Risk of Recurrent Stroke Among Patients With Patent Foramen Ovale vs Pulmonary Arteriovenous Malformation: A Nationwide Study.

Clinical management of patients with acute stroke and the approach used for secondary prevention depends upon clarification of pathogenesis. Although most strokes are a consequence of cerebrovascular disease, ≈15% to 20% of ischemic (nonhemorrhagic) strokes have been attributed to cardiogenic embolism.1 In practice, determination of the stroke mechanism is fraught with uncertainty, particularly when the possibility of thromboembolism emanating from atherosclerotic lesions in the aorta or cervical arteries is considered. When cardiogenic embolism is suspected, cardiac ultrasound is the principal method used to identify the potential source. The finding of left atrial enlargement has been shown to bear a significant relationship to the risk of stroke in a multivariate analysis of population-based data from the Framingham Heart Study2. The most frequent confounding variable is atrial fibrillation, occurring in >2 million patients in North America and in over half of all patients with cardiogenic embolism. Criteria for selection of patients with acute ischemic stroke for transesophageal echocardiography (TEE) to search for a potential cardiac source of embolism are controversial, particularly because cardiogenic embolism is often an uncertain diagnosis that is inferred merely on the basis of the finding of potential cardiac source. Even after extensive investigation, ≈40% of ischemic stroke patients have no clearly identifiable pathogenesis (cryptogenic stroke).3 In one study, 62% of patients younger than 60 years of age without an obvious source of cerebral infarction and 23% of those with arterial lesions had potential sources of cardiogenic embolism identified by TEE ( P =0.0007 for the difference).4 See p 2625 Among the cardiac anomalies detected by TEE that have been implicated as risk factors for stroke are patent foramen ovale (PFO) and atrial septal aneurysm (ASA).5,6⇓ The foramen ovale, a remnant of the fetal circulation, remains patent through adulthood in ≈1 in 4 …

NobleStitch Patent Foramen Ovales Closure for Recurrent Strokes in a Patient with COVID-19 on Extracorporeal Membrane Oxygenation

Stroke remains the third leading cause of death in the US and other Western countries,1 and at least 1 population-based study found that the incidence of stroke was greater than that of acute coronary syndromes.2 Although there have been substantial falls in stroke incidence in some countries over the last 2 decades,3 a large US study found that the advances in stroke prevention during the 1990s were not associated with decreases in the rate of stroke hospitalizations or in case-fatality rates between 1993 and 1999.4 Moreover, based solely on demographic changes in the population of selected countries within the European Union, the World Health Organization predicts a 27% increase in stroke events between the years 2000 and 2025.5 The proportion of deaths attributed to stroke is even higher in Asian countries.6 Although much of stroke risk may be related to socioeconomic factors, more effective prevention strategies are critical. Several studies have contributed to the body of knowledge related to primary stroke prevention over the last year. Numerous studies support an association between elevated homocysteine levels and atherosclerotic disease.7 The B vitamins (folic acid, B12, and B6) reduce homocysteine serum levels raising the hope that treatment would be associated with reduced risk. That hope was diminished with publication of results of the Vitamin Intervention for Stroke Prevention (VISP) trial in 2004.8 Although a secondary rather than a primary stroke prevention trial, VISP had compared high- and low-dose B-vitamin supplementation and found no treatment effect on the risk of recurrent stroke (risk ratio [RR] 1.0; 95% CI, 0.8 to 1.3), or in the combined risk of any stroke, coronary heart event, or death (RR, 1.0; 95% CI, 0.8 to 1.1). The difference in homocysteine levels between treatment groups, however, was small …

