Secondary stroke prevention in patients with patent foramen ovale.

PURPOSE OF REVIEW: Although a patent foramen ovale (PFO) is an established risk factor for cryptogenic ischemic stroke, strategies for secondary prevention remain controversial. Increasing evidence over the past decade from well designed clinical trials supports transcatheter PFO closure for selected patients whose stroke was likely attributable to the PFO. However, patient selection using imaging findings, clinical scoring systems, and in some cases, thrombophilia testing, is crucial for determining patients most likely to benefit from closure, anticoagulation, or antiplatelet therapy. RECENT FINDINGS: Recent studies have found that patients with a high Risk of Paradoxical Embolism (RoPE) score and those with a thrombophilia benefit more from closure than medical therapy (including antiplatelet or anticoagulant therapy) alone. Meta-analyses have demonstrated an increased short-term risk of atrial fibrillation in closure patients, and that residual shunt after closure predicts stroke recurrence. Last, recent data have been inconclusive as to whether patients receiving medical therapy only benefit more from anticoagulation or antiplatelet therapy, so this remains an area of controversy. SUMMARY: Transcatheter PFO closure is an evidence-based, guideline-supported therapy for secondary stroke prevention in patients with a PFO and cryptogenic stroke. However, proper patient selection is critical to achieve benefit, and recent studies have helped clarify those patients most likely to benefit from closure.

Efficacy and safety of percutaneous patent foramen ovale closure in patients with a hypercoagulable disorder.

BACKGROUND: Transcatheter closure of patent foramen ovale (PFO) in patients with cryptogenic stroke reduces the rate of recurrent events. Although presence of thrombophilia increases the risk for paradoxical emboli through a PFO, such patients were excluded from large randomized trials. OBJECTIVES: We compared the safety and efficacy of percutaneous PFO closure in patients with and without a hypercoagulable state. METHODS: Data from 800 consecutive patients undergoing percutaneous PFO closure in our medical center were analyzed. All patients were independently evaluated by specialists in neurology, cardiology, hematology, and vascular medicine. A post-procedural treatment of at least 3 months of anticoagulation was utilized in patients with thrombophilia. Follow-up events included death, recurrent neurological events, and the need for reintervention for significant residual shunt. RESULTS: A hypercoagulable state was found in 239 patients (29.9%). At median follow-up of 41.9 months, there were no differences in the frequencies of stroke or transient ischemic attack between patients with or without thrombophilia (2.5% in non-hypercoagulable group vs. 3.4% in hypercoagulable group, log-rank test p = 0.35). There were no significant differences in baseline demographics, echocardiographic characteristics, procedural success, or complications between groups. CONCLUSION: Percutaneous PFO closure is a safe and effective therapeutic approach for patients with cryptogenic stroke and an underlying hypercoagulable state.

Concomitant acute myocardial infarction and acute pulmonary embolism caused by paradoxical embolism: a case report.

BACKGROUND: Due to its low incidence and diverse manifestations, paradoxical embolism (PDE) is still under-reported and is not routinely considered in differential diagnoses. Concomitant acute myocardial infarction (AMI) and acute pulmonary embolism (PE) caused by PDE has rarely been reported. CASE PRESENTATION: A 45-year-old woman presented with acute chest pain and difficulty with breathing. Multiple imaging modules including ECG, echocardiography, emergency cardioangiogram (CAG), and CT angiography of the pulmonary arteries showed acute occlusion of the posterolateral artery and acute PE. After coronary aspiration, no residual stenosis was observed. One month later, a bubble study showed inter-atrial communication via a patent foramen ovale (PFO). The AMI in this patient was finally attributed to PDE via the PFO. PFO closure was performed, and long-term anticoagulation was prescribed to prevent recurrent thromboembolic events. CONCLUSIONS: PDE via PFO is a rare etiology of AMI, especially in patients with concomitant AMI and PE. Clinicians should be vigilant of this possibility and close the inter-atrial channel for secondary prevention.

Stroke Prevention in Patients with Patent Foramen Ovale.

