European Position Paper On The Management of Patients With Patent Foramen Ovale. General Approach and Left Circulation Thromboembolism

INTERVENTIONS FOR HYPERTENSION AND STROKE
EXPERT REVIEW
EuroIntervention 2019;14:1389-1402 published online ahead of print August 2018

European position paper on the management of patients with
patent foramen ovale. General approach and left circulation
thromboembolism
Christian Pristipino1*, MD; Horst Sievert2,3, MD; Fabrizio D’Ascenzo4, MD;
Jean Louis Mas5, MD; Bernhard Meier6, MD; Paolo Scacciatella4, MD;
David Hildick-Smith7, MD; Fiorenzo Gaita4, MD; Danilo Toni8, MD; Paul Kyrle9, MD;
John Thomson10, MD; Genevieve Derumeaux11, MD, PhD; Eustaquio Onorato12, MD;
Dirk Sibbing13, MD; Peter Germonpré14, MD; Sergio Berti15, MD; Massimo Chessa16, MD;
Francesco Bedogni16, MD; Dariusz Dudek17, MD; Marius Hornung2, MD; Jose Zamorano18, MD;
joint task force of European Association of Percutaneous Cardiovascular Interventions (EAPCI),
European Stroke Organisation (ESO), European Heart Rhythm Association (EHRA), European Association for
Cardiovascular Imaging (EACVI), Association for European Paediatric and Congenital Cardiology (AEPC),
ESC Working group on GUCH, ESC Working group on Thrombosis, European Haematological Society (EHA),
European Underwater and Baromedical Society (EUBS).
EVIDENCE SYNTHESIS TEAM: Fabrizio D’Ascenzo (lead)4, MD; Pierluigi Omedè4, MD; Flavia Ballocca4, MD;
Umberto Barbero4, MD; Francesca Giordana4, MD; Sebastiano Gili4, MD; Mario Iannaccone4, MD
EAPCI SCIENTIFIC DOCUMENTS AND INITIATIVES COMMITTEE: Davide Capodanno19, MD, PhD;
Marco Valgimigli6, MD, PhD; Robert Byrne20, MB, BCh, PhD
INTERNATIONAL EXPERTS: Teiji Akagi21, MD; John Carroll22, MD; Bharat Dalvi23, MD; Junbo Ge24, MD;
Scott Kasner25, MD; Ina Michel-Behnke26, MD; Carlos Pedra27, MD; John Rhodes28, MD; Lars Søndergaard29, MD;
Lars Thomassen30, MD; Giuseppe G.L. Biondi-Zoccai31,32, MD
1. S. Filippo Neri Hospital - ASL Roma 1, Rome, Italy; 2. CardioVascular Center (CVC) Frankfurt, Frankfurt, Germany;
3. Anglia Ruskin University, Chelmsford, United Kingdom, and University of California San Francisco (UCSF), San Francisco,
USA; 4. Città della Salute e della Scienza Hospital, University of Turin, Turin, Italy; 5. Hôpital Sainte-Anne, Université Paris
Descartes, Paris, France; 6. University Hospital, Bern, Switzerland; 7. Sussex Cardiac Centre, Brighton and Sussex University
Hospitals, Brighton, United Kingdom; 8. Hospital Policlinico Umberto I, Sapienza University, Rome, Italy; 9. Medical University,
Vienna, Austria; 10. Leeds General Infirmary, Leeds, United Kingdom; 11. Hôpital Henri Mondor, Faculté de Médecine de
Créteil, Créteil, France; 12. Humanitas Gavazzeni, Bergamo, Italy; 13. Campus Großhadern, Ludwig-Maximilians-Universität
(LMU), Munich, Germany; 14. Military Hospital, Brussels, Belgium; 15. Heart Hospital, Massa, Italy; 16. Policlinico San
Donato, University Hospital, San Donato Milanese, Milan, Italy; 17. University Hospital, Krakow, Poland; 18. University
Hospital Ramón y Cajal, Madrid, Spain; 19. Azienda Ospedaliero-Universitaria “Policlinico-Vittorio Emanuele”, University of
Catania, Catania, Italy; 20. Deutsches Herzzentrum München, Technische Universität München, Munich, Germany;
21. Okayama University Hospital, Okayama, Japan; 22. University of Colorado Hospital, Denver, CO, USA; 23. Glenmark
Cardiac Centre, Mumbai, India; 24. Shanghai Institute of Cardiovascular Disease, Shanghai, China; 25. University of
Pennsylvania, Philadelphia, PA, USA; 26. Kinderherzzentrum University of Vienna, Vienna, Austria; 27. Dante Pazzanese
Instituto de Cardiologia, Sao Paulo, Brazil; 28. Nicklaus Children’s Hospital, Miami, FL, USA; 29. Rigshospitalet, Copenhagen,
Denmark; 30. Haukeland University Hospital, Bergen, Norway; 31. Sapienza University of Rome, Latina, Italy; 32. Department
of AngioCardioNeurology, IRCCS Neuromed, Pozzilli, Italy
DOI: 10.4244/EIJ-D-18-00622
H. Sievert and F. D’Ascenzo contributed equally to the manuscript.
GUEST EDITOR: David R. Holmes, MD, MACC; Department of Cardiology, Mayo Clinic, Rochester, MN, USA
This paper also includes supplementary data published online at: http://www.pcronline.com/eurointervention/146th_issue/252
*Corresponding author: San Filippo Neri - ASL Roma 1 Hospital, Via Alessandro Poerio 140, 00152 Rome, Italy.
E-mail: [email protected]
© Europa Digital & Publishing 2019. All rights reserved. SUBMITTED ON 12/04/2018 - REVISION RECEIVED ON 1st 22/07/2018 / 2 nd 13/08/2018 - ACCEPTED ON 16/08/2018
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EuroIntervention 2019;14:1389-1402
Abstract Introduction
The presence of a patent foramen ovale (PFO) is implicated in The presence of a patent foramen ovale (PFO) is implicated in the
the pathogenesis of a number of medical conditions; however, the pathogenesis of a number of medical conditions. Recent randomised
subject remains controversial and no official statements have been clinical trials (RCTs) have shown evidence of benefit for device
published. This interdisciplinary paper, prepared with involvement closure as compared with medical therapy in patients with cryp-
of eight European scientific societies, aims to review the available togenic stroke. However, we are rarely able to be categoric about
trial evidence and to define the principles needed to guide decision the role of PFO in any given clinical setting, stressing the need for
making in patients with PFO. In order to guarantee a strict pro- specific clinical and research approaches for complex scenarios1-5.
cess, position statements were developed with the use of a modi- Moreover, most studies on the subject are observational, with an
fied grading of recommendations assessment, development, and ensuing low certitude of effects and very disparate, often contradic-
evaluation (GRADE) methodology. A critical qualitative and tory, clinical choices in different local realms in the absence of offi-
quantitative evaluation of diagnostic and therapeutic procedures cial positions. To address these concerns, the European Association
was performed, including assessment of the risk/benefit ratio. The of Percutaneous Cardiovascular Interventions (EAPCI) Scientific
level of evidence and the strength of the position statements of Documents and Initiatives Committee invited eight European sci-
particular management options were weighed and graded accord- entific societies and international experts to develop shared and
ing to predefined scales. Despite being based often on limited and rational position statements on the management of PFO to help clini-
non-randomised data, while waiting for more conclusive evidence, cians in decision making. To address that request, this paper aims to
it was possible to conclude on a number of position statements define interdisciplinary rational principles needed to guide manage-
regarding a rational general approach to PFO management and ment of patients with PFO by using a strict methodology to prepare
to specific considerations regarding left circulation thromboem- position statements with different underlying quality of evidence,
bolism. For some therapeutic aspects, it was possible to express based on systematic literature reviews for each of the considered
stricter position statements based on randomised trials. This issues and performing quantitative assessments whenever possible.
position paper provides the first largely shared, interdisciplinary The present paper reports the approach to patients with PFO and
approach for a rational PFO management based on the best avail- left circulation thromboembolisms, that affect large numbers of
able evidence. patients6-8. A subsequent paper will report on decompression sick-
ness, desaturation syndromes, migraine, and other clinical settings.
Abbreviations Editorial, see page 1350
AF atrial fibrillation
AUC area under the receiver operating curve Methods
c-TCD contrast-enhanced transcranial Doppler In order to guarantee a strict evidence-based process, position
c-TOE contrast transoesophageal echocardiography statements were developed with the use of a modified grading
c-TTE contrast-enhanced transthoracic echocardiography of recommendations assessment, development, and evaluation
DOAC direct oral anticoagulants (GRADE) methodology (http://gdt.guidelinedevelopment.org/app/
DVT deep vein thrombosis handbook/handbook.html), by answering population-intervention-
ECG electrocardiogram comparator-outcome (PICO) questions and non-PICO questions.
GRADE Grading of recommendations assessment, development, A detailed review of the methodology used can be found in Sup-
and evaluation plementary Appendix 1, Supplementary Appendix 2, Supplemen-
ICM insertable cardiac monitors tary Appendix 3 and Supplementary Table 12. Systematic reviews
LAE left atrium enlargement and statistical analysis were performed by a dedicated evidence
LVH left ventricle hypertrophy synthesis team.
NNH number needed to harm
NNT number needed to treat IS PFO ASSOCIATED WITH CRYPTOGENIC LEFT
OAC oral anticoagulants CIRCULATION THROMBOEMBOLISM?
OR odds ratio The association between PFO and cryptogenic left circulation
OSAS obstructive sleep apnoea syndrome thromboembolism has mainly been addressed in studies includ-
PE pulmonary embolism ing cryptogenic stroke and is strongly supported by epidemio-
PICO population-intervention-comparator-outcome logical data9-13, clinical observational studies14-25 (Supplementary
PFO patent foramen ovale Appendix 4) and by RCTs showing that PFO closure reduces
RCT(s) randomised clinical trial(s) stroke recurrence in comparison with medical therapy26-29.
RoPE risk of paradoxical embolism However, the evidence has been controversial due to the dif-
R-T-L right-to-left ferent role that a PFO can play in different clinical scenarios
Rx therapy and to the lack of adequately dimensioned prospective studies.
TIA transient ischaemic attack Pathophysiological processes include paradoxical embolism,
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European position paper on PFO
thrombus forming within the PFO, left atrial dysfunction, and An overview of the general approach to PFO management is sum-
atrial arrhythmias (Supplementary Appendix 4). Research aimed marised in Table 1.
at identifying individual patients’ phenotypes is needed to improve THE MAIN AXES OF EVALUATION
clinical management. In all clinical scenarios, the two main axes guiding assessment and
treatment of PFO should be: 1) the probability that any PFO has
DEFINITIONS OF PFO-RELATED LEFT CIRCULATION a relevant role in the observed clinical picture; 2) the likelihood
THROMBOEMBOLISM that the observed clinical event will recur. For patients with the
PFO has been associated with left circulation thromboembolism highest probability of both, closure of the PFO should be advised.
to several organs30; therefore we promote the use of standardised For patients with the lowest probability, medical therapy should
definitions. be considered. For patients with intermediate probabilities, clini-
Cryptogenic ischaemic left circulation embolisms are defined as cal judgement is required to allow good decision making in liaison
any definite ischaemia (symptomatic or asymptomatic) occurring with the patient.
in an arterial bed which lacks a known cause despite investigation. PROACTIVE APPROACH: AN INTERDISCIPLINARY
Patients presenting with this clinical picture should be screened COLLABORATION, SHARED DECISION MAKING, AND OPEN
for the presence or absence of a PFO. However, when a PFO is INFORMED CONSENT
thought likely to be implicated in a cryptogenic embolism, the Interdisciplinary involvement in decision making regarding PFO
event should be classified as PFO-related instead of cryptogenic31. management is axiomatic and should include an interventional
Current classifications do not yet generally include this aspect32-35. cardiologist and other specialists dictated by the patient’s clinical
manifestations. Active involvement of the patient in the decision-
GENERAL APPROACH TO PFO MANAGEMENT making process is mandatory36,37 and should be documented in an
The management we propose in this paragraph applies to systemic individualised, open, informed consent. The development of spe-
thromboembolism as well as to all PFO-associated syndromes. cific decision aids and the use of narrative tools are encouraged38-43.
Table 1. Summary of statements.

Strength of Level of
Position statements Ref.
the statement evidence
General management of PFO-associated syndromes
Interdisciplinary assessment and decision making should be done Strong C –
The decision making should be done taking into account an estimation of the Strong C –
individual:
a) Probability of a causal role of the PFO in the clinical picture
b) Risk of recurrence
Individual risk stratification should take into account clinical, anatomical and Strong C –
imaging characteristics
Shared decision making should be documented in an open, individualised, Strong C –
informed consent
Decision aids and narrative tools are suggested to enhance patients’ involvement Conditional C 38-43
Standardised definitions of candidate events should be adopted in research and Strong C –
clinical settings
PFO diagnosis
To achieve the maximal accuracy in PFO diagnosis, the combined use of different Strong A 45, 54, 55 + Original
techniques is warranted meta-analyses page 1392 and
Supplementary Appendix 4
The technique achieving the highest sensitivity should be used as a first-line Strong C –
investigation in PFO diagnosis
c-TCD has a higher sensitivity than c-TTE as a first-line investigation to detect Conditional A 55 + Original meta-analyses
a R-T-L shunt page 1392 and
Supplementary Appendix 4
c-TTE has a lower sensitivity for small shunts than other techniques Conditional A Original meta-analyses page
1392 and Supplementary
Appendix 4
c-TOE should be performed by experienced operators in PFO assessment Strong C 45-47
A strict methodology should be used performing c-TOE Strong C 46-47
c-TOE should be performed to stratify the risk Strong C 31, 48-52
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DIAGNOSING PFO also showed superior overall diagnostic yield of c-TCD compared
The diagnosis of PFO is required only for deciding on a treatment. to c-TTE55.
Several techniques can be used to diagnose PFO44. Their charac- At present, grounded on the accrued low-quality evidence, no
teristics are summarised in Supplementary Table 1. High-quality technique can be considered a gold standard and, in most cases,
comparative studies are still needed to express a conclusive posi- a precise diagnosis of PFO needs the combined use of different
tion on the best diagnostic strategies. techniques, prescribed according to their different characteristics. As
Contrast transoesophageal echocardiography (c-TOE) provides first-line investigations must warrant accuracy by minimising false
unparalleled visualisation of the interatrial septum and other rele- negative screenings, we propose a diagnostic algorithm in Figure 1
vant structures and can show the shunt itself. A meta-analysis that can be adapted to satisfy disparate clinical and logistic needs.
of the accuracy of c-TOE in the diagnosis of PFO compared to
autopsy, cardiac surgery, and/or catheterisation yielded a weighted
sensitivity of only 89%45. Inability to perform an adequate Valsalva c-TTE OR
c-TCD STOP
manoeuvre during transoesophageal echocardiography is probably
responsible46,47 (Supplementary Figure 1). Nonetheless, c-TOE is
necessary to characterise the PFO and stratify the risk in the diag- NEGATIVE OR
nostic phase31,48-52, and systematic reporting of a set of parameters EQUIVOCAL
could help in guiding assessment (Table 2). Bleeding, aspiration,

or oesophageal perforation are rare TOE complications53.
c-TOE
Table 2. PFO variables to be assessed for decision making and
interventional treatment. Figure 1. Algorithm for the diagnosis of PFO. c-TCD: contrast-
– PFO morphology: size, location, length of the tunnel
enhanced transcranial Doppler; c-TOE: contrast-enhanced
transoesophageal echocardiography; c-TTE: contrast-enhanced
– Spatial relationship and distances between the PFO and the
transthoracic echocardiography; – negative test for the presence of
aortic root, vena cava, valves and the free walls of the atrium
right-to-left shunt; + positive test for the presence of right-to-left
– Comprehensive evaluation of the atrial septum, including shunt
inspection for atrial septal aneurysms, movement, and other
atrial septal defects
ASSESSMENT OF THE ROLE OF A PFO IN LEFT
– Presence/absence of a Eustachian valve and/or Chiari network
CIRCULATION EMBOLISM
– Thickness of the septum primum and secundum A PFO is seen in ~25% of the general population and may there-
– Colour Doppler evaluation of the shunt at rest and after a Valsalva fore coexist by chance in a patient with an unexplained left circula-
manoeuvre tion embolism. Due to the complexity and number of the variables
influencing the process, and the low scientific quality of the related
In our updated meta-analysis of 29 studies comparing con- literature, no position can be expressed regarding the assessment of
trast-enhanced transcranial Doppler (c-TCD) with c-TOE across the role of a PFO in a quantitative way; therefore, this role should
2,751 patients (Supplementary Appendix 3, Supplementary be evaluated with critical clinical judgement in an interdisciplinary
Appendix 4, Supplementary Figure 19), c-TCD had a sensitiv- collaboration between physicians, weighting the following differ-
ity of 94% and a specificity of 92% (Supplementary Figure 2A) ent features on an individual basis. For a more detailed discussion
with an area under the receiver operating curve (AUC) of 0.97 of each of the following paragraphs please refer to Supplementary
(Supplementary Figure 2B). This meta-analysis was limited by Appendix 4. Position statements are summarised in Table 3.
the low quality of evidence (Supplementary Table 2) and by the IS IT POSSIBLE TO ESTIMATE THE LIKELIHOOD OF A PFO-
inconsistency across studies, being 67% for sensitivity and 73% MEDIATED STROKE?
for specificity. In a previous meta-analysis, the specificity of Patient characteristics
c-TCD was increased to 100% when the threshold for a positive A meta-analysis of observational studies showed a stronger relative
shunt was increased to 10 high-intensity transient signals54. association of PFO with cryptogenic stroke in patients <55 years
We also performed an original meta-analysis of 13 studies as compared to older patients56. However, the association was also
across 1,360 patients comparing contrast-enhanced transthoracic observed in older patients13,57,58. The presence of other comorbidities
echocardiography (c-TTE) against c-TOE (Supplementary or clinical risk factors for stroke does not, per se, exclude a patho-
Appendix 3, Supplementary Appendix 4, Supplementary physiological role of PFO in cryptogenic embolism, though their
Figure 20). c-TTE was only 88% sensitive and 82% specific with absence increases the likelihood of its pathogenic role59.
an AUC of 0.91 (Supplementary Figure 3A), a severe inconsist- Imaging stroke pattern
ency among studies (Supplementary Figure 3B) and a low qual- Neither the localisation nor type of infarct pattern in grey or white
ity of evidence (Supplementary Table 2). A recent meta-analysis matter was specific for PFO embolism in observational studies59-69.
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Table 3. Summary of statements on the assessment of PFO role in left circulation thromboembolism.
PFO can play a pathogenic role in cryptogenic left circulation thromboembolism Strong A 9-29, 51, 112, 132, Table 5
and Supplementary Table 7
It is essential to evaluate the role of the PFO in any given left circulation Strong A Table 5
thromboembolism
No statement is possible regarding the quantification of the role of PFO in left Strong C 13, 18, 27-29, 57-98
circulation thromboembolism
The evaluation of the role of the PFO in left circulation thromboembolism should Strong C 13, 18, 27-29, 57-98
be individualised with critical clinical judgement in an interdisciplinary
collaboration between physicians, weighting clinical, anatomical and imaging
characteristics
Estimating the probability of a PFO being embolism-related
No single clinical, anatomical or imaging characteristics are sufficient to make Strong A 26-28, 51, 112, 128, 132,
a quantitative estimation of the probability of a PFO causal role Table 5, 13, 59, 61, 77-79,
171
When a PFO is considered to play a pathogenic role in an embolism, the episode Strong A 26-28, 51, 112, 128, 132,
should not be classified as cryptogenic anymore Table 5
The presence of other risk factors does not exclude a causative role of PFO; Strong B 13, 56-59, 78, 79, 90
however, it is more likely when patients are young and lack other risk factors
Cortical infarcts are commonly embolic but, less frequently, also white matter Strong B 59, 60-63, 70
infarcts can be embolic
No specific imaging pattern has been associated with a causal role of PFO in Strong C 59-69, 77
stroke patients
ASA, shunt severity and an atrial septal hypermobility can be linked to a causal Strong A 27-29, 51, 112, 132,
role of PFO Table 5, Supplementary
Figure 5; 78, 79, 90, 122,
170, 171, 71-74, 91
PFO sizes, presence of Chiari network or Eustachian valve can be linked to Conditional C 64, 75, 76, 208, 256
a causal role of PFO
Deep vein thrombosis, immobilisation, long journeys, straining pre-stroke or Conditional C 81, 84, 85
obstructive sleep apnoea can be linked to a causal role of PFO
Simultaneous pulmonary embolism and/or deep vein thrombosis strongly suggest Strong C 15, 18, 80-83
a causal role of PFO
The role of thrombophilia cannot be generalised Strong C 86-89
The RoPE score should only be part of a comprehensive individual evaluation.
Further validation studies on the RoPE score are needed Strong B 59, Supplementary Table 3
Estimating the risk of recurrences
The risk of recurrent embolism in unselected patients with PFO is low Strong A 90-92, 259
No single variable allows a quantitative prediction of recurrences Strong A 94, 95, 26-28, 51, 112, 128,
132, Table 5, Supplementary
Table 7
Variables linked to a higher recurrence rate in PFO patients are: Conditional B 72, 95-98
– Atrial septal aneurysm and/or PFO diameter
– Older age
– Coagulation disorders
– Stroke at index
– D–dimer >1,000 at admission
– Acetylsalicylic acid use vs. OAC
Cortical infarcts are usually considered embolic but a recent hypermobility29. A Eustachian valve, Chiari network or a long
patient-level meta-analysis of RCTs plausibly suggests that non- PFO tunnel was suggested to be linked to PFO-associated strokes
cortical infarcts can also have an embolic origin70. but only in retrospective studies75,76. Other studies have failed to
Characteristics of the PFO detect one or more of these associations, however59,77-79, underlin-
An atrial septal aneurysm (ASA) and/or a moderate-to-severe ing the heterogeneity of phenotypes and the need to identify them.
shunt were strongly associated with a causal role of PFO in Clinical clues
patients with cryptogenic stroke in observational and randomised Candidate clinical clues have been addressed in retrospective studies
studies27-29,71-74. Other characteristics associated in randomised and infrequently in prospective observational studies. Logically, con-
studies with a causal PFO are large PFO size and atrial septal ditions that strongly suggest paradoxical embolism in the presence
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of a PFO include the simultaneous or previous occurrence of pul-

