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SYSTEMATIC / NARRATIVE REVIEW ARTICLE

Management of patent foramen ovale in embolic stroke of

undetermined source patients: Malaysian experts'
consensus

Stephenie Ann Albart, MD1, Abdul Hanif Khan Yusof Khan, MMed (Int Med)2,3, Wan Asyraf Wan Zaidi, MMed
(Int Med)4, Annamalar Muthu Muthuppalaniappan, MRCP5, Geetha Kandavello, MRCP (Paeds)6, Koh Ghee
Tiong, MRCPCH7, Leong Ming Chern, MRCPCH6, Liew Houng Bang, FRCP8, Ong Beng Hooi, MRCP9, Shanthi
Viswanathan, MRCP10, Hoo Fan Kee, MRCPS (Glasgow)2,3, Irene Looi, FRCP1,11, Yap Yee Guan, FRCP12, Law Wan
Chung, MRCP13

1
Clinical Research Centre, Hospital Seberang Jaya, Ministry of Health Malaysia, Seberang Jaya, Pulau Pinang, Malaysia,
2
Department of Neurology, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Serdang, Selangor, Malaysia,
3
Department of Neurology, Hospital Pengajar Universiti Putra Malaysia, Universiti Putra Malaysia, Serdang, Selangor,
Malaysia, 4Department of Medicine, Hospital Canselor Tuanku Muhriz (HCTM), Universiti Kebangsaan Malaysia, Kuala
Lumpur, Wilayah Persekutuan Kuala Lumpur, Malaysia, 5Gleneagles Hospital Penang, George Town, Pulau Pinang, Malaysia,
6
Institut Jantung Negara, Kuala Lumpur, Wilayah Persekutuan Kuala Lumpur, Malaysia, 7Paediatric Cardiology Unit, Hospital
Serdang, Kajang, Selangor, 8Department of Cardiology, Hospital Queen Elizabeth II, Ministry of Health Malaysia, Kota
Kinabalu, Sabah, Malaysia, 9Kedah Medical Centre, Alor Setar, Kedah, Malaysia, 10Department of Neurology, Hospital Kuala
Lumpur, Ministry of Health Malaysia, Kuala Lumpur, Wilayah Persekutuan Kuala Lumpur, Malaysia, 11Department of
Medicine, Hospital Seberang Jaya, Ministry of Health Malaysia, Seberang Jaya, Pulau Pinang, Malaysia, 12Sunway Medical
Centre, Petaling Jaya, Selangor, Malaysia, 13Department of Medicine, Hospital Umum Sarawak, Ministry of Health Malaysia,
Kuching, Sarawak, Malaysia

ABSTRACT by single antiplatelet therapy (APT) for six months, is

Introduction: About 20 to 40% of ischaemic stroke causes advised. Nonetheless, with joint care from a cardiologist and
are cryptogenic. Embolic stroke of undetermined source a neurologist, the multidisciplinary team will decide on the
(ESUS) is a subtype of cryptogenic stroke which is continuation of therapy.
diagnosed based on specific criteria. Even though patent
foramen ovale (PFO) is linked with the risk of stroke, it is KEYWORDS:
found in about 25% of the general population, so it might be Patent foramen ovale, embolic stroke of undetermined source,
an innocent bystander. The best way to treat ESUS patients cryptogenic stroke, PFO closure, stroke
with PFO is still up for discussion.

Materials and Methods: Therefore, based on current INTRODUCTION

evidence and expert opinion, Malaysian expert panels from Stroke is one of the major causes of mortality and disability
various disciplines have gathered to discuss the worldwide. In Malaysia, stroke is the third-leading cause of
management of ESUS patients with PFO. This consensus death and the second-leading cause of combined death and
sought to educate Malaysian healthcare professionals to disability.1 Based on the National Health and Morbidity
diagnose and manage PFO in ESUS patients based on local Survey in 2006 and 2011, there was an increase in stroke
resources and facilities. prevalence from 0.3% to 0.7% among the Malaysian
population.2-4 From 2010 to 2014, the age-adjusted incidence
Results: Based on consensus, the Malaysian expert and prevalence rates for ischaemic stroke almost tripled
recommended PFO closure for embolic stroke patients who (34.2–96.2 per 100 000 and 42.8–118.7 per 100 000,
were younger than 60, had high RoPE scores and did not respectively) in 5 years.5 A steady increase in the incidence of
require long-term anticoagulation. However, the decision ischaemic stroke by 29.5% annually was observed.5 The
should be made after other mechanisms of stroke have been Annual Report of the Malaysian Stroke Registry, 2009 to
ruled out via thorough investigation and multidisciplinary 2016, stated that 77% of stroke patients were between the
evaluation. The PFO screening should be made using ages of 50 and 79 years old, with the mean age of stroke onset
readily available imaging modalities, ideally contrast- being 62.5 years old.6 Hypertension, smoking, diabetes and
transthoracic echocardiogram (c-TTE) or contrast- hyperlipidaemia were the common risk factors for first and
transcranial Doppler (c-TCD). The contrast-transesophageal recurrent ischaemic strokes identified among the Malaysian
echocardiogram (c-TEE) should be used for the confirmation population.5,7
of PFO diagnosis. The experts advised closing PFO as early
as possible because there is limited evidence for late Ischaemic stroke is the most commonest type of stroke
closure. For the post-closure follow-up management, dual (79.4%), followed by haemorrhagic stroke (18.2%), transient
antiplatelet therapy (DAPT) for one to three months, followed ischaemic attack (2%) and strokes of unclassified causes
This article was accepted: 02 March 2023
Corresponding Author: Abdul Hanif Khan Yusof Khan
Email: [email protected]

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Systematic / Narrative Review Article

