Catheterization and Cardiovascular Interventions 82:E38–E51 (2013)

PEDIATRIC AND CONGENITAL HEART DISEASE

Original Studies

Management of Patients with Patent Foramen Ovale and

Cryptogenic Stroke: A Collaborative, Multidisciplinary,
Position Paper
Christian Pristipino,1* MD, Gian Paolo Anzola,2 MD, Luigi Ballerini,3 MD, Antonio
Bartorelli,4 MD, Moreno Cecconi,5 MD, Massimo Chessa,6 MD, Andrea Donti,7 MD,
Achille Gaspardone,8 MD, Giuseppe Neri,9 MD, Eustaquio Onorato,10 MD,
Gualtiero Palareti,11 MD, Serena Rakar,12 MD, Gianluca Rigatelli,13 MD, PhD,
Gennaro Santoro,14 MD, Danilo Toni,15 MD, Gian Paolo Ussia,16 MD,
Roberto Violini,17 MD, on behalf of: Italian Society of Invasive Cardiology (SICI-GISE);
Italian Stroke Association (ISA-AIS); Italian Association of Hospital Neurologists,
Neuroradiologists, Neurosurgeons (SNO); Congenital Heart Disease Study Group of
Italian Society Of Cardiology; Italian Association Of Hospital Cardiologists (ANMCO);
Italian Society Of Pediatric Cardiology (SICP); Italian Society of Cardiovascular
Echography (SIEC); Italian Society of Hemostasis and Thrombosis (SISET). , and ,

1
Clinical Research Centre and Cardiovascular Department, Conflict of interest: Massimo Chessa has a proctorship contract with
San Filippo Neri Hospital, Roma, Italy AGA medical, St Jude Medical, Gore, and Cardia. Andrea Donti has
2
Service of Neurology, S. Orsola Hospital FP, Brescia, Italy a proctorship contract with AGA medical. Achille Gaspardone has a
3
Women and Children Department, S. Carlo Hospital, proctorship contract with NMT Medical, Boston, MA (BioSTAR
Potenza, Italy device) and is investigator of BRAVO (A prospective multuicentre,
4
Interventional Cardiology Area, Monzino Cardiology Centre, registry for evaluation of the BioSTAR septal repair implant for the
Milano, Italy closure of patent foramen ovale) Eustaquio Onorato is the principle in-
5
Cardiological, Medical and Surgical Sciences Department, vestigator of INTUIRE IN TUnnel pfo closure Italian REgistry con-
University United Hospitals, Ancona, Italy cerning Coherex FlatStent EF (Coherex Medical) and has proctorship
6
Pediatric Cardiology and Adult with Congenital Heart Disease contract with Occlutech Italy. Gianluca Rigatelli has a consultant/proc-
Department, IRCCS Policlinico San Donato, San Donato tor contract with St Jude Medical Italy Gennaro Santoro has a proctor-
Milanese, Italy ship contract with AGA medical. Vittorio Ambrosini received honora-
7
Pediatric and Developmental Age Cardiology—Bologna Uni- ria for being a guest speaker in Occlutech sponsored symposia.
versity—S. Orsola Malpighi Hospital, Bologna, Italy
8
Cardiology Department, Sant’Eugenio Hospital, Roma, Italy Grant sponsor: AGA medical Italy, St. Jude Medical Italy,
9
Education, quality and clinical effectiveness assessment Occlutech Italy, and Biosense Webster Italy provided meeting
Unit, San Filippo Neri Hospital, Roma, Italy expenses
10
Montevergine Hospital, Mercogliano, Italy
11
Angiology and Coagulation Disorders Unit—S.Orsola An executive summary of this article has been printed in the jour-
Malpighi Hospital, Bologna, Italy nal.
12
Cardiology Department, Cattinara Hospital, Trieste, Italy
13
Cardiovascular Diagnosis and Endoluminal Interventions *Correspondence to: Christian Pristipino, San Filippo Neri Hospital,
Department, Rovigo General Hospital, Rovigo, Italy Via Alessandro Poerio 140, 00152 Rome, Italy.
14
Cardiology and Vessel Department, Careggi Hospital, E-mail: pristipino.c@gmail.com
Firenze, Italy
15
Neurology and Psychiatry Department, Sapienza University, Received 24 April 2012; Revision accepted 28 August 2012
Roma, Italy
16
Invasive Cardiology Unit, Ferrarotto Hospital, Catania Uni- DOI 10.1002/ccd.24637
versity, Catania, Italy Published online 8 April 2013 in Wiley Online Library
17
Interventional Cardiology Unit, San Camillo Hospital, Roma, Italy (wileyonlinelibrary.com)

C 2013 Wiley Periodicals, Inc.

V
 PFO Management E39

Objectives: To organize a common approach on the management of patent foramen

ovale (PFO) and cryptogenic stroke that may be shared by different specialists. Back-
ground: The management of PFO related to cryptogenic stroke is controversial,
despite an increase in interventional closure procedures. Methods: A consensus state-
ment was developed by approaching Italian national cardiological, neurological, and
hematological scientific societies. Task force members were identified by the president
and/or the boards of each relevant scientific society or working group, as appropriate.
Drafts were outlined by specific task force working groups. To obtain a widespread
consensus, these drafts were merged and distributed to the scientific societies for
local evaluation and revision by as many experts as possible. The ensuing final draft,
merging all the revisions, was reviewed by the task force and finally approved by
scientific societies. Results: Definitions of transient ischemic attack and both symptomatic
and asymptomatic cryptogenic strokes were specified. A diagnostic workout was identified
for patients with candidate event(s) and patient foramen ovale to define the probable
pathogenesis of clinical events and to describe individual PFO characteristics. Further
recommendations were provided regarding medical and interventional therapy considering
individual risk factors of recurrence. Finally, follow-up evaluation was appraised.
Conclusions: Available data provided the basis for a shared approach to management of
cryptogenic ischemic cerebral events and PFO among different Italian scientific societies.
Wider international initiatives on the topic are awaited. VC 2013 Wiley Periodicals, Inc.