Clinical event or
monary emboli18,80,81 or the documentation of a venous source of incidental finding of
embolism around the time of stroke. Absence of evidence of venous embolism at imaging
thrombus is unhelpful because of frequent false negatives15,80,82,83
but immobilisation, recent major surgery, or an extended car or air- First-line diagnostic
plane journey implies possible venous clot development. Activity workup for embolism
at the time of the stroke is also relevant – straining manoeuvres,
obstructive sleep apnoea with stroke-on-waking should be enquired DEFINITE
Plausible causes STOP
for81,84,85. Retrospective studies that have attempted to identify an NO OR
association between inherited thrombophilia and PFO-related stroke UNCERTAIN
have yielded conflicting results86-89. PFO diagnostic NO PFO Cryptogenic

workup embolism
The risk of paradoxical embolism (RoPE) score represents an
PFO YES
attempt to assign a causal relationship probability to individual PFOs
in the setting of stroke of unknown cause59 and may be useful in
PFO-associated
helping to guide management decisions. However, it should always embolism
be used in conjunction with other parameters because the quality of
evidence of internal validation studies has been rated moderate at Likelihood of
best (Supplementary Figure 15, Supplementary Table 3), and no Interdisciplinary causative role
evaluation of the
large external validation studies have been published. role of the PFO
Recurrence risk
In addition, the RoPE score does not account for high-risk PFO
features (e.g., septal aneurysm) that have been shown to correlate
with higher risk of paradoxical embolisation. Figure 2. Algorithm for the diagnostic workup of cryptogenic left
WHAT IS THE RISK OF RECURRENCE IN A PFO- circulation thromboembolism.
ASSOCIATED STROKE?
Meta-analyses of observational and/or randomised studies suggest
that the annual recurrence rate on medical therapy ranges from 0% telemetry or 24-hour Holter monitoring are sufficient to diag-
to 5.8% for stroke and from 0% to 14% for either stroke or tran- nose permanent AF and sufficiently long transient AF episodes.
sient ischaemic attack (TIA)90-92. This wide variability stresses the However, randomised and observational studies showed that
heterogeneity of phenotypes in these syndromes. Causes of recur- insertable cardiac monitors (ICM) are associated with an increased
rence can of course include non-PFO mediated mechanisms93,94. yield of paroxysmal AF diagnoses relative to standard monitor-
Some predictors of stroke recurrence have been identified pro- ing also in cryptogenic stroke99-104 (Supplementary Appendix 4,
spectively and retrospectively72,95-97 (Supplementary Figure 6). Supplementary Figure 16). Therefore, in high-risk patients for AF,
Supplementary Table 4 lists features that were statistically signi- an ICM period of six months can be reasonably considered to rule
ficant predictors in at least two studies. Atrial septal aneurysm out AF before deciding on PFO closure105. In Figure 3 we propose
anatomy is particularly predictive (Supplementary Appendix 4). a strategy based on risk stratification of patients to be applied with
In one study98, a high D-dimer level on admission was an inde- a critical clinical judgement (Supplementary Appendix 4). During
pendent predictor of recurrent ischaemic stroke in patients with ICM monitoring, patients should be maintained on medical ther-
PFO. Therefore, at present, the individual evaluation of the risk apy (see below). After six months, whatever the chosen treatment,
of recurrence also cannot be quantitatively scored and should the monitoring can be extended to the full duration of the ICM life
be based on interdisciplinary qualitative clinical evaluation. to identify episodes of paroxysmal AF106-112, to monitor the atrial
thrombosis burden in arrhythmic patients, and to aid diagnosis in
UNIFIED DIAGNOSTIC WORKUP IN LEFT CIRCULATION case recurrent ischaemia occurs.
THROMBOEMBOLISM
A diagnostic workup should follow logical steps (Figure 2). MEDICAL AND INTERVENTIONAL MANAGEMENT
Table 4 summarises position statements. Further details are pro- Further insights on each of the following paragraphs can be found
vided in Supplementary Appendix 4. in Supplementary Appendix 4.
The diagnostic process should always include interdisciplinary PICO questions for the choice of therapy are summarised in
clinical assessments and appropriate imaging. Table 5 and Supplementary Appendix 5. Figure 4 summarises the
Identifying atrial fibrillation (AF) is important because recur- flow of the choice of the therapy.
rences of left circulation embolism are, in the majority of cases, EFFICACY AND SAFETY OF MEDICAL THERAPY
due to left atrial appendage thrombosis instead of paradoxical A variety of medical treatments has been used, based upon data from
embolism. However, AF can be difficult to detect. A routine secondary prevention studies for stroke in general and from studies
12-lead electrocardiogram (ECG) and either in-patient cardiac on cryptogenic stroke in particular. No adequately dimensioned RCT
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Table 4. Summary of statements on the evaluation and treatment of concurrent diseases.
AF rule-out strategy
All patients should undergo a routine 12-lead ECG and either in-patient cardiac telemetry Strong B 260, 344
or 24-hour Holter monitoring
In patients >65 years old with negative routine monitoring, it is reasonable to consider Conditional C 99-102, 105, 166,
ICM before deciding on PFO closure or permanent OAC 173, 260-263
ICM evaluation period in cryptogenic left circulation embolism should be at least Conditional B 99-102,260-
6 months before deciding on PFO closure or permanent OAC 263,105
In patients 55 to 64 years old at risk for AF with negative routine monitoring, it is Conditional C 173, 264
reasonable to consider ICM before deciding on PFO closure or permanent OAC
In patients <55 years old with ≥2 high-risk factors for AF with negative routine monitoring, Conditional C –
it is reasonable to consider ICM before deciding on PFO closure or permanent OAC
Patients undergoing diagnostic procedures should be maintained on medical therapy Strong B Table 6
Medical therapy should be decided according to the statements of this position paper Strong C Table 6
In patients with clear evidence of a causal PFO (e.g., simultaneous pulmonary embolism), Strong C Table 5
ICM can be withheld so as not to delay percutaneous closure
In patients undergoing ICM, the monitoring should be extended for the full duration of the Strong C 102
device life, regardless of the choice of therapy after 6 months
Management of PFO in the presence of concomitant diseases
Patients on temporary OAC, on OAC for pulmonary embolism or those considered at high Conditional C 159, 160
risk of recurrences despite OAC may undergo PFO assessment for possible closure
Paroxysmal AF episodes >30 seconds detected with intermittent recordings, or Conditional B 163-168
≥5 minutes during ICM can be considered sufficient to evaluate the patient for OAC
according to current guidelines on AF
ICM results should always be interpreted with other clinical characteristics in order to Strong C 102
weigh the AF embolic risk against the PFO embolic risk
Routine laboratory tests for prothrombotic states (thrombophilia testing) are not warranted Strong C 161, 162
to indicate permanent OAC
First-line diagnostic workup

for arrhythmias
AF DETECTED
– 12-lead ECG STOP
– In-hospital telemetry
– 24-hour Holter ECG monitoring
NO AF
Evident PFO
causative role YES
NO
Age <55 years old Age 55-64 years old Age ≥65 years old
Evaluate major AF risk YES

AF risk factors factor(s) ICM
NO
STOP
AF RISK FACTORS
HIGH-RISK
– Uncontrolled hypertension – Obesity
– Structural heart alterations (LVH, LAE) – Atrial runs
– Uncontrolled diabetes – Pulmonary disease
– Congestive heart failure – Thyroid disease
Figure 3. Flow chart for the screening of overt atrial fibrillation in cryptogenic left circulation thromboembolism. The cut-off ages of 55 and
65 years old have been chosen according to data from large epidemiological studies166,173. Patients <55 years may be considered for ICM
when they have high clinical suspicion of AF (i.e., ≥2 high-risk factors for AF). ECG: electrocardiography; LAE: left atrium enlargement;
LVH: left ventricle hypertrophy
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Table 5. PICO question. Should percutaneous closure of PFO vs. medical therapy be used for secondary prevention of stroke or other left
circulation thromboembolism in patients with high-risk PFO features?
Population Secondary prevention of stroke, TIA, or other left circulation thromboembolism
Intervention Percutaneous closure of PFO
Comparison Medical therapy
Main outcomes Stroke, TIA, death, bleedings, atrial arrhythmias
TYPE OF
Strong statement for the intervention
STATEMENT
POSITION The position of our societies is to perform percutaneous closure of a PFO in carefully selected patients aged from 18 to
STATEMENTS 65 years with a confirmed cryptogenic stroke, TIA, or systemic embolism and an estimated high probability of a causal
role of the PFO as assessed by clinical, anatomical and imaging features.
The interventional procedure must be proposed to each patient evaluating the individual probability of benefit based on
an assessment of both the role of the PFO in the thromboembolic event (Table 4) and the expected results and risks of
a lifelong medical therapy. The role of the patient should be proactive, keeping in highest regard his/her values and
preferences regarding outcomes and therapy trade-offs, and informing him/her about the uncertainties of their condition.
With the same shared decision-making approach, PFO closure can also be considered in patients >65 or <18 years of
age, taking into account on a case-by-case basis the lack of evidence, the age-related confounders and additional risks of
interventional and drug therapies.
Although no specific data are available to date, consistent with some guidelines on the topic, it seems justified to
consider percutaneous closure in patients with a cryptogenic TIA, stroke, or systemic emboli that occurred while on
therapy with OAC or antiplatelet agents.
The choice of device should take into consideration that most available evidence has been obtained with the
AMPLATZERTM PFO Occluder and GORE® HELEX® Septal Occluder (not available anymore) or the GORE® CARDIOFORM
Septal Occluder. The use of the latter should be balanced against a lower complete closure rate and a higher risk of AF
as compared to medical therapy. The potential use of devices other than AMPLATZER and CARDIOFORM, and the
inherent risks, should also be part of the shared decision making with patients, in the light of technical, anatomical, and
clinical features.
JUSTIFICATION Overall justification

The last, comprehensive, study-level meta-analyses incorporating the most recent randomised trials on patients aged
18-65 years with prior cryptogenic stroke or TIA showed superiority of PFO closure over medical therapy for the
prevention of stroke in the first 5 years after the procedure (Supplementary Figure 17, Supplementary Figure 4A). One
exploratory analysis of one of these trials extended to a longer follow-up supports a growing benefit of percutaneous
closure over medical therapy after that time limit.
The CLOSE, and the early-terminated DEFENCE-PFO trials performed in characterised patients with confirmed
cryptogenic stroke and high-risk PFO features, and the REDUCE trial which also enrolled higher-risk patients as
compared to previous trials, are the main drivers of this evidence (Supplementary Figure 4B and Supplementary
Figure 5). The difference in results between studies enrolling higher-risk PFO patients and those enrolling unselected
patients with prior cryptogenic cerebral accidents stresses the existence of higher- and lower-risk phenotypes of patients
that need to be characterised before deciding on the therapy. This finding is furthermore supported by the cost-
effectiveness analysis which demonstrated a benefit over 15 years only in high-risk patients. However, the significant
effect in some subgroups, the heterogeneity still present at subgroup analysis even in high-risk patients, and the
individual study limitations (Supplementary Appendix 4) enforce the need for carefully informed choices which must be
shared with patients and tailored to their personal values and preferences.
Detailed justification
Problem. PFO-related stroke is an important health problem; therefore, its secondary prevention is a priority.
Unfortunately, its management is problematic because high-quality data are lacking in this very heterogeneous class of
patients. Nonetheless, the possibility of an efficient secondary prevention should be granted without causing harm with
unnecessary treatments. Given the very disparate practices that exist within the medical community in this regard, it is
urgent that clinicians follow a balanced approach that is based upon the present level of knowledge, while waiting for
more conclusive evidence on better classified populations of patients.
Desirable effects. Our study-level meta-analysis on the 6 RCTs showed a clear superiority of PFO closure over medical
therapy in terms of reducing the incidence of stroke recurrence (Supplementary Figure 4A). The two previously published
meta-analyses on the 6 RCTs, all of the first five RCTs (hence excluding the DEFENSE-PFO trial) and the highest-quality,
patient-level meta-analysis of the first three published RCTs are consistent with our results. Two meta-analyses of
comparative observational trials are in keeping with these results (Supplementary Table 7).
Undesirable effects. Interventional treatment does not imply higher complication rates, with the exception of a higher
frequency of AF after percutaneous closure relative to medical therapy (Supplementary Figure 9). However, the higher
risk of AF with closure versus medical therapy was considerably lowered (Supplementary Figure 10) if an AMPLATZER
PFO Occluder was used. In the REDUCE trial using the GORE HELEX or CARDIOFORM septal occluders, the incidence
of AF was 6.6% at 5 years, a large proportion of which were only intraprocedural or periprocedural arrhythmias. Bleeding
complications were similar in the young cohorts of patients enrolled in RCTs in the short term; however, long-term
follow-up data are missing in patients undergoing lifelong medical treatments, which are likely to increase the risk of
haemorrhage as patients grow older.
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Table 5 (continued). PICO question. Should percutaneous closure of PFO vs. medical therapy be used for secondary prevention of stroke
or other left circulation thromboembolism in patients with high-risk PFO features?
TYPE OF
Strong statement for the intervention
STATEMENT
JUSTIFICATION Certainty of evidence. The consistent results of all the meta-analyses performed so far were confirmed when considering
OR, RR and AR, even performing sensitivity analysis, and also when including CLOSURE I, the most outdated trial.
To date, despite several limitations of individual studies which implied an overall low score in the certainty of evidence
(Supplementary Table 9, Supplementary Table 10), in patients with high-risk PFO features the certainty is higher,
as shown by the reduction in heterogeneity in meta-analyses and by the recently published sequential analysis of the risk
of recurrent stroke74. Therefore, future studies are not likely to impact on the certainty of evidence, at least in high-risk
populations.
Values. Large variations in preferences of patients indicate the need for tailored informed consent and the explicit
evaluation of therapeutic trade-offs with individual patients.
Balance of effects. The NNT with percutaneous closure obtained in RCTs outweighed the NNH for atrial fibrillation after
percutaneous closure, especially when an AMPLATZER PFO Occluder was used and when patients with higher-risk PFO
were considered. Moreover, based on United States estimates, the cost-effectiveness analysis favours over 15 years
percutaneous closure in patients with high-risk PFO features and with the use of an AMPLATZER PFO Occluder.
SUBGROUP In published randomised studies, the age of patients was ≤65 years and 18 years. The DEFENSE-PFO trial, strongly
CONSIDERATIONS positive for PFO closure over medical therapy in the prevention of recurrent stroke, did not have age limitations for
enrolment and randomised patients aged up to 66 years old29.
In our study-level meta-analysis of the 6 RCTs, a statistically significant improvement in stroke recurrence with
percutaneous closure was observed only versus antiplatelet therapy (Supplementary Figure 12A), whereas OAT yielded
a similar risk of recurrence (Supplementary Figure 12B, Supplementary Figure 12C). Moreover, no differences were
noted regarding the outcomes of different pooled clinical inclusion criteria regarding the index event (Supplementary
Figure 13). However, some of the previous meta-analyses on the first 5 RCTs consistently found that patients with
moderate-to-severe shunt size experienced enhanced outcomes with percutaneous closure relative to medical
therapy78,79,90,122,170,171. Nonetheless, patients with ASA were associated with better outcomes with percutaneous closure
than with medical therapy only in some171,172 but not in other meta-analyses78,79. In our meta-analysis, we found that
patients with high-risk PFO features (ASA, hypermobility of atrial septum, moderate-to-severe shunt, or large PFO size)
reported enhanced outcomes with percutaneous closure relative to medical therapy, whereas in patients with low-risk
PFOs there was no additional benefit with PFO closure vs. medical therapy (Supplementary Figure 4B, Supplementary
Figure 5).
In our most recent analysis, no device was associated with statistically significant enhanced efficacy versus medical
therapy as compared to other devices (Supplementary Figure 14). The risk of new-onset atrial fibrillation was similar with
the AMPLATZER PFO Occluder and medical therapy while it was higher for the GORE CARDIOFORM device when
compared with medical therapy (Supplementary Figure 10).
In some meta-analyses other subgroups experienced enhanced outcomes with percutaneous closure relative to medical
therapy. These subgroups include males70,78,79,90 and age <45 years old78,79,90. However, these findings were not
confirmed in another meta-analysis171. Finally a single previous meta-analysis supported patients with a history of
migraines or non-cortical infarcts as having better outcomes with percutaneous closure as compared to medical
therapy70.
IMPLEMENTATION PFO closure incurs procedural cost. However, cost-effectiveness studies showed that PFO is associated with economic
CONSIDERATIONS and QUALY gain after 15 years, provided that the procedure was performed in high-risk patients. Performing the
procedure in unselected patients translates into a sharp decrease in cost-effectiveness.
Moreover, procedural costs and procedure times may be decreased with the use of sedation instead of general
anaesthesia or of intracardiac echocardiography versus transoesophageal echocardiography, thereby eliminating the need
for an anaesthesiologist.
MONITORING AND Each neurological index event should be confirmed by a neurologist or a stroke physician. The cardiologist and the stroke
EVALUATION physician must come to the conclusion that the stroke or TIA was cryptogenic and communicate in order to reach
consensus regarding therapeutic decisions. Patients should be actively involved at all stages of management and their
contribution to choices should be documented.
RESEARCH – To verify the existence of additional risk factors and their cut-offs for prediction of events in strict epidemiological series.
PRIORITIES – To identify new high-risk phenotypes encompassing different clusters of clinical, anatomical and biological
characteristics in prospective observational trials (systems and precision approaches) and to perform new randomised
trials in these populations.
– To design adequately dimensioned RCTs comparing single medical therapies (vitamin K antagonists or DOAC) with
percutaneous closure in patients with higher-risk PFO-related left circulation embolism.
– To assess outcomes of percutaneous closure vs. OAC.
– To assess long-term outcomes (>5 years) with different treatments.
– To address the evaluation of persisting disability and quality of life with different treatments.
– To design prospective registries to evaluate practices and outcomes in the real world.
– To obtain new, cost-effectiveness analyses based on contemporary practices.
– To obtain quantitative and qualitative data on patient preferences and values in the setting of cryptogenic stroke or
systemic embolism with PFO.
– To obtain data on the effectiveness and efficacy of organisational models to manage patients with cryptogenic stroke/
systemic emboli.
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Table 6. PICO question. Should oral anticoagulants (OAC) vs. antiplatelet therapy be used for secondary prevention of stroke or other left
circulation thromboembolism?
Population Secondary prevention of stroke or other left circulation thromboembolism
Intervention OAC
Comparison Antiplatelet therapy
Main outcomes Stroke; major bleedings
TYPE OF
Conditional statement for either the intervention or the comparison
STATEMENT
POSITION In patients in whom a medical therapy only is chosen, the position of our scientific societies is to choose the specific
STATEMENT drugs weighing the individual risk of bleeding against the risk of PFO-related stroke recurrence, in close connection with
the patient. Long-term OAC with vitamin K antagonists may be preferred if: a) the patient has a low haemorrhagic risk,
b) a probable good therapeutic compliance is foreseen, and c) a proper anticoagulant monitoring can be guaranteed.
In patients in whom these conditions are not satisfied, or the risk of stroke recurrence is deemed low, an antiplatelet
therapy should be prescribed. Reassessment of the risk/benefit ratio should be performed on a regular basis, especially
with advancing age and the increase in comorbidities which can affect both risk and benefit issues. No position can be
expressed for DOAC, although intuitively their reduced bleeding risk compared with vitamin K antagonists in other
clinical conditions is appealing.
JUSTIFICATION Overall justification
The randomised CLOSE trial shows a statistically non-significant reduction of stroke with OAC as compared to
antiplatelet therapy. However, a single trial enrolling only 300 patients reporting outcomes with wide confidence intervals
cannot be considered conclusive. Meta-analyses consistently indicate a statistically significant reduction in the risk of
stroke with OAC as compared to antiplatelet therapy, at the cost of a significantly higher risk of major bleeding. However,
the overall uncertainty of the evidence remains very high (Supplementary Table 11) and the inconsistency across studies
is severe (Supplementary Figure 7). Therefore, only a conditional statement for either OAC or antiplatelets can be
expressed, with the choice between them being guided by individual safety and expected risk of recurrence variables.
Detailed justification
Desirable effects. The randomised CLOSE trial shows a statistically non-significant reduction of stroke with OAC
as compared to antiplatelet therapy. Our meta-analysis indicates a statistically significant reduction of the odds ratio for
stroke of approximately 12% with OAC over antiplatelet therapy (Supplementary Figure 18). These results are in keeping
with previous meta-analyses.
Undesirable effects. An approximately 5-fold higher risk of major bleeding emerged from our meta-analysis with OAC
as compared to antiplatelet therapy. Also, these results are in line with previous analysis.
Certainty of evidence. The certainty of evidence is very low, because the results are mainly derived from non-randomised
comparisons (Supplementary Table 11), and the included randomised trial, enrolling only approximately 300 patients,
reported wide confidence intervals in effect estimates. Therefore, further RCTs will probably impact on effect estimates.
Values. Patients undergoing secondary pharmacological prevention for stroke appear to accept higher risk of bleeding if
a considerable certitude can be provided regarding the prevention of stroke.
Balance of effects. The balance of desirable and undesirable effects of therapy varies according to the expected benefits
of the therapy, as the risk of bleeding appears to be homogenous across studies. Therefore, therapy should be as
individualised as possible.
Feasibility. Feasibility of implementation of a safe OAC regimen with vitamin K antagonists is largely dependent on
availability of monitoring facilities of proper anticoagulation and on the possibility of accessing them by patients.
SUBGROUP No subgroup consideration can be derived from the accrued data. However, given the inconsistency of the studies and
CONSIDERATIONS the variability of results, subgroups should be identified for new study.
IMPLEMENTATION No cost-effectiveness studies have been performed in this field. However, as the costs of OAC and antiplatelet therapy
CONSIDERATIONS are low, the cost-effectiveness profile is dependent mainly on the costs of adverse events in the follow-up. The available
evidence shows that bleeding complications increase with age, rendering even more uncertain the cost-effectiveness of
this therapy in the long term.
MONITORING AND In antithrombotic therapy the risk/benefit ratio is highly dependent on time. It is therefore advised to reassess risks and
EVALUATION benefits of the chosen therapy on a regular basis, especially with advancing age and the increase in comorbidities. Local
registries for prospective evaluations of outcomes are strongly encouraged.
RESEARCH – To assess more precise risk factors and their cut-offs for prediction of events.
PRIORITIES – To identify new high-risk phenotypes encompassing different clusters of clinical, anatomical and biological
characteristics in prospective observational trials (systems and precision approaches).
– To design adequately dimensioned head-to-head RCTs comparing single medical therapies (e.g., acetylsalicylic acid,
clopidogrel, vitamin K antagonists, DOAC, etc.) in patients in whom percutaneous therapy has been excluded.
– To assess long-term outcomes (>5 years) with different treatments.
– To address the evaluation of persisting disability and quality of life with different treatments.
– To design prospective registries to evaluate practices and outcomes in the real world.
– To obtain new, cost-effectiveness analyses based on contemporary practices.
– To obtain quantitative and qualitative data on patient preferences and values in the setting of cryptogenic stroke or
systemic embolism with PFO.
– To obtain data on the effectiveness and efficacy of organisational models to manage patients with cryptogenic stroke/
systemic emboli.
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complication113. This surprisingly low proportion of bleeding
Individual evaluation of episodes can be explained by the young age of the patients and
probability of causal link
and risk of recurrence the short follow-up and, thus, must be interpreted with caution
because most of these patients will undergo a lifelong medical
Low or uncertain High therapy with an incremental risk of bleeding with age. Indeed, in
our meta-analyses on PFO patients, an odds ratio (OR) of 4.57
Evaluate Age 18-65 was found for major bleeding with OAC relative to antiplatelet
bleeding/recurrence risk NO years old
YES
drugs (Supplementary Figure 8). A previous meta-analysis con-
Shared decision Shared decision sidering secondary prevention of stroke in general revealed that
making making
the potential benefit of OAC might be outweighed by the risk of
both intracranial haemorrhage (OR 2.54) and major extracranial
PFO
Antiplatelet OAC closure haemorrhage (OR 3.43)117. In this respect, direct oral anticoagu-
LIKELIHOOD OF CAUSAL LINK RISK OF RECURRENCE
lants (DOAC) may alter the risk-benefit ratio118,119, although no
– Atrial septal aneurysm – Atrial septal aneurysm
High – Coagulation disorders data exist in these patients.
High – Atrial septal hypermobility
– Moderate/severe shunt SAFETY AND EFFICACY PROFILE OF PFO CLOSURE
– Simultaneous PE or DVT
OTHER FEATURES TO BE CONSIDERED OTHER FEATURES TO BE CONSIDERED Percutaneous procedure
– Imaging features of embolism (cortical vs. deep)
– PFO size and tunnel length – Older age
TO ASSESS RISK
Primary technical success approaches 100%78,113 and complete clo-
– Chiari network – PFO size sure is seen in 93-96% at one year122. The use of larger devices has
– Prominent Eustachian valve – Need for antiplatelets vs. OAC
– Clinical clues (long travel, immobilisation, straining – Stroke vs. TIA as index event a higher risk of residual shunts113,123-125; the AMPLATZER™ PFO
activity, recent major surgery, previous DVT or PE, OSAS) – Stroke on Rx with antiplatelets or OAC
– Age <55 years old Occluder (St. Jude Medical, St. Paul, MN, USA) may have lower
– Risk factors for stroke
– RoPE score residual shunt rates than other devices123,125-130. Individual ran-
domised data show a relative risk reduction of up to 80% for recur-
Figure 4. Treatment algorithm for secondary prevention of left rent strokes131,132. One meta-analysis of RCTs has shown the stroke
circulation cryptogenic thromboembolism. DVT: deep vein recurrence rate to be 0.29 per 100 person-years74 (Supplementary
thrombosis; OAC: oral anticoagulants; OSAS: obstructive sleep Appendix 3). In our study-level meta-analysis of RCTs with an
apnoea syndrome; PE: pulmonary embolism; Rx: therapy; average 3.8 years of follow-up, the incidence of recurrent stroke
TIA: transient ischaemic attack was 2% in the closure arms, and the number needed to treat (NNT)
with PFO closure to prevent one stroke overall was 37 (95% con-
fidence interval [CI]: 26 to 68) (Supplementary Figure 4A), and
has yet been published that has assessed the effectiveness of individ- 21 in patients with high-risk PFO features (95% CI: 16 to 61)
ual drugs specifically in PFO-associated cerebrovascular accidents. (Supplementary Figure 5). Results on TIA and on death were
Trials were almost exclusively observational with only one ade- neutral (Supplementary Figure 4C, Supplementary Figure 4D,
quately dimensioned RCT comparing oral anticoagulants (OAC) respectively). An increase of the treatment effects over time can
and antiplatelet agents. One meta-analysis of RCTs showed be expected28,133,134. No data are available on persisting disability
a recurrent stroke rate of 1.27 events per 100 patient-years with and quality of life.
drugs only74. In our meta-analysis of the RCTs, the incidence of Complications are summarised in Supplementary Table 5.
recurrent stroke on medical therapy was 4.6% after 3.8 years of Procedural complications had a 2.6% incidence in RCTs74. The
follow-up (Supplementary Figure 4A, Supplementary Figure 4B, most frequent late complication is device thrombosis, which
Supplementary Appendix 3), whereas in a meta-analysis of obser- is seen in 1.0-2.0%135. Device embolism is a serious event and
vational trials the recurrence rate was 5% per year113. occurs at a rate of 0.9-1.3%135,136. Atrial wall erosions are serious
Despite a severe heterogeneity of results, the most recent events that have been reported anecdotally. The risk of long-term
meta-analysis including the randomised study is consistent with pre- mortality or the need for cardiac surgery is less than one in 1,000.
vious meta-analyses of observational studies113-116, suggesting supe- Minor complications occur only in 1.0-1.7%.
riority of OAC over antiplatelet agents in the prevention of stroke The most frequent undesirable event following transcatheter per-
(Supplementary Figure 7, Supplementary Appendix 3). Although cutaneous closure is AF in RCTs and observational trials28,78,106-111,113.
the overall quality of the evidence in this meta-analysis was esti- In a meta-analysis of RCTs, a 4.6% incidence was reported after
mated to be very low (Supplementary Table 11), the superiority 3.8 years of follow-up74. In our meta-analysis, for incident AF, the
of OAC vs. antiplatelet agents was also evident when considering overall number needed to harm (NNH) was 25 (Supplementary
studies with multivariate adjustment only (Supplementary Figure 7). Figure 9A), whereas beyond 45 days there was no increased risk
No data are available on persisting disability and quality of life. for AF with PFO closure (Supplementary Figure 9B, Supplemen-
Reports on safety have often been incomplete or have yielded tary Figure 9C). The incidence of these events was lowest with the
inconsistent results. In a meta-analysis of observational studies, AMPLATZER PFO Occluder (Supplementary Figure 10). Inter-
1.1% of patients receiving medical therapy experienced a bleeding estingly, a statistically significant reduction of AF prevalence after
1399
percutaneous closure of PFO was also shown in other studies, sug- found (Supplementary Table 6)124,141-147, but studies were small,
gesting some antiarrhythmic effect of the procedure137. often plagued by partially incomplete follow-up, and problematic
Management after percutaneous closure regarding shunt detection accuracy139. Also, a persistent shunt after
No data on best management strategies after PFO closure are closure may reveal other sources of paradoxical embolism which
available. Position statements are summarised in Table 7. were missed during the diagnostic phase148.
Drug treatments No high-quality data are available to guide the optimal manage-
To decide on post-procedural therapy one should consider that: ment of a residual moderate-to-severe PFO patency. The literature
a) endocardialisation of the device can continue up to five years on acute and long-term results after repeat device implantation
post implantation128,138-140; b) one of the most frequent complica- for a residual shunt is scarce, but retrospective evaluations are
tions after closure is device thrombosis; and c) premature discon- encouraging149-156.
tinuation of therapy may cause minor cerebrovascular events after Empirically, antibiotic prophylaxis against endocarditis before
PFO closure, as suggested by a marked trend towards association an invasive procedure or surgical intervention should also be con-
between duration of dual antiplatelet therapy after PFO closure sidered routinely in all cases within the first six months after the
and the incidence of TIA in our study-level meta-regression analy- implantation and, probably, beyond six months in patients with
sis (Supplementary Figure 11). a residual shunt.
It is reasonable to decide on the post-procedural therapy accord- Surgical closure of PFO
ing to the strategies used in RCTs. Overall, 5/6 RCTs prescribed There are no current indications for surgical closure of a PFO as
or recommended a dual antiplatelet therapy in the first one to six first-line treatment. Closure of incidental PFOs is usually under-
months after closure, continuing with a single drug beyond two taken during valvular surgery or in the rare cases when surgery is
years in 3/4 RCTs that had a longer follow-up after that limit. In indicated for other conditions in which the PFO plays a role, such
all positive trials, an antiplatelet therapy was prolonged for the as a straddling thrombus in the PFO, or seldom when complica-
entire duration of the study in the majority of patients (in 2/4 stud- tions of percutaneous closure occur which cannot be managed by
ies it was prescribed for five years). In one negative trial, only percutaneous means.
50% and 41% of patients were still taking an antiplatelet therapy Management in the presence of concomitant diseases
after one and five years, respectively132. Position statements are summarised in Table 4.
Delayed complications In the setting of hypercoagulability, deep vein thrombosis
Supplementary Table 5 displays the main tools available to and/or pulmonary embolism159, PFO closure may be considered
detect complications. At present, no relationship between PFO when there is the need for only temporary OAC or a high risk
patency after closure and the incidence of recurrence has been of recurrence despite permanent OAC, particularly in pulmonary
Table 7. Summary of statements on the management after percutaneous closure of PFO.

