Search

Introduction: Migraine is an established risk factor for cerebral ischemic stroke, with an especially robust association in patients with migraine with aura. However, it is not known if migraine is a risk factor for retinal stroke (central or branch retinal artery occlusion; CRAO or BRAO)., Methods: We performed a retrospective, observational, cohort study using population-based data from the State Inpatient Databases and State Emergency Department Databases from New York (2006-2015), California (2003-2011), and Florida (2006-2015) to determine the association between hospital-documented migraine and retinal stroke. The primary exposure was hospital-documented migraine (ascertained from admission or emergency department diagnosis codes). The primary endpoint was time to hospital-documented CRAO (ICD-9-CM code 362.31 in the primary diagnosis position) and secondary endpoints included time to BRAO and any retinal artery occlusion (RAO). Cause-specific hazard models were used to model the association between migraine and subsequent CRAO., Results: Of 39,835,024 patients included in the study, 1109,140 had migraine documented during our two year ascertainment window. Patients with migraine were younger (40.2±15.2 vs. 46.9±19.8, standardized difference (SD) 0.38), more likely to be female (81.4 % vs. 54.7 %, SD 0.6), and had a lower burden of atrial fibrillation (4.5 % vs. 6.9 %, SD 0.1), chronic kidney disease (1.9 % vs. 3.6 %, SD 0.2), and congestive cardiac failure (2.7 % vs. 5.1 %, SD 0.12). Migraine was not associated with CRAO in the primary diagnostic position (adjusted hazard rate (aHR) 1.15 (95 % CI: 0.79-1.67). However, it was associated with CRAO in any diagnostic position (aHR 1.39 (95 % CI: 1.08-1.78). As positive controls, we replicated previously established associations of migraine with cerebral ischemic stroke (aHR 1.35 (95 % CI: 1.32-1.38) and embolic ischemic stroke (aHR 1.15 (95 % CI: 1.08-1.22)., Conclusions: In a large, nationally-representative, claims-based study of patients from 3 regions in the United States (US), we did not find an adjusted association between migraine and a primary discharge diagnosis of CRAO. Our hypothesis-generating finding that migraine was associated with CRAO when using a broader definition sets the stage for future work leveraging both outpatient and pharmacy based claims to further explore this finding., Competing Interests: Declaration of Competing Interest JL reported none. AS reported none. SU reported none. HRA reported none. ADH is supported by NIH-NINDS (K23NS105924), has received investigator initiated clinical research funding from the AAN, has received consultant fees from Integra and Novo Nordisk, has equity in TitinKM and Certus, and receives author fees from UpToDate. VB is supported by the National Institutes of Health’s National Eye Institute core grant P30-EY06360 (Department of Ophthalmology, Emory University School of Medicine) and by a departmental grant from Research to Prevent Blindness (New York, NY), and is a consultant for GenSight Biologics and Neurophoenix. MS is supported by the National Institutes of Health (R56AG074279, K76AG060001, R01AG078803, RF1NS129735, RF1NS130334 and R21AG070859). He has received fees from Labaton Sucharow and Raymond James and Associates for consulting unrelated to this work and receives a stipend for chairing the DSMB for the ongoing REVISION trial. ES reported none. SP received research support from BMS/Pfizer, Boehringer-Ingelheim, Daiichi Sankyo, European Union, German Federal Joint Committee Innovation Fund, and German Federal Ministry of Education and Research, Helena Laboratories and Werfen as well as speakers’ honoraria/consulting fees from Alexion, AstraZeneca, Bayer, Boehringer-Ingelheim, BMS/Pfizer, Daiichi Sankyo, Portola, and Werfen (all outside the submitted work). NOP reported none. YX is funded by the NIA (R01AG062770, R01AG066672), has research funding from the American Heart Association, Genentech, Daiichi Sankyo and Janssen and has received honoraria from Boehringer Ingelheim, and Portola. EO reported none. BMG is supported by the National Institutes of Health (K23HL161426) and the American Heart Association (23MRFSCD1077188)., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Importance: Clinical trials have suggested that prehospital management in a mobile stroke unit (MSU) improves functional outcomes in patients with acute ischemic stroke who are potentially eligible for intravenous thrombolysis, but there is a paucity of real-world evidence from routine clinical practice on this topic., Objective: To determine the association between prehospital management in an MSU vs standard emergency medical services (EMS) management and the level of global disability at hospital discharge., Design, Setting, and Participants: This was a retrospective, observational, cohort study that included consecutive patients with a final diagnosis of ischemic stroke who received either prehospital management in an MSU or standard EMS management between August 1, 2018, and January 31, 2023. Follow-up ended at hospital discharge. The primary analytic cohort included those who were potentially eligible for IV thrombolysis. A separate, overlapping cohort including all patients regardless of diagnosis was also analyzed. Patient data were obtained from the American Heart Association's Get With The Guidelines-Stroke (GWTG-Stroke) Program, a nationwide, multicenter quality assurance registry. This analysis was completed in May 2024., Exposure: Prehospital management in an MSU (vs standard EMS management)., Main Outcomes and Measures: The primary efficacy end point was the utility-weighted modified Rankin Scale (UW-mRS) score. The secondary efficacy end point was independent ambulation status. The coprimary safety end points were symptomatic intracranial hemorrhage (sICH) and in-hospital mortality., Results: Of 19 433 patients (median [IQR] age, 73 [62-83] years; 9867 female [50.8%]) treated at 106 hospitals, 1237 (6.4%) received prehospital management in an MSU. Prehospital management in an MSU was associated with a better score on the UW-mRS at discharge (adjusted mean difference, 0.03; 95% CI, 0.01-0.05) and a higher likelihood of independent ambulation at discharge (53.3% [468 of 878 patients] vs 48.3% [5868 of 12 148 patients]; adjusted risk ratio [aRR], 1.08; 95% CI, 1.03-1.13). There was no statistically significant difference in sICH (5.2% [57 of 1094] vs 4.2% [545 of 13 014]; aRR, 1.30; 95% CI, 0.94-1.75]) or in-hospital mortality (5.7% [70 of 1237] vs 6.2% [1121 of 18 196]; aRR, 1.03; 95% CI, 0.78-1.27) between the 2 groups., Conclusions and Relevance: Among patients with acute ischemic stroke potentially eligible for intravenous thrombolysis, prehospital management in an MSU compared with standard EMS management was associated with a significantly lower level of global disability at hospital discharge. These findings support policy efforts to expand access to prehospital MSU management.

Rationale: Meta-analyses of case series of non-arteritic central retinal artery occlusion (CRAO) indicate beneficial effects of intravenous thrombolysis when initiated early after symptom onset. Randomized data are lacking to address this question., Aims: The REperfusion therapy with intravenous alteplase for recovery of VISION in acute central retinal artery occlusion (REVISION) investigates intravenous alteplase within 4.5 h of monocular vision loss due to acute CRAO., Methods: This study is the randomized (1:1), double-blind, placebo-controlled, multicenter adaptive phase III trial., Study Outcomes: Primary outcome is functional recovery to normal or mildly impaired vision in the affected eye defined as best-corrected visual acuity of the Logarithm of the Minimum Angle of Resolution of 0.5 or less at 30 days (intention-to-treat analysis). Secondary efficacy outcomes include modified Rankin Score at 90 days and quality of life. Safety outcomes include symptomatic intracranial hemorrhage, major bleeding (International Society on Thrombosis and Haemostasis definition) and mortality. Exploratory analyses of optical coherence tomography/angiography, ultrasound and magnetic resonance imaging (MRI) biomarkers will be conducted., Sample Size: Using an adaptive design with interim analysis at 120 patients, up to 422 participants (211 per arm) would be needed for 80% power (one-sided alpha = 0.025) to detect a difference of 15%, assuming functional recovery rates of 10% in the placebo arm and 25% in the alteplase arm., Discussion: By enrolling patients within 4.5 h of CRAO onset, REVISION uses insights from meta-analyses of CRAO case series and randomized thrombolysis trials in acute ischemic stroke. Increased rates of early reperfusion and good neurological outcomes in stroke may translate to CRAO with its similar pathophysiology., Trial Registration: ClinicalTrials.gov: NCT04965038; EU Trial Number: 2023-507388-21-00., Competing Interests: Declaration of conflicting interestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Alteplase/placebo is provided by Boehringer Ingelheim at no costs. Boehringer Ingelheim was given opportunity to review the manuscript for medical/scientific accuracy and intellectual property considerations. The authors did not receive any payment related to trial/manuscript development.

Objectives: A reliable method of predicting large vessel occlusion (LVO) stroke in data sets without neuroimaging could be retrospectively applied to expand research efforts., Methods: We conducted a retrospective, cross-sectional cohort analysis of the Get With The Guidelines (GWTG)-Stroke registry. We included adult patients with a final diagnosis of ischemic stroke from 2016 to 2021 who had brain and vascular imaging and excluded those with missing data or posterior circulation stroke., Results: We included 416,022 patients of which 125,381 (30.1%) had LVO. The mean age was 71 years, and 48.2% were female. The area under the receiver operating curve (AUC) for the final model, including age, sex, hypertension, dyslipidemia, atrial fibrillation, diabetes, TOAST stroke mechanism, and NIH Stroke Scale (NIHSS), was 0.79 (95% CI 0.79-0.80). Without TOAST mechanism, the AUC was 0.74. The specificity did not exceed 0.5 using different cut points for the NIHSS., Discussion: We found that 30% of adult acute ischemic stroke patients in GWTG-Stroke have LVO and that the combination of clinical covariates and NIHSS is only moderately predictive of LVO status. These results are consistent with previous studies and suggest it may not be possible to retrospectively predict LVO with high accuracy in data sets without vascular neuroimaging.