(0.4%).5 Based on pathophysiology, the causes of ischaemic discuss a few specific related topics. Experts from the Kuala
stroke can be classified into large artery atherosclerosis Lumpur and Selangor regions reviewed the selection of
(20%), small vessel occlusion (25%), cardio-embolism (20%), patients for PFO closure, while experts from the North Zone
and other identified causes (5%).8 About 20-40% of ischaemic discussed the preferred screening and diagnostic technique
stroke causes remain undetermined and are classified as for PFO, as well as the timing of PFO closure in ESUS. Experts
cryptogenic stroke.8 Cryptogenic stroke is further classified from East Malaysia and the East Coast discussed post-PFO
into three types: 1) multiple causes of stroke identified; 2) no closure care and follow-up, medical treatment if PFO is not
causes identified due to insufficient diagnostic work-up; and closed despite an indication for closure, and the strategies to
3) no causes identified despite extensive work-up.9 Embolic raise awareness about PFO closure in ESUS. The experts'
stroke of undetermined stroke (ESUS) is a sub-type of recommendations and suggestions from these three meetings
cryptogenic stroke which is diagnosed based on specific were compiled into a Google form and emailed to all the
criteria. The diagnostics criteria for ESUS are described in the experts for voting on the level of consensus. Table I shows the
later section. The classification of stroke and the potential description of the level of consensus which was adapted from
causes of ESUS and other types of strokes are shown in Figure Diener et al.20 Twenty-eight out of fifty-two experts responded
1 which is generated based on Ntaios et al.9 and Hart et al.10 to the Google form, representing a 53% response rate. The
One of the possible causes of ESUS is patent foramen ovale data were retrieved and analysed to determine the
(PFO).10 PFO is the most common congenital cardiac percentages of the level of agreement for each consensus
abnormality in every 1 in 4 adults. The foramen ovale is a statement. The findings were presented to a small group of
normal foetal heart structure that allows oxygenated experts (14 volunteers) from all regions at the last meeting,
placental blood to circulate from the right to the left atrium held in March 2022. Those statements that lacked majority
to reach the arterial circulation of the foetus. If the foramen support or contradicted other guidelines were re-discussed
ovale does not close naturally after birth during infancy, it is before reaching the final consensus. The final consensus
known as PFO.11 The possible PFO-related stroke mechanisms among Malaysian experts is presented in this article. The co-
are hypothesised as paradoxical embolism of a venous clot authors reviewed and commented on the first draft of the
shunting through the PFO to the left atrium, in situ clot manuscript in June 2022. Subsequently, the draft was revised
formation within the PFO, and atrial arrhythmias.12 accordingly until no further comments were received from all
the co-authors. The final draft was sent to experts listed in
There are a few treatment options available for secondary Appendix A from the Malaysian PFO-Stroke Working Group
stroke prevention in ESUS patients with PFO, such as for review, and it was finalised in September 2022.
percutaneous transcatheter closure of PFO, antithrombotic
therapy or a combination of both. Several clinical trials
(CLOSURE, PC, RESPECT, CLOSE, REDUCE and DEFENSE-PFO PREFERRED SCREENING AND DIAGNOSTIC STRATEGY
trial) have been conducted to assess the efficacy and to Diagnostic strategy for ESUS
compare the available treatments.13-19 However, the outcomes A thorough investigation should be conducted to rule out any
of the trials were inconsistent due to the differences in study additional potential causes of the suspected ESUS before
design and efficacy of the device used. The optimal considering PFO closure.21
management of ESUS patients with PFO is still being debated.
Hart et al. (10) suggested the diagnostic criteria for ESUS and
PFO is common in 25% of the general population. Even the minimum diagnostic assessment that should be done.10
though it is associated with an increased risk of stroke, it These are shown in Table II.
could be just an innocent bystander. While we search for the
best treatment option for ESUS patients with PFO, it is also First of all, clinicians should get brain imaging from patients
crucial to consider whether treating such patients is whose PFO closure is being investigated to confirm the size
beneficial and outweighs the potential risk. Therefore, and distribution of the strokes and to look for embolic
Malaysian expert panels have gathered their thoughts and patterns or lacunar infarcts (which often involve a single
recommendations on managing ESUS patients with PFO deep perforator with a diameter of less than 1.5 cm).21
based on the current evidence and their expert opinion on
such patients. This consensus mainly aimed to educate the Occult atrial fibrillation (AF) is important in cryptogenic
healthcare professionals involved in the management of stroke as it is often asymptomatic and must be ruled out
acute ischaemic strokes regarding the diagnosis and before considering PFO closure. A few screening methods are
management of PFO in ESUS patients based on the available to detect AF, such as 12-lead ECG, 24 to 48-hour
availability and feasibility of local resources and facilities in Holter monitor, external event monitor, single-lead ECGs, in-
Malaysia. patient cardiac telemetry and invasive methods such as
implantable loop recorder.22 Even though prolonged cardiac
monitoring might not be easy to get in some hospitals, at
MATERIALS AND METHODS least a baseline ECG should be done to rule out persistent
The Stroke Council of the Malaysian Society of Neurosciences AF.21,23 However, comprehensive cardiac monitoring is
(MSN) has scheduled three virtual meetings with advised whenever possible because studies have shown that
neurologists, cardiologists, paediatric cardiologists, it increases the likelihood of detecting AF.24-27 The best
physicians and geriatricians from all regions of Malaysia: monitoring approach and duration are yet to be determined
Central and South region in November 2021; North region in and can be based on effectiveness, cost and patient
December 2021; and East Malaysia and the East Coast in preference.28 Some experts suggested continuous cardiac
January 2022. Each region was assigned to present and monitoring for at least 24 hours for AF detection.9,29 For

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Management of patent foramen ovale in embolic stroke of undetermined source patients

Table I: Description of the level of consensus

Consensus Level Explanation
Should do this Consensus to support a specific approach, treatment, or position
May do this Limited evidence, and mixed opinions. Sufficient confidence and no contradictions regarding supported
approach, treatment, or position
Should not do this Consensus to discourage a specific approach, treatment, or position
Unsure Insufficient data/experience, too many mixed opinions.
Additional clinical evidence is required
# Adapted from Diener et al. 20

Table II: Diagnostic criteria and recommended work-up for ESUS

ESUS Criteria Recommended Work-up
 Stroke detected by CT or MRI • Brain CT or MRI
that is not lacunar [Lacunar is defined as a subcortical infarct smaller than or equal to 1·5 cm
(≤2·0 cm on MRI diffusion images) in the largest dimension.]
 The absence of extracranial or • Imaging of both the extracranial and intracranial arteries supplying the area of brain
intracranial atherosclerosis causes ischaemia (catheter, MR, or CT angiography, or cervical duplex plus transcranial
≥50% luminal stenosis in arteries doppler ultrasonography)
supplying the area of ischaemia
 No major-risk cardioembolic source • 12-lead ECG
of embolism* • Precordial echocardiography
• Prolonged cardiac monitoring with automated rhythm detection
 No other specific cause of the stroke
was identified*
*Please refer to the examples of the major risk cardioembolic sources of embolism and other causes of stroke in Fig.1

