Intracranial Occlusion in Cryptogenic Stroke Is Not Predictive of Recurrent Ischemic Stroke: A Propensity-Score Matched Analysis of the Cardiac Abnormalities in Stroke Prevention and Risk of Recurrence Study.

Cryptogenic strokes constitute approximately 40% of ischemic strokes in young adults, and most meet criteria for the embolic stroke of undetermined source (ESUS). Two randomized clinical trials, NAVIGATE ESUS and RESPECT ESUS, showed a high rate of stroke recurrence in older adults with ESUS but the prognosis and prognostic factors among younger individuals with ESUS is uncertain. To determine rates of and factors associated with recurrent ischemic stroke and death and new-onset atrial fibrillation (AF) among young adults. This multicenter longitudinal cohort study with enrollment from October 2017 to October 2019 and a mean follow-up period of 12 months ending in October 2020 included 41 stroke research centers in 13 countries. Consecutive patients 50 years and younger with a diagnosis of ESUS were included. Of 576 screened, 535 participants were enrolled after 1 withdrew consent, 41 were found to be ineligible, and 2 were excluded for other reasons. The final follow-up visit was completed by 520 patients. Recurrent ischemic stroke and/or death, recurrent ischemic stroke, and prevalence of patent foramen ovale (PFO). The mean (SD) age of participants was 40.4 (7.3) years, and 297 (56%) participants were male. The most frequent vascular risk factors were tobacco use (240 patients [45%]), hypertension (118 patients [22%]), and dyslipidemia (109 patients [20%]). PFO was detected in 177 participants (50%) who had transthoracic echocardiograms with bubble studies. Following initial ESUS, 468 participants (88%) were receiving antiplatelet therapy, and 52 (10%) received anticoagulation. The recurrent ischemic stroke and death rate was 2.19 per 100 patient-years, and the ischemic stroke recurrence rate was 1.9 per 100 patient-years. Of the recurrent strokes, 9 (64%) were ESUS, 2 (14%) were cardioembolic, and 3 (21%) were of other determined cause. AF was detected in 15 participants (2.8%; 95% CI, 1.6-4.6). In multivariate analysis, the following were associated with recurrent ischemic stroke: history of stroke or transient ischemic attack (hazard ratio, 5.3; 95% CI, 1.8-15), presence of diabetes (hazard ratio, 4.4; 95% CI, 1.5-13), and history of coronary artery disease (hazard ratio, 10; 95% CI, 4.8-22). In this large cohort of young adult patients with ESUS, there was a relatively low rate of subsequent ischemic stroke and a low frequency of new-onset AF. Most recurrent strokes also met the criteria for ESUS, suggesting the need for future studies to improve our understanding of the underlying stroke mechanism in this population.

The concept of embolic stroke of undetermined source (ESUS) unifies a subgroup of cryptogenic strokes based on neuroimaging, a defined minimum set of diagnostic tests, and exclusion of certain causes. Despite an annual stroke recurrence rate of 5%, little is known about the etiology underlying recurrent stroke after ESUS. To identify the stroke subtype of recurrent ischemic strokes after ESUS, to explore the interaction with treatment assignment in each category, and to examine the consistency of cerebral location of qualifying ESUS and recurrent ischemic stroke. The NAVIGATE-ESUS trial was a randomized clinical trial conducted from December 23, 2014, to October 5, 2017. The trial compared the efficacy and safety of rivaroxaban and aspirin in patients with recent ESUS (n = 7213). Ischemic stroke was validated in 309 of the 7213 patients by adjudicators blinded to treatment assignment and classified by local investigators into the categories ESUS or non-ESUS (ie, cardioembolic, atherosclerotic, lacunar, other determined cause, or insufficient testing). Five patients with recurrent strokes that could not be defined as ischemic or hemorrhagic in absence of neuroimaging or autopsy were excluded. Data for this secondary post hoc analysis were analyzed from March to June 2019. Patients were randomly assigned to receive rivaroxaban, 15 mg/d, or aspirin, 100 mg/d. Association of recurrent ESUS with stroke characteristics. A total of 309 patients (205 men [66%]; mean [SD] age, 68 [10] years) had ischemic stroke identified during the median follow-up of 11 (interquartile range [IQR], 12) months (annualized rate, 4.6%). Diagnostic testing was insufficient for etiological classification in 39 patients (13%). Of 270 classifiable ischemic strokes, 156 (58%) were ESUS and 114 (42%) were non-ESUS (37 [32%] cardioembolic, 26 [23%] atherosclerotic, 35 [31%] lacunar, and 16 [14%] other determined cause). Atrial fibrillation was found in 27 patients (9%) with recurrent ischemic stroke and was associated with higher morbidity (median change in modified Rankin scale score 2 [IQR, 3] vs 0 (IQR, 1]) and mortality (15% vs 1%) than other causes. Risk of recurrence did not differ significantly by subtype between treatment groups. For both the qualifying and recurrent strokes, location of infarct was more often in the left (46% and 54%, respectively) than right hemisphere (40% and 37%, respectively) or brainstem or cerebellum (14% and 9%, respectively). In this secondary analysis of randomized clinical trial data, most recurrent strokes after ESUS were embolic and of undetermined source. Recurrences associated with atrial fibrillation were a minority but were more often disabling and fatal. More extensive investigation to identify the embolic source is important toward an effective antithrombotic strategy. ClinicalTrials.gov Identifier: NCT02313909.