Background: Small, randomized trials of patients with cervical artery dissection showed conflicting results regarding optimal stroke prevention strategies. We aimed to compare outcomes in patients with cervical artery dissection treated with antiplatelets versus anticoagulation., Methods: This is a multicenter observational retrospective international study (16 countries, 63 sites) that included patients with cervical artery dissection without major trauma. The exposure was antithrombotic treatment type (anticoagulation versus antiplatelets), and outcomes were subsequent ischemic stroke and major hemorrhage (intracranial or extracranial hemorrhage). We used adjusted Cox regression with inverse probability of treatment weighting to determine associations between anticoagulation and study outcomes within 30 and 180 days. The main analysis used an as-treated crossover approach and only included outcomes occurring with the above treatments., Results: The study included 3636 patients (402 [11.1%] received exclusively anticoagulation and 2453 [67.5%] received exclusively antiplatelets). By day 180, there were 162 new ischemic strokes (4.4%) and 28 major hemorrhages (0.8%); 87.0% of ischemic strokes occurred by day 30. In adjusted Cox regression with inverse probability of treatment weighting, compared with antiplatelet therapy, anticoagulation was associated with a nonsignificantly lower risk of subsequent ischemic stroke by day 30 (adjusted hazard ratio [HR], 0.71 [95% CI, 0.45-1.12]; P =0.145) and by day 180 (adjusted HR, 0.80 [95% CI, 0.28-2.24]; P =0.670). Anticoagulation therapy was not associated with a higher risk of major hemorrhage by day 30 (adjusted HR, 1.39 [95% CI, 0.35-5.45]; P =0.637) but was by day 180 (adjusted HR, 5.56 [95% CI, 1.53-20.13]; P =0.009). In interaction analyses, patients with occlusive dissection had significantly lower ischemic stroke risk with anticoagulation (adjusted HR, 0.40 [95% CI, 0.18-0.88]; P interaction =0.009)., Conclusions: Our study does not rule out the benefit of anticoagulation in reducing ischemic stroke risk, particularly in patients with occlusive dissection. If anticoagulation is chosen, it seems reasonable to switch to antiplatelet therapy before 180 days to lower the risk of major bleeding. Large prospective studies are needed to validate our findings., Competing Interests: Disclosures Disclosures provided by Dr Nguyen in compliance with American Heart Association annual Journal Editor Disclosure Questionnaire are available at https://www.ahajournals.org/editor-coi-disclosures. Dr Arnold reports compensation from Boehringer Ingelheim, AstraZeneca, Bayer, Bristol-Myers Squibb, Covidien, Daiichi Sankyo, Novartis, Sanofi, Pfizer, Medtronic, Novo Nordisk, and Amgen for consultant services. Dr Lester reports a provisional patent for Methods and compositions for disrupting tau aggregates. Dr Touze reports compensation from Elsevier for other services and employment by Caen. J.E. Kaufman reports grants from Goldschmidt Jacobson-Stiftung. Dr Traenka reports travel support from Bayer Healthcare. Dr Aguiar de Sousa reports compensation from Daiichi Sankyo, Bayer, AstraZeneca, Johnson & Johnson, and Fundação Bial for other services; compensation from the University of British Columbia for data and safety monitoring services; compensation from Organon & Co for consultant services. Dr Rosa reports grants from Merck Sharp & Dohme Corporation. Dr Field reports compensation from HLS Therapeutics, AstraZeneca Canada, and Roche for consultant services; service as a board member for Destine Health; and compensation from the Canadian Medical Protective Association for expert witness services; and grants from Bayer. Dr Leker reports compensation from Medtronic, Ischemaview, Bayer, Abbott Diabetes Care, Biogen, Janssen Biotech, and Boehringer Ingelheim for other services. Dr Nolte reports compensation from Daiichi Sankyo Europe GmbH, Boehringer Ingelheim, Pfizer, Bristol-Myers Squibb, and Alexion Pharmaceuticals for consultant services; and compensation from AstraZeneca, Abbott Canada, Deutsches Zentrum für Neurodegenerative Erkrankungen, Novartis, Portola Pharmaceuticals, Deutsches Zentrum für Herz-Kreislaufforschung, and Novartis for other services. Dr Poppe reports grants from Foundation Brain Canada, Heart and Stroke Foundation of Canada, and Stryker; and compensation from Roche for other services. Dr Liebeskind reports compensation from Medtronic, Genentech, Cerenovus, Stryker, and Rapid Medical Ltd, for consultant services. B. Mac Grory reports grants from the National Institutes of Health; employment by Duke University Medical Center; compensation from Bayer for other services; grants from the American Heart Association, Duke Bass Connections, and the Duke Office of Physician Scientist Development. Dr Al Kasab reports compensation from Stryker for other services and employment by Medical University of South Carolina. Dr Kicielinski reports compensation from Stryker, Penumbra Inc, Medtronic, and MicroVention Inc, for other services; travel support from MicroVention Inc; and employment by Medical University of South Carolina and Elsevier. Dr de Havenon reports stock options in TitinKM and Certus; grants from the National Institutes of Health; and compensation from Novo Nordisk for consultant services. Dr Siegler reports grants from Philips and employment by the University of Chicago. Dr Willey reports compensation from Edwards Lifesciences Corporation and Abbott Fund for end point review committee services; compensation from Uptodate for other services; and compensation from the Abbott Laboratories for consultant services. Dr Sharma reports a provisional patent for a stroke etiology classifier algorithm and grants from the National Institutes of Health Clinical Center. Dr Martins reports compensation from Pfizer, Medtronic, Servier Affaires Medicales, Daiichi Sankyo, Bayer, Novo Nordisk, Novartis, Penumbra Inc, and Boehringer Ingelheim for other services. Dr Simpkins reports grants from the National Institutes of Health. Dr Stretz reports grants from Massachusetts General Hospital. Dr Furie reports compensation from Janssen Biotech for consultant services. The other authors report no conflicts

Importance: Intracerebral hemorrhage (ICH) is the deadliest stroke subtype, and mortality rates are especially high in anticoagulation-associated ICH. Recently, specific anticoagulation reversal strategies have been developed, but it is not clear whether there is a time-dependent treatment effect for door-to-treatment (DTT) times in clinical practice., Objective: To evaluate whether DTT time is associated with outcome among patients with anticoagulation-associated ICH treated with reversal interventions., Design, Setting, and Participants: This cohort study used data from the American Heart Association Get With The Guidelines-Stroke quality improvement registry. Patients with ICH who presented within 24 hours of symptom onset across 465 US hospitals from 2015 to 2021 were included. Data were analyzed from January to September 2023., Exposures: Anticoagulation-associated ICH., Main Outcomes and Measures: DTT times and outcomes were analyzed using logistic regression modeling, adjusted for demographic, history, baseline, and hospital characteristics, with hospital-specific random intercepts to account for clustering by site. The primary outcome of interest was the composite inpatient mortality and discharge to hospice. Additional prespecified secondary outcomes, including functional outcome (discharge modified Rankin Scale score, ambulatory status, and discharge venue), were also examined., Results: Of 9492 patients with anticoagulation-associated ICH and documented reversal intervention status, 4232 (44.6%) were female, and the median (IQR) age was 77 (68-84) years. A total of 7469 (78.7%) received reversal therapy, including 4616 of 5429 (85.0%) taking warfarin and 2856 of 4069 (70.2%) taking a non-vitamin K antagonist oral anticoagulant. For the 5224 patients taking a reversal intervention with documented workflow times, the median (IQR) onset-to-treatment time was 232 (142-482) minutes and the median (IQR) DTT time was 82 (58-117) minutes, with a DTT time of 60 minutes or less in 1449 (27.7%). A DTT time of 60 minutes or less was associated with decreased mortality and discharge to hospice (adjusted odds ratio, 0.82; 95% CI, 0.69-0.99) but no difference in functional outcome (ie, a modified Rankin Scale score of 0 to 3; adjusted odds ratio, 0.91; 95% CI, 0.67-1.24). Factors associated with a DTT time of 60 minutes or less included White race, higher systolic blood pressure, and lower stroke severity., Conclusions and Relevance: In US hospitals participating in Get With The Guidelines-Stroke, earlier anticoagulation reversal was associated with improved survival for patients with ICH. These findings support intensive efforts to accelerate evaluation and treatment for patients with this devastating form of stroke.

Background: Patients with ischemic stroke and concomitant COVID-19 infection have worse outcomes than those without this infection, but the impact of COVID-19 on hemorrhagic stroke remains unclear. We aimed to assess if COVID-19 worsens outcomes in intracerebral hemorrhage (ICH)., Methods and Results: We conducted an observational study of ICH outcomes using Get With The Guidelines Stroke data. We compared patients with ICH who were COVID-19 positive and negative during the pandemic (March 2020-February 2021) and prepandemic (March 2019-February 2020). Main outcomes were poor functional outcome (defined as a modified Rankin scale score of 4 to 6 at discharge), mortality, and discharge to a skilled nursing facility or hospice. The first stage included 60 091 patients with ICH who were COVID-19 negative and 1326 COVID-19 positive. In multivariable analyses, patients with ICH with versus without COVID-19 infection had 68% higher odds of poor outcome (odds ratio [OR], 1.68 [95% CI, 1.41-2.01]), 51% higher odds of mortality (OR, 1.51 [95% CI, 1.33-1.71]), and 66% higher odds of being discharged to a skilled nursing facility/hospice (OR, 1.66 [95% CI, 1.43-1.93]). The second stage included 62 743 prepandemic and 64 681 intrapandemic cases with ICH. In multivariable analyses, patients with ICH admitted during versus before the COVID-19 pandemic had 10% higher odds of poor outcomes (OR, 1.10 [95% CI, 1.07-1.14]), 5% higher mortality (OR, 1.05 [95% CI, 1.02-1.08]), and no significant difference in the risk of being discharged to a skilled nursing facility/hospice (OR, 0.93 [95% CI, 0.90-0.95])., Conclusions: The pathophysiology of the COVID-19 infection and changes in health care delivery during the pandemic played a role in worsening outcomes in the patient population with ICH.