Table III: The advantages, limitations, sensitivity (Sn), and specificity (Sp) of different modalities for PFO detection
Imaging Modalities Advantages Limitation Weighted Mean Sn and Sp
Contrast transcranial • Non-invasive • Unable to distinguish intracardiac Sn: 97%
Doppler (c-TCD) • Cost-effective and intrapulmonary shunts Sp: 93%
• Can perform at the bedside • Unable to visualise cardiac
• Can repeat at different body structures
positions
• Able to detect small shunts
• Easy availability
Contrast transthoracic • Non-invasive • Limitations in discriminating Sn: 46%
echocardiogram (c-TTE) • Able to visualise cardiac against a small amount of RLS Sp: 99%
structures
• Easily available
Contrast transesophageal • Able to visualise precise • Semi-invasive Sn: 89.2%
echocardiogram (c-TEE) anatomy of PFO • Valsalva manoeuvre may be Sp: 91.4%
• Able to discriminate PFO shunt difficult to perform due to
from intrapulmonary shunt sedation
• Limitations in discriminating
against a small amount of RLS

individuals who are older than 40 and have a high risk for levels, prothrombin G20210A mutation and
AF, prolonged monitoring for AF detection for at least 28 days antiphospholipid antibodies test can be done.30 Brain and
may be an option.9,21 High risks for atrial fibrillation include pelvic Magnetic Resonance Venography (MRV) are
hypertension, obesity, sleep apnoea, an enlarged left atrium, recommended to look for cerebral venous sinus thrombosis
elevated NT-proBNP, frequent premature atrial contractions, and May–Thurner syndrome, respectively.30
increased P-wave dispersion, a prolonged PR interval, multi-
territorial infarcts, etc. PFO Detection
PFO does not increase the risk of early stroke recurrence in
Complete vascular imaging (Computed Tomography ESUS patients.31 However, the risk of recurrent stroke is
Angiography (CTA) and Magnetic Resonance Angiography generally high in the first few weeks after a stroke. Therefore,
(MRA)) of the cervical and intracranial vessels should be Asian-Pacific experts suggested that recent ESUS patients
obtained to look for dissection, vasculopathy and should be given higher priority for PFO screening, which may
atherosclerosis.21 be done within 2 weeks of stroke.20

If the hypercoagulable condition is suspected, a complete PFO can be diagnosed based on the direct or indirect
blood count (haemoglobin and platelet count), factor V visualisation of right-to-left shunting (RLS). A bubble contrast
Leiden, protein C, protein S, antithrombin III, homocysteine transthoracic echocardiogram (c-TTE), contrast

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Table IV: Preferred screening and diagnostic strategy

No Statements Consensus Level
Diagnostic Strategy For ESUS
1. In patients being considered for PFO closure, perform a thorough evaluation to rule out alternative Should do this
mechanisms of stroke.
2. In patients being considered for PFO closure, confirm stroke size and distribution, and assess for an Should do this
embolic pattern or a lacunar infarct via brain imaging (MRI or CT).
3. In patients being considered for PFO closure, obtain complete vascular imaging (MRA or CTA) of Should do this
the cervical and intracranial vessels to look for dissection, vasculopathy, and atherosclerosis.
4. In patients considered for PFO closure, perform a baseline ECG to look for atrial fibrillation. Should do this
5. In patients being considered for PFO closure, prolonged cardiac monitoring should be May do this
considered if there is a risk of atrial fibrillation.

PFO Detection
6. Highest priority: ensure that patients with recent ESUS are screened for PFO. Should do this
7. For PFO screening, use bubble contrast transthoracic echocardiography (c-TTE) or bubble contrast Should do this
transcranial Doppler ultrasound (c-TCD) with and without Valsalva manoeuver to assess for a
right-to-left shunt and determine the degree of shunting.
8. Use contrast transesophageal echocardiography (c-TEE) for confirmation of PFO. May do this
9. Use the imaging modalities that are readily available in the hospital and on which the technical Should do this
staff is best trained and most experienced (c-TTE, c-TCD, c-TEE, intracardiac echocardiography).
10. Ensure echocardiography is performed for imaging other cardiac structures to explore other Should do this
sources of cardioembolic stroke.
11. Echocardiography is to be performed within two weeks after the stroke, depending on the local May do this
availability of services.

Table V: RoPE Score

Patient Characteristic Points
No history of hypertension +1
No history of diabetes mellitus +1
No history of TIA or stroke +1
Non-smoker +1
Cortical infarct on imaging +1
Age (y)
18 to 29 +5
30 to 39 +4
40 to 49 +3
50 to 59 +2
60 to 69 +1
>70 +0
Total RoPE score 0-10
# Adapted from Kent et al. 43

Table VI: Patent Foramen Ovale - Associated Stroke Causal Likelihood (PASCAL) classification
PFO-related stroke Low RoPE Score (≤6) High RoPE Score (>6)
High-risk PFO Possible Probable
(e.g Large shunt PFO and/or ASA)
Low-risk PFO Unlikely Possible
(e.g Small shunt without ASA)
# Adapted from Kent et al. 49

transesophageal echocardiogram (c-TEE), and contrast the appearance of at least one bubble in the middle cerebral
transcranial Doppler (c-TCD) are the methods used to detect artery within 40 seconds of agitated saline injection during
shunting from a PFO. TEE is the gold-standard method for the TCD confirms the presence of shunting.30 (Note that late
detecting PFO. A bubble study is often performed together bubble arrival is also associated with extra-cardiac shunts)
with an echocardiogram or a transcranial Doppler study
(TCD) to assess the RLS when a PFO is suspected. In this A meta-analysis comparing c-TCD versus c-TTE showed that
study, the microbubbles (agitated saline or gaseous contrast c-TCD is reliable in ruling out PFO, whereas c-TTE is reliable
agent) are injected into the peripheral vein. The patient is in diagnosing PFO. Contrast TCD appeared to have a higher
asked to perform a Valsalva manoeuvre to raise the pressure overall diagnostic yield than c-TTE. In fact, contrast TCD (c-
on the right side of the heart. The appearance of bubbles in TCD) is more sensitive to RLS detection than contrast TTE (c-
the left atrium within three cardiac cycles during the TTE) or contrast TEE (c-TEE). It is suitable for use as an initial
echocardiogram confirms the presence of a shunt. Whereas screening approach for RLS.23,32-34 Nevertheless, this does not

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Table VII: Patient selection for PFO closure

