical em-
size. bolic events without obvious cause, including cryptogenic
stroke, transient ischemic attack (TIA), or other embolic
Hemodynamics arterial events such as peripheral embolism; (2) documented
In addition to the atrial anatomic variables, hemodynamic PFO on echocardiography, either TT or TE; and (3) original
alterations play a major role in determining the chances of manuscript available in English.
paradoxical embolization. Although transiently higher right For the purpose of creating a summary table, all-cause
atrial pressure can occur during normal cardiac cycle,86 mortality is included in the table. Thus, when discrepancies in
cardiac lesions more consistently elevating right atrial pres- the number exist in some of the cells compared with the
sure will increase the chance of right-to-left shunt. As a result, published manuscript, it is due to the difference in the criteria
paradoxical embolization is often reported in patients with used for end points. The number of events in each study was
pulmonary embolism.87,88 Similarly, patients with right ven- summed to obtain the total number of events. Similarly, the
tricular infarction89 or severe tricuspid regurgitation90 or total time at risk was determined by summing the number of
those on a mechanical left ventricular assist device have an subjects multiplied by the mean follow-up time for each
increased right-to-left shunt through a PFO.91 Although a study. Event rates were calculated as the ratio of the total
right-sided pressure elevation can increase the flow across number of events to the total years of follow-up divided by
PFO, left-sided pressure elevation will decrease it.92 100 to yield event rates per 100 patient-years. The 95% CI for
 Homma and Sacco Relationship of PFO With Stroke 1067

TABLE 5. Summary Table of Medical Therapy Studies

Stroke,
Mean Mean Stroke Stroke Death,
Patients, Age, Follow-Up, Stroke, Death, TIA, or Death, or TIA, or TIA,
Study n y mo n n n n n n
Hausmann et al33 44 46 59 1 䡠䡠䡠 2 䡠䡠䡠 3 䡠䡠䡠
Homma et al54 98 55 22 10 4 8 14 18 22
Hanna et al105 13 43 27 0 䡠䡠䡠 0 䡠䡠䡠 0 䡠䡠䡠
Mas and Züber106 107 39 22 2 䡠䡠䡠 3 䡠䡠䡠 5 䡠䡠䡠
Bogousslavsky et al107 129 44 36 8 5 8 13 16 21
Cujec and Mainra108 52 38 46 7 䡠䡠䡠 12 䡠䡠䡠 19 䡠䡠䡠
De Castro et al109 74 53 31 5 5 3 10 8 13
Mas et al110 267 40 38 12 1 9 13 21 22
111
Nedeltchev et al 159 51 29 7 䡠䡠䡠 14 䡠䡠䡠 21 䡠䡠䡠
Total 943 45 33 52 15 59 50 111 78
Events per 100 patient-years 䡠䡠䡠 䡠䡠䡠 䡠䡠䡠 1.98 0.94 2.24 3.12 4.22 4.86
95% CI 䡠䡠䡠 䡠䡠䡠 䡠䡠䡠 1.48–2.60 0.53–1.55 1.71–2.89 2.32–4.11 3.43–5.01 3.78–5.94

the pooled event rates was determined by assuming that
observed events followed the Poisson distribution. For the
studies of the effect of medical therapy on stroke recurrence
or TIA, homogeneity of event rates was assessed using
Cochran’s Q test after excluding the single study with 13
subjects and no events. A significant lack of homogeneity
was not detected for either recurrent stroke (Q⫽4.35,
P⫽0.74) or TIA (Q⫽6.89, P⫽0.44). Similar tests of homo-
geneity were not performed for percutaneous closure or
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estimated at 1% to 2% annually and minor bleeding risk 10%
to 20%, higher in those on warfarin compared with
aspirin.112,113
Percutaneous Closure of PFO
Because PFO represents a repairable lesion, interest in clos-
ing them is high. Currently, the most commonly used devices
in the United States are the Amplatzer PFO Occluder (AGA
Medical) and CardioSEAL (NMT Medical) devices.114,115