Importance: Understanding is needed of racial and ethnic-specific trends in care quality and outcomes associated with the US nationwide quality initiative Target: Stroke (TS) in targeting thrombolysis treatment for acute ischemic stroke., Objective: To examine whether the TS quality initiative was associated with improvement in thrombolysis metrics and outcomes across racial and ethnic groups., Design, Setting, and Participants: This retrospective cohort study included patients who presented within 4.5 hours of ischemic stroke onset at hospitals participating in the Get With The Guidelines-Stroke initiative from January 1, 2003, to December 31, 2021. The data analysis was performed between December 15, 2022, and November 27, 2023., Exposures: TS phases I (2010-2013), II (2014-2018), and III (2019-2021)., Main Outcomes and Measures: The primary outcomes were thrombolysis rates and time metrics. Patient function and mortality were secondary outcomes., Results: Analyses included 1 189 234 patients, of whom 1 053 539 arrived to the hospital within 4.5 hours. The cohort included 50.4% female and 49.6% male patients and 2.8% Asian [median (IQR) age, 72 (61-82) years], 15.2% Black [median (IQR) age, 64 (54-75) years], 7.3% Hispanic [median (IQR) age, 68 (56-79) years], and 74.1% White [median (IQR) age, 75 (63-84) years] patients). Unadjusted thrombolysis rates increased in both the pre-TS (2003-2009) and TS periods in all racial and ethnic groups from 10% to 15% in 2003 to 43% to 46% in 2021, but disparities were observed in adjusted analyses and persisted in TS phase III, with Asian, Black, and Hispanic patients having significantly lower odds of receiving thrombolysis than White patients (adjusted odds ratio, 0.85 [95% CI, 0.81-0.90], 0.76 [95% CI, 0.74-0.78], and 0.86 [95% CI, 0.83-0.89], respectively). Door-to-needle (DTN) times improved in all racial and ethnic groups during TS, with DTN times of 60 minutes or less increasing from 26% to 28% in 2009 to 66% to 72% in 2021. However, in adjusted analyses, racial and ethnic disparities emerged. During TS phase III, compared with White patients, Asian, Black, and Hispanic patients had significantly lower odds of receiving thrombolysis with a DTN time of 60 minutes or less compared with White patients (risk-adjusted odds ratios, 0.91 [95% CI, 0.84-0.98], 0.78 [95% CI, 0.75-0.81], and 0.87 [95% CI, 0.83-0.92], respectively). During TS, clinical outcomes improved for all racial and ethnic groups from pre-TS, with TS phase III showing higher odds of ambulation at discharge among Asian, Black, Hispanic, and White patients. Asian, Black, and Hispanic patients were less likely to present within 4.5 hours., Conclusions and Relevance: In this cohort study of patients with ischemic stroke, the TS quality initiative was associated with improvement in thrombolysis frequency, timeliness, and outcomes for all racial and ethnic groups. However, disparities persisted, indicating a need for further interventions.

BACKGROUND: Rivaroxaban and dabigatran were not superior to aspirin in trials of patients with embolic stroke of undetermined source (ESUS). It is unknown whether apixaban is superior to aspirin in patients with ESUS and known risk factors for cardioembolism. METHODS: We conducted a multicenter, randomized, open-label, blinded-outcome trial of apixaban (5 mg twice daily) compared with aspirin (100 mg once daily) initiated within 28 days after ESUS in patients with at least one predictive factor for atrial fibrillation or a patent foramen ovale. Cardiac monitoring was mandatory, and aspirin treatment was switched to apixaban in case of atrial fibrillation detection. The primary outcome was any new ischemic lesion on brain magnetic resonance imaging (MRI) during 12-month follow-up. Secondary outcomes included major and clinically relevant nonmajor bleeding. RESULTS: A total of 352 patients were randomly assigned to receive apixaban (178 patients) or aspirin (174 patients) at a median of 8 days after ESUS. At 12-month follow-up, MRI follow-up was available in 325 participants (92.3%). New ischemic lesions occurred in 23 of 169 (13.6%) participants in the apixaban group and in 25 of 156 (16.0%) participants in the aspirin group (adjusted odds ratio, 0.79; 95% confidence interval, 0.42 to 1.48; P=0.57). Major and clinically relevant nonmajor bleeding occurred in five and seven participants, respectively (1-year cumulative incidences, 2.9 and 4.2; hazard ratio, 0.68; 95% confidence interval, 0.22 to 2.16). Serious adverse event rates were 43.9 per 100 person-years in those given apixaban and 45.7 per 100 person-years in those given aspirin. The Apixaban for the Treatment of Embolic Stroke of Undetermined Source trial was terminated after a prespecified interim analysis as a result of futility. CONCLUSIONS: Apixaban treatment was not superior to cardiac monitoring-guided aspirin in preventing new ischemic lesions in an enriched ESUS population. (Funded by Bristol-Myers Squibb and Medtronic Europe; ClinicalTrials.gov number, NCT02427126.)

Rationale: Oxygen is essential for cellular energy metabolism. Neurons are particularly vulnerable to hypoxia. Increasing oxygen supply shortly after stroke onset could preserve the ischemic penumbra until revascularization occurs., Aims: PROOF investigates the use of normobaric oxygen (NBO) therapy within 6 h of symptom onset/notice for brain-protective bridging until endovascular revascularization of acute intracranial anterior-circulation occlusion., Methods and Design: Randomized (1:1), standard treatment-controlled, open-label, blinded endpoint, multicenter adaptive phase IIb trial., Study Outcomes: Primary outcome is ischemic core growth (mL) from baseline to 24 h (intention-to-treat analysis). Secondary efficacy outcomes include change in NIHSS from baseline to 24 h, mRS at 90 days, cognitive and emotional function, and quality of life. Safety outcomes include mortality, intracranial hemorrhage, and respiratory failure. Exploratory analyses of imaging and blood biomarkers will be conducted., Sample Size: Using an adaptive design with interim analysis at 80 patients per arm, up to 456 participants (228 per arm) would be needed for 80% power (one-sided alpha 0.05) to detect a mean reduction of ischemic core growth by 6.68 mL, assuming 21.4 mL standard deviation., Discussion: By enrolling endovascular thrombectomy candidates in an early time window, the trial replicates insights from preclinical studies in which NBO showed beneficial effects, namely early initiation of near 100% inspired oxygen during short temporary ischemia. Primary outcome assessment at 24 h on follow-up imaging reduces variability due to withdrawal of care and early clinical confounders such as delayed extubation and aspiration pneumonia., Trial Registrations: ClinicalTrials.gov: NCT03500939; EudraCT: 2017-001355-31., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Stroke is the fifth leading cause of death in the United States, one of the leading contributors to Medicare cost, including through Medicare hospice benefits, and the rate of stroke mortality has been increasing since 2013. We hypothesized that hospice utilization among Medicare beneficiaries with stroke has increased over time and that the increase is associated with trends in stroke death rate., Methods: Using Medicare Part A claims data and Centers for Disease Control mortality data at a national and state level from 2013 to 2019, we report the proportion and count of Medicare hospice beneficiaries with stroke as well as the stroke death rate (per 100 000) in Medicare-eligible individuals aged ≥65 years., Results: From 2013 to 2019, the number of Medicare hospice beneficiaries with stroke as their primary diagnosis increased 104.1% from 78 812 to 160 884. The number of stroke deaths in the United States in individuals aged ≥65 years also increased from 109 602 in 2013 to 129 193 in 2019 (17.9% increase). In 2013, stroke was the sixth most common primary diagnosis for Medicare hospice, while in 2019 it was the third most common, surpassed only by cancer and dementia. The correlation between the change from 2013 to 2019 in state-level Medicare hospice for stroke and stroke death rate for Medicare-eligible adults was significant (Spearman ρ=0.5; P <0.001). In a mixed-effects model, the variance in the state-level proportion of Medicare hospice for stroke explained by the state-level stroke death rate was 48.2%., Conclusions: From 2013 to 2019, the number of Medicare hospice beneficiaries with a primary diagnosis of stroke more than doubled and stroke jumped from the sixth most common indication for hospice to the third most common. While increases in stroke mortality in the Medicare-eligible population accounts for some of the increase of Medicare hospice beneficiaries, over half the variance remains unexplained and requires additional research., Competing Interests: Disclosures Dr de Havenon has received investigator-initiated clinical research funding from the American Academy of Neurology, has received consultant fees from Integra and Novo Nordisk, has equity in TitinKM and Certus, and receives author fees from UpToDate. Dr Sheth reports investigator-initiated clinical research funding to Yale from Hyperfine, Biogen, and Bard, from Sense and Zoll for data and safety monitoring services, from Cerevasc, Astrocyte, CSL Behring, Certus, and Rhaeos for consultant services, and a patent pending for Stroke wearables licensed to Alva Health. Dr Burke reports employment by Ohio State University and University of Michigan and funding from the American Heart Association. Dr Creutzfeldt reports funding from the National Institutes of Health NIH-NINR. Dr Mac Grory reports employment by Duke University and funding from NIH-National Institute of Neurological Disorders and Stroke (NINDS) and the American Heart Association. Dr Skolarus reports employment by Northwestern University and funding from NIH-NINDS and the American Heart Association. The other author reports no conflicts.