PURPOSE OF REVIEW: Patent foramen ovale (PFO) is widely prevalent and studies have suggested an association with ischemic stroke. In this review, we aim to highlight current management of patients with ischemic stroke in the setting of PFO and discuss some areas of controversy. RECENT FINDINGS: Upon reviewing the literature, we have found that the evidence regarding the management of patients with cryptogenic stroke and PFO has come a long way in the past several years, and many uncertainties remain in clinical practice. The Risk of Paradoxical Embolism (RoPE) score helps to predict the probability of a pathogenic PFO, and recent trial data confirms the benefit of closure in carefully selected patients. The benefit of closure in older patients and in patients with alternate, competing mechanisms is still uncertain, and the long-term risks of closure are not known. Finally, the efficacy of direct oral anticoagulants (DOACs) in this patient population as compared to other medical therapy or mechanical closure has not yet been investigated. Randomized data is needed to help answer these questions. PFO closure is a safe and effective strategy in reducing stroke risk in carefully selected patients with cryptogenic stroke in the setting of a PFO. More studies are needed to test optimal medical treatment strategies and the safety and efficacy of PFO closure in patient subgroups not included in prior PFO closure trials.

Modified percutaneous suture-mediated patent fossa ovalis closure for prevention of cerebral ischemic events.

Percutaneous suture-mediated transcatheter patent fossa ovalis (PFO) closure has been shown to be an effective and safe technique with self-evident advantages due to the lack of a permanent device heart implant. The success of this novel technique relies on an optimal catch of the interatrial septa, especially the septum primum which is floppier than the bulkier muscular septum secundum. We hypothesized that double suture of septum primum would further improve the efficacy of the procedure by increasing the surface contact between the septa when the septum primum is bent into the right atrium. We have provided proof of this concept by implementing a modified technique in two patients with PFO and cerebral ischemic events.

The Closure of Patent Foramen Ovale in Preventing Subsequent Neurological Events: A Bayesian Network Meta-Analysis to Identify the Best Device.

BACKGROUND: Randomized-controlled trials (RCTs) reported a finding on the safety and efficacy of percutaneous patent foramen ovale (PFO) closure to prevent stroke recurrence. It showed that the Amplatzer (AMP) device appears to be superior to medical therapy (MT) in preventing strokes and episodes of atrial fibrillation (AF), than other devices. We performed a network meta-analysis (NMA) to evaluate the closure of PFO in preventing subsequent neurological events while investigating the results obtained by specific devices. METHODS: We searched 3 databases (MEDLINE, EMBASE, CENTRAL/CCTR) and identified 6 RCTs until March 2019. We performed an NMA and used pooled ORs. Analyses were done in NetMetaXL1.6-WinBUGS1.4. RESULTS: Six RCTs with 3,560 patients (mean age 45.2-46.2 years) were included in the present NMA. Depending on the device, 4 groups of patients were compared with MT: 1,889 patients undergoing PFO closure were significantly less likely to experience a stroke than 1,671 patients treated with MT (ORs 0.41; 95% Cr.I. 0.27-0.60 with fixed-effects model and ORs 0.22; 95% Cr.I. 0.05-0.70 with random-effects model). The patients with AMP showed a similar risk than those treated with Helex/Cardioform (HLX/CF) or with a group of 11 multiple devices. This suggests the equality between the 2 most currently used devices. When assessing TIA and, for the safety analysis, major bleeding, both models confirm no significant difference between any devices and MT. PFO closure increased the risk of new-onset AF: MT induces AF significantly less than all the devices. In favor of the AMP, there is a reduced number of cases of AF versus MT; however, no device superiority has been established in comparing HLX/CF and other devices in a random effect model. CONCLUSIONS: Our NMA provides evidence in favor of PFO closure with all the devices currently in use. We can conclude that these devices are better than MT, but not that 1 device is better than the rest in reducing stroke recurrences and AF episodes in the follow-up.

Correlations between serum homocysteine levels and RoPE score in patients with patent foramen ovale.

The pathophysiological relationship between elevated serum homocysteine (Hcy) levels and patent foramen ovale (PFO) has not yet been completely clarified. In the present study, we assess the correlation between serum homocysteine levels and the RoPE score in PFO patients. We retrospectively reviewed clinical and instrumental data of 244 subjects referred to a single tertiary center for PFO evaluation and/or treatment between January 2010 and January 2018,stratified as closure and control group, respectively. Patients in the closure group had an higher serum Hcy levels compared to the control group (28.5 ± 8.5 vs 10.2 ± 6.6 µg/dL, p < 0.0001). A significant direct correlation was observed between serum Hcy levels and the RoPE Score in the entire population. A positive significant correlation continued to exist also in the closure and control groups (r = 0.472, p < 0.0001 and r = 0.378, p < 0.0001, respectively). A receiver operating characteristics curve identified the optimal cutoff value of homocysteinemia as a predictor of RoPE score > 7 in the closure group (AUC 0.90, 95% CI 0.81-0.94, p < 0.0001) when 19.5 µg/dL. Multivariate logistic regression analysis demonstrated that an Hcy serum level ≥ 19.5 µg/dL predict an RoPE score > 7 (OR 3.21, 95% CI 2.82-3.26, p < 0.0001) in closed patients independently from the presence of permanent right-to-left (RLS) (OR 2.28, 95% CI 2.01-2.43, p = 0.001) and atrial septal aneurysm (ASA) (OR 3.04, 95% CI 2.64-3.51, p < 0.0001). Serum homocysteine levels in PFO patients are positively correlated with the RoPE score. Moreover, a homocysteinemia ≥ 19.5 µg/dL predicts an RoPE score > 7 independently from the presence of a permanent RLS and a concomitant ASA.

