SENIOR: Stroke Prevention in the Elderly by Patent Foramen Ovale closuRe vs Anticoagulation

Overview

Patent foramen ovale (PFO) is an important mechanism of embolic stroke of undetermined source (ESUS). Current guidelines recommend PFO closure for high-risk PFO in patients younger than 60 years, and a recent retrospective cohort study from Taichung Veterans General Hospital has shown that closure is effective and safe in older adults; however, the optimal treatment strategy for those \>60 years and direct head-to-head comparisons of PFO closure versus direct oral anticoagulants (DOACs) remain insufficient. Robust evidence from a multicenter study combining prospective and retrospective cohorts is warranted. The SENIOR study is a multicenter observational cohort registry with a combined retrospective and prospective design. The prospective period is from September 15, 2025 to December 31, 2031, and the retrospective period covers January 1, 2013 to September 1, 2025; target sample sizes are 400 (prospective) and 500 (retrospective). We will enroll adults with ESUS and PFO; the prospective arm will focus on patients aged \>60 years with PFO related stroke. Treatments will be assigned as PFO closure, standard-dose DOAC, or antiplatelet agents (if DOAC intolerance) by local principal investigator. The primary outcome is recurrent ischemic stroke or transient ischemic attack. Secondary outcomes include 6-month functional outcome, all stroke, and serial comparison of atrial cardiopathy changes. Safety endpoints include peri-procedural adverse events (including newly-onset atrial fibrillation), hemorrhagic stroke, and all caused mortality. Clinical presentation, imaging, cardiac testing, biomarker, and genetic data will be collected for stratified and multivariable analyses.

Patent foramen ovale-related stroke management and outcome: age-dependent risk prediction and atrial cardiopathy study (SENIOR study) is a multicenter, hybrid retrospective-prospective observational registry designed to address a critical therapeutic gap in the management of embolic stroke of undetermined source (ESUS) associated with patent foramen ovale (PFO), particularly in patients older than 60 years. While randomized controlled trials and contemporary international guidelines support transcatheter PFO closure in carefully selected patients younger than 60 years with high-risk anatomical features, robust evidence remains lacking for older adults, despite the fact that the majority of stroke patients worldwide are now above this age threshold and emerging data suggest that recurrence risk in medically treated elderly patients with PFO may be even higher than in younger cohorts. Furthermore, although anticoagulation-especially with direct oral anticoagulants (DOACs)-has been hypothesized to offer protection comparable to closure in preventing paradoxical embolism, prior trials included very few DOAC-treated patients and did not provide adequately powered head-to-head comparisons between closure and modern anticoagulation strategies. Building upon preliminary real-world data from Taichung Veterans General Hospital demonstrating substantial recurrence reduction with PFO closure in older adults but limited representation of DOAC therapy, the SENIOR registry aims to generate generalizable, decision-relevant evidence by enrolling approximately 900 patients across participating centers, combining retrospective cases (2013-2025) with prospective enrollment (2025-2031). Eligible participants are adults aged 18-90 years with ESUS and confirmed PFO after standardized etiologic work-up, with the prospective arm emphasizing patients ≥60 years who demonstrate high-risk PFO features defined by transcranial Doppler or transesophageal echocardiographic microbubble criteria, atrial septal aneurysm, or long-tunnel anatomy. Treatment allocation is determined through shared decision-making as part of routine care and may include transcatheter PFO closure, standard-dose DOAC therapy, or antiplatelet therapy when anticoagulation is contraindicated, with detailed documentation of clinical rationale to enable rigorous risk adjustment. The primary endpoint is recurrent ischemic stroke or transient ischemic attack, and secondary outcomes include overall stroke events, functional status at one year, safety endpoints such as new-onset atrial fibrillation and major bleeding, and all-cause mortality. In addition to comparative effectiveness analysis using time-to-event modeling and multivariable adjustment, the study incorporates a mechanistic cardiac physiological substudy that longitudinally characterizes atrial cardiopathy and left atrial remodeling through echocardiographic strain, volumetric assessment, and, in closure cases, direct catheter-based left atrial pressure waveform recording to estimate compliance and explore the interaction between structural atrial substrate and paradoxical embolism. By integrating anatomical risk stratification (RoPE and PASCAL classification), age-dependent risk prediction modeling, contemporary antithrombotic strategies, and mechanistic atrial physiology, the SENIOR study seeks to clarify whether advanced age modifies the balance between device-based and pharmacologic stroke prevention, to refine individualized treatment selection for older patients with PFO-related stroke, and to provide the multicenter real-world evidence necessary to inform future randomized trials and guideline evolution. Study Aims This is a multicenter, observational cohort study that includes both retrospective and prospective enrollment of patients with patent foramen ovale (PFO)-related 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 ≥60 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 parameters-such as left atrial (LA) compliance and LA strain-before and after PFO closure and medical therapy alone (optional nested substudy).