Central retinal artery occlusion (CRAO; retinal stroke or eye stroke) is an under-recognized, disabling form of acute ischemic stroke which causes severe visual loss in one eye. The classical risk factor for CRAO is ipsilateral carotid stenosis; however, nearly half of patients with CRAO do not have high-grade carotid stenosis, suggesting that other cardiovascular risk factors may exist for CRAO. Specifically, prior studies have suggested that cardioembolism, driven by underlying atrial fibrillation, may predispose patients to CRAO. We describe the design of an observational, population-based study in this protocol. We evaluate two specific objectives: 1) To determine if atrial fibrillation is an independent risk factor for CRAO after adjusting for medical and cardiovascular risk; 2) To determine if use of oral anticoagulation can modify the risk of CRAO for patients with atrial fibrillation. This protocol lays out our strategy for cohort definition, case and control definition, comorbidity ascertainment, and statistical methods., Competing Interests: “I have read the journal’s policy and the authors of the manuscript have the following interests: J.B. Lusk is supported by the American Heart Association. Dr Biousse is supported by the National Institutes of Health National Eye Institute core grant P30-EY06360 (Department of Ophthalmology, Emory University School of Medicine) and by a departmental grant from the Research to Prevent Blindness (New York, NY) and is a consultant for GenSight Biologics and Neurophoenix. Dr Schrag reports compensation from the REVISION trial for data and safety monitoring services; compensation from Raymond James for consultant services; grants from the National Institutes of Health; and compensation from Labaton Sucharow for consultant services. Dr Poli reports grants from the Helena Laboratories Corporation, Bristol Myers Squibb, Boehringer Ingelheim, and the Daiichi Sankyo Company; compensation from Alexion Pharmaceuticals, Inc, Portola Pharmaceuticals LLC, Werfen USA LLC, and AstraZeneca for consultant services; and compensation from Boehringer Ingelheim, Bristol Myers Squibb, the Daiichi Sankyo Company, and Bayer Healthcare for other services. Dr Piccini reports compensation from Biotronik, Inc, Philips, Medtronic, Boston Scientific Corporation, ResMed Foundation, Ablacon, LivaNova USA, Inc, AltaThera Pharmaceuticals LLC, AbbVie Biotherapeutics, Abbott Laboratories, ElectroPhysiology Frontiers, Itamar Medical, Inc, ARCA biopharma, Pfizer, Bristol Myers Squibb, Sanofi US Services, Inc, and Milestone Scientific, for consultant services; employment by the Duke University; and grants from the American Heart Association and iRhythm Technologies. Dr O’Brien reports compensation from Boehringer Ingelheim for consultant services and employment by the Duke University. B. Mac Grory is supported by a grant from the National Institutes of Health (K23HL161426). The other authors report no conflicts. This does not alter our adherence to PLOS ONE policies on sharing data and materials.”, (Copyright: © 2023 Lusk et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: The thrombectomy-capable stroke center (TSC) is a recently introduced intermediate tier of accreditation for hospitals at which patients with acute ischemic stroke receive care. The comparative quality and clinical outcomes of reperfusion therapies at TSCs, primary stroke centers (PSCs), and comprehensive stroke centers (CSCs) have not been well delineated., Methods: We conducted a retrospective, observational, cohort study from 2018 to 2020 that included patients with acute ischemic stroke who received endovascular thrombectomy (EVT) and intravenous thrombolysis reperfusion therapies at CSCs, TSCs, or PSCs. Participants were recruited from Get With The Guidelines-Stroke registry. Study end points included timeliness of intravenous thrombolysis and EVT, successful reperfusion, discharge destination, discharge mortality, and functional independence at discharge., Results: Among 84 903 patients, 48 682 received EVT, of whom 73% were treated at CSCs, 22% at PSCs, and 4% at TSCs. The median annual EVT volume was 76 for CSCs, 55 for TSCs, and 32 for PSCs. Patient differences by center status included higher National Institutes of Health Stroke Scale score, longer onset-to-arrival time, and higher transfer-in rates for CSCs, TSCs, and PSCs, respectively. In adjusted analyses, the likelihood of achieving the goal door-to-needle time was higher in CSCs compared with PSCs (odds ratio [OR], 1.39 [95% CI, 1.17-1.66]) and in TSCs compared with PSCs (OR, 1.45 [95% CI, 1.08-1.96]). Likewise, the odds of achieving the goal door-to-puncture time were higher in CSCs compared with PSCs (OR, 1.58 [95% CI, 1.13-2.21]). CSCs and TSCs also demonstrated better clinical efficacy outcomes compared with PSCs. The odds of discharge to home or rehabilitation were higher in CSCs compared with PSCs (OR, 1.18 [95% CI, 1.06-1.31]), whereas the odds of in-hospital mortality or discharge to hospice were lower in both CSCs compared with PSCs (OR, 0.87 [95% CI, 0.81-0.94]) and TSCs compared with PSCs (OR, 0.86 [95% CI, 0.75-0.98]). There were no significant differences in any of the quality-of-care metrics and clinical outcomes between TSCs and CSCs., Conclusions: In this study representing national US practice, CSCs and TSCs exceeded PSCs in key quality-of-care reperfusion metrics and outcomes, whereas TSCs and CSCs demonstrated a similar performance. With more than one-fifth of all EVT procedures during the study period conducted at PSCs, it may be desirable to explore national initiatives aimed at facilitating the elevation of eligible PSCs to a higher certification status., Competing Interests: Disclosures Dr Raychev reports equity for consulting for Rapid Medical, Perflow Medical, Spartan Micro, and fees for consulting for Boehringer Ingelheim, NeuroVasc, Medtronic. Dr Grory reports funding from the National Heart, Lung, and Blood Institute (K23HL161426). Dr Fonarow reports receiving research support from the Patient Centered Outcome Research Institute and the National Institutes of Health, and employee of University of California which holds a patent on an endovascular device for stroke. Dr Messé reports receiving research support from the National Institutes of Health, WL Gore, Mallinkrodt, Biogen; consulting fees from Terumo, Boston Scientific, and EmStop; and reports equity in Neuralert Technologies. Dr Schwamm reports fees for consulting regarding trial design and conduct to Genentech (late window thrombolysis) and as a steering committee member (TIMELESS NCT03785678); user interface design and usability to LifeImage; stroke systems of care design to the Massachusetts Department of Public Health; as a member of a Data Safety Monitoring Board (DSMB) for Penumbra (MIND NCT03342664) and for Diffusion Pharma PHAST-TSC NCT03763929); Serving as National principal investigator for Medtronic (Stroke AF NCT02700945); Site PI, StrokeNet Network NINDS (New England Regional Coordinating Center U24NS107243) PRIME® Education: stroke systems of care and improving time to thrombolysis, and Boehringer-Ingelheim: stroke systems of care and improving time to thrombolysis. Dr Smith reports no relevant disclosures.

Objective: We aimed to characterize the association of hospital procedural volumes with outcomes among acute ischemic stroke (AIS) patients undergoing endovascular therapy (EVT)., Methods: This was a retrospective, observational cohort study using data prospectively collected from January 1, 2016 to December 31, 2019 in the Get with the Guidelines-Stroke registry. Participants were derived from a cohort of 60,727 AIS patients treated with EVT within 24 hours at 626 hospitals. The primary cohort excluded patients with pretreatment National Institutes of Health Stroke Scale (NIHSS) < 6, onset-to-treatment time > 6 hours, and interhospital transfers. There were 2 secondary cohorts: (1) the EVT metrics cohort excluded patients with missing data on time from door to arterial puncture and (2) the intravenous thrombolysis (IVT) metrics cohort only included patients receiving IVT ≤4.5 hours after onset., Results: The primary cohort (mean ± standard deviation age = 70.7 ± 14.8 years; 51.2% female; median [interquartile range] baseline NIHSS = 18.0 [13-22]; IVT use, 70.2%) comprised 21,209 patients across 595 hospitals. The EVT metrics cohort and IVT metrics cohort comprised 47,262 and 16,889 patients across 408 and 601 hospitals, respectively. Higher procedural volumes were significantly associated with higher odds (expressed as adjusted odds ratio [95% confidence interval] for every 10-case increase in volume) of discharge to home (1.03 [1.02-1.04]), functional independence at discharge (1.02 [1.01-1.04]), and lower rates of in-hospital mortality (0.96 [0.95-0.98]). All secondary measures were also associated with procedural volumes., Interpretation: Among AIS patients primarily presenting to EVT-capable hospitals (excluding those transferred from one facility to another and those suffering in-hospital strokes), EVT at hospitals with higher procedural volumes was associated with faster treatment times, better discharge outcomes, and lower rates of in-hospital mortality. ANN NEUROL 2023., (© 2023 American Neurological Association.)

