Patent Foramen Ovale-Related Stroke Management and Outcome: Age-dependent Risk Prediction and Atrial Cardiopathy Study (SENIOR Study)
Conditions: Ischemic Stroke, Embolic Stroke of Undetermined Source, Patent Foramen Ovale (PFO), Elderly
Sponsor: Taichung Veterans General Hospital

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Study Protocol and Statistical Analysis Plan 
Title: 
Patent foramen ovale3related stroke management and outcome: age-dependent risk prediction and 
atrial cardiopathy study: 
SENIOR: Stroke prevention in the elderly by patent foramen Ovale closuRe vs anticoagulation 
 
Last update date: 13/ March/ 2026 
Chi-Sheng Wang1,2*, Po-Lin Chen1,2,3, Sung-Chun Tang4, I-Hui Lee2,5* 
1Division of Neurology, Neurological Institute, Taichung Veterans General Hospital, Taiwan 
2Institute of Brain Science, School of Medicine, National Yang Ming Chiao Tung University, Taipei, 
Taiwan 
3Department of Post-Baccalaureate Medicine, College of Medicine, National Chung Hsing University, 
Taichung, Taiwan 
4Stroke Center & Department of Neurology, National Taiwan University Hospital, Taipei, Taiwan 
5Division of Cerebrovascular Diseases, Neurological Institute, Taipei Veterans General Hospital, Taiwan 
* Correspondence: 
1. 
Chi-Sheng Wang, at: Division of Cerebrovascular Diseases, Neurological Institute, Taipei Veterans 
General Hospital, Taiwan  
Taichung Veterans General Hospital, No. 1650, Taiwan Boulevard, Sec. 4, Taichung City 40705, 
Taiwan 
Tel. +886 933375721 

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e-mail: sam7227632@gmail.com 
Fax: +886-4-23584403 
2. I-Hui Lee, at: Division of Cerebrovascular Diseases, Neurological Institute, Taipei Veterans General 
Hospital, Taiwan  
Tel. +886 4 23592525 #3325 
e-mail: ihui_lee@hotmail.com 
 
 
 
 
 
 
 
 
 
 
 
 

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Research Background and Motivation 
 
Current treatment for patent foramen ovale related stroke 
Acute ischemic stroke is a leading cause of disability. Even after comprehensive evaluation, one quarter 
of patients are classified as embolic stroke of undetermined source (ESUS), for which patent foramen ovale 
(PFO) is a key mechanism [1]. Current international guidelines recommend transcatheter PFO closure for 
patients <60 years with high-risk PFO, showing superiority over antiplatelet therapy in preventing 
recurrence [2]. For patients >60 years, however, the optimal strategy remains uncertain. Nevertheless, 
emerging evidence indicates that the risk profile in older adults is shifting. In particular, studies show that 
ESUS patients with PFO aged >60 have a 1.64-fold higher risk of recurrent stroke than their younger 
counterparts [3]. Moreover, with an aging population, over 65% of stroke patients are now older than 60 [4]. 
There is a substantial cohort that warrants re-evaluation of PFO management strategies. Furthermore, studies 
focused on elderly PFO related stroke were justified [3]. 
 
The comparison between PFO closure vs. antiplatelet vs. anticoagulant 
Prior investigations indicate that anticoagulation is associated with a lower risk of recurrent events than 
antiplatelet therapy in PFO related stroke [5], and pooled analyses suggest effectiveness approaching that of 
PFO closure [6]. However, the historical evidence base is predominantly warfarin-based and therefore 
accompanied by higher hemorrhagic risk. Data on direct oral anticoagulants (DOACs) point to a more 
favorable safety profile [7], but rigorous head-to-head evaluations of PFO closure versus optimized DOAC 
therapy, particularly in older adults, are absent. Notably, only one randomized controlled trial in patients 

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younger than 60 years with PFO-related stroke included a very small number of participants treated with a 
DOAC [5]. Accordingly, the comparative benefits and risks of closure, antiplatelet therapy, and DOACs in 
patients aged g60 years remain insufficiently defined. 
 