Meta-Analysis of Secondary Prevention of Cryptogenic Stroke

Background Cryptogenic strokes comprise 20 to 30% of ischemic strokes and include a substantial proportion classified as embolic stroke of undetermined source (ESUS). However, the optimal antithrombotic strategy for cryptogenic stroke remains contentious. Purpose We conducted a systematic review and meta-analysis to compare the efficacy and safety of oral anticoagulants (OAC) versus antiplatelets in patients with cryptogenic stroke. Methods Six electronic databases of PubMed, Embase, Web of Science, the Cochrane Library, Google Scholar and ClinicalTrials.gov were searched from inception to Feb 15, 2024 to identify relevant randomized controlled trials (RCTs) comparing stroke recurrence and major bleeding rates between OAC and antiplatelets in cryptogenic stroke patients. We included trials adhering to a stringent diagnostic work-up for cryptogenic stroke, defined as cerebral infarction not attributed to definite sources of cardioembolism, large artery atherosclerosis, or small artery disease despite undergoing comprehensive investigations. The primary outcome was recurrent ischemic stroke, and the secondary outcome was major bleeding based on International Society of Thrombosis and Hemostasis criteria. Subgroup analysis was conducted for ESUS patients with an increased risk of cardiac emboli, such as patent foramen ovale (PFO) and atrial cardiopathy, defined as lead V1 terminal P-wave > 5000 μV × ms in electrocardiogram, serum N-terminal pro-B-type natriuretic peptide level > 250 pg/mL, and left atrial diameter (LAE) > 4 cm, or LAE index ≥ 3 cm/m2 on echocardiogram. Hazard ratio (HR) with 95% confidence (CI) was used as a measure of the effect estimates for aforementioned outcomes. Random-effects meta-analysis was performed using a restricted maximum likelihood model given between-study variance is inevitable. Results Our meta-analysis included 9 RCTs with a total of 15,139 patients (OAC = 7,343; antiplatelets = 7,796). ARCADIA, RE-SPECT ESUS, and NAVIGATE ESUS Trial investigated apixaban, dabigatran, and rivaroxaban, respectively, while warfarin was primarily used as OAC in the remaining six trials. Aspirin was predominantly utilized for antiplatelet therapy. There was no significant difference in recurrent ischemic stroke between OAC and antiplatelets (HR, 0.90; 95% CI, 0.78 to 1.04; I2 = 0%). However, OAC use was associated with a significantly higher risk of major bleeding (HR, 1.66; 95% CI, 1.07 to 2.56; I2 = 36%). Subgroup analysis in ESUS patients revealed comparable rates of recurrent ischemic stroke in those with atrial cardiopathy (HR, 0.91; 95% CI, 0.65 to 1.29; I2 = 0%) and PFO (HR, 0.72; 95% CI, 0.49 to 1.07; I2 = 0%). Conclusions Our meta-analysis suggests that OAC use does not decrease the risk of recurrent ischemic stroke compared with antiplatelet use but is associated with a significantly higher risk of major bleeding in patients with cryptogenic stroke.Primary (A) and secondary (B) outcomesSubgroup analysis for recurrent stroke