Background: Existing data and clinical trials could not determine whether faster intravenous thrombolytic therapy (IVT) translates into better long-term functional outcomes after acute ischemic stroke among those treated with endovascular thrombectomy (EVT). Patient-level national data can provide the required large population to study the associations between earlier IVT, versus later, with longitudinal functional outcomes and mortality in patients receiving IVT+EVT combined treatment., Methods: This cohort study included older US patients (age ≥65 years) who received IVT within 4.5 hours or EVT within 7 hours after acute ischemic stroke using the linked 2015 to 2018 Get With The Guidelines-Stroke and Medicare database (38 913 treated with IVT only and 3946 with IVT+EVT). Primary outcome was home time, a patient-prioritized functional outcome. Secondary outcomes included all-cause mortality in 1 year. Multivariate logistic regression and Cox proportional hazards models were used to evaluate the associations between door-to-needle (DTN) times and outcomes., Results: Among patients treated with IVT+EVT, after adjusting for patient and hospital factors, including onset-to-EVT times, each 15-minute increase in DTN times for IVT was associated with significantly higher odds of zero home time in a year (never discharged to home) (adjusted odds ratio, 1.12 [95% CI, 1.06-1.19]), less home time among those discharged to home (adjusted odds ratio, 0.93 per 1% of 365 days [95% CI, 0.89-0.98]), and higher all-cause mortality (adjusted hazard ratio, 1.07 [95% CI, 1.02-1.11]). These associations were also statistically significant among patients treated with IVT but at a modest degree (adjusted odds ratio, 1.04 for zero home time, 0.96 per 1% home time for those discharged to home, and adjusted hazard ratio 1.03 for mortality). In the secondary analysis where the IVT+EVT group was compared with 3704 patients treated with EVT only, shorter DTN times (≤60, 45, and 30 minutes) achieved incrementally more home time in a year, and more modified Rankin Scale 0 to 2 at discharge (22.3%, 23.4%, and 25.0%, respectively) versus EVT only (16.4%, P <0.001 for each). The benefit dissipated with DTN>60 minutes., Conclusions: Among older patients with stroke treated with either IVT only or IVT+EVT, shorter DTN times are associated with better long-term functional outcomes and lower mortality. These findings support further efforts to accelerate thrombolytic administration in all eligible patients, including EVT candidates., Competing Interests: Disclosures Dr Mac Grory received funding from the National Institutes of Health (NIH; K23HL161426). Dr Uchino reported being on the data safety monitoring board for clinical trials sponsored by Genentech, Inc. and Evaheart, Inc. He is a consultant for Abbott Laboratories, Inc. Dr Saver reported receiving research support from the National Institute of Health and the American Heart Association; receiving contracted hourly payments from Medtronic, Stryker, Cerenovus, and Boehringer Ingelheim (prevention only) and stock options from Rapid Medical for service on clinical trial steering committees advising on rigorous trial design and conduct; an employee of the University of California which holds a patent on an endovascular device for stroke. Dr Xian reported receiving research funding from the American Heart Association and Genentech and honoraria from Boeheim Ingelheim. Dr Bhatt disclosed the following relationships: Advisory Board: AngioWave, Bayer, Boehringer Ingelheim, Cardax, CellProthera, Cereno Scientific, Elsevier Practice Update Cardiology, High Enroll, Janssen, Level Ex, McKinsey, Medscape Cardiology, Merck, MyoKardia, NirvaMed, Novo Nordisk, PhaseBio, PLx Pharma, Regado Biosciences, Stasys; Board of Directors: AngioWave (stock options), Boston VA Research Institute, Bristol Myers Squibb (stock), DRS.LINQ (stock options), High Enroll (stock), Society of Cardiovascular Patient Care, TobeSoft; Chair: Inaugural Chair, American Heart Association Quality Oversight Committee; Consultant: Broadview Ventures; Data Monitoring Committees: Acesion Pharma, Assistance Publique-Hôpitaux de Paris, Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute, for the PORTICO trial (Portico Re-sheathable Transcatheter Aortic Valve System IDE), funded by St. Jude Medical, now Abbott), Boston Scientific (Chair, PEITHO trial [PEITHO Pulmonary Embolism Thrombolysis Study]), Cleveland Clinic (including for the ExCEED trial [CENTERA THV System in Intermediate Risk Patients Who Have Symptomatic, Severe, Calcific, Aortic Stenosis], funded by Edwards), Contego Medical (Chair, PERFORMANCE 2 [Protection Against Emboli During Carotid Artery Stenting Using the Neuroguard IEP System]), Duke Clinical Research Institute, Mayo Clinic, Mount Sinai School of Medicine (for the ENVISAGE trial [Edoxaban Compared to Standard Care After Heart Valve Replacement Using a Catheter in Patients With Atrial Fibrillation], funded by Daiichi Sankyo; for the ABILITY-DM trial [Randomized Comparison of Abluminus DES+ Sirolimus-Eluting Stents Versus Everolimus-Eluting Stents in Coronary Artery Disease Patients With Diabetes Mellitus Global], funded by Concept Medical), Novartis, Population Health Research Institute; Rutgers University (for the NIH-funded MINT trial [Myocardial Ischemia and Transfusion]); Honoraria: American College of Cardiology (Senior Associate Editor, Clinical Trials and News, ACC.org; Chair, ACC Accreditation Oversight Committee), Arnold and Porter law firm (work related to Sanofi/Bristol-Myers Squibb clopidogrel litigation), Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute; RE-DUAL PCI clinical trial [Evaluation of Dual Therapy With Dabigatran vs. Triple Therapy With Warfarin in Patients With AF That Undergo a PCI With Stenting] steering committee funded by Boehringer Ingelheim; AEGIS-II [Study to Investigate CSL112 in Subjects With Acute Coronary Syndrome] executive committee funded by CSL Behring), Belvoir Publications (Editor in Chief, Harvard Heart Letter), Canadian Medical and Surgical Knowledge Translation Research Group (clinical trial steering committees), Cowen and Company, Duke Clinical Research Institute (clinical trial steering committees, including for the PRONOUNCE trial [A Trial Comparing Cardiovascular Safety of Degarelix Versus Leuprolide in Patients With Advanced Prostate Cancer and Cardiovascular Disease], funded by Ferring Pharmaceuticals), HMP Global (Editor in Chief, Journal of Invasive Cardiology), Journal of the American College of Cardiology (Guest Editor; Associate Editor), K2P (Co-Chair, interdisciplinary curriculum), Level Ex, Medtelligence/ReachMD (CME steering committees), MJH Life Sciences, Oakstone CME (Course Director, Comprehensive Review of Interventional Cardiology), Piper Sandler, Population Health Research Institute (for the COMPASS [Cardiovascular Outcomes for People Using Anticoagulation Strategies] operations committee, publications committee, steering committee, and USA national co-leader, funded by Bayer), Slack Publications (Chief Medical Editor, Cardiology Today’s Intervention), Society of Cardiovascular Patient Care (Secretary/Treasurer), WebMD (CME steering committees), Wiley (steering committee); Other: Clinical Cardiology (Deputy Editor), NCDR-ACTION Registry Steering Committee (Chair), VA CART Research and Publications Committee (Chair); Patent: Sotagliflozin (named on a patent for sotagliflozin assigned to Brigham and Women’s Hospital who assigned to Lexicon; neither I nor Brigham and Women’s Hospital receive any income from this patent.) Research Funding: Abbott, Acesion Pharma, Afimmune, Aker Biomarine, Amarin, Amgen, AstraZeneca, Bayer, Beren, Boehringer Ingelheim, Boston Scientific, Bristol-Myers Squibb, Cardax, CellProthera, Cereno Scientific, Chiesi, CSL Behring, Eisai, Ethicon, Faraday Pharmaceuticals, Ferring Pharmaceuticals, Forest Laboratories, Fractyl, Garmin, HLS Therapeutics, Idorsia, Ironwood, Ischemix, Janssen, Javelin, Lexicon, Lilly, Medtronic, Merck, Moderna, MyoKardia, NirvaMed, Novartis, Novo Nordisk, Owkin, Pfizer, PhaseBio, PLx Pharma, Recardio, Regeneron, Reid Hoffman Foundation, Roche, Sanofi, Stasys, Synaptic, The Medicines Company, 89Bio; Royalties: Elsevier (Editor, Braunwald’s Heart Disease); Site Co-Investigator: Abbott, Biotronik, Boston Scientific, CSI, Endotronix, St. Jude Medical (now Abbott), Philips, SpectraWAVE, Svelte, Vascular Solutions; Trustee: American College of Cardiology; Unfunded Research: FlowCo, Takeda. Dr Schwamm reported serving on the American Heart Association/Get With The Guidelines stroke systems of care advisory group and American Stroke Association Advisory Committee; stroke systems consultant to the Massachusetts Department of Public Health; scientific consultant regarding trial design and conduct to Genentech (late window thrombolysis, member of steering committee TIMELESS [Tenecteplase in Stroke Patients Between 4.5 and 24 Hours; NCT03785678]); member of a Data Safety Monitoring Board (DSMB) for Penumbra (MIND [MIND: Artemis in the Removal of Intracerebral Hemorrhage; NCT03342664]); Diffusion Pharma (PHAST-TSC [Efficacy and Safety of Trans Sodium Crocetinate (TSC) for Treatment of Suspected Stroke; NCT03763929]); National principal investigator (PI) or member of National Steering Committee for Medtronic (Stroke AF [Rate of Atrial Fibrillation Through 12 Months in Patients With Recent Ischemic Stroke of Presumed Known Origin; NCT02700945]); PI, StrokeNet Network National Institute of Neurological Disorders and Stroke (NINDS; New England Regional Coordinating Center U24NS107243); Co-I, The Impact of Telestroke on Patterns of Care and Long-Term Outcomes, NINDS (R01NS111952). Dr Hussain reported serving on the scientific advisory board and clinical events committee of Cerenovus, the principal investigator of Medtronic Core laboratory, data safety monitoring board for Stryker Neurovascular, and clinical events committee of Rapid Medical. Dr Fonarow reported receiving research support from the Patient Centered Outcome Research Institute and the National Institutes of Health, and employee of University of California which holds a patent on an endovascular device for stroke. Drs Man, Solomon, Alhanti, and Smith reported no relevant disclosure.