The preliminary data from TCVGH 
An institutional retrospective cohort from Taichung Veterans General Hospital (201332023), published in 
June 2025, demonstrated that among ESUS patients with PFO, transcatheter closure was associated with an 
approximately 90% reduction in recurrent stroke compared with antiplatelet therapy, with safety outcomes 
comparable to those observed in younger populations [8]. These findings suggest that advanced age alone 
should not be considered a contraindication to closure. However, the analysis did not include patients using 
DOAC, leaving an important evidence gap. As a real-world study, it also encountered substantial challenges 
related to treatment selection and baseline imbalance; notably, patients who underwent closure had a higher 
prevalence of high-risk PFO features. Consequently, the comparison may be more accurately conceptualized 
as closure in patients with PFO related stroke versus medical therapy in patients with incidental PFO [9]. 
These limitations underscore the need for a prospective, multicenter investigation with rigorous eligibility 
criteria, standardized assessments, and prespecified treatment allocation to more definitively establish 
comparative effectiveness [10]. 
 
The cardiac physiology from PFO closure 
During transcatheter PFO closure, catheter access to the left atrium permits direct recording of left atrial 
(LA) pressure waveforms. Prior investigations in PFO cohorts have relied predominantly on noninvasive 

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speckle-tracking measures, with reports of early, transient decrements in LA strain after closure and device-
related alterations in atrial function [11]; however, systematic, serial profiling that integrates invasive 
hemodynamics with imaging remains limited [12]. The cardiac physiological substudy in our protocol, 
leveraging catheter-accessed LA pressure waveforms, is pivotal for elucidating post-closure remodeling 
dynamics and for directly linking mechanistic changes in LA compliance to clinical outcomes. 
 
Motivation 
Therapeutic uncertainty persists for patients aged >60 years with ESUS and concomitant PFO due to the 
paucity of head-to-head data directly comparing transcatheter closure with DOAC therapy, underscoring the 
need for robust multicenter evidence. The SENIOR registry is a hybrid retrospective and prospective 
observational cohort designed to evaluate the comparative effectiveness and safety of PFO closure, DOACs, 
and antiplatelet therapy in real-world practice, incorporating prespecified endpoints, standardized outcome 
adjudication, and rigorous risk adjustment. A cardiac physiological substudy will longitudinally quantify left 
atrial compliance and heart rhythm before and after closure. The objective is to generate generalizable, 
decision-relevant evidence to inform individualized management of older adults with PFO related stroke. 
  
 
 
 

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Study Aims 
This is a multicenter, observational cohort study that includes both retrospective and prospective enrollment 
of patients with patent foramen ovale (PFO)3related stroke. The study aims are: 
1. To optimize an age-inclusive risk prediction system for the causal attribution of PFO-related stroke 
across all age. 
2. To compare the effectiveness and safety of transcatheter PFO closure versus medical therapy alone 
(direct oral anticoagulants [DOAC] or antiplatelet agents if protocol-defined DOAC ineligibility) for 
prevention of recurrent stroke among patients aged g60 years with high-risk PFO. 
3. To investigate the role of atrial cardiopathy (AC) in PFO-related stroke, and to further analyze 
changes in cardiac physiological parameters4such as left atrial (LA) compliance and LA strain4
before and after PFO closure and medical therapy alone (optional nested substudy). 
 
 
 

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Literature Review 
Based on anatomical and imaging studies, the prevalence of PFO in healthy adults is approximately 25%3
30% [13]. Among stroke patients4particularly those diagnosed with embolic stroke of undetermined source 
(ESUS)4the detection rate of PFO reaches 40% or higher [14]. Using Taichung Veterans General Hospital 
(TCVGH) as an example, real-world data from Taiwan show that approximately 31% of ESUS patients have 
concomitant PFO; the positivity rate is 24.0% in patients younger than 60 years, while PFO is identified in 
44% of those aged 60 years or older [10], indicating that advanced age is not an exclusion factor for the 
presence of PFO (Figure 1). Notably, multiple randomized controlled trials evaluating PFO closure for 
stroke prevention restricted enrollment to patients younger than 60 years, resulting in limited data for older 
patients and constraining the applicability of current international guidelines in this population [5, 15]. 
 