Strength of
Level of
Position statements the Ref.
evidence
statement
Drug therapy and follow up after percutaneous closure
It is reasonable to propose dual antiplatelet therapy for 1 to 6 months after PFO closure Conditional A 27, 29, 51, 112,
132, Supplementary
Figure 11
We suggest a single antiplatelet therapy be continued for at least 5 years Conditional C 27-29, 51, 112,
132, 128, 138-140
The extension of the therapy with single antiplatelet beyond 5 years should be based on Strong C –
the balance between patient’s overall risk of stroke for other causes and haemorrhagic risk
The choice of the type of antiplatelet drug in the follow-up is currently empiric Strong A 27-29, 51, 112,
132
The value of residual shunt after percutaneous closure cannot be deduced from available Strong C 124, 141-47
studies
Systematic, high-quality data on follow-up are needed Strong C –
To obtain comparable data we propose to perform: Conditional C 124, 141-147, 55 +
a) a TTE prior to hospital discharge Original meta-
b) c-TCD at least once beyond six months to assess effective PFO closure and thereafter, analyses page 1392
if residual shunt persists, annually until closure and Supplementary
c) c-TOE or c-TTE in case of severe residual shunt at c-TCD, or recurrent events, or Appendix 4
symptoms during follow-up
Patients should undergo antibiotic prophylaxis for any invasive procedure performed in the Conditional C –
first six months from PFO closure
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embolism, where PFO was reported to be an independent predic- B. Meier declares a conflict of interest in the form of speaker fees
tor of new brain lesions in the follow-up, despite optimal OAC160. received from Abbott. M. Chessa reports personal fees from Abbott
Routine laboratory tests for prothrombotic states (thrombophilia and Occlutech. D. Toni reports personal fees from Boehringer
testing) are not generally warranted to guide the need for perma- Ingelheim, Bayer, Pfizer Bristol-Myers Squibb, Daiichi Sankyo, and
nent OAC161,162. Medtronic. P. Scacciatella reports personal fees from Abbott Medical
Although no study has assessed this issue as yet, it is reason- and Gore Medical. J. Thomson reports being a proctor and consult-
able that excluding patients with AF from PFO closure and treat- ant for Abbott Medical and Gore Medical. D. Hildick-Smith reports
ing them with permanent OAC should translate into an increased having consultancy/advocacy for Abbott, Gore and Occlutech.
effectiveness of secondary prevention of left circulation throm- D. Sibbing reports personal fees outside the submitted work from
boembolism. However, as in the CRYSTAL-AF study, a higher Roche Diagnostics, Daiichi Sankyo, Eli Lilly, Bayer Healthcare,
incidence of AF at ICM did not translate into a higher stroke inci- Sanofi, Pfizer and AstraZeneca. S. Kasner reports personal fees
dence102; the presence of short bursts of AF on an ICM may carry from Bristol-Myers Squibb, Boehringer Ingelheim, Medtronic
a lower pathogenic value than a high-risk PFO. Therefore, the and AbbVie, grants from W.L. Gore, and grants and personal fees
burden of AF should be weighed against the burden of PFO by from Janssen and Bayer, outside the submitted work. G. Biondi-
considering other clinical characteristics to decide for or against Zoccai reports having been a consultant for Abbott Vascular and
PFO closure. For patients with paroxysmal AF, there is uncertainty Bayer. J. Carroll reports personal fees from AGA Medical, St. Jude
regarding the duration of arrhythmic episodes which increases the Medical, and Abbott. The Chairman of the task force and all the
risk of embolism. According to the HRS/EHRA/ECAS expert con- other authors have no conflicts of interest to declare. The Guest
sensus statement on AF ablation, AF episodes ≥30 seconds con- Editor has no conflicts of interest to declare.
stitute clinically significant AF163. During prolonged monitoring,
episodes of AF ≥5 minutes have a predictive value for embo- References
lism164-168. These criteria should be combined with a thromboem- The references can be found in the Supplementary data document.
bolic score to evaluate the need for OAC169.
Supplementary data
Conclusions Supplementary Appendix 1. Detailed methods.
The management of patients with cryptogenic left circulation throm- Supplementary Appendix 2. Statistical methods.
boembolism and PFO has been controversial, giving rise to hetero- Supplementary Appendix 3. Systematic review of evidence,
geneous strategies across different local realms in Europe. Based on assessment of its quality and meta-analyses.
the best available evidence, we were able to reach, in this interdisci- Supplementary Appendix 4. Detailed evaluation of specific issues.
plinary position paper, a consensus among eight European scientific Supplementary Appendix 5. GRADE evaluation of evidences for
societies on key diagnostic, therapeutic and research issues, from the PICO questions.
index event to follow-up. It was possible to express strict position Supplementary Figure 1. Comparison of the rate of PFO detection
statements based on randomised trials for some therapeutic aspects, in studies using TOE or autopsy.
whereas other aspects were often based on limited and non-ran- Supplementary Figure 2. Meta-analysis of diagnostic accuracy
domised data. This position paper provides the first largely shared studies comparing c-TCD vs. c-TOE.
approach for a rational PFO management based on the best avail- Supplementary Figure 3. Meta-analysis of diagnostic accuracy
able evidence. This may help physicians to offer coherent strategies studies comparing c-TTE vs. c-TOE.
throughout Europe and focus the research on high-priority subjects. Supplementary Figure 4. Outcomes in patients undergoing percu-
taneous closure or medical therapy.
Guest Editor Supplementary Figure 5. Subgroup analysis according to PFO
This paper was guest edited by David R. Holmes, MD, MACC; features.
Department of Cardiology, Mayo Clinic, Rochester, MN, USA. Supplementary Figure 6. PRISMA flow chart for the review of
studies on the predictors of stroke in patients with cryptogenic
Acknowledgements stroke and a PFO.
We are indebted to Marielle De La Torre, Jenny Pena, Laurence Supplementary Figure 7. Forest plot for the risk of stroke recur-
Fani and the entire Specialty Centre Division of the European rence in studies comparing OAC with antiplatelet therapy for
Association of Percutaneous Cardiovascular Interventions for their cryptogenic solid systemic embolism.
invaluable and highly professional support throughout the phases Supplementary Figure 8. Forest plot for the risk of major bleed-
of development of this position paper. ings in studies comparing OAC with antiplatelet therapy for cryp-
togenic cerebral or systemic embolism.
Conflict of interest statement Supplementary Figure 9. Risk of atrial fibrillation in studies com-
H. Sievert reports institutional fees from Carag and Lifetech, outside paring PFO closure with medical therapy for cryptogenic cerebral
the submitted work. B. Dalvi reports being a consultant to Abbott. or systemic embolism.
1401
Supplementary Figure 10. Forest plot for the risk of atrial fibrilla- Supplementary Figure 20. PRISMA flow chart for the review of
tion according to the type of device used for PFO closure in stud- studies investigating the accuracy of PFO diagnostic tests.
ies comparing PFO closure with medical therapy for cryptogenic Supplementary Figure 21. Simplified scheme of the interacting
cerebral or systemic embolism. network of processes underlying clinical manifestations associated
Supplementary Figure 11. L’Abbé plots for the risk of TIA and with PFO.
stroke after PFO closure according to the length of dual antiplate- Supplementary Table 1. PFO diagnostic methods.
let therapy. Supplementary Table 2. Qualitative evaluation of diagnostic studies.
Supplementary Figure 12. Risk of stroke recurrence in patients Supplementary Table 3. Qualitative evaluation of the studies on
undergoing OAC or antiplatelet therapy in studies comparing PFO RoPE score.
closure with medical therapy for cryptogenic cerebral or systemic Supplementary Table 4. Predictors of cryptogenic stroke recur-
embolism. rence in the presence of a PFO.
Supplementary Figure 13. Risk of stroke recurrence according to Supplementary Table 5. Complications of percutaneous closure.
the type of index event in studies comparing PFO closure with Supplementary Table 6. Prognosis of patients with PFO patency.
medical therapy for cryptogenic cerebral or systemic embolism. Supplementary Table 7. Summary of meta-analyses on closure
Supplementary Figure 14. Risk of stroke recurrence according to vs. medical therapy trials.
the type of device used for PFO closure in studies comparing PFO Supplementary Table 8. Observational studies comparing PFO
closure with medical therapy for cryptogenic cerebral or systemic closure with medical therapy.
embolism. Supplementary Table 9. RCTs comparing percutaneous closure
Supplementary Figure 15. PRISMA flow chart for the review of and medical therapy.
studies on the RoPE score. Supplementary Table 10. Qualitative and quantitative assessment
Supplementary Figure 16. PRISMA flow chart. of the evidence on the comparison between PFO closure versus
Supplementary Figure 17. PRISMA flow chart for the review of medical therapies.
RCTs comparing PFO closure with medical therapy. Supplementary Table 11. Qualitative assessment of the evidence
Supplementary Figure 18. PRISMA flow chart for the review of on the comparison between antiplatelet versus OAC therapies.
studies comparing OAC with antiplatelet therapy for secondary Supplementary Table 12. Quality of evidence grades.
prevention of stroke, TIA or systemic solid embolism in patients
with previous cryptogenic left embolism. The supplementary data are published online at:
Supplementary Figure 19. PRISMA flow chart for the review of http://www.pcronline.com/
studies investigating the accuracy of PFO diagnostic tests. eurointervention/146th_issue/252
1402
Supplementary data
Supplementary Appendix 1. Detailed methods.
General outline of the process

The European Association for Percutaneous Cardiovascular Interventions (EAPCI) planned to create
position statements on PFO management. Relevant European scientific bodies were invited to collaborate,
and task force members were chosen by each society. External international experts were also asked to join
the initiative as reviewers. Systematic reviews and statistical analysis were performed by a dedicated
evidence synthesis team. Grading of recommendations assessment, development, and evaluation (GRADE)
methodology (http://gdt.guidelinedevelopment.org/app/handbook/handbook.html) was used to develop
patients-interventions-comparators-outcomes (PICO) questions, evaluate evidence and formulate position
statements. Not all topics could be addressed by the PICO methodology and therefore additional non-PICO
questions were developed. Some PICO questions were reclassified as non-PICO after the literature search,
due to a lack of clear evidence. Non-PICO questions were formally defined by e-mail exchange.
The evidence synthesis team undertook relevant systematic literature searches for each question using a
combination of controlled vocabulary and free text terms. The databases searched for this purpose were:
Pubmed, Scopus, Google Scholar and ISI. Preliminary literature searches were performed in
September/October 2016 with an update in March 2018.
Evidence was evaluated qualitatively and where possible by quantitative methods. Each evaluation was
performed according to a pre-defined ranking of outcomes made by the task force. Grading of the quality of
evidence was made by consensus by the evidence synthesis team and the task force using the following
criteria: the type of studies included, limitations in study design and methodology (i.e., risk of bias),
inconsistency (or else: heterogeneity) of results, indirectness of evidence, imprecision, reporting bias, the
magnitude of the treatment effect, evidence of a dose–response relationship, and the effect of all plausible
confounding. Quality of evidence was evaluated by the means of GRADE-PRO GDT online tool
(https://gradepro.org) and graded as high, moderate, low and very low (Supplementary Table 12). When
several outcomes were assessed for a clinical question, the grade for the overall quality of evidence was
based on the grade for the most important outcome(s).
Quantitative absolute risk reduction, as classically performed in the GRADE method, was not deemed
sufficient to formulate position statements because of the low event rate frequency. Therefore, original meta-
analyses were undertaken for all PICO questions and some non-PICO topics.
Subsequently, the task force was structured in working groups, each addressing one question and writing the
relevant draft. These drafts were merged and distributed to the task force members for individual editing in
three consecutive editing rounds. Discrepancies were resolved by consensus and the final manuscript
1
underwent a formal approval by the task force, before being distributed to the relevant scientific societies for
the final endorsement. The final version was approved July 22nd 2018 and submitted for publication July
23rd 2018.
GRADE process and position statements

Formulation of the PICO questions was suggested and concluded by consensus among the members of the
working group. Twenty-two PICO questions were initially formulated. Only two of these could be addressed
by a modified GRADE methodology after the evidence evaluation ("Should percutaneous closure of PFO vs.
medical therapy be used for secondary prevention of stroke or other left-circulation thromboembolism ?" and
"Should oral anticoagulants (OAC) vs. antiplatelet therapy be used for secondary prevention of stroke or
other left-circulation thromboembolism ?").
The nature and strength of position statements was agreed by task force consensus.
Specifications of PICO are detailed in the relevant sections and tables of the document.
Population
These position statements refer to patients with PFO with various forms of putatively associated syndromes
and are specified throughout the text.
Interventions
Interventions addressing PFO-associated syndromes vary according to the relevant clinical scenario. We
have focused on percutaneous closure, pharmacological interventions and behavioural measures.
Pharmacological interventions include: oral anticoagulants, antiplatelet agents, and combinations of these
interventions. Behavioural measures consist in change of specific activities when they expose subjects to
risk. These activities include: lifestyle, surgical techniques when an operation is required, and habits or
working activities.
Comparators
As no gold standard therapies are available in PFO-associated syndromes, we compared different
interventions among those that are commonly used.
Outcomes
The GRADE methodology recommends that evidence-based guidelines consider outcomes which are of
importance to patients and/or their families and that more emphasis is placed on outcomes of greatest
importance to them. Therefore, we focussed on patients’ chance of survival, quality of life, working status,
and functional outcome. However, apart from death risk, those outcomes have seldom been considered in
published literature regarding PFO-related syndromes. We also considered the risks of adverse effects of
therapies (e.g., haemorrhage or arrhythmias). The position statements of this position paper are expressed on
2
agreement by consensus and on a grading of outcomes performed with a formal online poll. Therefore, the
priority is based on the lone judgement of the task force.
Non-PICO questions definition and position statements