SCAI expert consensus statement on operator and institutional requirements for PFO closure for secondary prevention of paradoxical embolic stroke: The American Academy of Neurology affirms the value of this statement as an educational tool for neurologists.

Until recently, evidence to support Patent Foramen Ovale (PFO) closure for secondary prevention of recurrent stroke has been controversial. Publication of high-quality evidence from randomized clinical trials and the subsequent FDA approval of two devices for percutaneous PFO closure is expected to increase the volume of PFO closure procedures not only in the United States but worldwide. As this technology is disseminated broadly to the public, ensuring the safe and efficacious performance of PFO closure is essential to mitigate risk and avoid unnecessary procedures. This document, prepared by a multi-disciplinary writing group convened by the Society for Cardiovascular Angiography and Interventions and including representatives from the American Academy of Neurology, makes recommendations for institutional infrastructure and individual skills necessary to initiate and maintain an active PFO/stroke program, with emphasis on shared decision making and patient-centered care.

The Fragility Index in Randomized Controlled Trials for Patent Foramen Ovale Closure in Cryptogenic Stroke.

BACKGROUND AND PURPOSE: The routine use of percutaneous transcatheter patent foramen ovale closure (PPFOC) to prevent recurrent stroke in patients with cryptogenic stroke is still a matter of debate after completion major randomized controlled trials (RCTs). METHODS: The fragility index of RCTs evaluating effect of PPFOC against medial therapy alone in stroke prevention was calculated to assess the robustness of statistically significant findings. RESULTS: Literature search with PubMed identifies 6 RCTs on PPFOC. Median number of patients who underwent PPFOC and medical treatment were 340 and 229, respectively. Median number of the patients lost to follow-up was 20 in PPFOC and 18 in medical group. Fragility index was 0 for 4 studies. Median fragility index was also 0 for both "stroke" (interquartile range: 0-5.3) and "combined stroke and TIA" (interquartile range: 0-2) endpoints. In all studies except CLOSE, fragility index was smaller than or equal to the number of the subjects lost to follow-up. CONCLUSIONS: Recent positive results of PFO closure studies should be interpreted cautiously because of their fragile characteristics. Routine PFO closure should be reserved for prevention of recurrence when suspicion for paradoxical embolism is high. Detailed individualized decision-making is crucial before ordering PPFOC for stroke prevention in patients with cryptogenic embolism.

Use of a NobleStitch™ EL Device for PFO Closure.

Cryptogenic stroke is the final diagnosis in almost 40% of ischemic acute cerebrovascular events. There is currently no definitive clinical evidence that percutaneous closure of patent foramen ovale (PFO) can prevent the recurrence of stroke or transient ischemic attack (TIA). Identification of the causes of neurologic ischemic syndromes is essential for any strategy intended to prevent the catastrophic consequences of cerebral infarction. Since the initial reports of an unexpectedly high prevalence of PFO in younger patients with cryptogenic stroke in 1988, there has been growing interest and experience in diagnosing and treating these patients, both medically and/or with percutaneous closure, in particular for the potential to eliminate paradoxical embolism via PFO, which is a likely mechanism for stroke in these patients. Selection of the appropriate occluder device is of paramount importance for the success of the procedure. While devices like the Amplatzer™ PFO Occluder (St. Jude Medical), which, based on the extended follow-up of the RESPECT Trial, was approved by the U.S. Food and Drug Administration last year for recurrent stroke prevention, have become generally accepted as being better than medical therapy for patients needing treatment, concerns remain regarding device- and procedure-related complications. NobleStitch™ EL is a novel device that offers a simple non-prosthetic implant method of PFO closure without the inherent risks seen with septal occluders: no risk of device embolization, device thrombosis or late erosion, and probably no risk of arrhythmia. Futhermore, there is no material that would hinder future access to the left atrium and no requirement for anti-coagulation.