surgery because of the small number of events. Tables are
made that include number of patients in the study, mean age,
and mean follow-up in months. In terms of the end points,
stroke, any-cause death, TIA, stroke or death, stroke or TIA,
and stroke death or TIA are included. A similar summary, but
with somewhat different criteria, has been recently
published.104
Medical Therapy
A total of 943 patients are considered in the analysis (Table
5).33,54,105–111 The mean age of the patients is 45 years; mean
duration of follow-up is 33 months. Medications used include
both warfarin and aspirin. There were 15 deaths (any cause),
52 strokes, and 59 TIAs. The annual rate of stroke is 1.98%
(95% CI, 1.48 to 2.60) and of stroke or death is 3.12% (95%
CI, 2.32 to 4.11). Individual studies demonstrate variable
recurrent event rates. This is due in part to the difference in
the age of subjects; younger cryptogenic stroke patients with
PFO have a significantly lower event rate compared with the
older cryptogenic stroke patients with PFO.103 Only one study
randomized patients to warfarin or aspirin therapy.54 In this
study, there is no difference in event rates between those with
and without PFO on medical therapy. When patients treated
with warfarin are compared with those treated with aspirin,
there is no significant difference, although the study is not
adequately powered for this purpose.
Some studies identified the combination of ASA and PFO
as a predisposing factor for increased recurrent event rates,
whereas another has not.79,106,110 Major bleeding risk from
medical therapy, particularly from the use of warfarin, is
The Amplatzer device is made of self-expanding nickel-
titanium alloy wire mesh with double disks that contain inner
polyester fabric patches. The CardioSEAL device is con-
structed from a low-profile nickel-cobalt alloy framework
shaped like an umbrella to which a knitted polyester fabric is
attached. Under the Humanitarian Device Exemption (HDE)
program of the US Food and Drug Administration (FDA),
these devices are approved for use in patients with recurrent
cryptogenic stroke caused by presumed paradoxical embo-
lism through a PFO who have failed therapeutic dosage of
oral anticoagulants.
Using the same criteria as for Table 5, Table 6 shows the
event rates in patients undergoing percutaneous PFO clo-
sure.53,116 –126 Again, when overlap in patient population
occurs, only one study appears in Table 6 or the numbers are
adjusted. A total of 1430 patients are considered in the
analysis. Of note, some of the studies include patients
receiving a device other than an Amplatzer or a CardioSEAL,
and many of studies are performed outside the United States
where the devices can be clinically used. The mean age of the
patients is 46 years; the mean duration of follow-up is 18
months. There is variable use of warfarin or antiplatelet
agents after closure. There were 4 deaths, 4 strokes, and 32
TIAs. The annual rate of stroke is 0.19% (95% CI, 0.05 to
0.49) and of stroke or death 1.15% (95% CI, 0.46 to 2.37).
Complications from device implantation include major
complications such as death, major hemorrhage, cardiac
tamponade, and fatal pulmonary emboli. These occur in
⬇1.5% of the patients.104 Minor complications such as atrial
arrhythmias, device arm fractures, device embolization, de-
 1068 Circulation August 16, 2005