No Statements Consensus Level
1. PFO closure in patients younger than 60 with an embolic-appearing infarct with no other May do this
mechanism of stroke was identified.
2. PFO closure in patients with RoPE score >6.* Should do this
3. PFO closure in patients with RoPE score ≤6 is on a case-by-case basis where no other attributable May do this
causes for the cryptogenic stroke are identified and where the benefit outweighs the immediate
and long-term risk.*
4. PFO closure in patients with a lacunar stroke by imaging (single, small, deep infarct Insufficient data
(infarct size <1.5cm)).
5. PFO closure in younger patients (e.g., <30 years) with a lacunar stroke (single, small, deep infarct May do this /
(infarct size <1.5cm)), a large shunt, and absence of any vascular risk factors. Insufficient data
6. PFO closure in patients with a large PFO shunt (defined by the passage of > 20 microbubbles or May do this
maximum separation of septum of ≥2mm).*
7. PFO closure in patients with an atrial septal aneurysm.* May do this

PFO in Patients Aged More Than 60 Years

8. PFO closure in patients over 60 years of age who are in biologically good condition and with strong May do this
indications of PFO causality in the embolic stroke mechanism, e.g., significant right-to-left shunt, / Insufficient data
atrial septal aneurysm.
9. PFO closure in patients over 60 years of age without high-risk PFO. Should not do this

PFO Closure in Patient Requiring Oral Anticoagulant (OAC)

10. PFO closure in patients with evidence of thrombi/ emboli and requirement for prolonged but not May do this
indefinite OAC (likely to be related to deep venous thrombosis).
11. PFO closure in patients with an unrelated requirement for indefinite OAC. Should not do this

Multidisciplinary Approach
12. Before undergoing PFO closure, clinicians with expertise in stroke assess patients and ensure that Should do this
the PFO is the most plausible mechanism of stroke.
13. Before undergoing PFO closure, clinician with expertise in assessing the degree of shunting and Should do this
anatomical features of a PFO, and performing PFO closure, to assess whether the PFO is anatomically
appropriate for closure, to ascertain whether other factors are present that could modify the risk of
the procedure, and to address post procedural management.
14. In a patient for whom PFO closure is being considered, a shared decision-making approach Should do this
between clinicians and the patient is to be used.
15. Comply with indications for PFO closure according to international/global guidelines/consensus Should do this
statements.
*Note that PASCAL classification can be considered for patient selection for PFO closure.

Table VIII: Timing of PFO closure in ESUS

No Statements Consensus Level
1. ESUS with evidence of significant PFO: Close as early as possible. Should do this
2. Late (> 1 year) PFO closure in ESUS patients with evidence of significant PFO and no additional risk May do this
factors developed since the stroke.

Table IX: Post-PFO closure treatment and follow-up

No Statements Consensus Level
1. Dual antiplatelet therapy (DAPT) for one to three months, followed by single APT for six months. Should do this
The decision on continued therapy is to be made by the multidisciplinary team.
2. Echocardiography to assess erosion and other major devices-, procedures-, or cardiac-related Should do this
complications when there is a high index of suspicion.
3. Follow-up by echocardiography every three months depending on the resources (in case of a residual May do this
shunt to inform the decision on DAPT)
4. Monitoring of patients is based on the remnant risk of stroke, and the frequency is based on Should do this
patients' needs and local resources. For centers that do not have resources to monitor and quantify
residual shunt, patients should be referred to the appropriate clinicians with expertise and resources.
5. In the event of a rare residual shunt after PFO closure, the subsequent management is to be May do this
individualised with the team approach to weighing the options of the repeat procedure and/or
antiplatelet regimes based on the patient's overall risk assessment. Such patients are on lifelong
follow-up because risk assessment is dynamic as age increases and other comorbidities may develop
in the future.
6. In case of recurrent ischemic stroke: explore any secondary cause and confirm (non-) compliance Should do this
to antithrombotic therapy.

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Table X: Medical therapy if the PFO is not closed despite an indication for closure
No Statements Consensus Level
1. In patients who opt to receive medical therapy alone without PFO closure, clinicians may May do this
recommend either an antiplatelet medication such as aspirin or anticoagulation (using a vitamin
K antagonist, a direct thrombin inhibitor, or a factor Xa inhibitor).

Table XI: Creating awareness about PFO closure in ESUS

No Statements Consensus Level
1. Industry's role: continue supporting training and education programmes at general neurology Should do this
meetings and events.
2. Set up online training and national forums. Should do this
3. Conferences: create awareness and organise screening training for technicians. Should do this
4. Hospital CMEs Should do this