Introduction: Patent foramen ovale (PFO) is a potential source of cardiac embolism in cryptogenic ischemic stroke, but it may also be incidental. Right-to-left shunt (RLS) size may predict PFO-related stroke, but results have been controversial. In this cohort study of medically-managed PFO patients with cryptogenic stroke, we aimed to investigate the association of shunt size with recurrent stroke, mortality, newly detected atrial fibrillation (AF), and to identify predictors of recurrent stroke. Methods: Patients with cryptogenic stroke who screened positive for a RLS using a transcranial Doppler bubble study were included. Patients who underwent PFO closure were excluded. Subjects were divided into two groups: small (Spencer Grade 1, 2, or 3; n = 135) and large (Spencer Grade 4 or 5; n = 99) shunts. The primary outcome was risk of recurrent stroke, and the secondary outcomes were all-cause mortality and newly detected AF. Results: The study cohort included 234 cryptogenic stroke patients with medically-managed PFO. The mean age was 50.5 years, and 31.2% were female. The median period of follow-up was 348 (IQR 147-1096) days. The rate of recurrent ischemic stroke was higher in patients with large shunts than in those with small shunts (8.1% vs. 2.2%, p = 0.036). Multivariate analyses revealed that a large shunt was significantly associated with an increased risk of recurrent ischemic stroke [aOR 4.09 (95% CI 1.04–16.0), p = 0.043]. Conclusions: In our cohort of cryptogenic stroke patients with medically managed PFOs, those with large shunts were at a higher risk of recurrent stroke events, independently of RoPE score and left atrium diameter.

Background: Randomized controlled trials indicate that patent foramen ovale (PFO) closure reduces risk of stroke recurrence in patients with cryptogenic stroke and PFO. However, the optimal time point for PFO closure is unknown and depends on the risk of stroke recurrence.Objective: We aimed to investigate risk of early new ischemic lesions on cerebral magnetic resonance imaging (MRI) in cryptogenic stroke patients with and without PFO.Methods: Cryptogenic stroke patients underwent serial MRI examinations within 1 week after symptom onset to detect early new ischemic lesions. Diffusion-weighted imaging (DWI) lesions were delineated, co-registered, and analyzed visually for new hyperintensities by raters blinded to clinical details. A PFO was classified as stroke-related in patients with PFO and a Risk of Paradoxical Embolism (RoPE) score >5 points.Results: Out of 80 cryptogenic stroke patients, risk of early recurrent DWI lesions was not significantly different in cryptogenic stroke patients with and without PFO. Similar results were observed in patients ≤60 years of age. Patients with a stroke-related PFO even had a significantly lower risk of early recurrent ischemic lesions compared to all other patients with cryptogenic stroke (unadjusted odds ratio 0.23 [95% confidence interval 0.06–0.87], P = 0.030).Conclusion: Our data argue against a high risk of early stroke recurrence in patients with cryptogenic stroke and PFO.

Risk of recurrent ischemic stroke in patients with patent foramen ovale: The role of D-dimer

Patent foramen ovale (PFO) closure may prevent recurrent stroke after cryptogenic transient ischemic attack (TIA) or stroke (TIA/stroke) in patients aged 60 years or younger. Patent foramen ovale is associated with cryptogenic stroke in the older population, but risk of recurrence is unknown. Data on prognosis of patients receiving medical treatment at older ages (≥60 years) are essential to justify trials of PFO closure. To examine the age-specific risk of recurrence in patients with cryptogenic TIA/stroke with PFO. A prospective study was nested in the population-based Oxford Vascular Study between September 1, 2014, and March 31, 2019, with face-to-face follow-up for 5 years. A total of 416 consecutive patients with a diagnosis of cryptogenic TIA or nondisabling stroke, screened for PFO at a rapid-access TIA/stroke clinic, were included. A systematic review and meta-analysis of cohort studies reporting on ischemic stroke recurrence after cryptogenic TIA/stroke in patients with PFO who were receiving medical therapy alone, or with PFO vs no-PFO was conducted. Sample size calculation for future trials on PFO closure was performed for patients aged 60 years or older. Patent foramen ovale and age as modifiers of risk of recurrent stroke after cryptogenic TIA/stroke in patients receiving only medical therapy. Risk of ischemic stroke recurrence in patients with cryptogenic TIA/stroke and PFO receiving medical therapy only, and in patients with vs without PFO, stratified by age (<65 vs ≥65 years), as well as sample-size calculation for future trials of PFO closure in patients aged 60 years or older. Among the 153 Oxford Vascular Study patients with PFO (mean [SD] age, 66.7 [13.7] years; 80 [52.3%] men), recurrent ischemic stroke risk (2.05 per 100 patient-years) was similar to the pooled estimate from a systematic review of 23 other studies (9 trials and 14 observational studies) (2.00 per 100 patient-years; 95% CI, 1.55-2.58). However, there was heterogeneity between studies (P < .001 for heterogeneity), owing mainly to risk increasing with mean cohort age (meta-regression: R2 = 0.31; P = .003). In the pooled analysis of 4 studies including patients with or without PFO, increased risk of stroke recurrence with PFO was seen only at age 65 years or older (odds ratio, 2.5; 95% CI, 1.4-4.2; P = .001 for difference; P = .39 for heterogeneity). The pooled ischemic stroke risk was 3.27 per 100 patient-years (95% CI, 2.59-4.13) in 4 cohorts with mean age 60 years or older. Assuming the more conservative 2.0 per 100 patient-years ischemic stroke risk in the PFO nonclosure arms of future trials in patients aged 60 years or older, projected sample sizes were 1080 per arm for 80% power to detect a 33% relative risk reduction. The findings of this study suggest that age is a determinant of risk of ischemic stroke after cryptogenic TIA/stroke in patients with PFO, such that trials of PFO closure at older ages are justified; however, projected sample sizes are large.