Section Editor: Marc Fisher MD Eleven years ago, on June 1, 1991, Dr J.P. Mohr addressed delegates of the International Conference on Stroke, Geneva, about anticoagulants as a therapeutic strategy in stroke. He bemoaned the fact that heparin and warfarin had the “bad luck” to be manufactured initially in the post-World War II period, before drugs were evaluated by controlled clinical trials. As a consequence, clinicians judged their effectiveness on the basis of theory and compared their personal experience with historical controls and with those found in the literature. With the passage of time, the drug patents expired, the views and practices of clinicians became polarized, and any commercial and scientific motive to conduct controlled clinical trials of anticoagulation in secondary stroke prevention, once called for, disappeared. Dr Mohr sadly concluded that “there are no [reliable] data really” for anticoagulation after ischemic stroke. This was probably the platform from which he planned, with colleagues, the Warfarin-Aspirin Recurrent Stroke Study (WARSS).1 Noncardioembolic ischemic stroke underpins ≈60% of all first-ever and recurrent strokes. The major causes are (1) thrombotic occlusion of large and medium-sized arteries that is due to in situ atherothrombosis or atherothromboembolism and (2) thrombotic occlusion of small perforating intracerebral arteries affected by microatheroma/lipohyalinosis. The formation of thrombus on the subendothelial tissue of arteries depends on the initial formation of a platelet plug (by means of platelet adhesion, activation, and aggregation) and the generation of a meshwork of fibrin (by means of the coagulation cascade). Antiplatelet drugs are designed to prevent the formation of the “white” platelet plug, and anticoagulants are designed to prevent the formation of the “red” fibrin clot. Theoretically, antiplatelet and anticoagulant therapy should be effective in preventing recurrent noncardioembolic stroke, provided that they can both be administered safely over a long period of time. ### Indirect Comparisons of Effectiveness Compared With Control A …

Rivaroxaban or aspirin for patent foramen ovale and embolic stroke of undetermined source: a prespecified subgroup analysis from the NAVIGATE ESUS trial

Embolic stroke of undetermined source (ESUS) can be attributed to a variety of potential embolic sources, with differential response to anticoagulation. A multicenter, retrospective observational cohort study (27 sites) of consecutive adult patients with acute ischemic stroke due to ESUS (admitted 2015-2024) was conducted. The aim was to compare outcomes after antiplatelet(s) vs anticoagulant (±antiplatelet) treatment in patients with ESUS across potential embolic sources. The time from admission to the primary composite outcome of recurrent stroke, major bleeding, or death was assessed using adjusted Cox proportional hazard regression (clustered by site) and propensity score (PS) matching with (1) inverse probability of treatment weighting (IPTW) and (2) 10:1 nearest-neighbor matching with replacement, adjusting for age, stroke severity, and potential embolic sources (e.g., left ventricular injury and patent foramen ovale). Recurrent stroke, major bleeding, and death were also assessed as secondary outcomes, with stratification by potential embolic sources. Of the 2,328 included patients (n = 230 treated with anticoagulation), the median age was 65 years (interquartile range [IQR] 54-75), 50% were female, and the median NIH Stroke Scale score was 4 (IQR 2-11). Compared with patients treated using antiplatelet(s) therapies, those treated with anticoagulants were not at a lower risk of the primary outcome in the adjusted Cox model (adjusted hazard ratio [aHR] 1.00, 95% CI 0.69-1.45), adjusted IPTW regression model (aHR 1.15, 95% CI 0.79-1.66), or 10:1 PS-matched regression model (aHR 1.00, 95% CI 0.70-1.44). In patients with left ventricular injury, anticoagulation was associated with a lower rate of the primary outcome (aHR 0.35, 95% CI 0.16-0.77; p-interaction <0.01) and trended toward a lower rate of recurrent ischemic stroke (aHR 0.22, 95% CI 0.05-1.08; p-interaction = 0.04) when compared with patients treated with antiplatelet(s). These real-world data validate randomized trial results in ESUS, which reported no net benefit of anticoagulation over antiplatelet therapy. These data suggest possible benefit of anticoagulation in patients with left ventricular injury, as in previous cohort studies, although the findings are limited by the small number of patients treated with anticoagulation. Future trials should evaluate treatment differences in this subgroup. Cardiac Abnormalities in Stroke Prevention and Risk of Recurrence; registration ID: NCT06398366. Registered on May 3, 2024. This study provides Class III evidence that in patients with ESUS, anticoagulation was not superior to antiplatelet therapy in reducing the risk of recurrent stroke, bleeding, or death.