Importance: Use of oral vitamin K antagonists (VKAs) may place patients undergoing endovascular thrombectomy (EVT) for acute ischemic stroke caused by large vessel occlusion at increased risk of complications., Objective: To determine the association between recent use of a VKA and outcomes among patients selected to undergo EVT in clinical practice., Design, Setting, and Participants: Retrospective, observational cohort study based on the American Heart Association's Get With the Guidelines-Stroke Program between October 2015 and March 2020. From 594 participating hospitals in the US, 32 715 patients with acute ischemic stroke selected to undergo EVT within 6 hours of time last known to be well were included., Exposure: VKA use within the 7 days prior to hospital arrival., Main Outcome and Measures: The primary end point was symptomatic intracranial hemorrhage (sICH). Secondary end points included life-threatening systemic hemorrhage, another serious complication, any complications of reperfusion therapy, in-hospital mortality, and in-hospital mortality or discharge to hospice., Results: Of 32 715 patients (median age, 72 years; 50.7% female), 3087 (9.4%) had used a VKA (median international normalized ratio [INR], 1.5 [IQR, 1.2-1.9]) and 29 628 had not used a VKA prior to hospital presentation. Overall, prior VKA use was not significantly associated with an increased risk of sICH (211/3087 patients [6.8%] taking a VKA compared with 1904/29 628 patients [6.4%] not taking a VKA; adjusted odds ratio [OR], 1.12 [95% CI, 0.94-1.35]; adjusted risk difference, 0.69% [95% CI, -0.39% to 1.77%]). Among 830 patients taking a VKA with an INR greater than 1.7, sICH risk was significantly higher than in those not taking a VKA (8.3% vs 6.4%; adjusted OR, 1.88 [95% CI, 1.33-2.65]; adjusted risk difference, 4.03% [95% CI, 1.53%-6.53%]), while those with an INR of 1.7 or lower (n = 1585) had no significant difference in the risk of sICH (6.7% vs 6.4%; adjusted OR, 1.24 [95% CI, 0.87-1.76]; adjusted risk difference, 1.13% [95% CI, -0.79% to 3.04%]). Of 5 prespecified secondary end points, none showed a significant difference across VKA-exposed vs VKA-unexposed groups., Conclusions and Relevance: Among patients with acute ischemic stroke selected to receive EVT, VKA use within the preceding 7 days was not associated with a significantly increased risk of sICH overall. However, recent VKA use with a presenting INR greater than 1.7 was associated with a significantly increased risk of sICH compared with no use of anticoagulants.

Background: Prior systematic reviews have compared the efficacy of intravenous tenecteplase and alteplase in acute ischemic stroke, assigning their relative complications as a secondary objective. The objective of the present study is to determine whether the risk of treatment complications differs between patients treated with either agent., Methods: We performed a systematic review including interventional studies and prospective and retrospective, observational studies enrolling adult patients treated with intravenous tenecteplase for ischemic stroke (both comparative and noncomparative with alteplase). We searched MEDLINE, Embase, the Cochrane Library, Web of Science, and the www., Clinicaltrials: gov registry from inception through June 3, 2022. The primary outcome was symptomatic intracranial hemorrhage, and secondary outcomes included any intracranial hemorrhage, angioedema, gastrointestinal hemorrhage, other extracranial hemorrhage, and mortality. We performed random effects meta-analyses where appropriate. Evidence was synthesized as relative risks, comparing risks in patients exposed to tenecteplase versus alteplase and absolute risks in patients treated with tenecteplase., Results: Of 2226 records identified, 25 full-text articles (reporting 26 studies of 7913 patients) were included. Sixteen studies included alteplase as a comparator, and 10 were noncomparative. The relative risk of symptomatic intracranial hemorrhage in patients treated with tenecteplase compared with alteplase in the 16 comparative studies was 0.89 ([95% CI, 0.65-1.23]; I 2 =0%). Among patients treated with low dose (<0.2 mg/kg; 4 studies), medium dose (0.2-0.39 mg/kg; 13 studies), and high dose (≥0.4 mg/kg; 3 studies) tenecteplase, the RRs of symptomatic intracranial hemorrhage were 0.78 ([95% CI, 0.22-2.82]; I 2 =0%), 0.77 ([95% CI, 0.53-1.14]; I 2 =0%), and 2.31 ([95% CI, 0.69-7.75]; I 2 =40%), respectively. The pooled risk of symptomatic intracranial hemorrhage in tenecteplase-treated patients, including comparative and noncomparative studies, was 0.99% ([95% CI, 0%-3.49%]; I 2 =0%, 7 studies), 1.69% ([95% CI, 1.14%-2.32%]; I 2 =1%, 23 studies), and 4.19% ([95% CI, 1.92%-7.11%]; I 2 =52%, 5 studies) within the low-, medium-, and high-dose groups. The risks of any intracranial hemorrhage, mortality, and other studied outcomes were comparable between the 2 agents., Conclusions: Across medium- and low-dose tiers, the risks of complications were generally comparable between those treated with tenecteplase versus alteplase for acute ischemic stroke.

Background: Carotid stenosis is thought to be the primary risk factor for central retinal artery occlusion (CRAO); however, it is not known whether atrial fibrillation (AF)-a cardiac arrhythmia that underlies over 25% of cerebral ischemic strokes-predisposes patients to CRAO., Methods: A retrospective, observational, cohort study was performed using data from the State Inpatient Databases and State Emergency Department Databases from New York (2006-2015), California (2003-2011), and Florida (2005-2015) to determine the association between AF and CRAO. The primary exposure was hospital-documented AF. The primary end point was hospital-documented CRAO, defined as having an International Classification of Diseases, Ninth Revision, Clinical Modification , code 362.31 in the primary diagnosis position. Cause-specific hazard models were used to model CRAO-free survival among patients according to hospital-documented AF status., Results: Of 39 834 885 patients included in the study, 2 723 842 (median age, 72.7 years; 48.5% women) had AF documented during the exposure window. The median follow-up duration was 6 years and 1 month. Patients with AF were older, more likely to be of non-Hispanic White race/ethnicity, and had a higher burden of cardiovascular comorbidities compared with patients without AF. The cumulative incidence of CRAO determined prospectively after exclusions was 8.69 per 100 000 at risk in those with AF and 2.39 per 100 000 at risk in those without AF over the study period. Before adjustment, AF was associated with higher risk of CRAO (hazard ratio, 2.55 [95% CI, 2.15-3.03]). However, after adjustment for demographics, state, and cardiovascular comorbidities, there was an inverse association between AF and risk of CRAO (adjusted hazard ratio, 0.72 [95% CI, 0.60-0.87]). These findings were robust in our prespecified sensitivity analyses. By contrast, positive control outcomes of embolic and ischemic stroke showed an expected strong relationship between AF and risk of stroke., Conclusions: We found an inverse association between AF and CRAO in a large, representative study of hospitalized patients; however, this cohort did not ascertain AF or CRAO occurring outside of hospital or emergency department settings.

Background: The aim of this study was to determine the effect of smoking status on subsequent stroke risk in patients with minor ischemic stroke or TIA and to determine whether smoking modifies the effect of clopidogrel-based DAPT on subsequent stroke risk., Methods: This was a post-hoc analysis of the Platelet Oriented Inhibition in New TIA and Minor Ischemic Stroke (POINT) trial, which had a 90-day follow-up period. We used multivariable Cox regression and subgroup interaction analysis to determine the effect of smoking on the risk of subsequent ischemic stroke and major hemorrhage, respectively., Results: Data from 4877 participants enrolled in the POINT trial were analyzed. Among these, 1004 were current smokers and 3873 were non-smokers at the time of index event. Smoking was associated with a non-significant trend toward an increased risk of subsequent ischemic stroke during follow up (adjusted HR, 1.31 (95% CI, 0.97-1.78), p  = 0.076). The effect of clopidogrel on ischemic stroke did not differ between non-smokers (HR, 0.74 (95% CI, 0.56-0.98), p  = 0.03) and smokers (HR, 0.63 (95% CI, 0.37-1.05), p  = 0.078), p for interaction = 0.572. Similarly, the effect of clopidogrel on major hemorrhage did not differ between non-smokers (hazard ratio, 1.67 (95% CI, 0.40-7.00), p  = 0.481) and smokers (HR, 2.59 (95% CI, 1.08-6.21), p  = 0.032), p for interaction = 0.613., Conclusions: In this post-hoc analysis of the POINT trial we found that the effect of clopidogrel on reducing subsequent ischemic stroke as well as risk of major hemorrhage did not depend on smoking status, indicating that smokers benefit to a similar degree from DAPT as non-smokers., Competing Interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article. Dr. de Havenon is funded by NIH-NINDS, has received investigator initiated clinical research funding from Regeneron, AMGEN, and AMAG pharmaceuticals, has received consultant fees from Integra and Novo Nordisk, has equity in TitinKM and Certus, and receives author fees from UpToDate. Dr. Easton received funding for his role in the POINT trial which was sponsored by NIH/NINDS but received drug and placebo from Sanofi. Dr. Johnston received research support from AstraZeneca. The POINT trial was sponsored by NIH/NINDS but received drug and placebo from Sanofi. Dr. Lang reported previously owning stock in Walmart, Target, and Johnson & Johnson outside the submitted work., (© European Stroke Organisation 2022.)