preclude echocardiography to rule out cardio-embolism study population.41 Subsequently, from 2017 onwards, trials
mechanisms and confirm the presence of an intracardiac that included high-risk PFO patients (CLOSE, REDUCE, and
shunt, of which c-TCD is unable to differentiate.20,21,24 Contrast DEFENSE-PFO trials) or prolonged the follow-up period
TTE, however, showed limitations in diagnosing PFO with the (RESPECT follow-up trial), showed a significant reduction in
small or delayed shunt.35 Therefore, HSC/HSO experts stroke recurrence among the patients who had undergone
suggested that c-TCD and/or c-TTE should be used for initial PFO closure compared with the medical therapy group.15,16,18,19
screening of RLS to diagnose PFO.9 AAN also emphasised The DEFENSE-PFO is the only trial that recruited subjects
using bubble contrast, with and without Valsalva manoeuvre above 60 years old; the others were mostly below 60 years old.
to assess for RLS and grade the shunting.21 Test sensitivity was Thus, the trial outcome might not be generalised for all.
shown to improve with the Valsalva manoeuvre.36 It is
unlikely to be a high-risk PFO if there is minimal or no shunt Approximately 50% of all young patients with ischaemic
on c-TCD after the Valsalva manoeuvre.37 As TEE is stroke have a PFO.42 PFO is more common in younger
particularly helpful in establishing the anatomy of the PFO cryptogenic stroke patients and is more likely to be
and its adjacent structures, it continues to be the gold pathogenic than in older patients.34 The European Society of
standard for PFO diagnosis.28 Cardiology (ESC) stated that when the patients are young
and have no other risk factors, PFO is more likely to be
Each modality has its advantages and limitations.32 These are pathogenic.23 The guidelines from the American Heart
listed in Table III along with the sensitivity and specificity of Association/American Stroke Association (AHA/ASA) and the
different modalities for RLS and PFO detection.38-40 American Academy of Neurology (AAN) recommended PFO
closure in patients younger than 60 years with an embolic-
HSC/HSO experts advised that a skilled operator conduct a c- appearing infarct and no other mechanism of stroke
TEE for PFO detection and PFO closure assessment.9 Some identified.21,24 AAN additionally mentioned that such
modalities are not widely available in all acute stroke recommendation may be following a discussion of the
settings, especially in Malaysia. Asian-Pacific experts potential benefits of reducing stroke recurrence and the risks
suggested using the best available modalities that the of complications from the procedures.21
operator is trained in and most experienced in.20
The Risk of Paradoxical Embolism (RoPE) scores can also be
The consensus among Malaysian expert panels regarding the considered before deciding on PFO closure. The RoPE score is
preferred screening and diagnostic strategy has been an assessment tool to determine the probability that a PFO is
summarised in Table IV. related to a cryptogenic stroke.43 Table V shows the scoring for
the RoPE score. A higher score indicates a higher probability
that a PFO is associated with a cryptogenic stroke. A score of
PATIENTS SELECTION FOR PFO CLOSURE above 7 indicates a causative risk of above 72%. However, the
To answer which patients can benefit from PFO closure, we risk of recurrent stroke decreases with increasing RoPE scores.
need to carefully evaluate the inclusion criteria of the clinical The estimated 2-year stroke/TIA recurrence rates decreased
trials that demonstrated the superiority or efficacy of PFO from 20% in the lowest RoPE score to 2% in the highest.
closure over the control groups. Therefore, it cannot be solely used to determine which
individuals with PFO-related strokes may benefit from
In the earlier randomised control trials published in 2012 closure. The RoPE score does not consider the PFO's high-risk
(CLOSURE) and 2013 (PC and RESPECT), PFO closure failed to anatomic or physiological aspects and should be used in
show a significant reduction in stroke recurrence compared to conjunction with other factors.34
antithrombotic medication alone in a cryptogenic stroke
patient with PFO less than 60 years old.13,14,17 The main Kuijpers et al. (44) suggested the closure of a PFO in
reasons for the trial failure were probably due to the lack of cryptogenic stroke patients with a RoPE score of more than
high-risk PFO patient inclusion, unclear methods of eight and at least one clinical risk factor.44 The Asian-Pacific
confirmation of cryptogenic stroke, and a short follow-up region experts stated that PFO closure should be considered in
period for a low annual risk of recurrent stroke among the patients with a RoPE score of six or more and may be

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Fig. 1: Classification of stroke and the potential causes of ESUS

considered in patients with a score of less than six.20 The (ASA), a condition characterised by hypermobility of the
recent review by Elzanaty et al. (45) mentioned that in inter-atrial septum (phasic septal excursion into either
patients aged 60 or younger with recent cryptogenic stroke atrium ≥10 mm), or PFO size (maximum separation of the
with PFO, guideline recommendations consider the need for septum primum from the secundum) ≥2 mm.15 Besides that,
PFO closure on a case-by-case basis and individual risk a prominent Eustachian valve and large (≥20 microbubbles)
factors.45 right-to-left shunt were also anatomical characteristics of
high-risk PFO.42 The European Society of Cardiology (ESC)
Cortical infarction is mostly due to embolism, but it is still stated that ASA and PFO size are linked to the association
possible that the subcortical infarct or lacunar stroke can be between PFO and cryptogenic stroke.23 The presence of ASA
embolic.23 Lacunar infarcts are a subtype of ischaemic stroke was related to stroke recurrence in PFO-associated stroke
that occurs in small, deep-penetrating arteries of the brain. patients but not in large PFO patients.47 In contrast, AAN
Up to 25% of all ischaemic strokes are due to a lacunar suggested that patients with a large shunt may benefit from
infarct.46 Since lacunar strokes are unlikely due to a distant PFO closure, but ASA without a large PFO is questionable.21 In
embolic source, PFO closure may be appropriate in young a recent review, PFO patients with ASA likely have a stronger
patients with a lacunar stroke plus a PFO if other risk factors link to the risk of recurrent stroke.48 A large PFO and ASA do
for cerebral small vessel disease and atrial fibrillation (AF) not necessarily indicate a significant risk factor for a
have been ruled out.46 However, the Asian-Pacific experts do recurrent stroke, but they may indicate that the PFO is likely
not recommend PFO closure in a lacunar stroke.20 Moreover, very pathogenic and may benefit from closure.34 Patients with
lacunar stroke was one of the trial exclusion criteria.15,19 a RoPE score ≥7 with high-risk PFO may be good candidates
According to AAN, PFO closure, however, may be for PFO closure.26
recommended for younger patients (e.g., 30 years old) with a
single, small, deep stroke (1.5 cm) with the presence of a large The Patent Foramen Ovale - Associated Stroke Causal
shunt and no vascular risk factors that would lead to intrinsic Likelihood (PASCAL) classification system combines RoPE
small-vessel diseases, such as hypertension, diabetes or score and PFO features to assess patients who will benefit
hyperlipidaemia.21 from PFO closure to prevent recurrent stroke.49 As shown in
Table VI, PASCAL classifies patients into three categories
As mentioned earlier, trials that included high-risk PFO based on their causal relatedness: unlikely, possible, and
patients showed a favourable outcome with PFO closure. probable.
High-risk PFO is defined as PFO with atrial septal aneurysm

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Fig. 2: Diagnostic approaches of PFO in cryptogenic stroke

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Management of patent foramen ovale in embolic stroke of undetermined source patients

About 15% of patients in the PASCAL "unlikely" classification Multidisciplinary Approach