Background: A patent foramen ovale (PFO) discovered in the setting of a cryptogenic stroke (CS) may be incidental or pathogenic. Based on Bayes theorem, the proportion of CS that is PFO-attributable among patients found to have a PFO has been shown to be related to PFO prevalence in CS versus control patients. However, the prevalence of PFO in CS patients is itself dependent on the presence or absence of other risk factors. We exploited this relationship to create an index to stratify CS patients with PFO by their likelihood that the CS is PFO-attributable. Methods This project is part of the Risk of Paradoxical Embolism (RoPE) Study, an international, multicenter collaboration that has combined data for patients with CS and cryptogenic TIA who have known PFO status from 12 component studies (n=3665). For this study, we included those subjects within the 7 databases enrolling subjects both with and without PFO (n=3023). We used generalized linear mixed models to identify variables associated with the presence of a PFO, accounting for clustering within study. Based on this model, we created a simple index. Bayes theorem was used to estimate the PFO-attributable fraction in each stratum assuming a PFO prevalence in the general population of ∼25%. Results: Variables negatively associated with the presence of a PFO included: age (odds ratio [OR] = 0.97 per 1 year increase, p &lt;0.0001); diabetes (OR= 0.65, p &lt; 0.001); hypertension (OR =0.68, p &lt; 0.0001); smoking (OR = 0.70, p&lt;0.60); prior stroke or TIA (OR = 0.78, p=0.04). Cortical stroke on neuroimaging (OR = 1.46, p &lt; 0.001) was also associated with PFO. Based on this, a simple index was created in which the absence of each stroke risk factor was assigned a point, with age dichotomized at 50 years. PFO prevalence in each stratum is shown in the table for patients &lt; age 60, i.e. the subset of patients likely to be considered for PFO closure trials. Conclusion: Even among CS patients in the younger age range considered eligible for closure trials, there is considerable heterogeneity in the distribution of risk factors for stroke and other characteristics that identify subgroups of CS patients with variation in PFO prevalence. This reflects substantial and clinically important variation in the probability that a discovered PFO is likely to be pathogenic rather than incidental. This score may be useful in selecting patients for closure trials, or for stratification within trials, particularly if combined with a recurrence risk model.