The treatment of PFO related stroke 
According to the 2021 guidelines from the American Heart Association/American Stroke Association and 
 
Figure 1 Single center study from TCVGH 
AIS: acute ischemic stroke; TIA: transient ischemic attack; LAA: large artery atherosclerosis; SVO: small 
vessel occlusion; CS: cryptogenic stroke; Elderly: aged g60; PFOC: patent foramen ovale closure 

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the 2024 European Stroke Organisation guidelines [2, 16], in patients aged 18360 years who have been 
appropriately evaluated and diagnosed with PFO-related ischemic stroke, transcatheter PFO closure 
significantly reduces the risk of recurrent stroke compared with antiplatelet therapy alone. 
If, after shared decision-making between physicians and patients, medical therapy alone is chosen, evidence 
regarding drug selection is limited. A meta-analysis published by Turc et al. in 2018 [17], which included 
six randomized controlled trials, compared three strategies4PFO closure, antiplatelet therapy, and 
anticoagulation4in terms of stroke recurrence and safety. PFO closure was clearly superior to antiplatelet 
therapy alone in preventing recurrent stroke (RR 0.36, 95% CI 0.1730.79), but showed no statistically 
significant difference when compared with all medical therapies combined, including anticoagulants (RR 
0.57, 95% CI 0.2831.15), suggesting that anticoagulation may be more effective than antiplatelet therapy. 
However, it should be noted that only one randomized controlled trial included anticoagulant therapy [5], 
with a limited sample size, and its study design did not directly compare PFO closure with anticoagulation 
alone. Therefore, it remains unclear whether anticoagulation can be considered a definitive treatment option 
for PFO-related stroke at this stage. 
In addition, the 2018 treatment guideline published in the BMJ [18], which synthesized multiple studies, 
suggested that anticoagulation may have a comparable effect to PFO closure in reducing recurrent stroke, 
but with a relatively higher risk of bleeding4particularly in older patients or those with bleeding risk 
factors4necessitating careful clinical assessment. 
Importantly, the number of patients treated with DOACs in these randomized trials was very small (with 
explicit reporting only in the CLOSE trial, totaling 13 patients [5]), which is insufficient to provide evidence 
for a DOAC versus PFO closure comparison. Currently, a phase III trial, CLOSE-2 (NCT05387954), is 

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ongoing to include DOAC ad the medication arm in high-risk PFO patients aged 60380 years.
 
The justification of research in elderly PFO related stroke 
In older patients, although evidence from randomized controlled trials is lacking, an increasing number of 
retrospective studies suggest that patients aged >60 years may also benefit from PFO closure, highlighting 
the need for new RCT evidence integrating anatomical risk factors and individualized assessment [20, 21]. 
In a meta-analysis published in 2020 by Sara Mazzucco et al., among patients with ESUS and concomitant 
PFO treated with medical therapy alone, those aged g60 years had a 1.64-fold higher risk of recurrent stroke 
than those aged <60 years, supporting the rationale for PFO closure in older patients [3]. 
 
Our retrospective study published in the European Stroke Journal in 2025 included 239 patients with ESUS 
or cryptogenic TIA, of whom 127 underwent PFO closure and 112 did not (Figure 1). The overall mean age 
 
Figure 2 The treatment efficacy between different therapy 
(1) Y-axis is truncated from 90% to 100% event-free survival. (2) Mixed medical therapy includes 
studies where the proportion of antiplatelet agents was 25%. (3) Proportion of patients: patent foramen 
ovale (PFO) closure+antiplatelettherapy (n=1829; 50%), mixed medical therapy (n=1153; 32%), 
antiplatelet therapy (n=458; 13%) and anticoagulation (n=210; 6%) 
Mir H, et al. BMJ Open 2018 [19] 

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was 57.2 years, and the mean follow-up duration was 3.1 years. The study specifically analyzed 49 patients 
aged >60 years who underwent PFO closure. The results showed that PFO closure significantly reduced the 
risk of recurrent ischemic stroke by nearly 90% (adjusted HR 0.10; 95% CI 0.0330.29; p = 0.001). A 
significant benefit was also observed in the older subgroup (adjusted HR 0.11; 95% CI 0.0330.49; p = 
0.003), and the effectiveness did not differ significantly between older and younger groups. Regarding 
safety, the rates of procedural complications (subcutaneous hematoma, pericardial effusion, etc.) were 
comparable between younger and older patients (5.1% vs. 6.1%, p = 1.000), and there was no significant 
difference in peri-procedural atrial fibrillation (3.8% vs. 6.1%, p = 0.675) [8]. However, the control group 
did not control for the use of antiplatelet therapy alone versus anticoagulation, and a prospective multicenter 
registry study is still needed to confirm effectiveness. 
 