Long-term follow-up after PFO device closure: Outcomes and Complications in a Single-center Experience.

OBJECTIVES: To describe medium- to long-term follow-up of patients undergoing device closure of patent foramen ovale (PFO) for stroke or transient ischemic attack (TIA). BACKGROUND: Transcatheter device closure of PFO continues to be used for secondary prevention of cryptogenic stroke or TIA, but data are lacking regarding long-term outcomes. METHODS: We reviewed the Mayo Clinic Rochester PFO database for patients who underwent device closure of PFO for secondary prevention of stroke/TIA from December 2001 to June 2012. Demographic, clinical, procedural, and follow-up data were reviewed. Recurrence rate of stroke/TIA were calculated. Data were analyzed to identify risk factors of recurrent neurologic events. RESULTS: Seven hundred and thirty patients (mean age 53 years; 40% female) were included in our study. Most patients (72%) had cryptogenic stroke as their qualifying event for PFO closure. There were no procedure-related deaths or strokes. The most commonly used device was the Amplatzer Septal Occluder (82%). Median follow-up was 6 years. A 3.9% of patients had documented residual right-to-left shunting at last echocardiogram. Recurrent stroke and/or TIA were reported in 45 patients, (6.3% of patients with follow-up data). Patients who experienced recurrent stroke/TIA were older and had a higher rate of diabetes and hypertension than those who did not. The presence of residual shunt did not correlate with risk of recurrent events. CONCLUSIONS: Device closure of PFO can be performed safely with very good long-term resolution of atrial shunting. Recurrent neurologic events after PFO closure may reflect additional comorbid risk factors unrelated to the potential for paradoxical embolism. © 2016 Wiley Periodicals, Inc.

Diagnostic Yield of Echocardiography in Transient Ischemic Attack.

BACKGROUND: Echocardiography is often performed to identify a cardiac source of embolism (CSE) causing transient ischemic attack (TIA). However, the diagnostic yield of echocardiography in TIA remains uncertain, and its role in routine evaluation of TIA is controversial. METHODS: Patients with acute TIA were prospectively enrolled at 4 stroke centers. A CSE was defined using the Causative Classification of Stroke system; patent foramen ovale was considered a relevant CSE only if the patient underwent closure or was placed on anticoagulation. Patients with a known CSE at time of admission were excluded from analysis of the yield of echocardiography. RESULTS: A total of 869 patients were enrolled at stroke centers, and 129 had a known CSE at presentation. Of the 740 remaining patients, 603 (81%) underwent echocardiography. A potential CSE was identified in 60 (10%) of these patients. The most common CSEs noted on echocardiography were complex aortic arch atherosclerosis and patent foramen ovale. History of coronary artery disease (P < .001), lack of prior stroke or TIA (P = .007), and presence of acute infarction on magnetic resonance imaging (MRI) (P < .001) were predictors of CSE on echocardiography. The yield of echocardiography was 29% in patients with both history of coronary artery disease and acute infarction on MRI, 14% with one of these features, and 5% with neither of these features (P < .0001). A CSE identified by echocardiography prompted initiation of anticoagulation in 15 of the 603 (2.5%) subjects. CONCLUSIONS: Echocardiography demonstrates a relevant CSE in a significant portion of patients with TIA. However, changes in antithrombotic therapy resulting from echocardiography are infrequent.

Closure or medical therapy for cryptogenic stroke with patent foramen ovale.

BACKGROUND: The prevalence of patent foramen ovale among patients with cryptogenic stroke is higher than that in the general population. Closure with a percutaneous device is often recommended in such patients, but it is not known whether this intervention reduces the risk of recurrent stroke. METHODS: We conducted a multicenter, randomized, open-label trial of closure with a percutaneous device, as compared with medical therapy alone, in patients between 18 and 60 years of age who presented with a cryptogenic stroke or transient ischemic attack (TIA) and had a patent foramen ovale. The primary end point was a composite of stroke or transient ischemic attack during 2 years of follow-up, death from any cause during the first 30 days, or death from neurologic causes between 31 days and 2 years. RESULTS: A total of 909 patients were enrolled in the trial. The cumulative incidence (Kaplan-Meier estimate) of the primary end point was 5.5% in the closure group (447 patients) as compared with 6.8% in the medical-therapy group (462 patients) (adjusted hazard ratio, 0.78; 95% confidence interval, 0.45 to 1.35; P=0.37). The respective rates were 2.9% and 3.1% for stroke (P=0.79) and 3.1% and 4.1% for TIA (P=0.44). No deaths occurred by 30 days in either group, and there were no deaths from neurologic causes during the 2-year follow-up period. A cause other than paradoxical embolism was usually apparent in patients with recurrent neurologic events. CONCLUSIONS: In patients with cryptogenic stroke or TIA who had a patent foramen ovale, closure with a device did not offer a greater benefit than medical therapy alone for the prevention of recurrent stroke or TIA. (Funded by NMT Medical; ClinicalTrials.gov number, NCT00201461.).