ImportanceA patent foramen ovale (PFO), an opening between the right and left atria during normal fetal development that fails to close after birth, is present in approximately 25% of all adults. Paradoxical embolism, a venous thromboembolism that travels to the systemic circulation typically through a PFO, accounts for about 5% of all strokes and 10% of strokes in younger patients.ObservationsApproximately 50% of patients 60 years or younger with an embolic stroke of undetermined source (cryptogenic stroke) have a PFO, compared with 25% of the general population. The Risk of Paradoxical Embolism (RoPE) score incorporates clinical characteristics (age, history of stroke or transient ischemic attack, diabetes, hypertension, smoking, cortical infarct on imaging) to predict the likelihood that embolic stroke of undetermined source was caused by a PFO. Among patients in the lowest RoPE score category (score <3), PFO prevalence was similar to that in the general population (23%), while PFO prevalence was 77% in patients with a RoPE score of 9 or 10. The PFO-Associated Stroke Causal Likelihood (PASCAL) classification system combines the RoPE score and anatomical criteria from echocardiography (large shunt, atrial septal aneurysm) to classify PFO as the “probable,” “possible,” or “unlikely” cause of otherwise cryptogenic stroke. PFO closure reduces recurrent ischemic stroke in patients 60 years or younger with cryptogenic stroke. In a pooled analysis of 6 trials (3740 patients), the annualized incidence of stroke over a median follow-up of 57 months was 0.47% (95% CI, 0.35%-0.65%) with PFO closure vs 1.09% (95% CI, 0.88%-1.36%) with medical therapy (adjusted hazard ratio, 0.41 [95% CI, 0.28-0.60]). However, the benefits and harms of closure were highly heterogeneous across the trial populations. In patients categorized as PASCAL “probable” (ie, younger patients without vascular risk factors and high-risk PFO anatomical features), there was a 90% decreased relative rate of recurrent ischemic stroke after PFO closure at 2 years (hazard ratio, 0.10 [95% CI, 0.03-0.35]; absolute risk reduction, 2.1% [95% CI, 0.9%-3.4%]). PASCAL “unlikely” patients (eg, older patients with vascular risk factors and no high-risk PFO anatomical features) did not have a lower recurrent stroke rate with PFO closure but had higher risk of procedure- and device-related adverse events, such as atrial fibrillation.Conclusions and RelevancePatent foramen ovale is present in approximately 25% of all adults and is a common cause of stroke in young and middle-aged patients. The PASCAL classification system can help guide patient selection for PFO closure. Percutaneous PFO closure substantially reduces the risk of stroke recurrence in well-selected patients younger than 60 years after cryptogenic stroke.

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

Predictors of Recurrent Ischemic Stroke in Patients with Embolic Strokes of Undetermined Source and Effects of Rivaroxaban Versus Aspirin According to Risk Status: The NAVIGATE ESUS Trial

E112 Parenting a deaf child and coping with stress

Association of Global Cardiac Calcification with Atrial Fibrillation and Recurrent Stroke in Patients with Embolic Stroke of Undetermined Source

Background and Purpose- The sources of emboli in patients with embolic stroke of undetermined source (ESUS) are multiple and may not respond uniformly to anticoagulation. In this exploratory subgroup analysis of patients with carotid atherosclerosis in the NAVIGATE (New Approach Rivaroxaban Inhibition of Factor Xa in a Global Trial Versus ASA to Prevent Embolism)-ESUS trial, we assessed whether the treatment effect in this subgroup is consistent with the overall trial population and investigated the association of carotid atherosclerosis with recurrent ischemic stroke. Methods- Carotid atherosclerosis was analyzed either as the presence of mild (ie, 20%-49%) atherosclerotic stenosis or, separately, as the presence of carotid plaque. Primary efficacy outcome was ischemic stroke recurrence. Safety outcomes were major bleeding and symptomatic intracerebral bleeding. Results- Carotid plaque was present in 40% of participants and mild carotid stenosis in 11%. There was no significant difference in ischemic stroke recurrence between rivaroxaban- and aspirin-treated patients among 490 patients with carotid stenosis (5.0 versus 5.9/100 patient-years, respectively, hazard ratio [HR], 0.85; 95% CI, 0.39-1.87; P for interaction of treatment effect with patients without carotid stenosis 0.78) and among 2905 patients with carotid plaques (5.9 versus 4.9/100 patient-years, respectively, HR, 1.20; 95% CI, 0.86-1.68; P for interaction of treatment effect with patients without carotid stenosis 0.2). Among patients with carotid plaque, major bleeding was more frequent in rivaroxaban-treated patients compared with aspirin-treated (2.0 versus 0.5/100 patient-years, HR, 3.75; 95% CI, 1.63-8.65). Patients with carotid stenosis had similar rate of ischemic stroke recurrence compared with those without (5.4 versus 4.9/100 patient-years, respectively, HR, 1.11; 95% CI, 0.73-1.69), but there was a strong trend of higher rate of ischemic stroke recurrence in patients with carotid plaque compared with those without (5.4 versus 4.3/100 patient-years, respectively, HR, 1.23; 95% CI, 0.99-1.54). Conclusions- In ESUS patients with carotid atherosclerosis, we found no difference in efficacy between rivaroxaban and aspirin for prevention of recurrent stroke, but aspirin was safer, consistent with the overall trial results. Carotid plaque was much more often present ipsilateral to the qualifying ischemic stroke than contralateral, supporting an important etiological role of nonstenotic carotid disease in ESUS. Clinical Trial Registration- URL: https://www.clinicaltrials.gov. Unique identifier: NCT02313909.