 
Figure 3 
Dotted circles represent the medical arm of patent foramen ovale closure trials. 
Mazzucco S, et al. JAMA Neurol. 2020 [3] 

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Methods 
1. Inclusion and exclusion criteria 
Prospective registration: as table 
Inclusion criteria for prospective registration  
Aged: 18-90 years old  
Patient or his/her legal representative signs a written informed consent  
Participants who have diagnosed as PFO related stroke  
ESUS diagnosed by Neurologist by standard 
pathway, aged 18-59 years 
And 
PFO diagnosed by TCD-microbubble test, or 
TEE-microbubble test 
And 
PASCAL classification possible/probable 
 
ESUS diagnosed by Neurologist by standard 
pathway, aged 60-90 years  
And  
High risk PFO, diagnosed by TCD-microbubble test 
(>10 HITS in 30 s), or TEE-microbubble test (>30 
bubbles in 3 cardiac cycle)  
OR  
PFO diagnosed by TCD-microbubble test, or TEE-
microbubble test, with RoPE score g 4, with cortical 
infarct 
 
Exclusion criteria for prospective registration 
Follow-up less than 6 months 
Extracardiac right-to-left shunt 
Inability to provide informed consent 
Known stroke mechanism other than PFO 
 
 

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Retrospective registration: 
Inclusion criteria: 
(1) Patients with ESUS and concomitant PFO. 
(2) Age between 18 and 90 years. 
 
Exclusion criteria: 
(1) Incomplete clinical data (missing data). 
(2) Human immunodeficiency virus (HIV)3positive patients. 
 
2. Sample size 
(1) For the prospective registry, a total of 200 patients aged >60 years and 200 patients aged f60 years are 
planned to be enrolled (total across all participating centers). 
(2) For the retrospective registry, a total of 500 patients across all age groups are planned to be enrolled 
(total across all participating centers). 
 
3.1 PFO related patient enrolled 
This multicenter, observational registry combines a retrospective cohort (Jan 1, 20133Sep 1, 2025) and a 
prospective cohort (Sep 15, 20253Dec 31, 2031). Eligible participants are adults (g18 years) with ESUS and 
concomitant PFO based on a standardized etiologic work-up (CTA/MRA, ECG, carotid ultrasound and TCD, 
24-hour Holter ECG, transthoracic echocardiography [TTE]/ transesophageal echocardiography [TEE], blood 
test, including hypercoagulable state, autoimmune disease, hereditary diseases, malignancy; and an optional 

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cardiac MRI), with TOAST classification applied to ischemic stroke and prespecified criteria for TIA 
(unilateral weakness, lasting for > 10 minutes and diagnosed by Neurologist). Genetic testing data 
(array/WES/WGS per site) may be incorporated for secondary analyses (optional). While an etiology for the 
index ischemic event could not be identified, the ESUS was diagnosed. A TCD and/or TEE based microbubble 
test was performed to ascertain the presence of PFO. Patients with an abnormal microbubble test were 
assumed to have PFO.  
The retrospective arm will enroll patients aged between 18-90 years with ESUS and concomitant PFO. The 
prospective arm will focus on patients aged g60 years with high-risk PFO. Inclusion and exclusion criteria 
are presented as section 1. 
 
3.2 The diagnosis of high-risk PFO 
After ESUS is established, right-to-left shunt testing is performed by TCD and/or TEE based microbubble 
test. High-risk PFO is defined as: (1) TCD with >10 high-intensity transient signals within 30 seconds, or 
(2) TEE/TTE with >20 microbubbles entering left-sided chambers within three cardiac cycles, or (3) 
presence of atrial septal aneurysm. RoPE and PASCAL scales are recorded to estimate PFO-attributable 
stroke probability. To confirmed the diagnosis, an anatomic PFO is documented by TEE or catheter passage. 
 