TABLE 6. Summary Table of Percutaneous PFO Closure Studies

Stroke,
Mean Mean Stroke Stroke Death, Peripheral
Patients, Age, Follow-Up, Stroke, Death, TIA, or Death, or TIA, or TIA, Embolism,
Study n y mo n n n n n n n
Bridges et al53 36 39 8 0 䡠䡠䡠 4 䡠䡠䡠 4 䡠䡠䡠 䡠䡠䡠
Ende et al116 10 40 32 0 䡠䡠䡠 0 䡠䡠䡠 0 䡠䡠䡠 䡠䡠䡠
Hung et al117* 28 46 31 0 2 3 2 2 5 䡠䡠䡠
Sievert et al118 281 47 12 2 0 7 2 9 9 0
Beitzke et al119 162 40 19 0 䡠䡠䡠 3 䡠䡠䡠 3 䡠䡠䡠 䡠䡠䡠
Butera et al120 35 48 12 0 䡠䡠䡠 0 䡠䡠䡠 0 䡠䡠䡠 䡠䡠䡠
Wahl et al121 152 59 20 1 䡠䡠䡠 6 䡠䡠䡠 7 䡠䡠䡠 2
Martin et al122* 110 47 28 1 2 1 3 3 4 䡠䡠䡠
Du et al123 18 42 26 0 䡠䡠䡠 0 䡠䡠䡠 0 䡠䡠䡠 䡠䡠䡠
Braun et al124 276 45 15 0 䡠䡠䡠 8 䡠䡠䡠 8 䡠䡠䡠 0
Bruch et al126 66 48 20 0 䡠䡠䡠 0 䡠䡠䡠 0 䡠䡠䡠 0
Onorato et al126 256 48 19 0 䡠䡠䡠 0 䡠䡠䡠 0 䡠䡠䡠 䡠䡠䡠
Total 1430 46 18 4 4 32 7 36 18 2
Events per 100 patient-years 䡠䡠䡠 䡠䡠䡠 䡠䡠䡠 0.19 0.66 1.52 1.15 1.62 2.95 0.20
95% CI 䡠䡠䡠 䡠䡠䡠 䡠䡠䡠 0.05–0.49 0.18–1.69 1.04–2.15 0.46–2.37 1.13–2.24 1.75–4.66 0.02–0.72
*Number of patients is adjusted.

vice thrombosis, ECG changes, and AV fistula formation are
reported in 7.9%.104 Thrombus formation on the device may
depend largely on the device used.127 PFO represents a
potential space, bordered by 2 overlapping membranes, some
with tunnel-like anatomy. “PFO-specific” devices may sim-
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closure devices, the surgical approach is no longer widely
used. Even with the use of a minimally invasive approach,133
it is very likely that the surgical approach will be replaced by
percutaneous approaches.

plify closure in the future, and there are a variety of newer
devices and methods conceptualized and tested to close a
PFO. These include anatomically fitting devices, staplers, and
tissue glues.
Surgical Closure of PFO
Table 7 shows the event rates in surgically treated patients
with PFO.128 –132 A total of 161 patients are considered in this
analysis. The mean age of the patients is 43 years, and the
mean duration of follow-up is 22 months. There were 2
deaths, 1 stroke, and 11 TIAs. The annual rate of stroke is
0.34% (95% CI, 0.01 to 1.89) and of stroke or death is 0.85%
(95% CI, 0.10 to 3.07). However, the number of patients in
this analysis is small, and with the advent of percutaneous
Comparison of Modalities and Current Trials
Although Tables 5 through 7 demonstrate summary outcome
measures for the different treatment approaches, there are no
direct randomized comparisons of treatment modalities. In a
collective analysis, there are no convincing data to indicate
that the presence of PFO increases recurrent events in
medically treated patients.134 Whether PFO closure decreases
the event rate further remains unanswered. Some analyses
suggest possible superiority of percutaneous closure com-
pared with medical therapy.135
Using our tables, we compared medical therapy with
percutaneous closure, with stroke or stroke and TIA as end
points. For both comparisons, percutaneous closure gives
lower event rates compared with medical therapy