Key words: embolic stroke; patent foramen ovale; treatment

INTRODUCTION shared by different specialists, expecting updates as

Cryptogenic stroke, defined as stroke caused by
unknown, undetermined, or unclear causes, comprises
30–40% of all strokes [1,2].
The possible correlation between cryptogenic cere-
bral ischemia and patent foramen ovale (PFO) was
hypothesized more than 130 years ago [3], later dem-
onstrated in anectodical cases but its role and implica-
tions in the general population still remain disputed
[4–13]. Only one, recently published, randomized trial
is available to date, therefore existing guidelines have
been previously proposed based on data from observa-
tional trials but different organizations have issued var-
ied and limited recommendations because of the lack
of evidence [14–16]. As a consequence, the referral of
patients is still based on individual factors or local
usual practice that often are not considered in guide-
lines but come from different interpretations of con-
temporary literature. The resulting untidy behavior of
medical community translated in an increase in percu-
taneous closures of PFO (e.g., twofold to threefold
increase in the past 3 years in Italy), which in turn
resulted in important consequences at the medical,
social, and legal level [17]. To help in overcoming
cumbersome concerns in a controversial environment,
it is part of the mission of scientific societies to express
shared official positions to be locally translated in
rational health policies. Traditionally, this is done with
guidelines, but when available evidences are not at the
highest level this may be effected with position papers,
while waiting for more consistent evidences. Therefore
to address the urgent need of adopting a comprehen-
sive and rationale workflow in the management of
patients with cryptogenic stroke and PFO, we
attempted to organize a common approach that may be
Published on behalf of The Society for Cardiovascular Angiography and Interventions (SCAI).
soon as more convincing evidences will be released.
METHODS
Although PFO may be associated with several differ-
ent clinical pictures (e.g., peripheral embolism, platyp-
nea-orthodeoxia syndrome, embolism-prone surgery,
decompression sickness, vocational hazards, etc), this
position paper is focusing exclusively on the associa-
tion of PFO with stroke. Moreover, even in the pres-
ence of PFO, stroke at large remains a complex multi-
factorial syndrome in which several pathogenic factors
(such as atrial fibrillation, thrombophilia, or atheroscle-
rosis) come into play and mutually interact. However,
given the absence of data regarding these aspects and
to simplify this first wide consensus initiative, we lim-
ited the interest to the very cryptogenic stroke, exclud-
ing further additional complex mechanisms. Based on
a previous feasibility initiative [18], a consensus state-
ment of recommendations was developed by approach-
ing national scientific societies (see Aknowledge-
ments). SICI-GISE selected task force members based
on their previous work in relevant topic areas (both
publications and procedural volume concerning percu-
taneous closure of PFO). The other scientific societies
or working group independently identified task force
members. After an initial in person meeting of the task
force members, specific subjects were identified, corre-
sponding working groups were defined, and specific
drafts were outlined. The task force used systematic lit-
erature reviews (by searching Medline/Pubmed,
Embase, Scopus, CENTRAL, Google scholar),
Catheterization and Cardiovascular Interventions DOI 10.1002/ccd.
E40 Pristipino et al.
reference to previously published guidelines, personal
files, and expert opinion to summarize existing evi-
dence, indicate gaps in current knowledge, and when
appropriate, formulate recommendations. These drafts
were merged by the writing committee and distributed
to the scientific societies for local evaluation and revi-
sion by as many experts as possible. The revisions
were merged to create a final draft that was revised by
the task force and distributed to the scientific societies
for final approval.
Evidence basis for a contemporary
consensus on PFO
Evidence-based medicine is classically centered on
randomized controlled trials (RCT) and observational
registries; both have important strengths but also limitations.
By controlling for the highest number of biases,
RCTs are the highest hierarchical form of evidence-
based medicine. Indeed, the United States Food and
Drug Administration have recommended that RCTs
should be done for different drug therapies (antiplatelet
and anticoagulant drugs) and for techniques and devi-
ces for percutaneous closure of a PFO [19]. There are
four large ongoing trials in the United States, Europe,
and Australia [20] and only one trial has been pub-
lished to date [21]. General limitations of RCT
addressing PFO therapies include: (1) difficult extrapo-
lation of RCT results to unselected populations encoun-
tered in clinical practice; (2) short duration of follow-
up (2–5 years) to compare long-term efficacy and
safety of life-long drug treatments with interventional
procedures; (3) difficult generalizability of any result
obtained with a specific implantable device to other
devices; (4) long enrolment phase raising concerns on
homogeneity of therapies; (5) selection bias with enrol-
ment of low risk patients.
In contrast, by capturing data on all interventions,
large observational registries may more accurately
reflect routine clinical practice. In the absence of ran-
domization, however, their fundamental limitation is
that they cannot control for all confounding factors,
which may influence both the choice and the outcome
of different interventions. Propensity matching can
only partially mitigate this problem. Accepting these
limitations, to obtain a timely document which may
help in contemporary clinical practice while waiting
for conclusive evidence coming from RCT, it should
be kept in mind that independent registries and obser-
vational trials have been the main basis to build this
management workflow. Therefore, this document
should be used as a guide, helping in building a
rational approach, while clinical judgment and multi-
disciplinary approach remain essential.
Catheterization and Cardiovascular Interventions DOI 10.1002/ccd.
Published on behalf of The Society for Cardiovascular Angiography and Interventions (SCAI).
MULTISCIPLINARY DECISION MAKING (HEART/
BRAIN TEAM) AND PATIENT ENPOWERMENT
Except in anectodical cases where a direct observa-
tion of a thrombus crossing the interatrial septum is possi-
ble, a possible cause-effect correlation between a cerebral
ischemic event and a PFO in any individual patient is
based on the Bayesian likelihood of this association, cen-
tered on clinical and anatomic factors. Moreover, therapeu-
tic decision must be proposed to patients on the basis of re-
currence probability, individually estimated on clinical
grounds. Given the complexity of these assessments, the
creation of a multidisciplinary team serves the purpose of a
balanced multidisciplinary decision process. It is recom-
mended that a case-by-case evaluation be performed in
expert centers by a heart/brain team coming to a consensus
involving neurological and cardiological (clinical, inter-
ventional, and imaging) issues. Additional inputs may be
required from hematologists and radiologists. In hospital or
in outpatient settings where any of these professionals are
not available, it is recommended to refer to protocols
designed with expert neurologists and interventional cardi-
ologists, or seek their advice for complex cases.
Although evaluating the diagnosis and treatment
options, high priority should be given to patients’
detailed information regarding the issues connected with
a probabilistic approach to their cryptogenic cerebrovas-
cular accident. They also should be clearly informed
about the strengths, limitations, and uncertainties of the
available evidences on their condition and on different
treatment options. It is therefore recommended that
patients fully understand goals, risks, and potential bene-
fits of each phase of the management of their disease and
participate actively throughout the decision-making pro-
cess. Patients must have sufficient time to reflect on the
trade-offs of the estimates and weigh this information in
the light of their personal values.
EVALUATION FOR CRYPTOGENIC
STROKE AND PFO
Definitions
Cryptogenic stroke. Cryptogenic stroke is defined
as a clinical syndrome consisting of focal or global
neurologic deficit, associated with a related lesion on a
computed tomography (CT) or magnetic resonance
(MR) scan, that has no known underlying cause despite
a thorough evaluation with diagnostic procedures that
are currently available (Fig. 1).
Silent cryptogenic stroke is defined as an asymptom-
atic lesion (single or multiple) of white or grey matter
that is documented with a CT or MR scan, for which
no underlying cause is identified despite a thorough
 PFO Management E41