Background: In 2015, endovascular therapy (EVT) for large vessel occlusions became standard of care for acute ischemic stroke. Lower utilization of IV alteplase has been reported in women, but whether sex differences in EVT use in the United States exists has not been established., Methods: We identified all acute ischemic stroke discharges from Get With The Guidelines-Stroke hospitals between 2012 and 2019 who were potentially eligible for EVT, based on National Institutes of Health Stroke Scale score ≥6 and arrival <6 hours, according to 2018 American Heart Association/ASA guidelines. Multivariable regression analyses were used to determine the association between sex and EVT utilization, and outcomes (including mortality, discharge home, functional status) after EVT. Separate analyses were conducted for the 2 time periods: 2012 to 2014, and 2015 to 2019., Results: Of 302 965 patients potentially eligible for EVT, 42 422 (14%) received EVT. Before 2015, EVT treatment rates were 5.3% in women and 6.6% in men. From 2015 to 2019, treatment rates increased in both sexes to 16.7% in women and 18.5% in men. The adjusted odds ratio for EVT in women compared with men was 0.93 (95% CI, 0.87-0.99) before 2015, and 0.98 (95% CI, 0.96-1.01) after 2015. There were no significant sex differences in outcomes except that after 2015, women were less able to ambulate at discharge (adjusted odds ratio, 0.95 [95% CI, 0.95-0.99]) and had lower in-hospital mortality (adjusted odds ratio, 0.93 [95% CI, 0.88-0.99])., Conclusions: EVT utilization has increased dramatically in both women and men since EVT approval in 2015. Following statistical adjustment, women were less likely to receive EVT initially, but after 2015, women were as likely as men to receive EVT. After EVT, women were more likely to be disabled at discharge but less likely to experience in-hospital death compared with men.

Background: High level evidence for direct oral anticoagulants (DOACs) in patients with cerebral venous thrombosis is lacking. We performed a systematic review and meta-analysis to assess the efficacy and safety of DOACs versus vitamin K antagonists in patients with cerebral venous thrombosis., Methods: This systematic review was registered in PROSPERO (CRD42021228800). We searched MEDLINE (via Ovid), EMBASE, CINAHL, and the Web of Science Core Collection between January 1, 2007 and Feb 22, 2022. Search terms included a combination of keywords and controlled vocabulary terms for cerebral venous thrombosis, vitamin K antagonists/warfarin, and DOACs. We included both randomized and nonrandomized studies that compared vitamin K antagonists and DOACs in 5 or more patients with cerebral venous thrombosis. Where studies were sufficiently similar, we performed meta-analyses for efficacy (recurrent venous thromboembolism and complete recanalization) and safety (major hemorrhage) outcomes, using relative risks (RRs)., Results: Out of 10 665 records identified, we screened 254 as potentially eligible. Nineteen studies (16 observational studies [n=1735] and 3 randomized controlled trials [n=215]) met the inclusion criteria. All 3 randomized controlled trials had some concerns, and all 16 observational studies had at least moderate risk of bias. When compared with vitamin K antagonist treatment, DOAC had comparable risks of recurrent venous thromboembolism (relative risk [RR], 0.85 [95% CI, 0.52-1.37], I 2 =0%), major hemorrhage (RR, 0.70 [95% CI, 0.40-1.21], I 2 =0%), intracranial hemorrhage (RR, 0.58 [95% CI, 0.30-1.12]; I 2 =0%), death (RR, 1.14 [95% CI, 0.54-2.43], I 2 =1%), and complete venous recanalization (RR, 0.98 [95% CI, 0.87-1.11]; I 2 =0%)., Conclusions: This systematic review and meta-analysis suggest that in patients with cerebral venous thrombosis, DOACs, and warfarin may have comparable efficacy and safety. Given the limitations of the studies included (low number of randomized controlled trials, modest total sample size, rare outcome events), our findings should be interpreted with caution pending confirmation by ongoing randomized controlled trials and large, prospective, observational studies.

Importance: The effectiveness and safety of intravenous alteplase given before or concurrently with endovascular thrombectomy (EVT) is uncertain. Randomized clinical trials suggest there is little difference in outcomes but with only modest precision and insufficient power to analyze uncommon outcomes including symptomatic intracranial hemorrhage (sICH)., Objective: To determine whether 8 prespecified outcomes are different in patients with acute ischemic stroke treated in routine clinical practice with EVT with alteplase compared with patients treated with EVT alone without alteplase. It was hypothesized that alteplase would be associated with higher risk of sICH., Design, Setting, and Participants: This was an observational cohort study conducted from February 1, 2019, to June 30, 2020, that included adult patients with acute ischemic stroke treated with EVT within 6 hours of time last known well, after excluding patients without information on discharge destination and patients with in-hospital stroke. Participants were recruited from Get With The Guidelines-Stroke, a large nationwide registry of patients with acute ischemic stroke from 555 hospitals in the US., Exposures: Intravenous alteplase or no alteplase., Main Outcomes and Measures: Prespecified outcomes were discharge destination, independent ambulation at discharge, modified Rankin score at discharge, discharge mortality, cerebral reperfusion according to modified Thrombolysis in Cerebral Infarction grade, and sICH., Results: There were 15 832 patients treated with EVT (median [IQR] age, 72.0 [61.0-82.0] years; 7932 women [50.1%]); 10 548 (66.7%) received alteplase and 5284 (33.4%) did not. Patients treated with alteplase were younger, arrived via Emergency Medical Services sooner, were less likely to have certain comorbidities, including atrial fibrillation, hypertension, and diabetes, but had similar National Institutes of Health Stroke Severity (NIHSS) scores. Compared with patients who did not receive alteplase treatment, patients treated with alteplase were less likely to die (11.1% [1173 of 10 548 patients] vs 13.9% [734 of 5284 patients]; adjusted odds ratio [aOR] 0.83; 95% CI, 0.77-0.89; P < .001), more likely to have no major disability based on modified Rankin scale of 2 or less at discharge (28.5% [2415 of 8490 patients] vs 20.7% [894 of 4322 patients]; aOR, 1.36; 95% CI, 1.28-1.45; P < .001), and to have better reperfusion based on modified Thrombolysis in Cerebral Infarction grade 2b or greater (90.9% [8474 of 9318 patients] vs 88.0% [4140 of 4705 patients]; aOR, 1.39; 95% CI, 1.28-1.50; P < .001). However, alteplase treatment was associated with higher risk of sICH (6.5% [685 of 10 530 patients] vs 5.3% [279 of 5249 patients]; OR, 1.28; 95% CI, 1.16-1.42; P < .001)., Conclusions and Relevance: In this observational cohort study of patients treated with EVT, intravenous alteplase treatment was associated with better in-hospital survival and functional outcomes but higher sICH risk after adjusting for other covariates.

Importance: After the publication of the CHANCE (Clopidogrel in High Risk Patients With Acute Nondisabling Cerebrovascular Events) and POINT (Platelet-Oriented Inhibition in New Transient Ischemic Attack and Minor Ischemic Stroke) clinical trials, the American Heart Association/American Stroke Association (AHA/ASA) issued a new class 1, level of evidence A, recommendation for dual antiplatelet therapy (DAPT; aspirin plus clopidogrel) for secondary prevention in patients with minor ischemic stroke (National Institutes of Health Stroke Scale [NIHSS] score ≤3). The extent to which variations in DAPT prescribing patterns remain and the extent to which practice patterns in the US are consistent with evidence-based guidelines are unknown., Objective: To evaluate the discharge DAPT prescribing patterns after publication of the new AHA/ASA guidelines and assess the extent of hospital-level variation in the use of DAPT for secondary prevention in patients with minor stroke (NIHSS score ≤3), as indicated by guidelines, and in patients with nonminor stroke (NIHSS score >3), for whom the risks and benefits of DAPT have not been fully established., Design, Setting, and Participants: This multicenter retrospective cohort study involved 132 817 patients from 1890 hospitals participating in the AHA/ASA Get With The Guidelines-Stroke program. Patients who were hospitalized for acute ischemic stroke and prescribed antiplatelet therapy at discharge between October 1, 2019, and June 30, 2020, were included., Exposures: Minor ischemic stroke (NIHSS score ≤3) vs nonminor ischemic stroke (NIHSS score >3)., Main Outcomes and Measures: The primary outcome was DAPT prescription at discharge. The extent to which variations in DAPT use were explained at the hospital level was assessed by calculating the median odds ratio (OR), which was derived using multivariable logistic regression analysis and compared the likelihood that 2 patients with identical clinical features admitted to 2 randomly selected hospitals (1 with higher propensity and 1 with lower propensity for DAPT use) would receive DAPT at discharge. Associations between hospital-level DAPT use among patients with minor vs nonminor stroke were evaluated using Pearson ρ correlation coefficients., Results: Among 132 817 patients (median [IQR] age, 68 [59-78] years; 68 768 men [51.8%]), 4282 (3.2%) were Asian, 11 254 (8.5%) were Hispanic, 27 221 (20.5%) were non-Hispanic Black, 84 468 (63.6%) were non-Hispanic White, and 5592 (4.2%) were of other races and/or ethnicities (including American Indian or Alaska Native, Native Hawaiian or Pacific Islander, and unable to determine). Overall, 86 551 patients (65.2%) presented with minor ischemic stroke, and 46 266 patients (34.8%) presented with nonminor ischemic stroke. After the 2019 AHA/ASA guideline updates, 40 661 patients (47.0%) with minor stroke (NIHSS median [IQR] score, 1 [0-2]) and 19 703 patients (42.6%) with nonminor stroke (NIHSS median [IQR] score, 6 [5-9]) received DAPT at discharge. Despite guideline recommendations, 45 890 patients (53.0%) with minor stroke did not receive DAPT. After accounting for patient characteristics, substantial hospital-level variations were found in the use of DAPT in those with minor stroke (median [IQR] hospital-level DAPT prescription rate, 44.8% [33.7%-57.7%]; range, 0%-91.7%; median OR, 2.03 [95% CI, 1.97-2.09]) when comparing 2 patients with identical risk factors discharged from 2 randomly selected hospitals, 1 with higher propensity and 1 with lower propensity for DAPT use. The use of DAPT in patients with nonminor stroke also varied significantly (median [IQR] hospital-level DAPT prescription rate, 41.4% [30.0%-53.8%]; range, 0%-100%; median OR, 1.90 [95% CI, 1.83-1.97]). Overall, hospitals that were more likely to prescribe DAPT for minor strokes were also more likely to prescribe DAPT for nonminor strokes (Pearson ρ = 0.72; P < .001)., Conclusions and Relevance: This cohort study found that despite updated AHA/ASA guidelines, more than 50% of patients with minor acute ischemic stroke did not receive DAPT at discharge. In contrast, more than 40% of patients with nonminor stroke received DAPT despite lack of evidence in this setting. These findings suggest that enhancing adherence to evidence-based DAPT practice guidelines may be a target for quality improvement in the treatment of patients with ischemic stroke.