Individualized Treatment of Foramen Ovale and Stroke

Stroke remains one of the most feared and devastating complications for patients to envisage. This remains true regardless of the age of the patient and the presence or absence of comorbidities, but it may be relatively more important the younger the patient is. Establishing the pathogenesis of stroke is fundamentally important for attempts at prevention. In some patients, the diagnosis of the underlying cause is relatively straightforward—eg, the presence of a high-grade, ulcerated lesion in the carotid artery in the distribution of the central nervous system symptoms or neurological deficit. In other cases, it may be considerably more difficult; then, the question of a cardiac source is often raised. See p 1121 Echocardiography has become an integral part of the evaluation in many such patients. Early in the history of this field, attention was focused on the left atrial appendage as a putative source. In addition, however, abnormalities of the atrial septum were documented and have since come to occupy an important position. These abnormalities were further characterized after the introduction of contrast studies and transesophageal echocardiography, which helped in the documentation of patent foramen ovale (PFO), atrial septal aneurysm (ASA), and right-to-left shunt. In such patients, emboli potentially could pass from the venous to the systemic arterial circulation.1,2⇓ It must be remembered that there may be other mechanisms, including thrombus forming in the ASA or thrombus from supraventricular arrhythmias. In a recent meta-analysis,3 there were 2738 references of case-control studies that identified the keywords PFO, ASA, or right-to-left shunt. In this meta-analysis, combined odds ratios were calculated with the use of both fixed and random-effect methods. There are several important issues that can be addressed, including: (1) the frequency of each of these conditions in control populations versus patients with cryptogenic stroke or stroke of known …

Patent Foramen Ovale Closure for Remote Stroke: Better Late Than Never?

Differential Lesion Patterns on T2-weighted Magnetic Resonance Imaging and Fluid-attenuated Inversion Recovery Sequences in Cryptogenic Stroke Patients with Patent Foramen Ovale

Index Event Bias as an Explanation for the Paradoxes of Recurrence Risk Research

Background: Nearly one-quarter of ischemic strokes (IS) in the U.S. are recurrent. We aimed to determine the risk of recurrent IS associated with reduced left ventricular ejection fraction (LVEF) in patients enrolled in the ARCADIA trial. Methods: We performed a post-hoc exploratory analysis in the ARCADIA trial, a phase III RCT of 1,015 cryptogenic stroke patients with atrial cardiopathy from February 2018 to February 2023. Those with LVEF &lt;30% were not eligible. We dichotomized patients with LVEF into &lt;50% and &gt; 50% and built adjusted Cox proportional hazard models to estimate the hazard ratio (HR) of recurrent IS within each LVEF strata by treatment strategy of apixaban versus aspirin. Significance of the interaction was assessed after adjustment for imbalanced covariates found among these groups. Results: The analytic cohort comprised 963 participants, with LVEF &lt;50% in 74 (7.7%) and ≥50% in 889 (92.3%). Participants with LVEF&lt;50% compared to &gt; 50% were younger (65 vs 68 years, p=0.006), more likely male (63.5% vs 44.4%, p=0.002) and of non-White race (45.9% vs 23.8%, p&lt;0.001), and to have coronary artery disease (25.7% vs 8.9%, p&lt;0.001) and CHF (33.8% vs 4.7%, p&lt;0.001), higher N-terminal pro-BNP (median 487 vs 292 pg/mL, p&lt;0.001), larger left atrial diameter index (median 2.1 vs 1.9 cm, p&lt;0.001), and lower LVEF (median 43% vs 62%, p&lt;0.001); P-wave terminal force in V1 was similar. Recurrent IS occurred in 10 (13.5%) patients with LVEF &lt;50% and 61 (6.9%) with LVEF ≥ 50%. The incidence rates of recurrent stroke per 100 person-years were 7.1 (95% CI, 3.8-13.3) with LVEF &lt;50% and 3.9 (95% CI, 3.0-5.0) with LVEF ≥ 50%. In the adjusted analysis, the risk of recurrent stroke was significantly higher with LVEF &lt;50% vs ≥50% (HR 2.23, 95% CI 1.03-4.83). There was no significant interaction between LVEF stratum and the treatment effect (p=0.35; Figure). The risk of recurrent stroke was nominally lower among patients randomized to apixaban than aspirin with LVEF &lt;50% (HR 0.11, 95% C.I. 0.01-1.12), and EF &gt; 50% (HR 0.87, 95% C.I. 0.52-1.45) but did not reach statistical significance. Conclusion: Recurrent stroke risk was higher among patients with LVEF &lt;50% vs ≥50%. The risk of recurrent stroke was not different among patients randomized to apixaban compared to aspirin. Further study is needed to identify the optimal anti-thrombotic treatment for patients with cryptogenic stroke and left ventricular dysfunction.

IS THE PATENT FORAMEN OVALE AN INNOCENT BYSTANDER OR THE REAL CULPRIT? THE MILLION-DOLLAR QUESTION