Fig. 1. Diagnostic algorithm for stroke. AF, Atrial fibrillation; AG, cerebral angiogram; AMI,
acute myocardial infarction; VHD, valvular heart disease; DD, duplex and transcranial Dopp-
ler; lac syndrome, currently described classic lacunar syndromes, possibly including other
syndromes from focal-deep infarction (e.g., cognitive changes from thalamic or caudate
infarcts); LV, left ventricular; MRA, magnetic resonance angiography; TIA, transient ischemic
attack. Reproduced from Ref. [22], permission from Elsevier.

evaluation with diagnostic procedures that are presently
available.
Cryptogenic transient ischemic attack. Crypto-
genic transient ischemic attack (TIA) is defined as a
clinical syndrome consisting of a transient episode of
neurological dysfunction caused by focal brain, spinal
cord, or retinal ischemia without acute infarction as
assessed by CT of MR scan [23]. A cryptogenic TIA is
clinically evident as any combination of speech, motor,
and visual deficit, and without any known underlying
cause despite a thorough evaluation with diagnostic
procedures that are currently available.
Diagnosis
The aim of any diagnostic workflow in this context
is to identify a link between the index cryptogenic cer-
ebral ischemic event and any given PFO. Therefore, if
an association is found, the resulting diagnosis at the
end of the process would be different from ‘‘crypto-
genic stroke,’’ as a cause has been identified. However,
it has to be kept in mind that the association between
any stroke and a PFO is not causative but still proba-
bilistic. The degree of probability of the association
Published on behalf of The Society for Cardiovascular Angiography and Interventions (SCAI).
will lead the following decision-making. With this
respect, it has to be kept in mind that paradoxical em-
bolism is difficult to be precisely diagnosed, because
the causes of cryptogenic stroke are heterogeneous.
Therefore, a reasonable certitude regarding a causal
link has to be reached before any patient enters this
workflow. The introduction of newer and more sensi-
tive diagnostic techniques likely will reduce the num-
ber of cases of cryptogenic strokes in the future, allow-
ing more precise treatment allocations to patients.
An initial neurologic examination is performed in all
patients with recent or previous cryptogenic stroke or
TIA (both symptomatic and asymptomatic). Albeit
improvements in available diagnostic tests have been
achieved, it is still challenging to diagnose the patho-
genic mechanism for an ischemic stroke. The mecha-
nism for a stroke cannot be determined from clinical
evaluation alone; a thorough diagnostic evaluation,
with proper timing, must be performed, and the results
must be unequivocal for a stroke to be classified as
cryptogenic (Fig. 1) [24].
Most TIAs persist less than 1 hr, and are not directly
observed by a physician but are described by patients
or witnesses. Although motor and speech deficits are
Catheterization and Cardiovascular Interventions DOI 10.1002/ccd.
E42 Pristipino et al.
more reliable, sensory deficits are evanescent, for a
definite diagnosis [25]. Patients usually describe visual
deficits as transient blindness even if the deficit is a
hemianopsia; therefore, these deficits frequently have
not been included in prognostic scores, but are
included in this document. An accurate neurological
evaluation is required to differentiate a TIA from syn-
cope, peripheral vertigo, or transient focal deficits such
as those that may occur after a seizure or associated
with a migraine attack. When the diagnosis of TIA is
considered, the cryptogenic cause is determined as
described for cryptogenic stroke.
Stroke is rare in childhood, and usually is associated
with a congenital heart defect; rarely, there is no evi-
dence of a pathogenic mechanism and the role of a
PFO remains debated [26].
In young patients, rare genetic causes of stroke
should be considered [26–30].
Silent cryptogenic strokes located in the white matter
usually are lacunar infarcts and often are a result of
lipohyalinosis (stenosis of deep penetrating arteries)
[24]. However, multiple deep infarcts also may be car-
dioembolic events [31,22], especially when they are
located in both hemispheres and at the boundary
between white and grey matter [32]. Unfortunately,
standardized and generally accepted imaging criteria
for a definite diagnosis of a cardioembolic event are
unavailable [33,34]. Therefore, the possibility that
silent white matter infarcts have a cardioembolic origin
should be considered, especially in young patients who do
not have risk factors for lacunar infarcts (i.e., hyperten-
sion, diabetes), preclinical CADASIL, or Fabry disease.
Silent cryptogenic strokes also may be located in the grey
matter, which may indicate an embolic cause even when
they are small. A past medical history of pulmonary em-
bolism may be a clue to the possible embolic cause of
white matter and grey matter silent infarcts [35].
As the cryptogenic nature of any TIA or stroke may
be difficult to determine, it is recommended that a special
attention is given to the following aspects: (1) given the
higher incidence of atrial fibrillation and supraventricular
arrhythmias in patients with PFO [36], an accurate diag-
nostic workout for arrhythmias including a 12-lead elec-
trocardiogram (ECG) and a 24–72 hr dynamic Holter
ECG monitoring, or continuous monitoring is mandatory
in patients admitted to a stroke unit or intensive care unit.
If there is strong clinical suspicion of atrial arrhythmias,
loop recorder implantation may be advised; (2) a routine
chest radiograph is recommended to rule out macroscopic
pulmonary arteriovenous malformations. In the presence
of a family history of Rendu-Osler syndrome, chest MR
and CT scans may be appropriate.
The diagnostic assessment for PFO can be per-
formed after the diagnosis of cryptogenic stroke or as
Catheterization and Cardiovascular Interventions DOI 10.1002/ccd.
Published on behalf of The Society for Cardiovascular Angiography and Interventions (SCAI).
part of the initial assessment if the PFO is likely to be
the most probable cause of the event (e.g., in young-
sters). This assessment will (1) further exclude causes
of cardiovascular systemic embolism other than an
atrial right-to-left shunt, (2) evaluate the functional se-
verity of the atrial right-to-left shunt, and (3) assess the
anatomy of cardiac and vascular structures.
Clinical history. Before any invasive testing, an
accurate clinical history is taken, focusing on symptoms
potentially related to cardiac embolism and symptoms
suggestive of arrhythmias. Circumstances during which
symptoms occur should be assessed and an accurate
evaluation of risk factors for stroke be performed.
Blood tests. In many institutions, a comprehensive
assessment of hypercoagulable state is performed in
cryptogenic stroke patients, particularly in those who
may be under consideration for device-based closure.
Indeed, despite there is insufficient evidence that inher-
ited thrombophilia is a risk factor for embolism in
patients with PFO, blood tests to screen for thrombo-
philia may be considered in selected patients. Although
the presence of high or moderate antiphospholipid levels
or lupus anticoagulant are associated with ischemic cere-
brovascular disease [37], a recent study failed to find a
significantly increased risk of cerebrovascular events in
subjects with the combined presence of elevated anti-
phospholipid antibodies levels and a PFO [38].
Diagnostic studies for PFO. Several instrumental
techniques are available for the assessment of PFO.
Their relative characteristics are summarized in Table I.
In contrast-enhanced transcranial Doppler ultraso-
nography (TCD), the detection of more than 10 air
microbubble spikes in the middle cerebral artery is
considered indicative of a significant right-to-left shunt
[42]. The procedure is well tolerated by patients, sim-
ple to administer, inexpensive, and widely available.
Specialized training is required to perform the proce-
dure correctly. Although reliable examinations cannot
be obtained in 20% of the patients because of cranial
bone thickness, this limitation can be minimized with
the use of contrast media. Other limitations of TCD
include the lack of standardization, and methods vary-
ing between different investigators. Methodological pa-
rameters (e.g., volume and velocity of contrast injected,
relative timing of the Valsalva maneuver and contrast
injection, and body position) can influence the results
of the procedure. Furthermore, it is impossible to visu-
alize the site of shunt, therefore TCD alone is not able
to make the diagnosis of PFO.
Transthoracic echocardiography (TTE) is widely
used to evaluate cardiac structure, interatrial septum
motility, and potential causes of cardiac embolism such
as left atrial mass and thrombus. TTE, done with a
bubble test, is useful in diagnosing a clinically relevant