without high-risk PFOs and vascular risk factors, did not During the decision-making process for PFO closure, the
benefit from PFO closure. However, 90% relative risk probability of the PFO being a cause for ESUS and the risk of
reduction was noted for PASCAL "probable" patients with recurrence of a person must be considered.23 PFO features
high-risk PFO and a high RoPE score after PFO closure.49 need to be assessed before deciding on PFO closure.23 A
Therefore, the PASCAL classification system should guide trained, experienced clinician should evaluate the degree of
clinicians during the individualised decision-making for PFO shunting and anatomic aspects of a PFO and whether it is
closure patient selection. suitable for closure. Clinicians should also ensure no
additional factors may affect the procedure's risk and should
PFO Closure in Patients More Than 60 Years be competent to handle the post-closure management.21
More randomised trials to assess the safety and efficacy of
PFO closure in people over 60 years old are needed to provide Shared decision-making is an integral part of patient-
recommendations for these. For patients over 60 years of age, centered care. Clinicians should explain the available
Asian-Pacific experts suggested that PFO closure may be treatment options, provide risk, and benefit information,
suitable if they are in biologically good condition and have understand their concerns, and assist them in making
strong indications of PFO causality in the embolic stroke decisions. The decision for PFO closure or medical therapy in
mechanism, e.g., significant right-to-left shunt and ASA.20 ESUS patients with a PFO should be made jointly by the
The ANN and Thaler et al. (50) suggested we may offer PFO patient, a neurologist, and a cardiologist.9,24,34,54
closure if they have very limited vascular risk factors and
thorough evaluation has ruled out other mechanisms of Indications for PFO closure should be in accordance with the
stroke, including AF.21,50 Even though elderly patients are updated international guidelines and consensus statements.20
more prone to additional stroke risks and may be excluded The consensus among Malaysian expert panels regarding the
for PFO closure, they may still be at risk of venous patient selection for PFO closure has been summarised in
thromboembolism and right-to-left shunt in the presence of a Table VlI. (*Note that PASCAL classification can be
PFO.26 However, the benefit of PFO closure in elderly patients, considered during patient selection for PFO closure.)
especially those with competing stroke mechanisms, is still
unknown. Figure 2 illustrates the Malaysian experts' suggested
diagnostic approaches of PFO in ESUS.
The risk of stroke in PFO patients is much higher in the older
age group.51 However, the risk of adverse events during PFO
closure is also considerably higher (10.9%) in this age TIMING OF PFO CLOSURE IN ESUS
group.52 The expert panellists from the Hellenic Stroke Experts from the Asian-Pacific region suggested that ESUS
Organisation and the Working Group for Stroke of the with evidence of significant PFO should be closed as soon as
Hellenic Society of Cardiology (HSO/HSC) are against the PFO possible.20 However, no duration was specifically mentioned.
closure in extreme age groups (<18 and >60 years) and may In addition, they suggested that late PFO closure (> 1 year)
be considered on a case-by-case basis following a thorough may be performed in ESUS patients with evidence of high-risk
examination.9 According to Asian-Pacific expert panels, PFO PFO and no new risk factors since the stroke.20 However, there
closure should not be performed in patients over 60 who do is no evidence from clinical trials to support this
not have a high-risk PFO.20 It should not be inferred that PFO recommendation. Most of the clinical trials that supported
closure will benefit older patients with high-risk PFO because PFO closure included patients who had a recent stroke within
a prior study found that stroke recurrence rates in high-risk 6 or 9 months.15,16,18,19 The French Neurovascular Society and
PFO patients > 60 years who underwent PFO closure were not the French Society of Cardiology (FNS/FSC) have
significantly different from those who received medical recommended PFO closure in patients with recent (≤ 6
therapy alone.53 months) ischaemic stroke. However, this time frame can be
extended if AF detection is required for a longer duration.55
PFO Closure in Patient Requiring Oral Anticoagulant
(OAC) The consensus among Malaysian expert panels regarding the
Some patients may be on long-term oral anticoagulation timing of PFO closure in ESUS has been summarised in Table
(OAC) due to suspected or confirmed hypercoagulabilities VIII.
such as thrombophilia, unprovoked deep venous thrombosis,
or unprovoked pulmonary embolism. If a stroke patient with
PFO with such a condition is considered for PFO closure, the POST-CLOSURE TREATMENT AND FOLLOW-UP
clinician should inform the patient that the benefit of PFO No procedure is risk-free, and PFO closure is no exception; not
closure in conjunction with anticoagulation is uncertain.21,34 only is it invasive, but PFO closure may also be accompanied
The Asian-Pacific expert panels suggested that PFO closure by complications such as thrombus formation on the device
may be considered in patients with evidence of thrombi or and the development of AF following the procedure.
emboli and a need for prolonged but not indefinite OAC,
such as those with deep venous thrombosis.20 However, PFO PFO closure device implantation increased
closure should not be performed in patients who have thromboembolism risk by 1-2%.41 In addition, the risk of AF
comorbidities that requires an indefinite OAC since it is likely was substantially higher in PFO closure than in medical
to cause more harm than benefit, in addition to the danger therapy, ranging from 2.9% to 6.6%, based on the previous
of OAC-related bleeding.20 clinical trial data.50 According to a meta-analysis of AF rates

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after PFO closure, AF developed in 3.7 patients per 100 despite being indicated for PFO closure. If this occurs, medical
patient-years of follow-up. The risk of AF was greatest in the therapy such as antiplatelet or anticoagulant can be
first 45 days after the procedure, and PFO closure increased considered.21
the odds of having AF by 5.3 times over medical therapy.56
Therefore, it is appropriate to administer dual antiplatelet Antiplatelet medications, such as aspirin, and
therapy (DAPT) after PFO closure. Furthermore, PFO closure anticoagulants, such as rivaroxaban, dabigatran, and
with medical therapy has been considered more cost-effective warfarin, are the treatments of choice for patients, although
than medical therapy alone.45 the superiority of one over another has never been
conclusively proven. In the RESPECT ESUS trial, although
Although no data supported the optimal DAPT duration, dabigatran did not significantly lower the risk of recurrent
most guidelines and consensus recommended DAPT for up to stroke in the general population, it did demonstrate a stroke
6 months, followed by a single antiplatelet agent.9,23,41 Experts reduction specifically in older stroke patients compared to
from FNS/FSC and the Asian-Pacific region suggested DAPT aspirin.58 Even though there were no differences in stroke
for up to 3 months, followed by a single APT.20,55 Uncertainty recurrence rates between aspirin and rivaroxaban in the
remains on the length of time that a single APT should be NAVIGATE ESUS trial, the risk of bleeding was significantly
continued. Still, some suggest that it may be continued for up higher in the rivaroxaban group.59 Therefore, the choice of
to 5 years.23,41,55 However, the decision to continue APT should medical therapy should be on a case-by-case basis. Patients
be made by an expert clinician, such as a neurologist, based with additional risk factors such as a large shunt or ASA,
on the overall risks and benefits for the patient.20,23 Low-dose those with multiple infarcts, the presence of deep vein
aspirin and clopidogrel were the common choices of APT.9,55 thrombosis, and the elderly may benefit from anticoagulant
therapy.29 Otherwise, antiplatelet therapy was reasonable to
Other long-term complications that may occur after PFO consider as the first choice for ESUS patients who were not
closure include the presence of residual shunt, scar tissue considered for PFO closure if there was no other justification
development, endocarditis, pericardial effusion, and the risk for anticoagulation.9,29,44,54,60
of aortic root dilation and erosion.41,45 About 2.6% of patients
may develop uncommon long-term complications following The consensus among Malaysian expert panels regarding the
PFO closure.23 If complications are suspected, imaging such as medical therapy if PFO is not closed despite an indication for
echocardiography should be performed.20,55 closure has been summarised in Table X.