[Management of patent foramen ovale in non-cardiac surgery]. / Gestione della pervietà del forame ovale nella chirurgia non cardiaca.

Patent foramen ovale (PFO) is a remnant of normal fetal anatomy which may persist into adulthood, mostly asymptomatic. In some adults, PFO may result in a potential for shunting venous thromboembolism to the arterial circulation; less frequently it can cause interatrial, right-to-left shunting of deoxygenated blood. The pathogenesis of several medical conditions is related to the presence of PFO. Some randomized clinical trials have shown evidence of benefit for device closure as compared with medical therapy in patients with cryptogenic stroke. The literature reported several cases of carbon dioxide embolism during general laparoscopic surgery and sometimes stroke after laparoscopic or neurosurgery but there are neither prospective studies addressing these issues, nor randomized clinical trials assessing the effectiveness of pharmacotherapy or interventional procedures at decreasing risk. The European position paper suggests routine monitoring in non-cardiac surgery of patients with a PFO and no actual indications for closure. This article aims to further stratify the risk of periprocedural stroke and paradoxical embolism in this category of patients.

Determinants of adverse outcomes following patent foramen ovale closure in elderly patients.

BACKGROUND: Limited data are available on transcatheter patent foramen ovale (PFO) closure outcomes in the elderly. AIMS: Through this study, we aimed to determine the incidence and predictors of adverse events (recurrent cerebrovascular events [CVE] and atrial fibrillation [AF]) post-PFO closure in older patients with cryptogenic events. METHODS: This multicentre international study included patients over 60 years undergoing PFO closure for cryptogenic thromboembolic events. A dedicated database compiled baseline, procedural, and follow-up data. Competing risk and adjusted outcome predictor analyses were conducted. RESULTS: A total of 689 patients were included (median age 65 years, 41.2% female, mean Risk of Paradoxical Embolism [RoPE] score 4.5). The procedural success rate was 99.4%. After a median follow-up of 2 (interquartile range 1-5) years, 66 patients (9.6%) had died. CVE and stroke rates were 1.21 and 0.55 per 100 patient-years, respectively. Diabetes (hazard ratio [HR] 3.89, 95% confidence interval [CI]: 1.67-9.07; p=0.002) and atrial septal aneurysm (ASA; HR 5.25, 95% CI: 1.56-17.62; p=0.007) increased the CVE risk. New-onset AF occurred at a rate of 3.30 per 100 patient-years, with 51.3% within one month post-procedure. Older age (HR 1.05 per year, 95% CI: 1.00-1.09; p=0.023) and the absence of hypertension (HR 2.04, 95% CI: 1.19-3.57; p=0.010) were associated with an increased risk of AF. CONCLUSIONS: Older patients undergoing PFO closure had a relatively low rate of CVE and new-onset AF after a median follow-up of 2 years. The presence of diabetes, ASA, and a more advanced age determined an increased risk of adverse clinical events. These factors may be considered in the clinical decision-making process regarding PFO closure in this challenging population.

Long-term propensity score-matched comparison of percutaneous closure of patent foramen ovale with medical treatment after paradoxical embolism.