TABLE I. PFO Diagnostic Methods
PFO diagnosis method Sensitivity Specificity
Transthoracic echocardiography 68–100% 93–100%
(TTE) [39,40,41]
Transesophageal 80–100% 80–99%
Echocardiography
(TEE)
Transcranial Doppler 95–98% 90–99%
(TCD)
intracardiac shunt at rest and after a Valsalva maneuver
[39,43]. The intra-atrial shunt is defined as the pres-
ence of contrast in the left atrium within the first 3–5
cardiac cycles after contrast has entered the right
atrium and quantified in mild or moderate shunt <20
bubbles and severe >20 bubbles. When bubbles are
detected in the left atrium after 3–5 cardiac cycles, an
intrapulmonary shunt is suspected [44].
Transesophageal echocardiography (TEE) provides
an excellent morphological characterization of inter-
atrial septum and atrial structures and an accurate eval-
uation of ascending aorta and its possible atherosclero-
sis [45]. Furthermore, preprocedural TEE is essential to
an accurate PFO closure planning and should comprise
at least all the following parameters and measurements:
length of the atrial septum; tunnel length and width of
the PFO; presence (and size) or absence of atrial septal
excursion (aneurism defined if excursion >10 mm into
the right or left atrium); septum thickness; size of ante-
rosuperior rim above PFO; size of the Eustachian
valve; presence or absence of a Chiari network; pres-
ence or absence of a multifenestrated defect; presence
or absence and direction of a transseptal shunt (at rest
and after a Valsalva maneuver).
Recommendations
1. A standard TTE must be performed in all patients
2. TCD or TTE with a saline bubble test are indicated
as a preliminary study to detect and quantify a
Published on behalf of The Society for Cardiovascular Angiography and Interventions (SCAI).
PFO Management E43
Advantages Limitations
 Well tolerated by the patient.  Reduced sensitivity for mild
 Low cost and reproducible. interatrial shunts
 Ease for Valsalva manoeuvre, sniff, coughing  Need for a sufficient
 Visualization and semiquantification echographic thoracic window
of the right-to-left shunt  Semiquantitative assessment
 Comparative follow-up method of the shunt
 Need for sonographers’
training
 Gold standard for visualization of  Patient discomfort
cardiac and aortic structures and  Impossibility to perform proper
sources of embolism (tumors, thrombi, Valsalva manoeuvre
vegetations, complex aortic plaques)  Training requested
 Semiquantitative assessment
of the shunt
 Well tolerated by the patient  Unable to be performed in
 Low cost and reproducible 20% of the patient for bone
 High sensitivity for any thickness
right-to-left shunt  Impossibility of directly
 Semiquantitative assessment visualize shunt location
of the shunt  Lack of standardization
 Contrast improves feasibility  Methodology influences results
loss due to bone thickness
 Magnitude of shunt is predictor
of relapse
shunt. TCD is more sensitive than TTE for small
shunts and can be useful to estimate the potential
for relapse during the initial follow-up [46].
3. TEE must be performed routinely in the diagnostic
evaluation of a PFO and acquire all the required
measurements for a possible interventional procedure.
THERAPY
The heart/brain team should jointly take all the deci-
sions regarding the treatment of patients.
In asymptomatic subjects with no past medical history
of symptomatic cryptogenic stroke or TIA, in whom PFO
is an incidental finding, no treatment is advised unless
silent cryptogenic stroke is diagnosed after imaging stud-
ies such as CT or MR scan. Therefore, primary prevention
of stroke, either with drugs or device-based therapies, is
not indicated in patients with an incidental PFO.
In patients with cryptogenic ischemic stroke, TIA, or
systemic embolism, the therapeutic strategy is based on
the evaluation of the probability that any given PFO is
causally related to the clinical event and of the risk of
recurrence. The overall risk of recurrent cerebral events
in patients with PFO is low. A recent meta-analysis
considering one RCT, three case–control studies, and
11 case series studies, reported a rate of recurrent
stroke or TIA of four events per 100 patient-years and
a rate of recurrent stroke of 1.6 events per 100 patient-
years [47]. Therefore, given the invasive procedure-
related adverse events, the indications for a
Catheterization and Cardiovascular Interventions DOI 10.1002/ccd.
E44 Pristipino et al.
progressively more aggressive or invasive therapy
should be limited to patients with higher likelihood of
a causative event and with a higher risk of recurrence.
The heart brain team should jointly evaluate both these
aspects.
Medical Treatment
No RCT have been conducted to assess the safety
and efficacy of medical therapy in the secondary pre-
vention of cryptogenic stroke in patients with PFO,
therefore no drug therapy can be considered as a ‘‘gold