There were no clear guidelines for the timing and frequency

of follow-up evaluations following the PFO closure. About CREATING AWARENESS ABOUT PFO CLOSURE IN ESUS
19.5% of post-closure patients had residual shunt at four Creating awareness among Malaysian clinicians regarding
months, which dropped to 8.4% at 11 months and 2.8% with the management of PFO in ESUS patients is crucial. This will
a persistent mild shunt at two years during follow-up.57 The help clinicians in performing adequate PFO and ESUS
ESC suggested c-TCD after six months post-closure to assess screenings and initiating early therapy.
for the residual shunt and annually in the presence of a
residual shunt.23 FNS/FSC experts recommended 12-lead ECG Malaysian experts supported the industry's role in sponsoring
and c-TTE at 1 and 12 months.55 Asian-Pacific experts training and education initiatives at general neurology
recommended more frequent imaging follow-ups every three meetings and events. Introducing PFO management in ESUS
months and advised re-evaluating the DAPT decision if a via online training and national forums could raise
residual shunt was seen.20 Long-term antithrombotic awareness. Providing technicians with screening training
medication should be considered after discussion with should enhance their ability to diagnose PFO.
cardiologists and neurologists for people with residual shunt
who are at risk for recurrent stroke. In the event of a recurrent Continuous medical education (CME) at the hospital might
stroke, the patient's compliance with antithrombotic be useful to keep the clinician up to date on the latest PFO
treatment must be verified, and additional causes must be management in ESUS.
investigated.20
Long-term follow-up of stroke patients with a PFO among the
The meta-analysis of AF following PFO closure revealed that Malaysian population may help to establish better
older patients have a considerably increased risk of management approaches for secondary stroke prevention in
developing AF after closure.56 Higher risk groups were hence our local setting. Further research and developing a
justifiable for more regular follow-up.20 CHA₂DS₂-VASc score standardised national registry on PFO management in
can be used to determine the higher-risk group. Nevertheless, Malaysia may aid in this endeavour.
the patient’s needs and resource availability must be
considered when determining the frequency of monitoring. The Malaysian expert panels suggested raising awareness
The consensus among the Malaysian expert panels regarding regarding PFO closure in ESUS by implementing the strategies
the post-closure treatment and follow-up has been outlined in Table XI.
summarised in Table IX.

CONCLUSION
MEDICAL THERAPY IF PFO IS NOT CLOSED DESPITE AN The role of PFO in ESUS is not well understood due to many
INDICATION FOR CLOSURE uncertainties in this condition, and it is often under-
In certain instances, a patient may decline PFO closure recognised in Malaysia. It is essential to identify PFO and

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Management of patent foramen ovale in embolic stroke of undetermined source patients

other aetiologies of ESUS in stroke patients and promptly refer 7. Nazifah SN, Azmi IK, Hamidon BB, Looi I, Zariah AA, Hanip MR.
them to appropriate clinicians with expertise and facilities. National Stroke Registry (NSR): Terengganu and Seberang Jaya
The list of public hospitals and institutions currently offering experience. Med J Malaysia 2012; 67(3): 302–4.
8. Ministry of Health Malaysia. Clinical Practice Guideline:
PFO closure services in Malaysia can be found in Appendix B.
Management of Ischaemic Stroke (3rd Edition) 2020 [cited Jun
Multidisciplinary involvement and action are needed to 2022]. Available from:
determine the diagnosis and prognosis of the patient. A https://www.moh.gov.my/index.php/pages/view/133.
shared decision-making process would help determine the 9. Ntaios G, Tzikas A, Vavouranakis E, Nikas D, Katsimagklis G,
patient's optimal management. Even though the most Koroboki E, et al. Expert consensus statement for the
effective management for this condition has not yet been management of patients with embolic stroke of undetermined
established, continuous efforts should be made to improve source and patent foramen ovale: A clinical guide by the working
clinicians’ awareness of this condition and begin the group for stroke of the Hellenic Society of Cardiology and the
Hellenic Stroke Organisation. Hellenic J Cardiol 2020; 61(6): 435–
necessary screening and treatment. Data on PFO studies
41.
continues to evolve and, as such, the consensus 10. Hart RG, Diener HC, Coutts SB, Easton JD, Granger CB,
recommendation currently put forward by Malaysian experts O'Donnell MJ, et al. Embolic strokes of undetermined source: the
may evolve too in the future. Therefore, this consensus should case for a new clinical construct. Lancet Neurol 2014; 13(4): 429–
provide an overview of how ESUS patients with PFO should be 38.
managed locally in Malaysia until robust evidence from 11. Homma S, Messe SR, Rundek T, Sun YP, Franke J, Davidson K, et
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ACKNOWLEDGEMENTS 13. Carroll JD, Saver JL, Thaler DE, Smalling RW, Berry S,
We thanked the Director-General of the Ministry of Health MacDonald LA, et al. Closure of patent foramen ovale versus
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Working Group experts listed in Appendix A for their 14. Furlan AJ, Reisman M, Massaro J, Mauri L, Adams H, Albers GW,
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CONFLICT OF INTEREST 17. Meier B, Kalesan B, Mattle HP, Khattab AA, Hildick-Smith D,
The authors declared no conflict of interest. There was no Dudek D, et al. Percutaneous closure of patent foramen ovale in
cryptogenic embolism. N Engl J Med 2013; 368(12): 1083–91.
influence from the industry in the decision-making process
18. Saver JL, Carroll JD, Thaler DE, Smalling RW, MacDonald LA,
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ovale-a brief review. Front Neurol 2022; 13: 855656.