Originally, 7 non-PICO questions were formulated for each PFO-associated clinical syndrome: four of which
are indicated in the chapter titles of the manuscript, two are incorporated into "Diagnostic workup" and one
in the "Efficacy and safety of therapies" chapters. After evidence evaluation, 20 questions formerly identified
as PICO questions were changed into non-PICO questions. Each question underwent the above described
process for developing position statements which were finally incorporated into the chapters of the position
paper.
Position statements were formulated by consensus among the members of the task force, based on the
evidence evaluation in the 3 Delphi editing rounds. Tables summarising position statements indicate the
strength of the position statement – strong or conditional (depending on patient values, physician opinion,
resources available or setting) according to GRADE method. We also indicated the quality of the data: A)
data derived from multiple RCTs or meta-analyses; B) data derived from single RCT or large non-
randomised studies; C) consensus of opinion of experts and/or small studies, retrospective studies and
registries. Despite a "C" level of evidence, some statements have been classified as "strong". The reasons for
this are because it is the low quality of evidence that supported the direction of the statement (e.g., more
research is needed in a sector because the lack of evidence) or because there were few or no specific studies
addressing the issue but the evidence on the PFO subject as a whole supported the statement (e.g.,
interdisciplinary assessment and decision making should be done in PFO-related syndromes although no
studies were performed comparing interdisciplinary approach with single professional management).
Conversely, in other situations, a statement may have been classified as "conditional" despite a level of
evidence "A" if the underlying evidence had a low quality despite being derived from randomised studies.
For strong statements, we use the terminology ‘should. . .’ or definitely affirmative sentences. In case of
conditional/discretionary statements, we used a wording implying that doctors and patients should consider
more carefully whether the suggested option is the right choice or case for that particular patient.
In the tables summarising position statements, "Ref." denotes both bibliography and/or original evidence
which has been produced in this document.
LIST OF PICO AND NON-PICO QUESTIONS

1. Should analytical risk factors (clinical or anatomical) be used to diagnose causal or high-risk PFO in
cryptogenic stroke or other left-circulation thromboembolism?
2. Should the risk of paradoxical embolism (ROPE) score be used to diagnose causal or high-risk PFO
in cryptogenic stroke?
3. Should insertable cardiac long-term monitoring be used to diagnose atrial fibrillation in patients with
PFO-associated ischaemic cryptogenic stroke or other left-circulation thromboembolism?
4. Should transcranial Doppler with bubble test vs. transthoracic contrast echography be used to
3
diagnose PFO in suspected PFO-associated clinical syndromes?
5. Should transoesophageal contrast-echocardiography vs. transthoracic contrast echocardiography be
used to diagnose PFO in suspected PFO-associated clinical syndromes?
6. Should transcranial Doppler vs transoesophageal contrast-echocardiography be used to diagnose
PFO in suspected PFO-associated clinical syndromes?
PFO patency in patients who underwent percutaneous closure?
8. Should transcranial Doppler vs. transthoracic contrast echocardiography be used to diagnose PFO
patency in patients who underwent percutaneous closure?
used to diagnose PFO patency in patients who underwent percutaneous closure?
10. Should percutaneous closure of PFO vs. medical therapy be used for secondary prevention of stroke
or left-circulation thromboembolism? (PICO question)
11. Should oral anticoagulants (OAC) vs. antiplatelet therapy be used for secondary prevention of stroke
or other left-circulation thromboembolism? (PICO question)
12. Should percutaneous closure of PFO vs. medical therapy be used for pregnant women with
indication to secondary prevention of stroke or other left-circulation thromboembolism?
13. Should primary prevention vs. no prevention measures be used in patients with PFO and very high
risk of paradoxical embolisation or cryptogenic ischaemic stroke?
14. Should percutaneous closure of PFO vs. diving avoidance be used for secondary prevention of
decompression sickness in professional divers?
decompression sickness in recreational divers?
16. Should percutaneous closure of PFO vs. flying avoidance be used for secondary prevention of
decompression sickness or asymptomatic embolisation in airplane pilots?
17. Should percutaneous closure of PFO vs. diving avoidance be used for primary prevention of
18. Should percutaneous closure of PFO vs. diving avoidance be used for primary prevention of
19. Should percutaneous closure of PFO vs. flying avoidance be used for primary prevention of
decompression sickness in airplane pilots?
20. Should percutaneous closure of PFO vs. medical therapy be used for platypnoea-orthodeoxia
syndrome?
21. Should percutaneous closure of PFO + medical therapy vs. medical therapy alone be used for
migraine with aura?
22. Should percutaneous closure of PFO vs. no therapy alone be used in patients scheduled for surgery
in the sitting position?
4
GRADING OF OUTCOMES FOR THE POSITION STATEMENTS
Position statements were expressed evaluating the relevant outcomes in each particular setting. Before the
systematic literature reviews, task force members formally defined outcomes for each questions using Delphi
rounds and successively, with an online poll, graded their importance for making a decision regarding the
position statements. Outcomes were graded as: critical, important but not critical or of limited importance for
decision making. Grading was performed by each member of the task force rating each outcome numerically
on a 1 to 9 scale (7 to 9 – critical; 4 to 6 – important; 1 to 3 – of limited importance). The final grading of
outcomes was the average of the individual grading. If for a question, no outcome reached an average rate ≥
7, we considered critical for decision making those items that had the highest prevalence of individual scores
≥ 7 in the poll. If some outcomes had more than four votes ≤3, the item was ranked as of limited importance
for expressing a position. When, comparing similar questions, the poll vote resulted to be inconsistent, the
most reliable vote was considered.
After the evidence review was performed, a reassessment of importance was necessary. Supplementary
Table 13 summarise the final grading of outcomes used for this position document.
LITERATURE SEARCH QUERIES

1. Should analytical risk factors (clinical or anatomical) be used to diagnose causal or high-risk PFO in
cryptogenic stroke or other left-circulation thromboembolism?
((pfo) OR (patent foramen ovale)) and ((risk factor) OR (aneurysm) OR (septal pouch) OR (deep vein
thrombosis)) and ((stroke) OR (transient ischaemic attack) OR (TIA) OR (migraine) or (embolism)) NOT
((review[pt] OR editorial[pt] OR letter[pt]))
2. Should ROPE score be used to diagnose causal or high-risk PFO in cryptogenic stroke?
((pfo) OR (patent foramen ovale)) and ((risk factor) OR (aneurysm) OR (septal pouch) OR (deep vein
thrombosis)) and ((stroke) OR (transient ischaemic attack) OR (TIA) OR (migraine) or (embolism)) and
((score) or (ROPE)) NOT ((review[pt] OR editorial[pt] OR letter[pt]))
3. Should insertable cardiac long-term monitoring be used to diagnose atrial fibrillation in patients with
PFO-associated ischaemic cryptogenic stroke or other left-circulation thromboembolism?
((pfo) OR (patent foramen ovale)) and ((ischaemic) OR (cryptogenic) OR (stroke) or (TIA) or (transient
ischaemic attack) or (embolism) or (migraine)) and ((atrial fibrillation) or (AF) or (asymptomatic) OR (loop
recorder) or (ILR) OR (insertable cardiac long-term monitoring )) NOT ((review[pt] OR editorial[pt] OR
letter[pt]))
4. Should transcranial Doppler with bubble test vs. transthoracic contrast echography be used to
diagnose PFO in suspected PFO-associated clinical syndromes?
ischaemic attack) or (embolism) or (migraine)) and ((transcranial Doppler) or (bubble) or (transthoracic
contrast echography) or (echocardiography)) NOT ((review[pt] OR editorial[pt] OR letter[pt]))
used to diagnose PFO in suspected PFO-associated clinical syndromes?
5
PFO in suspected PFO-associated clinical syndromes?
PFO patency in patients who underwent percutaneous closure?
((pfo) OR (patent foramen ovale) OR (patency)) AND ((closure) OR (percutaneous) or (Amplatzer) OR
(Watchman) OR (device) OR (Cardioseal/STARFlex) OR (Helix)) and ((ischaemic) OR (cryptogenic) OR
(stroke) OR (TIA) OR (transient ischaemic attack) OR (migraine) or (embolism)) and ((transcranial Doppler)
OR (bubble) OR (transthoracic contrast echography) OR (echocardiography) OR (trans oesophageal)) NOT
8. Should transcranial Doppler vs. transthoracic contrast echocardiography be used to diagnose PFO
patency in patients who underwent percutaneous closure?
(Watchman) OR (device) OR (Cardioseal/STARFlex) OR (Helex)) and ((ischaemic) OR (cryptogenic) OR
used to diagnose PFO patency in patients who underwent percutaneous closure?
(Watchman) OR (device) OR (Cardioseal/STARFlex) OR (Helex)) and ((ischaemic) OR (cryptogenic) OR
10. Should percutaneous closure of PFO vs. medical therapy be used for secondary prevention of stroke
or other left-circulation thromboembolism?
((pfo) OR (patent foramen ovale)) AND ((closure) OR (percutaneous) or (Amplatzer) OR (Watchman) OR
(device) OR (Cardioseal/STARFlex) OR (Helex)) and ((ischaemic) OR (cryptogenic) OR (stroke) OR (TIA)
OR (transient ischaemic attack) OR (embolism)) and ((medical) or (drug) or (aspirin) or (clopidogrel) or
(warfarin) or (antiplatelet) or (anticoagulation)) NOT ((review[pt] OR editorial[pt] OR letter[pt]))
11. Should oral anticoagulants (OAC) vs. antiplatelet therapy be used for secondary prevention of stroke
or other left-circulation thromboembolism?
6
((pfo) OR (patent foramen ovale)) AND ((ischaemic) OR (cryptogenic) OR (stroke) OR (TIA) OR (transient
ischaemic attack) OR (embolism)) and ((medical) or (drug) or (aspirin) or (clopidogrel) or (warfarin) or
(antiplatelet) or (anticoagulation)) NOT ((review[pt] OR editorial[pt] OR letter[pt]))
12. Should percutaneous closure of PFO vs. medical therapy be used for pregnant women with
indication to secondary prevention for left circulation embolism?
((pregnancy) OR (pregnant) OR (postpartum) OR (caesarean)) and ((pfo) OR (patent foramen ovale)) NOT
13. Should primary prevention vs. no prevention measures be used in patients with PFO and very high
risk of paradoxical embolisation or cryptogenic ischaemic stroke?
((primary prevention) or (primary) or (asymptomatic)) and ((pfo) OR (patent foramen ovale)) AND
((closure) OR (percutaneous) or (Amplatzer) OR (Watchman) OR (device) OR (Cardioseal/STARFlex) OR
(Helex)) NOT ((review[pt] OR editorial[pt] OR letter[pt]))
((decompression) or (sickness) or (professional) or (recreational) or (amateur) or (divers) or (diver) or (scuba
diving)) and ((pfo) OR (patent foramen ovale)) NOT ((review[pt] OR editorial[pt] OR letter[pt]))
((decompression) or (sickness) or (professional) or (recreational) or (amateur) or (divers) or (diver) or (scuba
16. Should percutaneous closure of PFO vs. flying avoidance be used for secondary prevention of
decompression sickness or asymptomatic embolisation in airplane pilots?
((decompression) or (sickness) or (airplane) or (pilot) or (fighter)) and ((pfo) OR (patent foramen ovale))
NOT ((review[pt] OR editorial[pt] OR letter[pt]))
17. Should percutaneous closure of PFO vs. diving avoidance be used for primary prevention in
professional divers?
18. Should percutaneous closure of PFO vs. diving avoidance be used for primary prevention in
recreational divers?
(decompression) or (sickness) or (professional) or (recreational) or (amateur) or (divers) or (diver) or (scuba
19. Should percutaneous closure of PFO vs. flying avoidance be used for primary prevention in airplane
pilots?
20. Should percutaneous closure of PFO vs. medical therapy be used for platypnea-orthodeoxia
syndrome?
7
((platypnea) OR (orthodeoxia) or (platypnea-orthodeoxia syndrome)) and ((pfo) OR (patent foramen ovale))
21. Should percutaneous closure of PFO + medical therapy vs. medical therapy alone be used for
migraine with aura?
(migraine) and ((pfo) OR (patent foramen ovale)) AND ((closure) OR (percutaneous) or (Amplatzer) OR
(Watchman) OR (device) OR (Cardioseal/STARFlex) OR (Helex)) NOT ((review[pt] OR editorial[pt] OR
letter[pt]))
22. Should percutaneous closure of PFO vs. no therapy be used in patients scheduled for surgery in the
sitting position?
((sitting) or (sitting position) or (semisitting position)) and ((pfo) OR (patent foramen ovale)) NOT
8
Supplementary Appendix 2. Statistical methods.
Continuous variables are reported as mean (standard deviation) or median (range). Categorical variables are
expressed as n/N (%). In order to support the expression of position statements, 4 original meta-analyses
were performed for PICO questions and for the accuracy of diagnostic tests for PFO. A meta-regression for
assessing the impact on outcomes of the length of dual antiplatelet therapy after closure was also performed.
Further details are provided in Supplementary Appendix 3.
Meta-analyses of association studies or of studies on therapy outcomes

Statistical pooling was performed according to a random-effect model with generic inverse-variance
weighting, computing risk estimates with 95% confidence intervals, using RevMan version 5.3, (The
Cochrane Collaboration, The Nordic Cochrane Centre, and Copenhagen, Denmark,
http://community.cochrane.org/tools/review-production-tools/revman). Hypothesis testing for superiority
was set at the two-tailed 0.05 level. Hypothesis testing for statistical homogeneity was set at the two-tailed
0.10 level and based on the Cochran Q test, with I2 values of 25%, 50%, and 75% representing, respectively,
mild, moderate, and extensive statistical inconsistency.
Meta-analysis of studies on diagnostic tests accuracy

Based on the frequencies of true-positive, false-positive, true-negative, and false-negative results in the
individual studies, the pooled sensitivity, specificity, and area under the summary receiver operating curve
(sROC) were estimated for TCD and TTE (vs TEE, which was treated as the gold standard procedure)
[174,175]. The area under the sROC values were compared between TCD and TTE using the appropriate z
tests. All statistical analyses were performed with Review Manager (RevMan) version 5.3 software
(Copenhagen, Denmark, Nordic Cochrane Centre, Cochrane Collaboration, 2014) and STATA/SE version
13 (Stata Corp, College Station, TX). Pooled analysis of sensitivity, specificity and AUC was performed
with Meta Disc (version 1.42).
Evaluation of risk predictors

Risk estimates were not pooled from individual studies as this approach would have been not feasible and
valid given the likelihood of small study effects. We instead adopted Ross et al. approach [176] and
appraised the prevalence of studies in which a given predictor proved significantly and independently
associated with the outcome of interest in at least 2 studies.
Supplementary Appendix 3. Systematic review of evidence, assessment of its quality and meta-
analyses.
A systematic review of evidence was performed for each question. Supplementary Figure 6,
Supplementary Figure 15, Supplementary Figure 16, Supplementary Figure 17, Supplementary
Figure 18, Supplementary Figure 19, Supplementary Figure 20, display PRISMA diagrams of the
selection of the main searches. PRISMA diagrams were not produced for the questions that yielded a low
number of publications.
9
High quality evidence is generally lacking in PFO-associated syndromes. An evaluation of the quality of
evidence was formally performed with GRADE method for: all the meta-analyses that have been performed
for the aims of this document and for the studies addressing internal ROPE score validation (Supplementary
Table 3).
We performed two original meta-analyses for supporting decisions on each PICO question and a meta-
regression of RCTs aimed at assessing the effects of the length of dual antiplatelet therapy after closure on
stroke and TIA recurrence. We also performed two meta-analyses aimed at assessing accuracy of testing: a)
Transcranial Doppler with bubble test vs. Transoesophageal contrast-echocardiography in the diagnosis of
PFO and b) Transthoracic contrast-echocardiography vs. Transoesophageal contrast-echocardiography in the
diagnosis of PFO.
Supplementary Figure 17 and Supplementary Table 10 respectively display the PRISMA diagram and the
GRADE evaluation of the quality of evidence of the studies included in the meta-analysis comparing PFO
closure with medical therapies for secondary prevention of stroke, TIA or other left-circulation
thromboembolism in patients with previous cryptogenic left embolism.
Supplementary Figure 18 and Supplementary Table 11 respectively display the PRISMA diagram and the
GRADE evaluation of the quality of evidence of the meta-analysis of the studies comparing OAC with
antiplatelet for secondary prevention of stroke, TIA or other left-circulation thromboembolism in patients
with previous cryptogenic left embolism.
Supplementary Figure 19 and Supplementary Figure 20 display the PRISMA diagram of the meta-
analysis of the studies investigating the accuracy of PFO diagnostic tests. Supplementary Table 2 displays
the GRADE evaluation of the quality of evidence included in the meta-analysis of the same studies.
The main results of these meta-analyses are displayed in the published text.
10
Supplementary Appendix 4. Detailed evaluation of specific issues.
The issue of complexity in PFO related syndromes

Even though its causal involvement in several diseases has been well-documented, the role of PFO in most
causal mechanisms remains intrinsically elusive. Two reasons for this are: a) because it can only be
presumed in most cases as its causal role is often transient and the medical observation is delayed; and b)
because of the “statistical noise” that is caused by the high prevalence of PFO in the general population and
competing causes. Moreover, some of the candidate PFO-associated clinical syndromes (e.g., decompression
sickness and transient ischaemic attacks) are themselves difficult to diagnose, which increases the
probabilistic nature of the argument.
Additionally, PFO is not simply a yes or no condition, and different anatomical variations and degrees of
patency might interfere with its causative role, thereby multiplying the possible phenotypes. To this, one
must add the fact that the anatomical characteristics of any PFO can vary according to changing clinical and
physiological conditions (e.g., a PFO can be more or less open depending on atrial pressure). As such,
existing diagnostic procedures might not be reliable or reproducible enough to assess the value and role of
the dynamic features of PFO in all its possible configurations (see "diagnosing PFO" paragraph in the
published text). Furthermore, as demonstrated by the accrued literature cited in this paper, clinical
classifications lump together populations of patients who are, in actuality, very heterogeneous from
pathophysiological, prognostic and therapeutic points of view. Indeed, the complex interacting network of
processes underlying clinical manifestations varies considerably between individuals, as well as within the
same person over the course of time, thereby masking the role of each individual node in studies performed
on large numbers of patients which are insufficiently characterised [1,2,112] (Supplementary Figure 21).
All of these characteristics, some improvable (i.e., due to imperfect knowledge or technology) and others not
(i.e., intrinsic factors), upsurge exponentially the incertitude of the system, and explain why randomised
studies performed in such patients have often yielded conflicting results [1] rendering assessments of the role
of PFO a complex paradigm in medicine. This complexity has important consequences because complex
systems are highly non-linear and cannot be addressed with classic deterministic approaches [177]. A
breakthrough is therefore warranted to define new classifications of patients with similar clinical
characteristics, prognosis, and therapeutic needs in a non-deterministic environment. Systems science and
precision medicine approaches are the major candidates to address these issues, because they have the
potential to guide decisions at the individual patient level [4,178].
While awaiting fresh systems medicine evidence-guiding decisions, individuals suffering from candidate
PFO-associated syndromes need to be approached within a multidisciplinary framework, wherein shared
decision making becomes essential.
Further details on diagnostic accuracy studies

Contrast transoesophageal echocardiography (c-TOE) has a lower sensitivity than previously believed. A
meta-analysis on this topic is discussed in the main text. This is confirmed by other studies [179–192], which
11
show a marked underestimation of the prevalence of PFO compared with historical autopsy studies [193–
203] (Supplementary Figure 1). This relatively high false negative result may influence the prediction of
recurrence related to the assessment of post-procedural shunt [96,139] and may in part explain the
inconsistent results of epidemiological studies [183].
Nonetheless, three-dimensional TOE is an ideal technique to understand the anatomy of the interatrial
septum and guide the interventional procedure [52].
Additionally, we performed an updated meta-analysis of 29 studies comparing contrast-enhanced
transcranial Doppler (c-TCD) with c-TOE across 2751 patients (Supplementary Appendix 3)
[44,126,147,204–230] and an original meta-analysis of 13 studies across 1360 patients comparing contrast-
enhanced transthoracic echocardiography (c-TTE) against c-TOE (Supplementary Appendix 3)
[189,216,218,229,231–239]. Results are discussed in the published text.
In a previous meta-analysis of 27 studies with 1,968 patients, the weighted mean sensitivity and specificity
for contrast-enhanced transcranial Doppler (c-TCD) in detecting right-to-left shunts, as compared to c-TOE,
were 97% (95% CI: 94%-98%) and 93% (95% CI: 86%-97%), respectively. However, when the threshold
for a positive shunt was increased from 1 high-intensity transient signal (HITS) to 10 HITS, c-TCD
specificity was increased to 100% without affecting sensitivity [54].
A recent meta-analysis of 35 studies comparing c-TCD and c-TTE to c-TOE in 3067 patients also showed a
superior overall diagnostic yield of c-TCD compared to that of c-TTE. In this study the AUC was
significantly greater (p < 0.001) in c-TCD (AUC = 0.98, 95% CI = 0.97-0.99) compared to c-TTE studies
(AUC = 0.86, 95% CI = 0.82-0.89), with a a higher sensitivity and lower specificity of c-TCD as compared
to c-TTE [55].
Is PFO associated with cryptogenic stroke? What are the underlying processes?
Clinical studies supporting a key role for PFO in paradoxical embolisation.