standard.’’ Also, no data are available regarding the du-
ration of treatment. Few studies on cryptogenic stroke
at large included patients with PFO but they did not
show a benefit of warfarin over aspirin. The most im-
portant is the PICCS trial, a prespecified subanalysis of
patients undergoing TEE enrolled in a larger random-
ized trial of stroke patients randomized to warfarin or
aspirin, which did not show any benefit of warfarin over
aspirin in the PFO subpopulation [48]. However, a rela-
tive risk for recurrent stroke or TIA of 0.5 (95% CI 0.4–
0.7) in patients treated with warfarin, compared with
those treated with antiplatelet agents, was reported in the
aforementioned meta-analysis [47]. Nevertheless, it
should be kept in mind that studies considering second-
ary prevention (although obtained only in stroke patients
at large) suggest that the possible benefit of oral anticoa-
gulation may be outweighed by the risk of bleeding com-
plications (2.22 and 2.0 per 100 patient-years in the
WARSS and in the ESPRIT study, respectively) [49,50].
Some conditions may be associated with increased
risk of recurrent ischemic events and may justify a more
aggressive therapeutic approach than the use of antipla-
telet agents. Therefore, it is important to identify patients
at higher risk who may benefit from different therapeutic
options. A higher risk of recurrence may be attributed to
those patients in whom there is evidence of recurrent is-
chemic events or an atrial septal aneurysm [11]. Some
guidelines include the recommendation of anticoagulant
treatment for patients who have both a PFO and an atrial
septal aneurysm [15], but this is controversial [51].
The relationship between the presence of thrombol-
philic alterations and the risk of thrombotic complica-
tions in subjects with PFO has been investigated in
several studies, with conflicting results. A recent meta-
analysis found that patients who have a PFO and either
the factor V Leiden (G1691A) mutation or the pro-
thrombin G20210A variant (the two most common pro-
thrombotic inherited alterations) have an odds ratio for
stroke of 1.98 compared with control subjects [52].
However, there is no sufficient evidence for screening
for thrombophilia all subjects with a cryptogenic stroke
Catheterization and Cardiovascular Interventions DOI 10.1002/ccd.
Published on behalf of The Society for Cardiovascular Angiography and Interventions (SCAI).
and for treating with vitamin K antagonists those
resulting positive.
Some patients with a cryptogenic stroke or TIA and
PFO may also have other conditions that require anti-
coagulation, such as deep vein thrombosis or pulmo-
nary embolism. In these cases, patients should receive
an anticoagulant instead of antiplatelet treatment.
Recommendations
1. Consistent with international guidelines [15,51,53],
we recommend that patients with PFO and crypto-
genic stroke/TIA be treated with antiplatelet ther-
apy, unless all the following conditions are present:
a percutaneous closure has been successfully per-
formed, the PFO residual patency has been excluded
at follow-up and the antiplatelet withdrawal is con-
sidered safe by the heart-brain team (i.e., in case of
the highest probability of paradoxical embolization
as the cause of an index event).
2. Oral anticoagulant therapy with vitamin K antago-
nists should be considered instead of antiplatelet
therapy in patients with specific conditions such as
recurrent ischemic events, coexisting atrial septal
aneurysm, prothrombotic inherited alterations, or
antiphospholipid syndrome. In these cases, anticoa-
gulant therapy may be provided if the risk of bleed-
ing is low, proper anticoagulant monitoring can be
performed, and patient compliance is satisfactory.
3. We recommend anticoagulant therapy in patients
with cryptogenic stroke or TIA and PFO who also
have clinical conditions that require anticoagulant
therapy such as venous thromboembolism.
4. Although studies are limited, it may be prudent to
consider anticoagulant therapy for patients who
have had an ischemic event while under antiplatelet
treatment or when percutaneous closure is either
contraindicated or refused by the patient.
Interventional Treatment
Indications. Percutaneous closure of a PFO is a
catheter-based technique using atrial septal occlusion
devices. The procedure initially was recommended in
1992 for prevention of recurrent stroke [54].
The only completed RCT showed similar outcomes
of percutaneous closure of a PFO over medical therapy
at 2 years follow-up, with a similar safety profile
between treatments [21]. In CLOSURE I study, 909
patients were randomly assigned to medical (antiplate-
let, oral anticoagulants, or other; to the physician dis-
cretion) or interventional treatment using STARFlex
septal occluder. The report shows a 5.5% incidence of
composite primary end-point (stroke or TIA) in the
 PFO Management E45