Introduction: Embolic strokes of an undetermined source may be caused by various potential embolic sources, which can be better managed by anticoagulant or antiplatelet therapy. Identifying these sources may have diagnostic and therapeutic implications. Our objectives were to assess the prevalence and overlap of different potential embolic sources identified in a population of patients with embolic strokes of undetermined sources, and to evaluate the stroke recurrence rate according to the type and number of potential embolic sources. Methods: We used data from consecutive patients with ischemic stroke admitted to the department of neurology in Fattouma Bourguiba hospital (Monastir, Tunisia), between January 2017 and December 2020. Patients who met the embolic strokes of undetermined source diagnostic criteria according to the criteria of the Cryptogenic Stroke “embolic strokes of undetermined source” International Working Group were selected. The presence of each potential embolic source was assessed, and patients were categorised according to the identified potential embolic sources. The main outcome was ischemic stroke recurrence, and it was collected prospectively during follow-up after the index stroke. Results: Among 330 patients admitted between 2017 and 2020, 66 (20.6%) were classified as embolic strokes of undetermined source (68.2% were men, mean age 57 ±11 years). The three most prevalent potential embolic sources were atrial cardiopathy (N = 47/66; 71.2%), arterial atherosclerosis (N = 46/66; 69.7%) and left ventricular disease (N = 26/66; 39.4%). Most patients (N = 56/66; 84.8%) had ≥2 potential embolic sources. After 6-month of follow up, ischemic stroke recurrence occurred in 18 (27.3%) patients. In survival analysis, the type and the number of potential embolic sources were not statistically associated with stroke recurrence. Conclusion: Most patients with embolic strokes of undetermined source had multiple potential embolic sources, which overlap considerably. The type and number of potential sources were not associated with stroke recurrence. This finding may explain the negative results of large trials of secondary prevention in the Embolic strokes of undetermined source population.

Background and Purpose- Aortic arch atherosclerosis (AAA) is a possible source of embolism in patients with embolic stroke of undetermined source. Previous studies reported high rates of embolic events in patients with AAA, especially those with high-risk AAA. This exploratory analysis of NAVIGATE ESUS (New Approach Rivaroxaban Inhibition of Factor Xa in a Global Trial Versus ASA to Prevent Embolism in Embolic Stroke of Undetermined Source) focused on patients with AAA and assessed their characteristics, stroke recurrence rates, and response to treatment. Methods- The detection of AAA and the assessment of its features were based on transesophageal echocardiography that was done in 19% of participants. AAA plaques were considered to have complex features when reported as complex or ulcerated or were ≥4 mm in thickness or had a mobile thrombus present. Results- Among 1382 participants who had transesophageal echocardiography, 397 (29%) had AAA and 112 (8%) had complex AAA. Mean (SD) age (63 [10] versus 67 [9] versus 69 [9]; P<0.001), prevalence of diabetes mellitus (19% versus 26%, versus 32%; P=0.002), and aortic valvulopathy (10 versus 20 versus 20; P<0.001) increased across no versus noncomplex versus complex AAA, respectively. In multivariable analyses, increasing age, diabetes mellitus, aortic valvulopathy, statin use before randomization, chronic infarcts on imaging, and region were independently associated with any AAA versus no AAA and also with complex AAA versus no AAA. Multiterritorial qualifying infarcts rather than single-territory infarcts were observed in 21% with complex AAA versus 17% noncomplex versus 13% no AAA (P=0.07). Annualized rates of ischemic stroke recurrence were 7.2% versus 4.2% versus 5.6% for complex versus noncomplex versus no AAA, respectively. While prevalence of complex AAA increased with increasing risk score, after adjusting for risk score, we did not observe increased risk of recurrent stroke for patients with complex AAA (hazard ratio, 1.1; 95% CI, 0.53-2.4), although the number of outcomes was limited. In patients with complex AAA, 4 strokes occurred among rivaroxaban-assigned patients and 4 strokes among aspirin-assigned patients. Conclusions- Complex AAA is prevalent in embolic stroke of undetermined source patients and is associated with atherosclerotic burden. Whether complex AAA independently increases recurrent stroke risk and whether a non-vitamin-K oral anticoagulant as compared with aspirin may be effective for reducing recurrent stroke requires additional study. Clinical Trial Registration- URL: https://www.clinicaltrials.gov. Unique identifier: NCT02313909.