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Appendix A

Malaysian PFO-Stroke Working Group Experts

Neurologists Dr. Ong Beng Hooi

Dr. Ahmad Shahir Mawardi Kedah Medical Centre
Hospital Kuala Lumpur Alor Setar, Kedah
Kuala Lumpur
Dr. Rishikesan Kuppusamy
Dr. Ang Chong Lip Pantai Hospital Kuala Lumpur
KPJ Ipoh Specialist Centre Bangsar, Kuala Lumpur
Ipoh, Perak
Dr. Rose Izura Abdul Hamid
Dr. Asha Prerna Hospital Raja Perempuan Zainab II
Loh Guan Lye Specialist Centre Kota Bharu, Kelantan
George Town, Pulau Pinang
Dr. Sally Tee Sow Kuan
Dr. Chai Chiun Hian Pantai Hospital Kuala Lumpur
KPJ Kuching Specialist Hospital Bangsar, Kuala Lumpur
Kuching, Sarawak
Dr. Sapiah Sapuan
Dr. Chia Yuen Kang Hospital Sungai Buloh
Hospital Queen Elizabeth Sungai Buloh, Selangor
Kota Kinabalu, Sabah
Dr. Sathindren T. Santhirathelagan
Dr. Hiew Fu Liong Gleneagles Hospital Penang
Sunway Medical Centre George Town, Pulau Pinang
Petaling Jaya, Selangor
Dr. Shanthi Viswanathan Shanthakumar
Assoc. Prof. Dr. Hoo Fan Kee Hospital Kuala Lumpur
Hospital Pengajar Universiti Putra Malaysia, Kuala Lumpur
Universiti Putra Malaysia (UPM)
Serdang, Selangor Dr. Sim Bee Fung
Gleneagles Hospital Penang
Dr. Hor Jyh Yung George Town, Pulau Pinang
Hospital Pulau Pinang
George Town, Pulau Pinang Dr. Sim Siew Hung
Borneo Medical Center
Dr. Irene Looi Kuching, Sarawak
Hospital Seberang Jaya
Seberang Jaya, Pulau Pinang Dr. Siva Seeta Ramaiah
Subang Jaya Medical Centre
Dr. Khairul Azmi Ibrahim Subang Jaya, Selangor
Hospital Sultanah Nur Zahirah
Kuala Terengganu, Terengganu Dr. Stefanie Hung Kar Yan
Hospital Tengku Ampuan Rahimah
Dr. Law Wan Chung Klang, Selangor
Hospital Umum Sarawak
Kuching, Sarawak Dr. Tan Kenny
Loh Guan Lye Specialist Centre
Dr. Linda Then Yee Yen George Town, Pulau Pinang
Hospital Umum Sarawak
Kuching, Sarawak Dr. Teh Pei Chiek
Hospital Tuanku Ja'afar
Dr. Loo Lay Khoon Seremban, Negeri Sembilan
Hospital Seberang Jaya
Seberang Jaya, Pulau Pinang Dr. Wan Asyraf Wan Zaidi
Hospital Canselor Tuanku Muhriz,
Dr. Mohd Azman M Aris Universiti Kebangsaan Malaysia (UKM)
Hospital Melaka Kuala Lumpur
Bandar Melaka, Melaka

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Systematic / Narrative Review Article

Dr. Wong Sing Keat Dr. Martin Wong Ngie Liong

Hospital Kuala Lumpur Pusat Jantung Sarawak
Kuala Lumpur Kota Samarahan, Sarawak

Dr. Wong Yee Choon Dr. Mohammad Tamim Jamil

Pantai Hospital Penang Hospital Pulau Pinang
Bayan Lepas, Pulau Pinang George Town, Pulau Pinang

Dr. Zariah Abdul Aziz Dr. Mohd Rizal Mohd Zain

Hospital Sultanah Nur Zahirah Hospital Universiti Sains Malaysia
Kuala Terengganu, Terengganu Kubang Kerian, Kelantan

Dr. Siva Rao Muniandy

Cardiologists Hospital Queen Elizabeth II
Kota Kinabalu, Sabah
Dr. Annamalar Muthu Muthuppalaniappan Geriatricians
Gleneagles Hospital Penang
George Town, Pulau Pinang Dr. Cheah Wee Kooi
Hospital Taiping
Dr. Liew Houng Bang Taiping, Perak
Hospital Queen Elizabeth II
Kota Kinabalu, Sabah Dr. Teh Hoon Lang
Hospital Sultanah Bahiyah
Dato' Dr. Muhamad Ali S K Abdul Kader Alor Setar, Kedah
Hospital Pulau Pinang
George Town, Pulau Pinang
Internal Medicine Physicians
Dr. Saravanan Krishinan
Hospital Sultanah Bahiyah Dr. Abdul Hanif Khan Yusof Khan
Alor Setar, Kedah Hospital Pengajar Universiti Putra Malaysia
Universiti Putra Malaysia (UPM)
Dato' Dr. Yap Yee Guan Serdang, Selangor
Sunway Medical Centre
Petaling Jaya, Selangor Dr. Aznita Ibrahim
Hospital Sultan Abdul Halim
Sungai Petani, Kedah
Paediatrics Cardiologist
Dr. Lee Aik Kheng
Assoc. Prof. Dr. Abdul Rahim Wong Hospital Pulau Pinang
Universiti Sultan Zainal Abidin George Town, Pulau Pinang
Kuala Terengganu, Terengganu
Dr. Neoh Kar Keong
Dr. Amir Hamzah Abd Rahman Hospital Seberang Jaya
Hospital Tengku Ampuan Afzan Seberang Jaya, Pulau Pinang
Kuantan, Pahang
Dr. Zainura Che Isa
Dr. Geetha Kandavello Hospital Sultan Abdul Halim
Institut Jantung Negara Sungai Petani, Kedah
Kuala Lumpur

Dr. Koh Ghee Tiong Medical Officer

Hospital Serdang
Kajang, Selangor Dr. Stephenie Ann Albart
Clinical Research Centre
Dr. Leong Ming Chern Hospital Seberang Jaya
Institut Jantung Negara Seberang Jaya, Pulau Pinang
Kuala Lumpur

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Appendix B

List of public hospitals and institutes that are currently offering PFO closure services in Malaysia. (Last updated: 22.07.2022)
List of public hospitals/institutes offering PFO closure services Location
Hospital Pulau Pinang Georgetown, Penang
Hospital Queen Elizabeth II Kota Kinabalu, Sabah
Hospital Raja Perempuan Zainab Kota Bharu, Kelantan
Hospital Serdang Serdang, Selangor
Hospital Universiti Sains Malaysia Kota Bharu, Kelantan
Institut Jantung Negara Kuala Lumpur
Pusat Jantung Sarawak Kota Samarahan, Sarawak
Pusat Perubatan Universiti Malaya Kuala Lumpur

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