Fig. 2. Scheme of the recommendations for treatment of cryptogenic stroke/TIA with PFO
and summary of the considered anatomical and clinical risk factors. PFO, patent foramen
ovale; R-L, right-to-left; AP, antiplatelet; OA, oral anticoagulants; CT, computer tomography
scan; MR, magnetic resonance imaging; DVT, deep vein thrombosis; PE, pulmonary embo-
lism; OSAS, obstructive sleep apnea syndrome.

interventional arm as compared to a 6.8% in the medi-
cal therapy arm in an intention-to treat analysis at 2
years (HR: 0.78; 95%CI: 0.45–1.35). However, as also
acknowledged by the authors, several limitations sig-
nificantly reduce the internal and external validity of
the study: lack of a therapeutic gold-standard as a con-
trol, selection bias in the enrollment phase (high preva-
lence of low risk patients: i.e., exclusion of patients
with a high likelihood of paradoxical embolization
such as those with deep-vein thrombosis; atrial septal
aneurism present in only 36% of the population and
moderate or substantial shunt present in only 53%;
exclusion of high risk patients by the enrolling physi-
cians), study under powered to detect smaller but still
clinically significant differences (dimensioning per-
formed to detect a 75% reduction in the primary end-
point), short duration of follow-up, low effectiveness
of the device in closing a PFO (86%) as compared to
other devices (up to 95%). Moreover, proficiency of
centers and operators can have an influence on out-
comes but this data were not reported while, in the fol-
low-up, the vast majority of recurrences where non-
cryptogenic, casting serious doubts on the effectiveness
of the selection of cryptogenic stroke patients at the
beginning of the study. Still, despite these limitations,
in this study interventional treatment appears as an
effective and safe alternative to drug treatment in the
Published on behalf of The Society for Cardiovascular Angiography and Interventions (SCAI).
medium term (2 years), while the longer-term out-
comes remain unaddressed.
A pooled analysis of 21 observational studies
showed 0.19 events of stroke recurrence per 100
patient/year after percutaneous closure of PFO (95%CI:
0.05–0.49), in contrast with 1.98 events of stroke recur-
rence per 100 patient/year during medical therapy only
(95%CI: 1.48–2.60) [55].
Observational studies have identified several ana-
tomic and clinical factors associated with PFO that
may increase the likelihood that PFO is the cause of
the primary or recurrent stroke [56–58] (Fig. 2—bot-
tom). However, there is no consensus about the predic-
tive value of these factors [21,47,59], and their rele-
vance in therapeutic decision-making is controversial.
When indicated, we recommend that closure of the PFO
be delayed until at least 1 month after a major stroke,
because the administration of heparin during the procedure
could be dangerous in patients with recent large cerebral
lesions. In a patient with a minor stroke or TIA, no delay is
necessary before performing interventional treatment.
Recommendations
1. Pending completion of a diagnostic evaluation for
patency of a foramen ovale, we recommend that
patients with cryptogenic stroke or TIA be treated
Catheterization and Cardiovascular Interventions DOI 10.1002/ccd.
E46 Pristipino et al.
with medical therapy (antiplatelet or anticoagulant
drugs, as appropriate).
2. In patients with an initial event, who have no ana-
tomic or clinical risk factor (as specified in Fig. 2),
we recommend treatment with the appropriate medi-
cal therapy.
3. In patients with an initial event, who have one or
more anatomic or clinical risk factors, we recom-
mend percutaneous closure of the PFO be offered as
an alternative to life-long medical therapy. Patients
should be informed that contemporary data show
that closure of the PFO is no more effective than
medical therapy in preventing recurrence at 2 years.
4. In patients with an initial or recurrent cryptogenic
ischemic event, who already are on antiplatelet
drugs, we recommend that transcatheter closure of
the PFO be offered. If the interventional procedure
is contraindicated, or if the patient declines the pro-
cedure, the patient may undergo anticoagulant ther-
apy instead of antiplatelet therapy.
5. Transcatheter closure of the PFO is indicated in
patients with an initial or recurrent ischemic event
while on anticoagulants.
6. Patients with a cryptogenic stroke or TIA who
should subsequently undergo chronic anticoagulation
because of other concomitant, reasons (e.g., recur-
rent pulmonary embolism, thrombophilia, or anti-
phospholipid antibody syndrome) should not be
offered interventional treatment unless the neurolog-
ical event is a recurrence occurred while already on
anticoagulants. Percutaneous closure can be offered
in case of the need of stopping anticoagulation.
7. Patients who had previous percutaneous closure of a
PFO, but who have at 6 months after the procedure a
significant (moderate or severe) residual shunt, which
is unchanged as compared to before the procedure,
can be considered for immediate repeat procedure
according to the baseline clinical risk of the patient.
Patients who reduced the degree of shunt at 6 months
after the procedure (to a mild or moderate degree)
should be considered for repeat percutaneous closure
only after a recurrent cryptogenic stroke.
Complications of Percutaneous Therapy and
Their Prevention
Complications may be procedural (during or imme-
diately after the procedure), subacute (<6 months after
the procedure), or late (>6 months after the proce-
dure), and may be major or minor. Major complica-
tions of percutaneous closure, including major hemor-
rhage, cardiac tamponade, erosion of cardiac structures
due to the device, emergency surgery, pulmonary em-
bolism, and death, have been reported in 1.5% patients;
Catheterization and Cardiovascular Interventions DOI 10.1002/ccd.
Published on behalf of The Society for Cardiovascular Angiography and Interventions (SCAI).
minor complications, including arrhythmia, fracture or
embolization of the device, air embolism, femoral hema-
toma, and fistula, have been reported in 7.9% patients
[60,61]. Complications are summarized in Table II.
In the absence of complications, the patient may be
discharged from the hospital 24 hr after the procedure.
Recommendations for prevention of complications
through device selection. Despite the growing trend of
device-based procedures, the morphology of PFO often
is neglected. A better understanding of the morphology
is needed for developing lesion-specific devices.
PFO has two types of morphology [69]: valve com-
petent and valve incompetent. In the valve competent
form, the thin valve of the oval foramen adequately
overlaps the firmer muscular rim of the foramen, leav-
ing a crevice-like aperture sandwiched between septum
primum and septum secundum. The valve-incompetent
form results from aneurysmal ballooning of the valve,
creating an interatrial communication in a previously
competent flap valve. Distinguishing between the two
forms can help in the selection of the most appropriate
device for implantation and possibly result in fewer
complications and higher success [78]. Other anatomic
factors that may influence device choice include the
presence of a multifenestrated PFO, the amplitude of
atrial septal aneurism, the distance between PFO and
the aorta and between PFO and atrial roof, the thick-
ness of atrial septum, the presence of a redundant Eu-
stachian valve, and the presence of Chiari network.
As some devices for closure of PFO may better fit
specific anatomic conditions, in the absence of con-
trolled data, it is reasonable to suggest that effort
should be put to select the device on an individual ba-
sis according to anatomic characteristics.
Size and type of device selection also may be influ-
enced by other patient factors such as clotting disorders
and vulnerability to atrial fibrillation.
Recommendations for prevention of complications
through ultrasound guidance. Despite some non-
randomized report described the feasibility of percuta-
neous closure without ultrasound guidance in high vol-
ume centers by expert and high-volume operators and
after very careful TEE assessment before the procedure
[79], we must acknowledge that during percutaneous
closure of PFO, ultrasonographic monitoring should
still be recommended in the majority of centers.
TEE with the patient in deep sedation allows: (a)
accurate visualization and measurement of the septum
and fossa ovalis in different views, (b) monitoring de-
vice delivery, and (c) detection of complications [80].
Intracardiac echography is a reliable alternative option
[81] allowing a procedure without sedation therefore
sparing costs of anesthesia, shortening procedure dura-
tion and catheterization laboratory occupancy, lowering
 PFO Management E47