In one study that involved over 205,000 subjects, after either deep vein thrombosis or pulmonary artery
embolism, the relative risk (RR) of stroke during the first year in patients with PFO increased 2.2-fold and
2.9-fold respectively, relative to patients without a PFO [14]. Another study identified a greater proportion of
pelvic deep vein thrombosis in patients with cryptogenic stroke and PFO than in patients with stroke of
determined reason [15]; while an additional study showed that the presence of a PFO was associated with
diffusion-weighted MRI-detected silent strokes in patients with recent pulmonary embolism [18].
Clinical studies supporting different pathophysiologic processes in PFO-associated embolism.

Pathogenic processes attributable to PFO presence include: paradoxical embolism [240]; thrombus forming
within the PFO [96,241]; left atrial dysfunction [242]; and atrial arrhythmias [56,243–245]. Indeed,
prevalence rates of atrial arrhythmias ranging from 1% to 10% were reported in a meta-analysis of a small
number of prospective observational and retrospective studies that were conducted in candidates for
percutaneous closure of PFO [137]; while new-onset atrial fibrillation following transcatheter percutaneous
closure, in rates ranging from 0.5% to 15%, has been detected in other studies [106–111]. Therefore, at least
12
in some patients, pre-existing misdiagnosed AF may become clinically evident only after PFO closure,
possibly unmasked by the irritating local stimuli of the device [111,246] .
IS IT CLINICALLY POSSIBLE TO ESTIMATE THE PROBABILITY OF A CAUSAL RELATIONSHIP

BETWEEN A PFO AND STROKE?
Patient characteristics
Although observed in patients of almost any age [13], in a meta-analysis of 23 case-control studies
examining the prevalence of PFO in patients with cryptogenic stroke versus controls with a stroke of known
cause, the OR for younger (< 55 years) and older patients (≥ 55 years) were 5.1 (3.3 to 7.8) and 2.0 (>1.0 to
3.7), respectively [56]. However, despite the comorbidities, in older patients the association is still observed,
perhaps due to the increasing prevalence of venous clots or to the increasing size of PFO with age [13,57].
Some meta-analyses of RCTs not including DEFENSE-PFO trial suggest that younger age and male gender
may be associated to a more probable causal role of PFO [78,79,90], however this was not found by another
meta-analysis [171].
During their patient-level meta-analysis of observational cohorts of cryptogenic stroke patients, the RoPE
(Risk of Paradoxical Embolism) group [59] found that patients who were younger; who did not have
hypertension, diabetes, smoking, or a prior stroke or TIA; and who had a cortical stroke on neuroimaging
were more likely to have a PFO and, thus, had a higher likelihood that the index event was related to a PFO
rather than to other causes.
Imaging stroke pattern

Cortical ischaemic lesions, whether symptomatic or asymptomatic, suggest probable embolisation even
when they are small [59]. However, deep white matter lesions can also be embolic [60,62,63], even though
they are more likely due to lipohyalinosis [247]. Indeed, in a recent patient-level meta-analysis of
randomised clinical trials (RCT) comparing percutaneous closure of PFO and medical therapy, patients with
non-cortical infarcts had a lower rate of recurrence after PFO closure than those on medical therapy,
suggesting an embolic origin of the index event [70].
No pattern in grey or white matter has been specifically observed in PFO-associated strokes [61,64–69],
though a single study identified an inverse relationship between PFO size and number of brain lesions
observed on MRI and a direct relationship between PFO size and infarct volume [77].
An embolisation pattern in the posterior circulation has been described in PFO-associated strokes in
retrospective studies [248–250]. However, another report did not find any topographical association with
PFO-associated embolisms [61].
Taken together, these data again indicate the heterogeneity of the underlying pathophysiologic processes in
PFO-caused strokes. No studies have been performed regarding imaging patterns of PFO-associated non-
cerebral cryptogenic embolism.
Characteristics of the PFO
13
The association between PFO and cryptogenic stroke has been reported to be stronger in patients who have
an atrial septal aneurysm (ASA) in addition to a PFO (with odds ratios as high as 33.3) [71–73,91].
However, in one study, the risk of recurrent stroke or TIA at four years of follow-up was 0% in patients with
an ASA but no PFO; 5.6% in patients with a PFO alone; and 19.2% in patients with both a PFO and ASA
[72]. Given that other studies have shown that the extent of the interatrial septum deviation correlates with
the anatomical size of a PFO [251,252], it is possible that a statistical interaction exist between ASA and the
size of the associated PFO and its aggregated time of gaping. Indeed, several studies have found that patients
with a more severe right-to-left shunt, a larger PFO opening, or the presence of right-to-left shunting at rest
are more likely to have had a cryptogenic stroke than controls lacking these [64,76,208,253–256].
Consistently, the recent interventional sub-study of the CLOSE trial performed in patients with an ASA or a
severe shunt showed that the closure of the PFO resulted in a statistically significant higher reduction of
stroke recurrences as compared to medical therapy [27]. The DEFENSE-PFO trial, performed in patients
with ASA or a severe shunt or a wide PFO opening or a interatrial septal hyper-mobility, also showed similar
outcomes [29]. Supplementary to this observation, also subgroup analysis of long term RESPECT study
results showed that patients with ASA or a larger shunt had a greater risk reduction with PFO closure [28].
Moreover, patients with a moderate-to-severe shunt were more likely to experience better outcomes with
percutaneous closure of PFO as compared to medical therapy alone in all meta-analyses of RCTs not
including DEFENSE-PFO study, suggesting a more probable causal PFO in these patients
[78,79,90,122,170,171].
However, as expected in heterogeneous patient populations, other studies have failed to detect these
associations, while others have shown that even small PFO can be causative, likely with different underlying
processes than large ones [59,77], stressing the need for multi-parametric risk stratification and
phenotypisation of patients.
The presence of anatomic atrial variants (e.g., a Eustachian valve or Chiari network) that can promote flow
from the inferior vena cava toward the PFO may favour the persistence of a patent foramen ovale and the
formation of an atrial septal aneurysm, thereby facilitating paradoxical emboli [75]. A long PFO tunnel has
also been linked to increased stroke risk in retrospective studies [76]
Clinical clues
Documentation of a venous source of embolism is a key criterion for a presumed diagnosis of paradoxical
embolism; but one first needs to exclude the possibility that the venous thrombosis is secondary to the
immobilisation that often results after the embolism becomes clinically manifest. The search for venous
thrombosis is often negative [80,82,83], though this may be due to an inability to detect small venous clots
[15]. Several acquired and hereditary pro-thrombotic states increase the risk of deep vein thrombosis [257]
(Supplementary Table 13) and may translate into a higher risk of PFO-associated emboli. Studies that have
attempted to identify an association between inherited thrombophilia and PFO-related stroke have yielded
conflicting results [87–89,258]. Indeed, in one meta-analysis, a significant association was identified
14
between factor II G20210A and PFO-related stroke [OR 3.9; (95% CI 2.2 to 6.7) relative to those patients
without a PFO (2.3; 95% CI 1.2 to 4.4) [87], but a more recent study failed to confirm this finding [88].
Moreover, in a study by Pezzini et al., patients having either the factor V Leiden (G1691A) mutation or the
prothrombin G20210A variant exhibited an odds ratio for stroke of 1.98 versus controls [87]. Another study
failed to detect a significantly-increased risk of cerebrovascular events in subjects with the combined
presence of elevated antiphospholipid antibodies levels and a PFO [89].
Simultaneous occurrence of symptomatic or asymptomatic pulmonary and left circulation emboli should
strongly indicate paradoxical embolism, [18,80] while a history of previous single or recurrent pulmonary
embolism can support a paradoxical mechanism with recurrent clinical or asymptomatic cryptogenic
embolisms [81].
Circumstances that predispose someone to DVT — like an immobilising injury/surgery or an extended

automobile or airplane ride — or activities that promote paradoxical embolism — like straining to defecate,
heavy lifting, and other activities associated with a Valsalva manoeuvre immediately prior to stroke onset,
strengthen the hypothesis that a given stroke is due to paradoxical embolism and should be investigated
further. With a similar mechanism, also obstructive sleep apnea can cause a paradoxical embolism and this
possibility should be enquired for in case of cryptogenic stroke-on-awakening [84]. However, it is not clear
whether these predisposing factors are more frequent in cryptogenic stroke patients with than without a PFO
[81,85].
Clinical risk scores

The RoPE score represents an attempt to assign a causal relationship probability to individual PFOs, based
on the assumption that identifying subjects with similar characteristics to subgroups in which a PFO was
found to be more prevalent implies a greater probability of causation [59]. Variables associated with a PFO
in cryptogenic stroke patients included younger age, the presence of a cortical stroke, and the absence of
diabetes, hypertension, smoking, or a prior stroke or TIA. RoPE developers incorporated these factors into
the 10-point RoPE score, whereby the higher the score (i.e., the fewer atherosclerotic vascular risk factors a
given patient has), the more likely it is that the patient has a PFO, with a cut-off of more than 6 points on a
10-point scale indicating a higher probability of association between PFO and the stroke [59]. However,
external validation studies still are to be published; and even the imprecision of internal validation studies
has been judged severely (Supplementary Table 3). Moreover, paradoxically, a higher causation probability
of a PFO as assessed by the RoPE score seem to be associated to a lower rate of recurrence [59], which is in
contrast to the findings of the most recent randomised studies.
RISK OF RECURRENCE IN PFO-ASSOCIATED STROKE

Risk of recurrence is a pivotal factor to consider during decision making in patients with a PFO-associated
stroke. One meta-analysis that incorporated one RCT, three case-control studies, and 11 case series,
identified a rate of recurrent stroke or TIA of four events per 100 patient-years (95% CI 3.0–5.1) and a rate
15
of recurrent stroke of 1.6 events per 100 patient-years (95% CI 1.1–2.1), while the pooled absolute rate of
recurrent ischaemic stroke or TIA was 4.0 events per 100 person-years overall [91]. However, in different
studies, these figures ranged 0 to 4.4% for stroke and 0 to 14% for either TIA or stroke [259], emphasising
the heterogeneity of the risk and of the characteristics of patients in these populations, and the need to
discriminate between them.
In another meta-analysis that assessed 14 observational studies encompassing 4251 patients, cryptogenic
stroke patients with a PFO exhibited no increased risk either of recurrent stroke alone of either stroke or TIA
recurrence, when compared to cryptogenic stroke patients without a PFO [95]. The finding that cryptogenic
stroke patients with and without a PFO have similar rates of stroke seems odd, but might just reflect that, in
patients without a PFO, other occult causes of stroke might similarly increase the risk of recurrence [92].
A few studies have examined the aetiology of recurrent cerebrovascular events in PFO patients [93,94]. One
important finding is that an alternative cause of stroke (e.g., large artery disease, small artery disease, cardio-
embolism, other causes), unrelated to PFO, was identified in many patients with recurrent stroke. This
finding does not exclude PFO as causal for the first (or recurrent) episode but shows that the causes of
recurrence may change over time, adding a dynamic pattern to the complexity of the overall picture. In
particular, in the CLOSURE 1 trial [94], in both arms of the study an aetiological alternative to paradoxical
embolism was frequently (37%) responsible for recurrent events.
The systematic review of literature revealed that few specific predictors of stroke recurrence in patients with
a PFO have been identified. A PRISMA diagram of the selection process in the literature review to obtain
these studies is displayed in Supplementary Figure 6. Some features were found to be statistically-
significant predictors in at least two studies (Table 3 in the published text). ASA seems to have a particular
role with this respect. In the RoPE database, septal hypermobility was a significant predictor of stroke
recurrence [97]. In the PFO-ASA study, cryptogenic stroke patients with both PFO and an atrial septal
aneurism (ASA) were more likely to have a recurrent stroke than cryptogenic stroke patients without a PFO.
The risk of recurrent stroke in this group was four times higher than in patients with no PFO, but the
confidence interval for this estimate was large[72]. Moreover, two meta-analyses not including DEFENSE-
PFO study, suggest that the subgroup patients with ASA had a greater risk reduction with PFO closure than
patients without these characteristics, hence supporting the role of ASA in stroke recurrences [170,171].
With regards to the size of the PFO, all studies that have examined this potential predictive factor have found
that cryptogenic stroke patients with small and large shunts have roughly equivalent stroke recurrence rates
[72,95,96], though this may reflect the unreliability of transoesophageal echocardiography in the prediction
of future events [96]. Indeed, the subgroup analysis of the randomised controlled trial RESPECT, supported
large shunts to be associated with more frequent stroke recurrences [28]. However, unexpectedly, in the
RoPE database [97] a small shunt was a significant predictor of stroke recurrence in patients who had a high
probability that their PFO was stroke-related rather than an incidental finding.
16
DIAGNOSTIC WORKUP
The diagnostic process must begin with a clinical assessment, based upon the clinical presentation or the
organ involved, as well as organ-specific and appropriate vessel imaging (colour-Doppler ultrasound, CT or
MRI angiography, or invasive angiography). Additional clinical assessments and imaging can be performed
to detect sub-clinical embolism in other organs, including pulmonary scans or scintigraphy, organ-specific
CT scans or abdominal sonography (e.g., spleen or kidney).
Whatever the embolism site, thorough transthoracic echocardiographic and neurological evaluation should
be performed.
In cases involving a cerebrovascular accident, an accurate neurological evaluation is required to differentiate

a TIA from syncope, peripheral vertigo, or transient focal deficits, such as those that may occur after a
seizure or associated with a migraine attack. Most TIAs persist less than one hour.
Assessing asymptomatic paroxysmal AF

Paroxysmal AF occurs without specific symptoms in the vast majority of patients with cryptogenic stroke
[102] and is under-detected after spontaneous resolution [99]. Randomised and observational studies
performed using insertable cardiac monitors [99–102] and external ECG monitoring [260,261] have
consistently demonstrated that prolonged monitoring and the selection of high-risk populations increases AF
detection in cryptogenic stroke, albeit at highly variable rates [164]. A systematic review of all the studies
conducted on detection of AF after ischaemic stroke or transient ischaemic attack with various monitoring
systems (inpatient cardiac monitoring, 24-hours, 48-hours and 72-hours Holter, external loop recorder,
mobile cardiac outpatient telemonitoring) demonstrated a highly variable rate of AF detection with
considerable heterogeneity among studies [260]. However, in this meta-analysis, a prolonged non-invasive
monitoring (>24 hours) increased yield of AF detection in patients with cryptogenic stroke and old age.
These data were confirmed by the randomised controlled trial Embrace, assessing the detection of AF with
external ECG monitoring in cryptogenic stroke [261]. Based on these data, the selection of candidates for
ICM monitoring based on risk factors for AF has been proposed, leading to silent AF detection in up to 35%
of patients at six months and 46% at a median follow-up of 14.5 months [262,263].
Given that, in the Cristal AF study, the insertable cardiac monitor (ICM) removal rate was 2.4%, due to
infection at the insertion site or pocket erosion, while the number of implanted ICM needed to detect a first
episode of AF was 14 over six months of monitoring, 10 over 12 months, and four over 36 months, an ICM-
based rule-out protocol of paroxysmal AF is a reasonable option in selected high-risk patients after a
cryptogenic stroke. Patients may be considered at high risk if: ≥55 years old, given the very low incidence of
AF in patients <55 years old in large cohorts [173,264]; or with an history of prior cortical or cerebellar
infarction on neuroimaging and a CHADS2 or CHA2DS2-VASc score > 1 [100,101,265]. However, the
CHA2DS2-VASc score was designed for stroke prediction in AF patients rather than for AF risk prediction,
but four of its six individual items have been repeatedly identified as strongly associated with AF, therefore
they can also be considered high risk markers: congestive heart failure [266,267], hypertension [268],
advanced patient age [101,265,266], and diabetes mellitus [267,269]. Furthermore, also frequent atrial runs
17
and left atrial dilation are known predictors of AF in patients with cryptogenic stroke [101,266,270,271].
Finally, left ventricular hypertrophy, pulmonary or thyroid disease, and obesity are also associated with an
increased AF risk [272] and can be considered high risk features. Likely, the same considerations apply to
any form of left-circulation thromboembolism.
Evaluating the need for anticoagulants in AF

The higher sensitivity of extensive monitoring poses the question that the detection of extremely brief
harbinger episodes alone may be less critical. Indeed, in a recent meta-analysis involving 1149 patients
across four randomised studies, despite the higher recognition rate of 30-second AF episodes with
monitoring prolonged over six days versus  48 hours, the outcomes of patients in the two groups were
similar [164]. In the Mode Selection Trial (MOST), high-rate atrial arrhythmic episodes lasting at least five
minutes predicted a higher incidence of the composite outcome of death or nonfatal stroke [165]. In the
Asymptomatic Atrial Fibrillation and Stroke Evaluation in Pacemaker Patients and the Atrial Fibrillation
Reduction Atrial Pacing Trial (ASSERT), an episode of high-rate atrial arrhythmia lasting more than six
minutes conferred a relative risk of 2.5 for subsequent ischaemic stroke or systemic embolism. A higher AF
threshold duration, as indicated by the SOS-AF study (1 hour), TRENDS trial (5.5 hours), and AT500
Registry (24 hours), may be inappropriate for secondary stroke prevention [166–168]. Patients with
cryptogenic stroke and PFO, and having a pre-stroke CHA2DS2-VASc score >1, are a cohort at elevated risk
of atrial fibrillation recurrence. Therefore, the relevance of transient episodes of AF may be greater in this
group than AF detected incidentally in patients without a prior stroke. The ICM-detected arrhythmia duration
may be combined with the baseline CHADS2 score to evaluate the risk of thromboembolic events. In
patients with a CHADS2 score ≥2, AF episodes lasting more than five minutes appear to significantly
increase the risk of stroke [169].
ADDITIONAL INSIGHTS ON EFFICACY AND SAFETY OF MEDICAL THERAPIES