TABLE 7. Summary Table of Surgical PFO Closure Studies

Stroke,
Mean Mean Stroke Stroke Death,
Patients, Age, Follow-Up, Stroke, Death, TIA, or Death, or TIA, or TIA,
Study n y mo n n n n n n
Harvey et al128 4 47 14 0 䡠䡠䡠 0 䡠䡠䡠 0 䡠䡠䡠
Devuyst et al129 30 38 23 0 䡠䡠䡠 0 䡠䡠䡠 0 䡠䡠䡠
Homma et al130 28 41 19 1 1 3 1 4 4
Giroud et al131 8 46 12 0 0 0 0 0 0
Dearani et al132 91 44 24 0 1 8 1 8 9
Total 161 43 22 1 2 11 2 12 13
Events per 100 patient-years 䡠䡠䡠 䡠䡠䡠 䡠䡠䡠 0.34 0.85 3.71 0.85 4.05 5.55
95% CI 䡠䡠䡠 䡠䡠䡠 䡠䡠䡠 0.01–1.89 0.10–3.07 1.8–5-6.64 0.10–3.07 2.09–7.07 2.96–9.49
 Homma and Sacco
(P⬍0.0001). However, very importantly, indirect comparison
of medical treatment and percutaneous closure is very diffi-
cult to interpret. Inclusion criteria for the studies reviewed are
not uniform, and definitions of what constitutes a cryptogenic
stroke or TIA vary widely among studies. The age of subjects
is variable, which may significantly affect the observed event
rates. Many of the studies are also subject to potential
selection bias and do not use independent blinded adjudica-
tion of events.136 There also is prolonged time from the index
event to percutaneous closure in some studies and the use of
medical therapy in patients undergoing PFO closure is not
accounted for in some studies. Devices may also carry a
placebo effect,137 and the number of events is small, partic-
ularly for percutaneous closure, resulting in estimates with
broad CIs. As such, results of ongoing randomized studies are
needed to provide convincing evidence with regard to treat-
ment options.138 –141
There are 3 ongoing randomized studies in the United
States comparing the efficacy of percutaneous closure with
medical therapy. The Randomized Evaluation of Recurrent
Stroke Comparing PFO Closure to Established Current Stan-
dard of Care Treatment (RESPECT) trial (sponsored by AGA
Medical) randomizes cryptogenic stroke patients with PFO to
percutaneous closure with an Amplatzer device or medical
therapy (antiplatelet or warfarin at the enrolling physician’s
discretion). CLOSURE I trial (sponsored by NMT Medical)
randomizes patients with stroke or TIA thought to be due to
paradoxical embolization to percutaneous closure with
STARFlex septal occluder (subsequent-generation Cardio
Downloaded from http://ahajournals.org by on December 12, 2018
SEAL but not FDA approved under the HDE program) or
medical therapy (aspirin and/or warfarin at the enrolling
physician’s discretion). The Cardia PFO trial (sponsored by
Cardia Inc) randomizes patients to PFO closure using its PFO
closure device (not FDA approved under the HDE program)
or warfarin. The Amplatzer device is also used in Europe and
Australia in the Patent Foramen Ovale and Cryptogenic
Embolism (PC) trial (sponsored by AGA Medical). This
study randomizes cryptogenic stroke patients with PFO to
device closure or medical therapy (antiplatelet or warfarin at
the enrolling physician’s discretion). Of note, in all trials,
patients randomized to the device arm also receive medical
therapy for a variable period of time, in some cases for the
study duration.
In a subset of patients with PFO and hypercoagulable state,
anticoagulation is required. In this group, the additional effect
of PFO closure (in addition to anticoagulation) is undefined,
and the ongoing trials do not address this issue because
hypercoagulable state is a contraindication to enrollment.
Conclusions
Because PFO is commonly found in normal populations, we
need to identify a subset of cryptogenic stroke patients who
are likely to have experienced paradoxical embolization.
Various factors need be considered such as atrial anatomic
variation (PFO size, ASA, eustachian valve anatomy), hemo-
dynamic parameters, presence of venous thrombus identified
through higher-sensitivity tests such as lower extremity/
abdominal/pelvic MRI, and the presence of hypercoagulable
genetic variables. The presence of any of these findings
Relationship of PFO With Stroke 1069
increases the chance of PFO contributing to stroke. As such,
tests to define these parameters are necessary. Currently, the
superiority of one method over another for recurrent event
prevention remains undefined. Randomized studies compar-
ing medical and percutaneous closure approaches are under-
way, but large patient enrollment is necessary because of the
low event rate in the younger patients. At this juncture, for
those meeting enrollment criteria, participation in ongoing
studies is recommended. For those requiring therapeutic
decision, once the likelihood of individual PFO association
with ischemic event is determined, the choice of therapy
needs be tailored to an individual patient’s lifestyle and
preference. Meanwhile, as the complication rate from device
implantation decreases and simpler devices are developed
with reliability further demonstrated, the threshold for percu-
taneous closure is likely to decline. Patients should also be
updated periodically on the developments in this field and
reassured that lifelong anticoagulation (for those placed on
warfarin) may not be necessary.
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KEY WORDS: anticoagulants 䡲 aspirin 䡲 embolism 䡲 heart septal defects,
atrial 䡲 stroke