BACKGROUND: Patients with ischemic stroke or transient ischemic attack presumably related to patent foramen ovale (PFO) are at risk for recurrent cerebrovascular events. Differences in long-term clinical outcome were investigated among patients with percutaneous PFO closure and those who received medical treatment. METHODS AND RESULTS: Between 1994 and 2000, 308 consecutive patients with cerebrovascular events presumably related to PFO underwent either percutaneous PFO closure (150 patients) or medical treatment (158 patients). Patients were followed up prospectively for up to 15 years. Seven patients were lost during follow-up. The primary outcome was a composite of stroke, transient ischemic attack, or peripheral embolism. We analyzed 103 propensity score-matched pairs of patients who underwent percutaneous PFO closure or medical treatment. At a median follow-up of 9 years, the primary composite outcome occurred in 11 patients slated to PFO closure (11%) and 22 patients slated to medical treatment (21%; hazard ratio=0.43; 95% confidence interval=0.20-0.94; P=0.033). The treatment effect was driven by a decrease in the risk of transient ischemic attack of 5% versus 14%, respectively (hazard ratio=0.31; 95% confidence interval=0.10-0.94; P=0.039). The risk of all-cause (6% in both groups) and cardiovascular (3% in both groups) mortality appeared to be identical. CONCLUSION: In this long-term observational, propensity score-matched study, percutaneous PFO closure was more effective than medical treatment for the secondary prevention of recurrent cerebrovascular events among patients with PFO-related transient ischemic attack or stroke.

Recurrent events after percutaneous closure of patent foramen ovale.

OBJECTIVES: To determine the incidence of symptomatic recurrent embolic events after patent foramen ovale (PFO) closure and potential causes for these events. BACKGROUND: It is well-known that cerebral or other embolic events may occur after PFO closure. METHODS: This is a retrospective analysis of consecutive patients who underwent PFO closure for secondary prevention of embolic events at a single institution. RESULTS: 1,930 patients (mean age of 50 ± 13.3 years) underwent transcatheter PFO closure. Complete closure occurred in 92%. The annual recurrence rate of embolic events before PFO closure was 22.4% (785 events in 3,497 patient-years). During follow-up (mean 39 months), 63 recurrent events were documented: 25 strokes, 36 transient ischemic attacks (TIAs), and 2 peripheral embolic events. The overall annual recurrence rate after the procedure was 1% per year (63 events in 6,211 patient-years). The majority of events occurred in patients without residual shunts (54/63). There was no significant association between the presence of a residual shunt and recurrent events [hazard ratio (HR) 1.7; 95% confidence interval (CI) 0.8-3.6, P = 0.16]. The most common cause for recurrent events was atherosclerosis. Nine out of 63 events were considered likely or possible paradoxical embolism due to residual shunt [stroke (2), TIA (5), and peripheral embolism (2)]. After PFO closure, the annual rate of events potentially related to paradoxical embolism was 0.14% (9 events in 6,211 patient-years). CONCLUSION: The incidence of symptomatic embolic events after PFO closure is low. Most recurrent events are related to coexistent conditions associated with thromboembolic risk rather than residual shunts.

Outcomes Following Patent Foramen Ovale Percutaneous Closure According to the Delay From Last Ischemic Event.

BACKGROUND: Randomised controlled trials evaluating percutaneous closure of patent foramen ovale (PFO) have included only patients with a recent embolic event. We aimed to evaluate outcomes after percutaneous PFO closure according to the delay from the last embolic episode. METHODS: This international ambispective cohort included consecutive patients from 2 centres in France and Canada undergoing PFO closure for secondary prevention of a paradoxical embolic event. The primary end point was the composite of stroke or transient ischemic attack (TIA). A logistic regression model was used to evaluate determinants of late PFO closure procedures. RESULTS: A total of 1179 patients (mean age 49 ± 12.7 years; 44.4% female) underwent PFO closure from 2001 to 2021. The median delay from last embolic event to procedure was 6.0 (interquartile range 3.4-11.2) months. The determinants of late PFO closure procedure were the centre (France vs Canada; adjusted odds ratio [aOR] 1.65, 95% confidence interval [CI] 1.25-2.19), year of procedure (since 2018 vs before 2018; aOR 1.43, 95% CI 1.08-1.90), female sex (aOR 1.63, 95% CI 1.28-2.07), and lower risk of paradoxical embolism score (aOR 1.10, 95% CI 1.03-1.19). After a median follow-up of 2.61 (1.13-7.25) years, the incidence rate of first stroke or TIA did not differ between early and late PFO procedures, with 0.51 vs 0.29 events per 100 patient-years, respectively (incidence rate ratio 1.74, 95% CI 0.66-5.08; P = 0.24), and the timing of PFO closure was not associated with the occurrence of stroke or TIA in univariate analysis (hazard ratio 0.54, 95% CI 0.22-1.34) for late vs early closure). CONCLUSIONS: This analysis provides indirect evidence that the delay from the last ischemic event does not affect outcomes after PFO closure for secondary prevention.