TABLE II. Complications of Percutaneous Closure

Complication Incidence Pathophysiology Symptoms/signs Diagnostic workup
Residual shunt [61,62] 4–49%  Temporary or persistent mild to  Possibly asymptomatic  TCD
severe device leak due to  Recurrent systemic embolism  TTE with
device-PFO mismatch and/or  Observed in different positions bubbles test
incomplete endocardial  TEE
coverage (up to 1 year)
Atrial arrhythmias [63,64] 0.5–7.6%  Related to age and/or ASA  Possibly asymptomatic  ECG Holter
[65–67].  Atrial fibrillation  Loop recorder
 Superaventricular
 Mechanical irritation related tachyarrhythmias
to device type and size [65].  Recurrent systemic
embolism
 Inflammatory reaction [63].
 Electrical barrier by the device
[63,65]
 P-wave dispersion [65,67]
Device thrombosis [68] 2%  Thrombosis of device arms not  Possibly asymptomatic  TTE
covered by endocardium  Systemic embolism  TEE
Pericardial effusion/ 0.5–1%  Perforation during procedure  Possibly asymptomatic  TTE
tamponade [69]  Early (24–48h) and late  Dyspnea  TEE (erosion)
erosion [68].  Chest pain
 Allergic reaction (mild effusion)
[70,71,76]
Device embolization Rare  Early and late mobilization  Possibly asymptomatic  TTE
[61,72–74]  Pulmonary embolism  TEE
 Chest X-ray
Endocarditis [75] Anecdotal  Colonization of device arms  Unexplained fever  TEE
not covered by endothelium  Systemic septic embolism
Atrio-aortic fistula [77] Anecdotal  Erosion of aortic wall  New onset murmur  TEE

risks and discomfort inherent with anesthesia and intu-
bation. However, the device is more expensive; requires
a specific training, and a second vascular access.
Although TTE can be an alternative in patients with
selected cases, this method usually is not sufficient to
allow accurate patient monitoring after the procedure.
Recommendations for prevention of complications
through patient care. Prophylactic antibiotics are
administered before the beginning of the procedure.
It is reasonable to start double antiplatelet therapy at
least 12 hr before the procedure (Table III). In patients
on oral anticoagulants, the anticoagulants are stopped,
and when international normalized ratio (INR) is less
than 2, the patient is started on intravenous, unfractio-
nated heparin. Anticoagulants are stopped before the
procedure to allow a proper and controlled heparin reg-
imen during the procedure.
Patients are maintained on heparin throughout the
procedure, maintaining an activated clotting time
greater than 200 sec.
Conflicting evidence exist also regarding drug therapy
following PFO closure. After the procedure, we suggest
to treat patients with aspirin and clopidogrel for 3–6
months, and aspirin alone for an additional 6 months.
Patients are also prescribed antibiotic prophylaxis
against endocarditis in case of invasive procedures or
Published on behalf of The Society for Cardiovascular Angiography and Interventions (SCAI).
surgical interventions during the first 6 months after the
procedure. Patients who require oral anticoagulation for
another condition resume warfarin as indicated for that
condition, and do not take antiplatelet therapy while on
anticoagulation unless otherwise indicated (e.g., some
patients who have implantation of drug eluting stents
may need ‘‘triple therapy’’ with oral anticoagulation, as-
pirin, and clopidogrel). The decision to continue therapy
beyond 6 months is at the discretion of the heart-brain
team, based on the evaluation of the residual shunt
resulting from incomplete device endothelialization and
on the relative weight of probability that further single
factors (needing antiplatelet therapy) others than PFO
may have come into play in the genesis of the index
cerebral ischemic event(s). Older patients who have
atherosclerotic disease (e.g., coronary artery disease)
may take antiplatelet therapy indefinitely.
FOLLOW-UP AFTER CLOSURE OF PFO
There are no guidelines or professional society rec-
ommendations about the method of follow-up of the
patient after percutaneous closure of PFO.
Patients are examined regularly to monitor the endo-
thelialization process, follow the resolution of the
right-to-left shunt, and detect complications.
Catheterization and Cardiovascular Interventions DOI 10.1002/ccd.
E48 Pristipino et al.