Contemporary medical treatments are based upon the extrapolation of data from secondary prevention
studies for stroke at large, from studies on cryptogenic stroke at large, or from their sub-group analysis. In
the different studies that have been published, medical therapy has always been heterogeneous, even within
each study. In most studies, the oral anticoagulants (OAC) used have consisted of vitamin K inhibitors while
direct oral anticoagulants (DOAC) were also allowed in CLOSE trial. Antiplatelet therapy has also been very
variable, consisting of acetylsalicylic acid, clopidogrel, and extended-release dipyridamole, alone or in
different combinations, and sometimes in conjunction with OAC.
Prior to the publication of CLOSE, REDUCE and DEFENSE-PFO trials, one meta-analysis of randomised
trials, comparing a mixed medical therapy to the percutaneous closure of PFO, identified in its medical
therapy arm a pooled incidence of primary endpoints of 1.8 events per 100 patients/year (95% CI, 0.7-2.9)
[273].
In the individual trials assessed in these meta-analyses, the event rate of stroke, TIA, peripheral embolism,
and/or death ranged between 2.5% (OAC) in the RESPECT trial [131] and 7.9% (acetylsalicylic acid) in the
18
CLOSURE I study [274]. In a meta-analysis of observational trials, mixed medical therapy yielded a pooled
incidence rate of recurrent neurological events of 5.0 per 100 person-years (95% CI: 3.6 to 6.9) [113]. One of
the last, comprehesive, meta-analyses of RCTs reported a stroke incidence of 1.27 events per 100
patients/year (95% CI, 0.84–1.78)[74].
Only one recent randomised sub-study, part of a larger one, has compared the use of OAC (vitamin K
inhibitors or DOAC) and antiplatelet therapy (acetylsalicylic acid, clopidogrel or a combination of
acetylsalicylic acid+dipyridamole) in 361 patients with cryptogenic stroke with a large PFO and/or an atrial
septal aneurism showing, after an average 5 years of follow-up, a statistically non-significant lower
incidence of stroke in patients receiving OAC as compared to those who received antiplatelet therapy [1.6%
vs 4.0%, respectively; p=0.21; OR=0.34 (95% CI: 0.10 to 1.53)] [27].
Five meta-analyses, not including CLOSE trial, have been published to date comparing antiplatelet therapy
and OAC for PFO-associated cryptogenic strokes. Four study-level meta-analyses (the first three involving
observational studies only and the last one both observational and randomised studies not comparing directly
OAC and antiplatelet therapy), incorporating up to 3311 patients, consistently found a statistically-significant
advantage of OAC over antiplatelet therapy, including an OR = 0.37 for stroke or TIA (95% CI: 0.23 to
0.60) [114], an incidence rate ratio of 0.42 (95% CI, 0.18–0.98) for stroke and/or TIA [115], a relative risk of
pooled recurrent neurological events of 0.58 (95% CI: 0.41 to 0.82) [113], and event rates for stroke and/or
TIA at or beyond 12 months of 7.7% versus 9.8%, respectively, p = 0.03 [116]. In a patient-level meta-
analysis of 12 databases and 2385 patients not including CLOSE trial, a point estimate of the reduction of
strokes, TIAs or death and stroke alone was noted with OAC of approximately 25% as compared to
antiplatelet therapy, but this reduction was not statistically significant [275]. However, similar to the results
of medical substudy of CLOSE trial, the number of events identified during follow-up was small,
underlining imprecision in the estimation of effects [275]. These findings may also be due, as for many other
of the aforementioned factors in this population, to heterogeneity within the populations classified as having
PFO-associated cryptogenic emboli, even when they are deemed to be at higher risk according to a few
indicators, such those enrolled in CLOSE trial. Indeed, OAC had a statistically-significant beneficial effect
on the primary composite outcome in analyses that were standardised to only include patients who had
actually received antiplatelet therapy (adjusted HR: 0.64, 95% CI 0.42–0.99) [275].
Overall the quality of the available evidence for safety issues is low. In the first three randomised studies on
PFO excluding CLOSE, REDUCE and DEFENSE-PFO trials, only 7/11 bleeds were major haemorrhages
amongst patients receiving medical therapy. In a meta-analysis of observational studies, 1.1% of the patients
receiving medical therapy experienced a bleeding complication [113]. The young age of patients and the
short follow-up may influence the estimate of bleedings. Indeed, in one of the above-mentioned meta-
analyses on PFO patients, an OR of 6.49 (95% CI: 3.25 to 12.99) was reported for major bleeding with OAC
relative to antiplatelet drugs [116]. In addition, another meta-analysis of 11 trials involving 2487 patients and
considering the secondary prevention of stroke at large revealed that the potential benefit of OAC might be
19
outweighed by the risk of both intracranial haemorrhage (OR 2.54, 95% CI 1.19 to 5.45) and major
extracranial haemorrhage (OR 3.43, 95% CI 1.94 to 6.08) [117].
ADDITIONAL INSIGHTS ON THE SAFETY AND EFFICAY OF PERCUTANEOUS CLOSURE
The initial report on percutaneous PFO closure pertained to an atrial septal defect device [120]. The first
dedicated PFO closure device was implanted in 1997 [121].
The main quantitative and quantitative characteristics of the RCTs are summarised in Supplementary Table
9 and in Supplementary Table 10.
Regarding more detailed qualitative characteristics, despite the fact that all these studies are RCT, therefore
the highest ranked source of evidence, all individual studies shared important limitations.
All studies were underpowered due to a lower incidence of outcomes as compared to forecasts and therefore
also reported wide confidence intervals in their results. It is likely that this probably also due to the short
duration of follow up for these kind of endpoints (usually 2 years, except in PC and the extended Respect
post-hoc analysis). All the studies also had a lower-than expected rate of recruitment which accounts for a
high risk of referral bias. All the studies were therefore concerned by the possibility of a high attrition bias,
with the possibility of some patients at higher risk treated outside the study. Moreover, all studies compared
PFO closure with mixed medical therapies. No study had a comprehensive AF rule-out strategy with ICM
before the randomisation, so that overt AF may be reliably excluded. Finally, the stroke risk attributable to
atrial fibrillation induced by PFO closure is unknown, therefore the impact of post-procedural AF in patients
undergoing percutaneous closure (mostly transient) is unclear.
The Closure I trial [51]was the first study to be published and evaluated the STARFlex PFO closure system
(now out of market) against the administration of warfarin, acetylsalicylic acid, or combined acetylsalicylic
acid and warfarin at the physician’s choice. It had a long enrolment phase from 2003 to 2008, which also
caused the need to amend the original protocol to lower the number of patients. Finally, 909 patients aged
18–60 with a cryptogenic stroke (including lacunar patern at imaging) or TIA and a PFO, were randomised
1:1: 447 to PFO closure (72.6 % stroke, 27.4 % TIA) and 462 to medical therapy (71.4 % stroke, 28.6 %
TIA). The primary endpoint was a composite of recurrent stroke or TIA at 2 years, any death within 30 days,
or death from neurologic causes at 2 years. Moderate to substantial shunts and atrial septal aneurysm
prevalence was similar in study arms (on average approximately 52 % and 36%, respectively). No relevant
deaths occurred. Procedural success was 89.4 % for implantation and 86.1 % for effective closure at 6
months of followup. In the follow-up 52 cerebrovascular outcome events occurred: 25 ischaemic strokes and
30 transient ischaemic attacks. There was no evidence that endovascular PFO closure was superior to
medical therapy alone in the prevention of stroke or TIA (5.5 % vs 6.8 %, HR 0.78, 95 % CI 0.45–1.35,
p00.37), stroke (2.9 % vs 3.1 %, HR 0.90, 95 % CI 0.41–1.98, p00.79), or TIA (3.1 % vs 4.1 %, HR 0.75, 95
% CI 0.36–1.55, p00.44). This lack of benefit persisted when the analysis was confined to modified intent-
to-treat or per-protocol patients only. However, there was a significant increase in the risk of major vascular
procedural complications after PFO closure (3.2 % vs 0, p=0.001). Among the main limitations of this study:
the high risk of referral bias due to the low number of enrolled patients per centre, the risk of selection bias
20
due to the low risk of patients, the short follow-up, the inclusion of interventional centres with low volume of
activity, the use of an outdated and probably less-effective device, the inclusion of TIA as index events and
as outcome measure, the inclusion of lacunar syndrome,.
The Respect trial [112] compared the Amplatzer PFO Occluder with four treatment regimens: monotherapy
with warfarin, acetylsalicylic acid or clopidogrel, or a combination of acetylsalicylic acid with extended-
release dipyridamole. Also this study suffered an 8 years enrolment phase, caused, among other factors, by a
double amendment in the protocol, needing an increase in patients to be included. At the end, 980 patients
aged 18–60 with a cryptogenic stroke only and a PFO were randomised 1:1: 499 to PFO closure and 481 to
medical therapy. The primary efficacy endpoint was a composite of recurrent nonfatal ischaemic stroke, fatal
ischaemic stroke, or early death after randomisation in the time span necessary to 25 events to occur. A
similar proportion of patients with an atrial septal aneurysm (36.1 % vs 35.1 %) and presence of substantial
shunting (defined as more than 10 microbubbles of right-to-left shunt, 77.9 % vs 74.1 %) was observed.
Procedural success was 96.1 % for implantation and 93.5 % for effective closure at 6 months of follow-up.
The primary publication in 2013 reported a total of 25 primary endpoint events (nine in the closure group
and 16 in the medical therapy group), all of which were recurrent nonfatal stroke (0.66 events per 100
patient-years, HR with closure = 0.49, 95 % CI: 0.22–1.11; p=0.08). The primary analysis showed similar
results in the prevention of stroke in the 2 arms (1.33 % vs 1.73 % at 1 year, 1.60 % vs 3.02 % at 2 years, and
2.21 % vs 6.40 % at 3 years, HR 0.492, 95 % CI 0.217–1.114, p=0.083. However, the per-protocol analysis
of 20 events suggested benefit for PFO closure (HR 0.366, 95 % CI 0.141–0.955, p=0.032). Subgroup
analyses suggested a benefit in the presence of a substantial shunt or atrial septal aneurysm. Atrial fibrillation
occurred in 0.6 % of patients in both groups. There were no cases of device thrombus or embolisation. Major
vascular complications were exclusively seen in the device group, but without a statistically significant
difference as compared to medical therapy.
In a second publication in 2017,[28] the investigators reported that after 10 years, in an intention-to-treat
analysis, PFO closure with the Amplatzer PFO Occluder resulted in a 62 % relative risk reduction (RRR) for
recurrent ischaemic stroke compared to medical management (HR 0.38; 95 % CI: 0.18–0.79; 10-year event
rates 2.3 % versus 11.1 %; p=0.007). Similar results were seen in patients <60 years of age (58 % RRR; HR
0.42; 95 % CI: 0.21–0.83; 10-year event rates 3.0 % versus 13.2 %; p=0.01). The rates of atrial fibrillation,
major bleeding, and death from any cause were comparable or lower in the device study arm. Specific
limitations of this trial are: a different drop-out rate in the two study arms and the caution to be used in per-
protocol analysis instead of in intention-to-treat analysis.
The PC trial [132]compared the Amplatzer PFO Occluder with any antiplatelet or anticoagulation therapy of
the physician’s choice, which resulted to be: acetylsalicylic acid, ticlopidine, clopidogrel and warfarin. Also
in this study a low enrolment rate was observed (9 years). 414 patients aged 18-60 years old with
neuroradiologically verified cryptogenic stroke or TIA or peripheral thromboembolism and a PFO were
randomised 1:1: 204 to closure and 210 to medical therapy groups. The primary endpoint was a composite of
death, nonfatal stroke, TIA, or peripheral embolism at 4.5 years Device implantation was successful in
21
95.9% of patients and effective in 95.9% of those. The prevalence of moderate-to-severe shunt and of ASA
was similar in the two study arms (on average approximately 65% and 24%, respectively). Eighteen primary
endpoint occurred (6 strokes, 12 TIA): 3.4% in the closure group and 5.2% in the medical therapy group
(hazard ratio for closure vs. medical therapy, 0.63; 95% confidence interval [CI], 0.24 to 1.62; P = 0.34). No
relevant deaths occurred. At subgroup analysis no significant differences emerged in the two study arms.
Except for a statistical trend towards a higher minor atrial fibrillation rate in PFO closure (2% vs. 0%,
p=0.058), the overall complication rate was similar in the two study groups.
Specific limitations of this trial were: a possible high attrition bias, the inclusion of TIA as index events and
as outcome measure and the considerable risk of selective reporting by the clinical event committee in this
open label trial.
The Reduce trial [26], evaluated PFO closure with the Gore Helex (not available any more) or Gore
Cardioform septal occluder plus antiplatelet therapy versus to antiplatelet treatment alone. Antiplatelet could
consist of: acetylsalicylic acid, a combination of acetylsalicylic acid and dipyridamole or clopidogrel,
Enrolment lasted 6 years. 664 patients with a cryptogenic ischaemic stroke a PFO aged 18-59 years old were
randomly 2:1: 441 patients to PFO closure group and 223 to medical therapy only group. The first co-
primary endpoint was freedom from clinical evidence of an ischaemic stroke (clinical ischaemic stroke)
through at least 24 months. The second co-primary endpoint, derived from a secondary endpoint with a
protocol amendment, was the incidence of new brain infarction (composite of clinical ischaemic stroke or
silent brain infarction detected by MRI). In 7.3% of patients of the interventional group no device was
implanted. In those who received the device, the implantation was successful in 98.8% of patients and
effective at 12 months in 75.6% of those. ASA was present in 20% of patients undergoing closure, whereas
this data is not available for patient on medical therapy only. A moderate-to large shunt was present in
approximately 80% of patients in both arms. Primary endpoint clinical ischaemic stroke occurred in 18
patients. The incidence of new brain infarctions was significantly lower in the PFO closure group than in the
antiplatelet-only group (5.7% vs. 11.3%; P = 0.04), but the incidence of silent brain infarction did not differ
significantly between the study groups (P = 0.97). Serious adverse events were similar in the two groups.
Atrial fibrillation occurred in 6.6% of patients after PFO closure vs 0.4% (p<0.001). Also in this study a
different dropout rate was observed in the two study arms, accounting for a possible selective reporting bias.
The Close study [27]was a 3 arm randomised study. The 3 arm of the study were: 1) antiplatelet therapy plus
trans-catheter PFO closure with any CE-mark of PFO closure device; 2) antiplatelet therapy alone; 3)
anticoagulant therapy alone (with OAC or DOAC). Antiplatelet therapy consisted of: acetylsalicylic acid,
clopidogrel or acetylsalicylic acid combined with extended release dipyridamole. Enrolment was stopped at
8 years, before reaching the planned target of 900 patients, because of budget limitations. As a compensation
for this, the follow-up period was prolonged. The study finally included 663 patients aged 16-60 years old,
with a cryptogenic ischaemic stroke and a PFO with an associated ASA or large interatrial shunt. Patients
were randomised 1:1:1: 235 to antiplatelet only, 238 to PFO closure and the remaining to anticoagulants.
Pre-specified comparisons included only the comparisons of closure vs. antiplatelets and antiplatelets vs.
22
anticoagulants. Primary endpoint was the occurrence of fatal or nonfatal stroke at 3 years. With the 11
different devices used (with a large majority being Amplatzer PFO occluder), the closure procedure was
successful in 98.6% of patients and the rate of effective PFO closure was 93.0%. ASA was present in
approximately 32% of patients in both arms, a large shunt was present in approximately 72% of patients in
both arms.
Recurrent fatal or non-fatal stroke occurred in 14 patients, but none in the PFO-closure group. Therefore, the
risk of recurrent stroke was significantly reduced in the PFO closure group as compared with the antiplatelet
therapy alone group (97 % RR; HR 0.03; 95 % CI: 0.00–0.26; p<0.001). A significantly higher rate of new-
onset paroxysmal atrial fibrillation in the PFO closure group compared to the antiplatelet only group was
also reported (4.6 % versus 0.9 %; p<0.02). In a post-hoc analysis comparing PFO closure vs.
anticoagulation, 3 patients on anticoagulants had a recurrent stroke over a follow-up of 967 patient-years,
compared with none in the PFO Closure group over a follow-up of 963 patient-years (intention-to-treat
analysis), which was statistically non-significant at the survival analysis.
The Defense-PFO study [29]compared PFO closure with Amplatzer PFO Occluder or medical therapy alone
as chosen by the caring physician (acetylsalicylic acid, acetylsalicylic acid in combination with clopidogrel,
acetylsalicylic acid in combination with cilostazol or warfarin). Enrolment lasted 6 years, when it was
terminated for the advantage in PFO closure arm which was evident before the end of the planned enrolment.
The study randomised, 1:1, 120 patients who experienced a cryptogenic ischaemic stroke and had a high risk
PFO (ASA, PFO width >2 mm or moderate-to-large shunt): 60 to percutaneous closure and 60 to medical
therapy only. ASA was present in approximately 10% of patients in both arms, atrial septal hypermobility in
45% and a large shunt in 90% of patients.
The primary endpoint was a composite of stroke, vascular death, or Thrombolysis In Myocardial Infarction
(TIMI)–defined major bleeding during 2 years of follow-up, and occurred in 6 patients undergoing medical
therapy only, and in none undergoing PFO closure (p=0.013). The study reports 2 cases of AF in the group
undergoing closure and none in the medical therapy-group. Specific limitation of this trial is the low number
of enrolling centres (i.e. two).
SURGICAL CLOSURE OF PFO

There are no current indications for surgical closure of a PFO as first-line treatment. Closure of incidental
PFOs at the time of coronary artery bypass surgery is not generally advocated because of the higher risk of
postoperative stroke [157], but during valvular surgery incidental PFO closure is usually undertaken.
Surgical PFO is also done in rare cases when surgery is indicated for other conditions in which the PFO
plays a role, such as a straddling thrombus in the PFO or a right-sided cardiac tumours causing hypoxaemia
or paradoxical embolism through a PFO [158]. Finally, PFO should be closed during surgery performed for
rare complications which cannot be managed by percutaneous means, such as infected or misplaced PFO
devices or erosion of the atrial free wall caused by a PFO device.
23
Supplementary Appendix 5. GRADE evaluation of evidences for PICO questions.
Should percutaneous closure of PFO vs. medical therapy be used for secondary prevention of stroke or
other left-circulation thromboembolism?
POPULATION: Secondary prevention of stroke,

TIA, other left-circulation
thromboembolism
INTERVENTION: Percutaneous closure of PFO
COMPARISON: Medical therapy
MAIN Stroke, TIA, death, bleedings,
OUTCOMES: atrial arrhythmias
SETTING: Hospital
Assessment
ADDITIONAL
JUDGEMENT RESEARCH EVIDENCE
CONSIDERATIONS
Is the problem a priority? Stroke is an important cause of Based on these data,
○ No morbidity and persistent disability, with PFO is causal in
○ Probably no 16.9 million people suffering a stroke between approximately
○ Probably yes each year. The incidence of stroke in 1.2 million and 3
● Yes young adults and in low-income million strokes each
countries is increasing. Cryptogenic year worldwide.
○ Varies strokes represent 30-40% of all strokes Cryptogenic non-
○ Don't know and there is evidence demonstrating a cerebral systemic
PROBLEM
causal role of PFO in this figure, varying embolism is similar to

from 25% to approximately 50% of the cryptogenic embolic
total. stroke, thereby
increasing the number
of people affected
yearly. Finding an
effective PFO
treatment would
translate into a
substantial population
effect.
How substantial are the Currently data are available on 7137 Studies are available
DESIRABLE EFFECTS
desirable anticipated effects? patients in 11 nonrandomised for cryptogenic stroke

○ Trivial comparisons, six randomised studies, 3 only; however
○ Small study-level meta-analysis of the 6 RCTs, cryptogenic non-
○ Moderate 2 study-level meta-analysis of 5 RCTs cerebral embolism can
○ Large and observational comparisons, 10 be considered a variant
study-level meta-analyses of 5 RCTs, of this condition.
● Varies one patient-level meta-analysis of the 3
○ Unknown first published RCTs, one meta-analysis
performed on observational trials only
24
How substantial are the ans 17 meta-analyses of the 3 first The NNH for atrial
undesirable anticipated effects? published RCTs(Supplementary Table fibrillation is likely to
○ Large 7, Supplementary Table 8). increase substantially
○ Moderate Three of the six RCTs (CLOSE, with more adequate
● Small REDUCE and DEFENSE-PFO trials) screening strategies for
○ Trivial showed superiority of PFO closure plus AF before treatment
medical therapy vs. medical therapy allocations.
○ Varies alone for reducing recurrent strokes. The
○ Don't know remaining 3 studies showed a similar
efficacy with interventional or medical
therapies, although one reported the
superiority of PFO closure only on pre-
specified as-treated analysis [112]. In
this study an exploratory analysis at
extended 5.9 years’ follow-up yielded a
superiority of PFO closure over medical
therapy [28].
Our study-level meta-analysis performed

on the 6 published RCTs, shows
superiority of PFO closure over medical
therapy for stroke recurrence on ITT
analysis with an odds ratio (OR) = 0.38
(95% CI: 0.18-0.80), with a
heterogeneity across studies which is
UNDESIRABLE EFFECTS
borderline between moderate and

significant (𝜒2=10.7, p=0.06; I2=53%)
(Supplementary Figure 4A). However,
when considering subgroups classified
as per risk characteristics of the PFO, in
the low risk subgroup this heterogeneity
disappeared (I2=0%) and was reduced in
the high-risk subgroup (I2=40%)
(Supplementary Figure 5). Moreover,
in the same analysis, the superiority of
percutaneous closure was clearly driven
by the high-risk patients
(Supplementary Figure 5). This was
also true when considering altogether the
studies which selected high risk patients
upstream (CLOSE, DEFENSE-PFO and
REDUCE), without subgroup analysis
(Supplementary Figure 4B).
The superiority of PFO closure was
confirmed also for the stroke reduction
of the studies when compared with
antiplatelet therapy with an OR = 0.38
(95% CI:0.17-0.84) (Supplementary
Figure 12A) but not with OAC,
although only 3 RCTs could be analysed
for the latter comparison
(Supplementary Figure 12B). Of note,
the only RCT of those allowing the
direct comparison of percutaneous
closure with OAC in a post-hoc analysis,
found no statistically significant
difference in stroke incidence in the
follow-up [74].
25
On the contrary, interventional and
medical therapy yielded similar results in
preventing TIA and Death
(Supplementary Figure 4C,
Supplementary Figure 4D).
On patient-level meta-analysis not
including CLOSE, REDUCE and
DEFENSE-PFO trials, PFO closure was
superior to medical therapy on ITT
analysis for stroke recurrence, with a
hazard ratio (HR) = 0.58 (95%CI: 0.34–
0.98), and for the primary composite
endpoint (stroke, TIA or death) only
after adjusting for covariates with an HR
= 0.68 (95%CI: 0.46–1.00) [70]. The 3
comprehensive study-level meta-
analyses and 11 study-level meta-
analyses not including DEFENSE-PFO
trials (Supplementary Table 7), all
showed superiority of PFO closure over
medical therapy only.
One of the study-level meta-analyses of
the 6 published RCTs revealed an
incidence rate of 1.27 per 100
patients/year with medical therapy (95%
CI, 0.84– 1.78; I2= 53%) and of 0.29
strokes per 100 person-years with
percutaneous closure (95% CI, 0.02–
0.76; I2= 83%) in the PFO closure group
[74].
Death rates were similar in medical and

interventional arms (pooled RR 0.79,
95% CI, 0.39– 1.60, P= 0.51; I2=
0%)[74]. No deaths were associated to
stroke.
Incidence rates for haemorrhage and

overall adverse events were similar in
the intervention and medical therapy
arms in all meta-analyses. However, it
should be taken into account that most of
the patients were young and follow-up
not very long, therefore a life-long
medical therapy may cause an
underdetected late rise in haemorrhages
with advancing age.
The risk of atrial arrhythmias,
particularly atrial fibrillation, was higher
after PFO closure than after medical
therapy in our meta-analysis of the 6
RCTs with an OR= 4.15 (95%CI: 2.42-
7.13) (Supplementary Figure 9A) and
also in all meta-analyses of the first 5
RCTs [78,79,90,122,170,171,276–278].
However, this difference was influenced
by the type of device received by
patients. With the use of Amplatzer
26
device, no difference in the risk of
postprocedural AF was found in our
meta-analysis (Supplementary Figure
10) and in four previous meta-analyses
including less studies than the last one.
Moreover a less significant difference in
AF risk war reported with Amplatzer
device in other three previous meta-
analyses [70,172,279–283]. Among the 6
RCTs, the use of GORE septal
occluders, in the REDUCE trial, was
associated with the highest probability of
AF with OR=15.6 (95%CI: 2.11-115.48)
(Supplementary Figure 10).
What is the overall certainty of All individual RCTs were underpowered
the evidence of effects? (Supplementary Table 9), mainly
○ Very low because of the discrepancy between the
● Low expected vs. observed incidence of
○ Moderate events, and meta-analyses should be
○ High interpreted accordingly.
Moreover, individual RCTs have low
○ No included studies internal and external validity
(Supplementary Table 10). Indeed,
event rates were low and confidence
intervals wide. Moreover, innumerable
CERTAINTY OF EVIDENCE
data from meta-analyses and randomised

and observational studies (see text) show
that substantial heterogeneity exists in
the populations studied. However, part
of this heterogeneity disappeared when
considering the subgroups of patients
according to PFO risk features,
suggesting that in part the PFO
characteristics may account for the
observed difference in study results.
Therefore, the conclusion in this
subgroups of patients are likely not to
change with new trials. Nonethelss, more
precise phenotyping with
multidimensional data is warranted to
design more appropriate randomised
trials indentifying new subgroups of
responders vs. non-responders to each
therapy.
Is there significant uncertainty No study addressed the issue of patient

about or variability in how preferences or values regarding
much people value the main outcomes and treatments for cryptogenic
outcomes? stroke with PFO. A systematic review
○ Important uncertainty or recently addressed these issues stroke
VALUES
variability prevention with medical therapy in

● Possibly important uncertainty patients with atrial fibrillation across 27
or variability studies [284]. Generally speaking, most
○ Probably no important patients were willing to accept even high
uncertainty or variability risks of a therapy if a certain threshold in
○ No important uncertainty or stroke risk reduction could be reached.
This acceptance went in many cases
27
variability beyond the judgement of physicians.
Moreover, significant differences in
preferences appeared also between
patients.
Does the balance between See the "desirable effects" and
desirable and undesirable "undesirable effects" sections of this
effects favour the intervention table for a summary of evidence.
or the comparison? On our study-level meta-analysis of the
○ Favours the comparison 6 RCTs, the number needed to treat
○ Probably favours the (NNT) over 3.9 years follow-up with
comparison percutaneous closure was 37 to avert one
○ Does not favour either the stroke as compared to medical therapy
intervention or the comparison on ITT analysis (Supplementary Figure
○ Probably favours the 4A), but it was only 21 in high risk PFOs
intervention and 27 to avert one primary endpoint as
● Favours the intervention compared to antiplatelet therapy only
(Supplementary Figure 5,
BALANCE OF EFFECTS
○ Varies Supplementary Figure 12A,