3.3Treatment allocation 
This is a non-interventional registry; therapy is determined by the treating physician and the local PI through 
shared decision-making. For patients aged <60 years, management follows international guidelines4 
transcatheter PFO closure for PFO-related stroke, defined after a standardized etiologic work-up and 

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adjudicated using the ROPE/PASCAL classification. In the prospective arm, patients aged 60-90 years may 
receive transcatheter PFO closure, standard-dose DOAC, or antiplatelet therapy when DOAC is 
contraindicated or intolerance. At each study center, the local PI finalizes treatment selection as part of routine 
care discussions, typically within 2 months of the index event. All decisions and their clinical rationale are 
prospectively documented. 
 
3.4 Cardiac physiological analysis 
Baseline transthoracic echocardiography will capture core measurements (LVIDs, LVIDd, IVSd, LVPWd, 
LAD, LA volumes in apical 2- and 4-chamber views, LA strain, and LVEF by modified Simpson9s in apical 
2- and 4-chamber views) and late contrast enhancement if cardiac MRI was performed. During PFO closure, 
left-atrial pressure waveforms may be recorded via catheter; when combined with chamber volumes, these 
data enable LA compliance estimation. Post-closure rhythm surveillance (ECG or 24-hour Holter) is 
performed within 1 week to detect procedure-related arrhythmias. A 6-month TTE repeats the core 
measurements to quantify remodeling; additional center-specific measures are permitted (e.g. optional cardiac 
MRI). 
 
3.5 Follow-up  
3.5.1 Retrospective arm 
Participants are followed from the index event until the occurrence of the primary outcome, all caused 
mortality, or the end of the retrospective observation window. 
 

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3.5.2 Prospective arm 
Follow-up is event-driven with a minimum observation period of 6 months. Participants are assessed at 
prespecified time points41 week, 3, 6, and 12  months4via clinic visit or structured telephone contact, with 
long term interim surveillance (typically 1 year) until an endpoint occurs. At each contact, we systematically 
ascertain the primary endpoint (date and mechanism of recurrent ischemic stroke/TIA) and all-stroke events. 
Functional status (mRS) is recorded at 6 months. A TTE is scheduled at 6-12 months to quantify LA 
structure/strain; centers may optionally arrange cardiac imaging for the cardiac pathophysiological aim. Peri-
procedural rhythm surveillance (ECG or 24-hour Holter within1 week after closure) is captured in the safety 
dataset.  
 
3.6 Data analysis and interpretation. 
The primary endpoint is recurrent AIS or TIA. Secondary endpoints include all strokes (ischemic, 
hemorrhagic, and TIA) and 3-month/1-year functional outcomes; safety endpoints include peri-procedural 
adverse events (including new-onset AF), major bleeding, and all-cause mortality. Clinical, imaging, cardiac, 
biomarker, and genetic variables will be recorded. For descriptive analyses, continuous variables will be 
summarized as mean±SD and categorical variables as percentages; between-group comparisons will use 
Mann3Whitney U tests and Ç² or Fisher9s exact tests. Variables with p<0.10 in univariable analyses and 
prespecified risk factors will enter multivariable logistic regression to assess associations with outcomes; 
significance is set at p<0.05. Retrospective and prospective cohorts will be analyzed separately and in pooled 
exploratory analyses, with subgroup analyses emphasizing patients g60 years with high-risk PFO. 
 

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3.7 Sample size calculation 
We will use an event-driven design with a two-sided ³=0.05 and 80% power, analyzed by a log-rank/Cox 
model (Schoenfeld event-count framework), assuming equal allocation and proportional hazards. The 
expected annual primary-endpoint rates are 1.4% for the PFO-closure group and 4.38% for medical 
treatment. The 4.38% control rate is a weighted average prespecified for real-world practice: ~50% treated 
with DOACs (estimated 2.96%/year in older adults according to Kasner SE, et al. Lancet Neurol. 2018 and 
Mazzucco S, et al. JAMA Neurol. 2020) and ~50% with antiplatelets (5.8%/year according to Farjat-Pasos 
JI, et al. J Stroke. 2023 ).  
Under these assumptions, the required information size is 11 primary events, with a minimum follow-up of 
g3 months and g30 participants per group to trigger the analysis. Accounting for ~10% overall attrition, the 
corresponding total sample size is at least 224 (at least 112 per group). 
 
3.8 Study flow diagram 

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