TABLE III. Proposed pharmacological protocol before, during and after percutaneous closure of PFO (expert consensus opinion)
Current 24 h before procedure During procedure Aftera Procedure
ASPIRIN ASPIRIN 100 mg AB (30 min. before) AB (tid, 24 h)
CLOPIDOGREL 300 mg UFH 70 UI/kg iv bolus ASPIRIN 100 mg þ CLOPIDOGREL 75 mg, 0–3 months
To reach ACT  200 ASPIRIN 100–300 mg, 3–12 monthsb
IE prophylaxis, 0–6 monthsc
WARFARIN Reach an INR < 2 AB (30 min. before) AB (tid, 24 h)
(PFOþASA, stroke on ASPIRIN 325 mg UFH 70 UI/kg iv bolus ASPIRIN 100 mg þ CLOPIDOGREL 75 mg, 0–3 months
antiplatlet Rx) CLOPIDOGREL 300 mg To reach ACT  200 ASPIRIN 100–300 mg, 3–12 monthsb
IE prophylaxis, 0–6 monthsc
WARFARIN Reach an INR < 2 AB (30 min. before) AB (tid, 24 h)
(other temporary Shift to UFH or LMWH UFH 70 UI/kg iv bolus WARFARIN (12 or 24 h), 0–6 months
indications) To reach ACT  200 (then recheck warfarin indication)
IE prophylaxis, 0–6 monthsc
a
See specific companies instructions.
b
> 6 months in case of residual shunt; indefinitely in older pts with atherovascular disease.
c
> 6 months at physician discretion.
PFO, patent forame ovale; ASA, atrial septal aneurysm; Rx, therapy; UFH, unfractioned heparin; LMWH, low-molecular weight heparin; AB, antibi-
otics; IE infective endocarditis; tid, ter in die.

Recommendations for follow-up evaluation. Because
of their characteristics (Table 1), contrast-enhanced
TCD or TTE with bubble study at 6 months is advised
to detect and measure a residual shunt.
The TTE at follow-up, with or without a bubble test,
may be useful to visualize the position of the device, the
contiguous cardiac structures, and the residual shunt, if
present. We also recommend recording the left ventricular
ejection fraction, atrial size, and morphology and function
of the valvular apparatus at the follow-up evaluation.
The TEE is mandatory when there is a positive
TCD, positive TTE with a bubble test, or suspicion of
a mechanical or thrombotic complication. When symp-
toms such as palpitations occur, an ECG and Holter
ECG are strongly recommended.
In summary, follow-up evaluation may include:
• TTE at discharge and at 1, 3, 6 (if TEE not per-
formed), and 12 months after the procedure. There-
after, TTE evaluation annually,
• contrast-enhanced TCD or TTE with bubble study at
6 months after the procedure,
• ECG and Holter ECG when clinically indicated
• TEE when TCD or TTE with bubble study positive
or when clinically indicated.
CONCLUSIONS
The management of patients with cryptogenic stroke
and PFO is controversial. In some communities, inter-
ventional procedures are sharply increasing while in
others these are being banned, giving rise to confusing
behaviors in patients as well as in the medical commu-
nity. Taking into account existing data, we outlined a
Catheterization and Cardiovascular Interventions DOI 10.1002/ccd.
Published on behalf of The Society for Cardiovascular Angiography and Interventions (SCAI).
multidisciplinary, shared approach that may become a
basis for a joint management of these patients, while
waiting for more consistent evidences. Team-based,
multidisciplinary, Bayesian clinical judgment on an
individual basis still remains the core of decision-mak-
ing. We must acknowledge that, albeit representing a
consensus of several interest groups and associations at
the national level, this is an Italian initiative limited to
the realm of PFO associated to cryptogenic ischemic
cerebral events. Further initiatives at the national and
international level are awaited to fill the gap between
patient’s needs and scientific community responses
regarding these and other aspects of PFO-related path-
ologies, while waiting for more robust evidence.
ACKNOWLEDGEMENTS
Scientific societies and task force members: Chris-
tian Pristipino, MD (Chairman); Giulio Guagliumi
(President of Italian Society of Invasive Cardiology—
SICI GISE); Italian Stroke Association—ISA-AIS:
Danilo Toni, MD; Maurizio Melis, MD; Maurizio
Paciaroni, MD; Paolo Bovi, MD; Italian Association
of Hospital Neurologists, Neuroradiologists, Neuro-
surgeons—SNO: Giuseppe Neri, MD; Congenital
Heart Disease Study Group of Italian Society of
Cardiology—SIC: Massimo Chessa, MD; Italian So-
ciety of Pediatric Cardiology—SICP: Luigi Ballerini,
MD; Italian Association of Hospital Cardiologists—
ANMCO: Serena Rakar, MD; Italian Society of Car-
diovascular Echography—SIEC: Moreno Cecconi,
MD; Italian Society of Hemostasis and Thrombosis.
SISET: Gualtiero Palareti, MD; As GISE members:
Gian Paolo Anzola, MD; Antonio Bartorelli, MD;
Mario Carminati, MD; Fausto Castriota, MD; Andrea
Donti, MD; Achille Gaspardone, MD; Sandra Giusti,

MD; Eustaquio Onorato, MD; Gianluca Rigatelli, MD;
Gennaro Santoro, MD; Gian Paolo Ussia, MD; Roberto
Violini, MD.
We are deeply indebted to Armando Liso, MD;
Maria Concetta Altavista, MD; Vittorio Ambrosini,
MD and Antonio Auriti, MD for their valuable contri-
bution in the revision process of this document.
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