○ Don't know respectively).
On patient-level meta-analysis of the
first 3 published RCTs, NNT with
percutaneous closure over 2.5 years was
50 to avoid 1 primary composite
outcome event; to avoid 1 ischaemic
stroke, the NNT was 67 [70]. On study-
level meta-analysis, the NNT for an
Amplatzer device to prevent one stroke
at 5 years was 29, while to prevent one
TIA it was 49 [282]. This benefit
continues to grow beyond 5 years
[28,70,133].
On our meta-analysis, the NNH to cause
an atrial fibrillation over 3.9 years is 25
as compared to medical therapy
(Supplementary Figure 9A), but this
value appears to be influenced by the
kind of device (Supplementary Figure
10).
Is the intervention acceptable to Based on a meta-analysis of the first 5 Calculations of the
key stakeholders? published randomised trials (therefore cost/effectiveness in
○ No excluding Defense-PFO trial), a recent the Stortecky meta-
○ Probably no study showed that over a 15-year time analysis were based on
● Probably yes horizon, PFO closure resulted in a gain the overall costs of one
○ Yes of 0.33 QALYs at cost savings of $3568 procedure with
as compared to medical therapy only, Amplatzer in the UK,
ACCEPTABILITY
○ Varies representing an incremental net which ranges from

○ Don't know monetary benefit of $52 761 (95% 6,300 to 10,000 Euros.
interval −$8284 to $158 910). However
this gain only applies when the hazard
ratio for stroke remains low (i.e. in
higher risk populations). With the rise of
HR, a sharp decline in cost-effectiveness
occurs [285]
Previous data from the three first
published RCTs comparing PFO closure
with medical therapy, showed that, at
31.0 years (29. 6- 33.6), the per-patient
28
mean cost of medical therapy exceeded
that of PFO closure. Among studies
utilising only the Amplatzer device, the
cost analysis more strongly favoured
closure: cost to prevent one stroke =
652,392 USD (318,955-26,888,272);
time to less than 50,000 USD/QALY-
gained, 2.4 years (1.3 to 10.1); time to
medical cost exceeding closure cost,
22.7 years (19.75 to 26.7)[273]
In another meta-analysis of the first 3
published trials, the costs to prevent one
stroke through PFO closure with an
Amplatzer device ranged between
182,000-290,000 Euros, whereas the
incremental cost-effectiveness ratio
would range from 40,000-63,000
Euros/QALY-gained [282].
Is the intervention feasible to
implement?
○ No
FEASIBILITY
○ Probably no
○ Probably yes
● Yes
○ Varies
○ Don't know
29
Should oral anticoagulants (OAC) vs. antiplatelet therapy be used for secondary prevention of stroke or
other left-circulation thromboembolism?
POPULATION: Secondary prevention of stroke or other left-

INTERVENTION: OAC
COMPARISON: Antiplatelet therapy
MAIN OUTCOMES: Stroke; major bleedings
Assessment
JUDGEMENT RESEARCH EVIDENCE
Is the problem a priority? PFO-related stroke, TIA and peripheral
○ No embolisms impact a considerable
○ Probably no proportion of patients yearly with deaths
PROBLEM
○ Probably yes and persisting disability. At present the

● Yes pharmacological therapy for secondary
prevention has been derived from stroke
○ Varies studies at large with no reference therapy
○ Don't know for PFO-related left circulation
thromboembolism.
How substantial are the desirable anticipated Only one randomised study has compared
DESIRABLE EFFECTS
effects? the use of OAC (vitamin K antagonists or

○ Trivial DOACS) and antiplatelet therapy
○ Small (acetylsalicylic acid, clopidogrel or a
○ Moderate combination of acetylsalicylic acid and
○ Large dipyridamole) in 361 patients with
cryptogenic stroke with a large PFO and/or
● Varies an atrial septal aneurism showing, after an
○ Don't know average 5 years of follow-up, a statistically
non-significant difference of stroke in
patients receiving OAC as compared to
How substantial are the undesirable anticipated those who received antiplatelet therapy
effects? [1.6% vs 4.0%, respectively; p=0.21;
○ Large OR=0.34 (95% CI: 0.10 to 1.53)] [27].
○ Moderate Only one meta-analysis including CLOSE
○ Small study has been performed to date and it is
○ Trivial reported in this document. It includes 20
UNDESIRABLE EFFECTS
studies (1 randomised, 4 adjusted

● Varies observational and 15 non-adjusted studies,
○ Don't know including sub-analysis of 3 randomised
studies) and 3509 patients. We report a
statistically significant OR: 0.85 (95%CI:
0.81-0.90) for stroke in favour of OAC
(Supplementry Figure 7). However, we
found a severe inconsistency across both
studies (I2: 98%) and subgroups (I2:
96.5%) with statistically significant
heterogeneity (p<0.00001). Moreover, the
quality of evidence was estimated very
low, because of risk of bias and
imprecision (Supplementary Table 11)
and because most of the evidence was
30
derived from nonrandomised comparisons,
although some were adjusted comparisons.
As compared to antiplatelet therapy, in a
previous patient-level meta-analysis of
non-randomised trials, OAC yielded a
statistically non-significant reduction of
strokes, TIAs or death and stroke alone
[275].
Four previous study-level meta-analyses
incorporating up to 3311 patients, again
not including CLOSE trial, (the first three
involving observational studies only and
the last one both observational and non-
randomised comparisons of randomised
studies), also consistently found a
statistically-significant advantage of OAC
over antiplatelet therapy, including an OR
= 0.37 for stroke or TIA (95% CI: 0.23 to
0.60)[114], an incidence rate ratio of 0.42
(95% CI, 0.18–0.98) for stroke and/or TIA
[115], a relative risk of pooled recurrent
neurological events of 0.58 (95% CI: 0.41
to 0.82) [113], and event rates for stroke
and/or TIA at or beyond 12 months of
7.7% versus 9.8%, respectively, p = 0.03
[116].
In our meta-analysis on 14 studies and

1426 patients we found an OR 4.57
(95%CI: 2.10-9.93) for increased bleeding
with OAC as compared to antiplatelet
therapy, with no inconsistency at all across
studies (Supplementary Figure 8).
This is in-keeping with a previous meta-
analysis of non-randomised comparisons
only where an OR of 6.49 (95% CI: 3.25
to 12.99) was reported for major bleeding
with OAC relative to antiplatelet drugs
[116].
What is the overall certainty of the evidence of Overall, the available meta-analyses are
effects? consistent with an advantage of OAC over
○ Very low antiplatelet therapy as a secondary
● Low prevention in patients with previous PFO-
CERTAINTY OF EVIDENCE
○ Moderate related stroke or TIA.

○ High Also in our meta-analysis, including the
only randomised study performed so far,
○ No included studies most of the benefit of OAC was due to
non-randomised studies, although in 4 of
them the comparisons were adjusted. In
the CLOSE study, a trend was observed
towards an advantage of OAC over
antiplatelet therapy, but it was not
statistically significant. However, this
study was underpowered due to a lower
than expected incidence of primary
endpoint in the control arm. Moreover,
other individual studies had a low quality
31
of evidence because of imprecision and
risk of bias. Therefore, more adequately
powered studies are needed to obtain a
higher certitude of the estimate of effects.
Is there important uncertainty about or No study addressed the issue of patient

variability in how much people value the main preferences or values regarding outcomes
outcomes? and treatments during medical therapy for
○ Important uncertainty or variability cryptogenic stroke with PFO.
○ Possibly important uncertainty or variability A systematic review addressed these
● Probably no important uncertainty or variability issues for stroke prevention in patients
○ No important uncertainty or variability with atrial fibrillation across 27
publication describing the results of
studies conducted in 12 different countries
[284]. Most studies showed that patients
VALUES
were willing to accept higher bleeding

risks if a certain threshold in stroke risk
reduction could be reached, resulting in
the fact that physicians appeared to be
more sensitive to bleeding risk than
patients. Moreover, patients preferred
easy-to-administer treatments, such as
treatments that are applied once daily
without any food/drug interactions and
without the need for bridging and frequent
blood controls, implying a preference for
DOACs.
Does the balance between desirable and Despite the high statistical significance of
undesirable effects favour the intervention or our meta-analysis favouring OAC, and its
the comparison? narrow confidence intervals, the severe
BALANCE OF EFFECTS
○ Favours the comparison inconsistency among studies disallows

○ Probably favours the comparison generalisations (Supplementary Figure
○ Does not favour either the intervention or the 7). On the contrary the higher risk of
comparison bleeding with OAC was consistent across
○ Probably favours the intervention all the considered studies (Supplementary
○ Favours the intervention Figure 8). This translates in that the
balance between desirable and undesirable
● Varies effects varies mainly according to the
○ Don't know magnitude of the benefit OAC, the risk of
major bleeding being similar across
subgroups.
Is the intervention acceptable to key Cost effectiveness evaluation of different
stakeholders? medical therapies has not been performed
ACCEPTABILITY
○ No in patients with PFO-related cryptogenic

○ Probably no stroke, TIA, and peripheral embolism.
● Probably yes
○ Yes
○ Varies
○ Don't know
32
Is the intervention feasible to implement? Feasibility of implementation appears
○ No evident but the feasibility of a safe OAC in
FEASIBILITY ○ Probably no comparison to vitamin K antagonists is
● Probably yes largely dependent on the availability of
○ Yes monitoring facilities of proper
anticoagulation and on the possibility to
○ Varies access them by patients.
○ Don't know
33
Supplementary Table 1. PFO diagnostic methods.
DIAGNOSIS
USE DIAGNOSTIC CRITERIA ADVANTAGES LIMITATIONS
METHOD
Transthoracic • Evaluation of cardiac structures, • Constrast in left atrium in • Well tolerated by the • Reduced sensitivity for mild
Echocardiography interatrial septum motility the first 3-5 cardiac patient. interatrial shunts
(TTE) cycles • Low cost and • Need for a sufficient
• Evaluation of potential causes of
• <20 bubbles echographic thoracic window
cardiac embolism (e.g. left atrial mass reproducible.
mild/moderate • Semi-quantitative assessment
or thrombus, left ventricular • Ease for Valsalva
thrombus, etc) • >20 bubbles severe of the shunt
manoeuvre, sniff,
• Need for training in
• Diagnosing a clinically relevant coughing sonographers
intracardiac shunt at rest and after a • Visualisation and
Valsalva maneuver (With Bubble semi-quantification of
Test)
the right-to-left shunt
• Comparative follow-
up method
Transesophageal • Morphological characterisation of • Constrast in left atrium in • Gold standard for • Patient discomfort
Echocardiography interatrial septum, atrial structures the first 3-5 cardiac visualisation of • Impossibility to perform
(TEE) cycles cardiac and aortic proper Valsalva manoeuvre
• Evaluation of ascending aorta
• <20 bubbles: structures and sources • Training requested
• Anatomical details of PFO indicated mild/moderate
of embolism (tumors,
for intervention • >20 bubbles: severe
thrombi, vegetations,
complex aortic
plaques)
Semi-quantitative
assessment of the
shunt
Transcranial • Diagnosing right-to-left shunts at rest • 3-10 HITS: • Well tolerated by the • Unable to be performed in
Doppler (TCD) and after a Valsalva maneuver mild/moderate patient 20% of the patient for bone
• >10 HITS / • Low cost and thickness
shower/curtain: severe • Impossibility of directly
reproducible.
visualise shunt location
34
• High sensitivity for any • Lack of standardisation
right-to-left shunt • Methodology influences
• Semi-quantitative results
assessment of the shunt
• Contrast improves
feasibility loss due to
bone thickness
• Magnitude of shunt is
predictor of relapse
35
Supplementary Table 2. Qualitative evaluation of diagnostic studies.
A: Transcranial Doppler with bubble test vs. Transoesophageal contrast-echocardiography in the diagnosis of PFO
№ of Factors that may decrease quality of evidence Test

Study
studies (№ accuracy
design
of patients) Risk of Publication QoE
Indirectness Inconsistency Imprecision
bias bias
29 studies Cohort Serious Not serious Not serious Serious b None ⨁⨁◯◯
2751 & a
LOW
patients case-
control
type
studies
Explanations
a. high risk of adjudication bias
b. no sample size calculation
B. Transthoracic costrast-echocardiography vs. Transoesophageal contrast-echocardiography in the diagnosis of PFO
№ of Factors that may decrease quality of evidence Test

studies Study
accuracy
(№ of design
Risk of Publication QoE
patients) Indirectness Inconsistency Imprecision
bias bias
13 Cross- Serious Not serious Not serious Serious b None ⨁⨁◯◯
studies sectional a LOW
1360 (cohort
patients type
accuracy
study)
Explanations
a. High risk of adjudication bias b. No sample size calculation
36
Supplementary Table 3. Qualitative evaluation of the studies on RoPE score.
№ of Factors that may decrease quality of evidence

studies Study Test accuracy
(№ of design Risk Indirectness Inconsistency Imprecision Publication QoE
patients) of bias bias
4 Cohort Not Not serious Not serious Very Strong ⨁⨁⨁◯

studies and serious serious a,b association MODERATE
6362 case-
patients control
type
studies
Explanations
a. 2 on 4 studies with multivariate analysis.
b. No studies with sample size calculation
Supplementary Table 4. Predictors of cryptogenic stroke recurrence in the presence of a PFO.
Kind of predictor N. of pts N. of OR/HR LCI UCI

studies
Older Age [73,97,286,287] 2171 4 1.47 1.2 1.8
Septal aneurysm [288–292] 630 5 3.0 1.8 4.8
Acetylsalicylic acid use vs. OAC [11,72,293– 1235 5 2.5 1.1 6.1
295]
Coagulation disorders [296,297] 258 2 2.75 1.17 6.49
Stroke at index [298,299] 367 2 3.0 1.4 6.5
PFO diameter (continuous variable) [11,290] 334 2 3 1.9 4.6
All predictors significant at multivariate analysis in 2 studies or more have been included, along with number of studies.
OR/HRs (Odds ratio/Hazard ratio) have been reported of the study with the smallest confidence interval. LCI: Lower
confidence interval, UCI: upper confidence interval
37
Supplementary Table 5. Complications of percutaneous closure.
COMPLICATION INCIDENCE PATHOPHYSIOLOGY SYMPTOMS/SIGNS DIAGNOSTIC

WORKUP
Residual shunt 10-15% • Temporary or persistent • Possibly • c-TCD
[123,124,300,301] mild to severe device leak asymptomatic • c-TTE
due to device-PFO • Recurrent systemic • c-TOE
mismatch and/or embolism
incomplete endocardial • Observed in
coverage different positions
Atrial arrhythmias 0.5-15% • Related to age and/or • Possibly • Holter ECG
[106–111,302] ASA asymptomatic • ICM
• Mechanical irritation • Atrial Fibrillation
related to device type and • Superaventricular
size tachyarrhythmias
• Inflammatory reaction • Recurrent systemic
• Electrical barrier by the embolism
device
• P-wave dispersion
Device thrombosis 1-2% • Thrombosis of device • Possibly • TTE
[135,303] arms not covered by asymptomatic • TOE
endocardium • Systemic embolism
Pericardial effusion/ 0.5-1% • Perforation during • Possibly • TTE
tamponade procedure asymptomatic • TOE
[48,49,301,303–305] • Early(24-48h) and late • Dyspnea (erosion)
erosion
• Chest pain
• Allergic reaction (mild
effusion)
Device embolisation 0.9-1.3% (early) • Early and late • Possibly • TTE
[135,136,301,306–309] Rare (late) mobilisation due to asymptomatic • TOE
erosion of the atrial • Pulmonary • Chest X-ray
septum or to device-PFO embolism
mismatch
Endocarditis Anecdotal • Colonisation of device • Unexplained fever • TOE
[127,310,311] arms not covered by • Systemic septic
endothelium embolism
Atrio-aortic fistula Anecdotal • Erosion of aortic wall • New onset murmur • TOE
[312]
c-TTE: contrast-enhanced transthoracic echocardiogram; c-TOE: contrast-enhanced transoesophageal echocardiogram; c-

TCD: contrast-enhanced transcranial doppler; ICM: internal cardiac monitor; ASA: aceytlsalycilic acid; ECG:
electrocardiogram
38
Supplementary Table 6. Prognosis of patients with PFO patency.
Author Nr. of Follow- % of positive % of positive N of events N of events N of events N of events

patien up TCD TOE in patients in patients in patients in patients
ts (months) with with with with
positive positive negative negative
TCD TOE TCD TOE
Anzola, 2004 [143] 112 12 9,00% 9,00% 0 0 1 1
Balbi, 2008 [144] 109 6 17,5% 21, 6 % 0 0 0 0

(6 months) (3 months)
Cifarelli, 2010 202 6 4% 4% 0 0 0 0
[141]
Caputi, 2013 [124] 243 12 32,00% 32,00% 4 4 8 8
de Cillis, 2010 72 6 6.9% 5,5% 0 0 0 0
[145]
Donti, 2006 [146] 11 1 36,00% - 0 0 0 0
Orzan, 2010 [147] 68 6 25,00% 11,76% 0 0 0 0
Ussia, 2009 [142] 14 6 (TCD) 21% 0% 0 0 1 1
12 (TOE)
TOE: transesophageal echocardiogram; TCD: transcranial Doppler;
39
Supplementary Table 7. Summary of meta-analyses on closure vs. medical therapy trials.
Study Design of N of N of N of Stroke, TIA; Stroke, TIA Stroke

the study study RCT observation all cause
(patients) (patient al studies death
s) (patients)
Turc, 2018 [74] Pairwise, 6 (3560) 6 (3560) - - - PFO closure
study reduced
level incidence of
stroke
(RR 0.36;
95%CI: 0.17-
0.79)
Wang, 2018 [313] Pairwise, 6 (3560) 6 (3560) - PFO closure PFO closure PFO closure
study reduced reduced reduced
level incidence of incidence of incidence of
stroke and TIA stroke stroke
and all cause (2.0% versus (HR 0.4;
death 4.5%, OR 95%CI:0.19-
(HR 0.60: 0.41, 95%CI: 0.88)
95%CI:0.42- 0.19–0.90
0.85)
Saber, 2018 [337] NMA, 6 (3497) 5 (3497) - PFO closure
study reduced
level incidence of
stroke
(RR 0.30;
95%CI: 0.17-
0.49)
Tsivgoulis, 2018 NMA, 6 (3497) 5 (3497) - PFO closure
[338] study reduced
level incidence of
stroke
(RR 0.42;
95%CI: 0.20-
0.91)
Lattanzi, 2018 Pairwise, 5 (3440) 5 (3440) - PFO closure
[339] study reduced
level incidence of
stroke
(RR 0.43;
95%CI: 0.21-
0.90)
Smer, 2018 [340] Pairwise, 5 (3440) 5 (3440) - PFO closure
study reduced
level incidence of
stroke
(RR 0.48;
95%CI: 0.27-
0.87)
40
Shah, 2018 [277] Pairwise, 4 (3216) 4 (3216) - PFO closure
study decreased the
level AR for
*[Closure recurrent
I trial was stroke by 3.2%
excluded (RD, -0.032;
because 95%CI: -0.05
using to
Starflex] -0.014)
compared
with medical
therapy
De Rosa, 2018 Pairwise, 4 (3216) 4 (3216) - PFO closure
[122] study reduced the
level risk for the
*[ main outcome
Closure I of stroke or
trial was TIA
excluded (RD: −0.029
because 95%CI:
using −0.050 to
Starflex] −0.007])
Abdelaziz, 2018 Pairwise, 5 (3440) 5 (3440) - PFO closure
[341] study reduced
level incidence of
stroke
(RR 0.43;
95%CI: 0.19-
0.91)
Ahmad, 2018 Pairwise, 5 (3440) 5 (3440) - PFO closure
[342] study reduced
level incidence of
stroke
(RR 0.32
95%CI: 0.13-
0.82)
Reinthaler, 2018 Pairwise, 5 (3440) 5 (3440) - PFO closure
[343] study reduced
level incidence of
stroke
(RR 0.32
95%CI: 0.13-
0.80)
Anantha- Pairwise, 5 (3440) 5 (3440) - - - PFO closure
Narayanan, 2018 study reduced
[314] level incidence of
stroke
(RR 0.59
95%CI: 0.40-
0.87)
Palaiodimos, 2018 Pairwise, 5 (3440) 5 (3440) - - - PFO closure
[315] study reduced
level incidence of
stroke
(HR 0.29
95%CI: 0.02-
0.56)
41
Chen, 2018 [316] Pairwise, 19 (6301) 5 (3440) 14 (2861) - - PFO closure
study reduced
level incidence of
stroke
(HR 0.38
95%CI: 0.24-
0.60)
Darmoch, 2018 Pairwise, 5 (3440) 5 (3440) - - - PFO closure
[317] study reduced
level incidence of
stroke
(HR 0.42
95%CI:0.20-
0.91)
Alushi, 2018 [318] Pairwise, 5 (3440) 5 (3440) - PFO closure PFO closure
study reduced the reduced
level composite of incidence of
stroke, TIA, stroke
all cause death (HR 0.39
and peripheral 95%CI: 0.19-
embolism 0.83)
(HR 0.52;
95%CI: 0.36-
0.77)
Ando, 2018 [278] Pairwise, 5 (3440) 5 (3440) - PFO closure PFO closure
study did not reduce reduced the
level the risk of risk
transient of recurrent str
ischaemia oke
attack (RR 0.42;
(RR 0.78; 95%CI:0.20-
95%CI:0.53- 0.91)
1.15)
Hakeem, 2018 Pairwise, 5 (3440) 5 (3440) - The

[78] study cumulative
level incidence of
recurrent
stroke was
2.02% in the
PFO closure
arm and 4.4%
in the medical
therapy group
(RR 0.42;
95%CI:0.20-
0.91).
42
Ntiatos, 2018 Pairwise, 5 (3627) 5 (3627) - PFO closure
[170] study reduce
level ischaemic
stroke
recurrence
(0.53 vs 1.1
per 100
patient-years;
OR: 0.43;
95%CI: 0.21-
0.90)
Abo Salem, 2018 Pairwise, 5 (3627) 5 (3627) - PFO closure

[90] study reduced
level stroke:
2.0% vs. 4.2%
RR 0.48;
95%CI: 0.3-
0.7
Zhang, 2018 Pairwise, 20 (6921) 5 (3627) 5 (3294) PFO closure PFO is
[171] study was associated associated
level with a with lower
significantly incidence of
lower stroke
incidence of (OR: 0.39;
the composite 95%CI:0.24-
outcome of 0.63)
ischaemic
stroke, TIA, or
all-cause death
(OR: 0.57;
95%CI: 0.38-
0.85
Schulze, 2018 Pairwise, 5 (3440) 5 (3440) - PFO closure PFO closure
[276] study reduced the significantly
level combination of reduced
recurrent recurrent
stroke + TIA stroke
(OR 0.53, (OR: 0.41,
95%CI: 0.36- 95%CI: 0.19-
0.80) 0.90]
Kheiri, 2018 [79] Pairwise, 5 (3440) 5 (3440) - Pooled
study analysis
level showed a
statistically
significant
reduction in
the rate of
recurrent
stroke with
PFO closure in
comparison to
medical
therapy (OR
0.41;
95%CI: 0.19-
0.90)
43
Stortecky, 2015 Network, 4 (2963) 4 (2963) - NA NA Superiority of
[282] study Amplatzer for
level stroke
RR (0.39;
95%CI:0.17–
0.84) No
difference for
Starflex
(RR 1.01;
95%CI:0.44-
2.41)
Bin Riaz, 2013 Pairwise, 3 (2303) 3 (2303) - Superiority of NA NA
[319] study PFO closure at
level per protocol
(HR: 0.64,
95%CI: 0.41-
0.98) and not
at intention to
treat analysis
(HR: 0.66,
95%CI:0.43-
1.01)
Capodanno, 2014 Pairwise, 14 (4634) 3 (2303) 11 (2331) NA NA No difference
[280] study for RCTs and
level for
observational
studies with
adjustement
(HR 0.62;
95%CI:0.34-
1.11)
Superiority of
RCTs with
Amplatzer
Occluder
(HR 0.44,
95%CI: 0.20-
0.95)
Li, 2015 [320] Pairwise, 3 (2303) 3 (2303) - NA NA No difference
study (RR 0.73, also for
level 95%CI:0.45- Amplatzer
1.17) occluder. (only
intention to
treat)
(RR 0.61,
95%CI:0.29-
1.27)
Hakeem, 2013 Pairwise, 3 (2303) 3 (2303) - No difference NA No difference
[321] study (RR 0.7; (RR 0.66;
level 95%CI: 0.48– 95%CI:0.35–
1.06) 1.24)
44
Kent, 2013 [322] Pairwise, 3 (2303) 3 (2303) - No difference NA Superiority of
patient at intention to PFO closure at
level treat analysis, intention to
superiority of treat, at as-
PCO closure at treated and
as-treated, after
persisting adjustement.
aftger (HR: 0.58;
adjustment. 95%CI: 0.34-
(HR: 0.68 0.99)
95%CI:0.46-
1.00)
Khan, 2013 [279] Pairwise, 3 3 - NA No difference
study at intention to
level treat analysis
(OR 0.67;
95%CI:0.44-
1.0)
superiority of
PFO closure
at as protocol
(OR 0.62;
95%CI: 0.40-
0.95) and as
treated (OR
0.61;
95%CI:0.40-
0.95)
Kitsios, 2012 Pairwise, 9 (8916) 1 (909) 8 (8007) NA Superiority of
[115] study PFO closure
level (HR 0.19;
95%CI: 0.07–
0.54)
Kwong, 2013 Pairwise, 3 (2303) 3 (2303) - No difference
[323] study (OR:0.65;
level 95%CI:0.36–
1.20)
Rengifo- Moreno, Pairwise, 3 (2303) 3 (2303) - No difference Superiority of
2013 [324] study at ITT analysis PFO closure at
level (HR:0.67; ITT (HR:0.60;
95%CI:0.44– 95%CI:0.36-
1.00) 0.98)
Nagaraja, 2014 Pairwise, 3 (2303) 3 (2303) - NA No difference No difference
[325] study (OR: 0.654;
level 95%CI:0.3-
61.19)
45
Ntaios, 2013 [172] Pairwise, 3 (2303) 3 (2303) - NA NA No difference
study overall
level (OR: 0.64,
95%CI:0.37–
1.1).
Superiority for
Amplatzer
device (OR:
0.46:
95%CI:0.21–
0.9) (ITT
analysis) but
not
STARFLEX
(OR: 0.93;
95%CI:0.45–
2.11)
Pandit, 2014 [326] Pairwise, 3 (2303) 3 (2303) - NA NA No difference.
study Superiority for
level Amplatzer
device (ITT
analysis)
(HR:0.44;
95%CI:0.21-
0.9)
Pickett, 2013 Pairwise, 3 (2303) 3 (2303) - No difference No difference No difference.
[273] study (HR 0.67; Superiority for
level 95%CI:0.44– Amplatzer
1.01) device (ITT
analysis)
(HR:0.44;
95%CI:0.21–
0.95)
Pineda, 2013 [327] Pairwise, 3 3 - No difference. No difference
study Superiority for (OR 5 0.65;
level PFO closure 95%CI:0.36–
only at as- 1.20)
treated
analysis
(OR:0.70;
95%CI:0.47–
1.0)
Udell, 2014 [283] Pairwise, 3 3 - NA No difference
study (RR:0.73;
level 95%CI:0.50-
1.0)
46
Wolfrum, 2014 Pairwise, 14 (2303) 3 (2303) 11 (2032) NA NA No difference
[328] study for RCTS
level (HR 0.58;
95%CI:0.33-
0.99),
superiority of
PFO closure
for
observational
studies
(RR 0.66;
95%CI:0.37-
1.19)
Agarwal, 2012 Pairwise, 48 - 48 (10327) NA Superiority of NA
[113] study (10327) PFO closure
level (pooling
univariate
analysis)
(RR:0.25;
95%CI:0.11-
0.58]
RR: relative risk; AR: absolute risk; OR: odds ratio; ITT: intention-to-treat; HR: hazard ratio; RD: risk
difference; CI: confidence interval;
47
Supplementary Table 8. Observational studies comparing PFO closure with medical therapy
Study Type N of Follow Control PE Follow ORE ERE Overall ITT PP PFO closure PFO
pts up up (PFO vs. (PFO vs. results vs. APL closure vs.
(mo) (yrs) medical medical AC
therapy) therapy)
Thanopoulos, P 92 24 antiplatelet 2 NA Superiority NA NA Superiority of NA
2006 [329] of PFO PFO closure
closure at at univariate
univariate analysis
analysis
Harrer, 2006 P 124 52 ASA 2.1 NA No No difference
[330] difference at
at multivariate
multivariate analysis
analysis
Paciaroni, 2011 P 238 24 antiplatelet 2 No No difference
[331] difference at
at multivariate
multivariate analysis for
analysis for stroke/TIA
stroke/TIA and for stroke
and for
stroke
Casaubon, R 121 70 medical 5.8 No

2006 [332] therapy difference
at
multivariate
analysis
Lee, 2010 [290] R 181 48 Surgical 3.5 Aspirin Aspirin
Pfo increased increased
Closure vs. risk of risk of
medical recurrence recurrence at
therapy at multivariate
multivariate analysis
analysis
Mirzada, 2015 P 314 60 medical 6.8 NA No
[333] therapy difference
at
multivariate
analysis
48
Pezzini, 2016 R 521 100 medical Stroke, 8.3 NA No No difference No
[334] therapy TIA difference at difference at
at multivariate multivariate
multivariate analysis analysis
analysis
Wahl, 2016 P 308 180 medical Stroke, 15 Superiority
[133] therapy TIA of PFO
closure at
multivariate
analysis
Weimar, 2009 P 899 28 medical No

[335] therapy difference
at
multivariate
analysis
Schuchlenz, R 280 medical Stroke, Superiority Superiority of Superiority
2005 [252] therapy TIA of PFO PFO closure of PFO
closure at at closure at
multivariate multivariate multivariate
analysis analysis analysis
Windecker, P 308 48 medical Stroke, 4 Superiority
2004 [336] therapy TIA of PFO
closure at
multivariate
analysis
PTS: patients; APL: antiplatelet drugs; AC: anticoagulant drugs; P: prospective: R: retrospective ; PP: per-protocol: ITT: itention-to-treat; ORE:
observed rate of events; ERE: expected rate of events; PE: primary endpoint; TIA: transitory ischemic attack
49
Supplementary Table 9. RCTs comparing percutaneous closure and medical therapy.
Study N of Follow- Comparison Primary endpoint Follow-up Median Observed rate Expected rate
patients up for sample follow up of events of events
(months) size (years) (Closure vs. (Closure vs.
calculation medical medical
(years) therapy) therapy)
CLOSURE 909 48 medical Stroke/tia and death 2 2 5.5% vs. 6.8% 3.0% vs.6.0%
I, 2012 [51] therapy from neurologica
causes
PC TRIAL, 414 48 medical Death, stroke, TIA, 4.5 4.1 3.4% vs. 5.2% 4.5% vs. 13.5%
2013 [132] therapy peripheral
embolims
RESPECT, 980 84 medical Stroke,TIA, death 2* 5.9 1.9% vs. 3.3%* 1.05% vs. 4.3%*
2012, 2017 therapy
[28,112]
REDUCE, 664 38 medical Stroke or imaging- 2 3.2 1.4% vs. 5.4% 3.6% Vs. 8%
2017 [26] therapy confirmed TIA at
24 months post-
randomisation
CLOSE, 473 64 medical Fatal or non-fatal 3 5.4 0% vs.6.2% 5.3%vs. 10.5%
2017 [27] therapy stroke
DEFENSE- 120 24 medical Stroke, vascular 2 2.8 0% vs. 12.9% 4% vs. 15%
PFO, 2018 therapy death and TIA
[29]
* These data refer to 2-year follow-up on which sample size computation was performed.
TIA: transient ischaemic attack
50
Supplementary Table 10. Qualitative and quantitative assessment of the evidence.
Percutaneous closure of PFO compared to medical therapy for secondary prevention of stroke or systemic solid embolisation in pts with
cryptogenic stroke or TIA and a PFO
Certainty assessment Summary of findings
No. of Risk Inconsisten Indirectne Imprecisio Publicatio Overall Study event rates Relativ Anticipated absolute
participant of cy ss n n bias certaint (%) e effect effects
s bias y of (95%
(studies) evidenc With With CI) Risk Risk
Follow-up e medic percutaneo with difference
al us closure medic with
therap of PFO al percutaneo
y therap us closure
y of PFO
RCT
3,441 seriou not serious serious d serious e all ⨁⨁◯ 85/161 46/1829 HR Study population
(7 RCTs) s a,b,c plausible ◯ 2 (2.5%) 0.38
residual LOW (5.3%) (0.18 to 53 per 1.000
confoundin 0.80) 32 fewer per 1.000
g would (43 fewer to 10 fewer)
reduce the
demonstrat
ed effect
51
COHORT STUDIES
2,481 seriou not serious not serious serious h all ⨁◯◯

(8 s f,g plausible ◯
observation residual VERY
al studies) confoundin LOW
g would
suggest
spurious
effect,
while no
effect was
observed
CASE-CONTROL STUDIES CI: Confidence interval; HR: Hazard Ratio
902 very not serious not serious h all plausible ⨁◯◯◯

(3 serious serious residual VERY
observational i confounding LOW
studies) would
suggest
spurious
effect, while
no effect
was
observed
52
Explanations
a. 7 available randomised trials have limitations: a) Different definitions of key terms (e.g., cryptogenic stroke. b) There may have been a significant
patient self-selection bias, whereby patients with a higher risk of recurrent stroke may opt out of clinical trials, and thus are not represented in this
trial. This is reflected in the fact that the inclusion of patients was very slow, especially in the CLOSURE, PC and RESPECT, and the number of
patients included was significantly lower than the number of patients treated with PFO occlusion in the respective centers. This means that patients
with an expected high risk of stroke recurrence were treated outside the study. And just these patients were the most likely to show a difference in the
treatment procedures. In particular, the CLOSURE I study shows considerable weaknesses. In CLOSURE I are potential bias that have influenced the
study: a) The trial was underpowered to detect small differences in the event rates. b) Patient selecti
b. 2/7 studies likely enrolled patients with misdiagnosed Atrial Fibrillation
c. 4/7 studies enrolled patients with TIA and used TIA as main outcome measure, instead of stroke
d. 6/7 studies with heterogeneity of drug treatments according to the physician preference
e. wide confidence intervals in CLOSURE, PC and RESPECT studies and lower than expected incidence of outcomes for 7/7 studies
f. high or unclear risk of blinding and of follow-up assessment
g. half of studies with high risk of incomplete reporting
h. most of studies without sample size calculation
i. high risk of unclear risk of blinding and of allocation concealment
53
Supplementary Table 11. Qualitative assessment of the evidence on the comparison between antiplatelet versus OAC therapies
Quality assessment
№ of Risk Inconsistency Indirectness Imprecision Publication Overall

participants of bias bias quality
(studies) of
follow-up evidence
OUTCOME: STROKE
361 Serious Not serious Not serious Serious b None ⨁◯◯◯ Explanations
(20 b
VERY a. 1 RCT on ASA vs. OAT, 3 studies with multivariate
observational LOW adjustement and 16 observational studies.
studies) a b. Due to large number of studies without randomisation or
multivariate adjustement (16/20)
OUTCOME: MAJOR BLEEDING c. 1 RTC, 13 studies without multivariate adjustement
d. Only one RCT
1436 Serious d Not serious Not serious Serious d None ⨁◯◯◯
(14 VERY
observational LOW
studies) c
54
Supplementary Table 12. Quality of evidence grades.
55
Supplementary Figure legends
Supplementary Figure 1. Comparison of the rate of PFO detection in studies using TOE or autopsy.
Top: TOE studies yielded a significantly lower prevalence of PFO 13% (95% CI: 8%-18%) as compared to
autopsy studies 25% (95% CI: 20%-29%), p=0.004.
Bottom: Results of the single studies [179–203]. For details see the text in Supplementary Appendix 4.
Supplementary Figure 2. Meta-analysis of diagnostic accuracy studies comparing c-TCD vs. c-TOE.
A. Forest plot for sensitivity and specificity. As compared with c-TOE, c-TCD yielded a sensitivity of 0.94
(0.92-0.95) and a specificity 0.92 (0.91-0.93). The inconsistency estimates were 67% for sensitivity and
73% for specificity.
B. At receiver operating characteristics (ROC) curve analysis, the AUC was 0.97.
Supplementary Figure 3. Meta-analysis of diagnostic accuracy studies comparing c-TTE vs. c-TOE.
A. Forest plot for sensitivity and specificity. As compared with c-TOE, c-TTE yielded a sensitivity 0.88
(0.86-0.89) and a specificity of 0.82 (0.78-0.84). The inconsistency estimates were 78% for sensitivity and
83% for specificity.
B. At ROC curve analysis, the AUC was 0.91.
Supplementary Figure 4. Outcomes in patients undergoing percutaneous closure or medical therapy.

A. Forest plot for the risk of stroke recurrence in overall RCTs
B. Forest plot for the risk of stroke recurrence in RCTs with a high prevalence of high-risk PFO patients vs.
those in which patients were unselected for PFO features
C. Forest plot for the risk of TIA recurrence
D. Forest plot for the risk of Death
Supplementary Figure 5. Sub-group analysis according to PFO features.

Overall, in this subgroup of patients selected only on the PFO characteristics [atrial septal aneurism,
moderate-to-severe shunt (i.e. "relevant shunt"), PFO size >2 mm, atrial septal hypermobility],
percutaneous closure yielded a lower risk reduction than observed in Panel A (OR 0.54 vs. 0.38),
suggesting that additional risk resides in other clinical and/or anatomical parameters.
In patients with high-risk PFO characteristics, PFO closure yielded a statistically significant lower risk of
stroke as compared to medical therapy. Moderate heterogeneity was still present in this high-risk subgroup,
suggesting different roles of the considered PFO features in different patients.
In patients with low-risk PFO characteristics, PFO closure did not yield statistically significant differences
as compared to medical therapy. No heterogeneity was found across the subgroups of different studies.
Supplementary Figure 6. PRISMA flow chart for the review of studies on the predictors of stroke in
patients with cryptogenic stroke and a PFO.
Supplementary Figure 7. Forest plot for the risk of stroke recurrence in studies comparing OAC with
antiplatelet therapy for cryptogenic solid systemic embolism.
Supplementary Figure 8. Forest plot for the risk of major bleedings in studies comparing OAC with
antiplatelet therapy for cryptogenic cerebral or systemic embolism.
Supplementary Figure 9. Risk of atrial fibrillation in studies comparing PFO closure with medical therapy
for cryptogenic cerebral or systemic embolism.
A. Forest plot for the risk of atrial fibrillation
B. Forest plot for the risk of atrial fibrillation in the first 45 days after the procedure
C. Forest plot for the risk of atrial fibrillation beyond 45 days after the procedure
Supplementary Figure 10. Forest plot for the risk of atrial fibrillation according to the type of device used
for PFO closure in studies comparing PFO closure with medical therapy for cryptogenic cerebral or
systemic embolism.
56
Supplementary Figure 11. L'Abbé plots for the risk of TIA and stroke after PFO closure according to the
length of dual antiplatelet therapy.
A. TIA (=-8.10; 95% CI: -10.11 to 0.45; p=0.98)
B. Stroke (=0.061; 95% CI: -0.14 to 0.25; p=0.57)
Supplementary Figure 12. Risk of stroke recurrence in patients undergoing OAC or antiplatelet therapy in
studies comparing PFO closure with medical therapy for cryptogenic cerebral or systemic embolism.
A. Forest plot for the risk of recurrent stroke in patients undergoing antiplatelet therapy or percutaneous
closure
B. Forest plot for the risk of recurrent stroke in patients undergoing OAC or percutaneous closure
(excluding CLOSE trial data)
C. Forest plot for the risk of recurrent stroke in patients undergoing OAC or percutaneous closure
(including CLOSE trial published data)
Supplementary Figure 13. Risk of stroke recurrence according to the type of index event in studies
comparing PFO closure with medical therapy for cryptogenic cerebral or systemic embolism.
Supplementary Figure 14. Risk of stroke recurrence according to the type of device used for PFO closure
in studies comparing PFO closure with medical therapy for cryptogenic cerebral or systemic embolism.
Supplementry Figure 15. PRISMA flow chart for the review of studies on the RoPE score.
Supplementary Figure 16. PRISMA flow chart for the review of RCTs comparing inseartable cardiac
monitors with intermittent recordings to diagnose atrial fibrillation in patients with PFO-associated left
Supplementary Figure 17. PRISMA flow chart for the review of RCTs comparing PFO closure with
medical therapy.
Supplementary Figure 18. PRISMA flow chart for the review of studies comparing OAC with antiplatelet
therapy for secondary prevention of stroke, TIA or systemic solid embolism in patients with previous
cryptogenic left embolism.
Supplementary Figure 19. PRISMA flow chart for the review of studies investigating the accuracy of PFO
diagnostic tests.
Supplementary Figure 20. PRISMA flow chart for the review of studies investigating the accuracy of PFO
diagnostic tests.
Supplementary Figure 21. Simplified scheme of the interacting network of processes underlying clinical
manifestations associated with PFO.
57
Supplementary Figures
Supplementary Figure 1.
58
59
60
61
62
63
64
65
66
67
68
69
70
71
72
73
74
75
76
77
78
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European Position Paper On The Management of Patients With Patent Foramen Ovale. General Approach and Left Circulation Thromboembolism

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INTERVENTIONS FOR HYPERTENSION AND STROKE

EuroIntervention 2019;14:1389-1402 published online ahead of print August 2018

H. Sievert and F. D’Ascenzo contributed equally to the manuscript.

Table 1. Summary of statements.

could help in guiding assessment (Table 2). Bleeding, aspiration,

of a PFO include the simultaneous or previous occurrence of pul-

have yielded conflicting results86-89. PFO diagnostic NO PFO Cryptogenic

First-line diagnostic workup

Evaluate major AF risk YES

Intervention Percutaneous closure of PFO

Comparison Medical therapy

Main outcomes Stroke, TIA, death, bleedings, atrial arrhythmias

JUSTIFICATION Overall justification

Table 7. Summary of statements on the management after percutaneous closure of PFO.

Supplementary Appendix 1. Detailed methods.

General outline of the process

GRADE process and position statements

Non-PICO questions definition and position statements

LIST OF PICO AND NON-PICO QUESTIONS

LITERATURE SEARCH QUERIES

Meta-analyses of association studies or of studies on therapy outcomes

Meta-analysis of studies on diagnostic tests accuracy

Evaluation of risk predictors

The issue of complexity in PFO related syndromes

Further details on diagnostic accuracy studies

Clinical studies supporting a key role for PFO in paradoxical embolisation.

Clinical studies supporting different pathophysiologic processes in PFO-associated embolism.

IS IT CLINICALLY POSSIBLE TO ESTIMATE THE PROBABILITY OF A CAUSAL RELATIONSHIP

Imaging stroke pattern

Characteristics of the PFO

Circumstances that predispose someone to DVT — like an immobilising injury/surgery or an extended

Clinical risk scores

RISK OF RECURRENCE IN PFO-ASSOCIATED STROKE

In cases involving a cerebrovascular accident, an accurate neurological evaluation is required to differentiate

Assessing asymptomatic paroxysmal AF

Evaluating the need for anticoagulants in AF

ADDITIONAL INSIGHTS ON EFFICACY AND SAFETY OF MEDICAL THERAPIES

ADDITIONAL INSIGHTS ON THE SAFETY AND EFFICAY OF PERCUTANEOUS CLOSURE

SURGICAL CLOSURE OF PFO

POPULATION: Secondary prevention of stroke,

causal role of PFO in this figure, varying embolism is similar to

desirable anticipated effects? patients in 11 nonrandomised for cryptogenic stroke

Our study-level meta-analysis performed

borderline between moderate and

Death rates were similar in medical and

Incidence rates for haemorrhage and

data from meta-analyses and randomised

Is there significant uncertainty No study addressed the issue of patient

variability prevention with medical therapy in

○ Varies Supplementary Figure 12A,

○ Varies representing an incremental net which ranges from

POPULATION: Secondary prevention of stroke or other left-

MAIN OUTCOMES: Stroke; major bleedings

○ Probably yes and persisting disability. At present the

effects? the use of OAC (vitamin K antagonists or

studies (1 randomised, 4 adjusted

In our meta-analysis on 14 studies and

○ Moderate related stroke or TIA.

Is there important uncertainty about or No study addressed the issue of patient