Background: There are limited data about the epidemiology and secondary stroke prevention strategies used for patients with depressed left ventricular ejection fraction (LVEF) and sinus rhythm following an acute ischemic stroke (AIS). We sought to describe the prevalence of LVEF ≤40% and sinus rhythm among patients with AIS and antithrombotic treatment practice in a multi-center cohort from 2002 to 2018., Methods: This was a multi-center, retrospective cohort study comprised of patients with AIS hospitalized in the Greater Cincinnati Northern Kentucky Stroke Study and 4 academic, hospital-based cohorts in the United States. A 1-stage meta-analysis of proportions was undertaken to calculate a pooled prevalence. Univariate analyses and an adjusted multivariable logistic regression model were performed to identify demographic, clinical, and echocardiographic characteristics associated with being prescribed an anticoagulant upon AIS hospitalization discharge., Results: Among 14 338 patients with AIS with documented LVEF during the stroke hospitalization, the weighted pooled prevalence of LVEF ≤40% and sinus rhythm was 5.0% (95% CI, 4.1-6.0%; I 2 , 84.4%). Of 524 patients with no cardiac thrombus and no prior indication for anticoagulant who survived postdischarge, 200 (38%) were discharged on anticoagulant, 289 (55%) were discharged on antiplatelet therapy only, and 35 (7%) on neither. There was heterogeneity by site in the proportion discharged with an anticoagulant (22% to 45%, P <0.0001). Cohort site and National Institutes of Health Stroke Severity scale >8 (odds ratio, 2.0 [95% CI, 1.1-3.8]) were significant, independent predictors of being discharged with an anticoagulant in an adjusted analysis., Conclusions: Nearly 5% of patients with AIS have a depressed LVEF and are in sinus rhythm. There is significant variation in the clinical practice of antithrombotic therapy prescription by site and stroke severity. Given this clinical equipoise, further study is needed to define optimal antithrombotic treatment regimens for secondary stroke prevention in this patient population.

Background/objective: This study compares the global disability status of patients who had a mild ischaemic stroke at 30 and 90 days poststroke, as measured by the modified Rankin Scale (mRS), and identifies predictors of change in disability status between 30 and 90 days., Methods: The study population included 1339 patients who had a ischaemic stroke enrolled in the Mild and Rapidly Improving Stroke Study with National Institutes of Health (NIH) stroke score 0-5 and mRS measurements at 30 and 90 days. Outcomes were (1) Improvement defined as having mRS >1 at 30 days and mRS 0-1 at 90 days OR mRS >2 at 30 days and mRS 0-2 at 90 days and (2) Worsening defined as an increase of ≥2 points or a worsening from mRS of 1 at 30 days to 2 at 90 days. Demographic and clinical characteristics at hospital arrival were abstracted from medical records, and regression models were used to identify predictors of functional improvement and decline from 30 to 90 days post-stroke. Significant predictors were mutually adjusted in multivariable models that also included age and stroke severity., Results: Fifty-seven per cent of study participants had no change in mRS value from 30 to 90 days. Overall, there was moderate agreement in mRS between the two time points (weighted kappa=0.59 (95% CI 0.56 to 0.62)). However, worsening on the mRS was observed in 7.54% of the study population from 30 to 90 days, and 17.33% improved. Participants of older age (per year OR 1.02, 95% CI 1.00 to 1.03), greater stroke severity (per NIH Stroke Scale (NIHSS) point at admission OR 1.17, 95% CI 1.03 to 1.34), and those with no alteplase treatment (OR 1.72, 95% CI 1.11 to 2.69) were more likely to show functional decline after mutual adjustment., Discussion: A quarter of all mild ischaemic stroke participants exhibited functional changes between 30 and 90 days, suggesting that the 30-day outcome may insufficiently represent long-term recovery in mild stroke and longer follow-up may be clinically necessary., Trial Registration Number: NCT02072681., Competing Interests: Competing interests: JGR: grant from Genentech to U Miami to support role as PI of MaRISS; personal fees from Genentech for role as a member of the steering committee for the PRISMS trial and member of the independent data monitoring committee of the TIMELESS Trial. HG: grant from Genentech to U Miami to support role as MaRISS Study Epidemiologist EE Smith: none I Campo-Bustillo: grant from Genentech to U Miami to support role as MaRISS Study Manager. YK: none S Tai: none N Riley: none. HMA: none. BMG: none. DG: none. NSS: none. KEO: none. CGB: none. AGK: none. SSB: none. ACK: none. RLS: grants from NIH grants (NINDS, NIMHD, NCATS), from the Florida Department of Health for the support of the Florida Stroke Registry, and fees from American Heart Association for work as Editor-in-Chief of Stroke. PK: funds to her institution from Genentech (PRISMS Trial National PI, HAMLET Steering Committee member), Diamedica (Scientific Advisory Board), Lumosa (Consultant and DSMB Representative), Nervive (NIH SBIR Co-Investigator) and Cerenovus (Investigator-Initiated ENDOLOW Trial MPI); fees from Bayer (PACIFIC-Stroke Trial National Leader). HMA: none. LHS: scientific consultant and steering committee member, TIMELESS Trial (Genentech); consultant (LifeImage); consultant on stroke systems of care, Massachusetts Department of Public Health; DSMB member, MIND Study (Penumbra) and PHAST-TSC Study (Diffusion Pharmaceutical); National PI, Stroke AF Study (Medtronic); National Co-PI, MR WITNESS Study (NINDS) (alteplase provided free of charge to Massachusetts General Hospital, supplemental per-patient payments sites by Genentech); Site PI, New England Regional Coordinating Center, StrokeNet (NINDS)., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

The past decade has seen significant advances in stroke prevention. These advances include new antithrombotic agents, new options for dyslipidemia treatment, and novel techniques for surgical stroke prevention. In addition, there is greater recognition of the benefits of multifaceted interventions, including the role of physical activity and dietary modification. Despite these advances, the aging of the population and the high prevalence of key vascular risk factors pose challenges to reducing the burden of stroke. Using a cause-based framework, current approaches to prevention of cardioembolic, cryptogenic, atherosclerotic, and small vessel disease stroke are outlined in this paper. Special emphasis is given to recent trials of antithrombotic agents, including studies that have tested combination treatments and responses according to genetic factors.

An 18-year-old woman with a history of Down syndrome (DS) presented with left upper extremity weakness. Neurological examination revealed moderate hypotonia throughout, with mild spasticity of the left ankle. She had 2/5 left upper and lower extremity strength, mild pronation with drift in the left arm and 3+ deep tendon reflexes in the left biceps, brachioradialis, patellar and Achilles. Strength was 5/5 in the right upper and lower extremities. A CT angiography of the head and neck with contrast demonstrated severe narrowing of the bilateral supraclinoid internal carotid arteries (ICAs), suggestive of moyamoya pattern. A diagnostic angiography confirmed stenosis in the right and left supraclinoid ICAs. The patient was started on aspirin therapy and underwent an indirect bypass procedure via encephaloduroarteriosynangiosis 6 weeks after initial presentation. DS is associated with a high risk of congenital heart disease, which in turn increases risk of stroke, namely cardioembolic events, including moyamoya disease. Intellectual disability is nearly ubiquitous in DS, thus adding to the challenges of making a diagnosis of moyamoya in this population., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Importance: In the Platelet-Oriented Inhibition in New TIA and Minor Ischemic Stroke (POINT) trial, acute treatment with clopidogrel-aspirin was associated with significantly reduced risk of recurrent stroke. There may be specific patient groups who are more likely to benefit from this treatment., Objective: To investigate whether the association of clopidogrel-aspirin with stroke recurrence in patients with minor stroke or high-risk transient ischemic attack (TIA) is modified by the presence of infarct on imaging attributed to the index event (index imaging) among patients enrolled in the POINT Trial., Design, Setting, and Participants: In the POINT randomized clinical trial, patients with high-risk TIA and minor ischemic stroke were enrolled at 269 sites in 10 countries in North America, Europe, Australia, and New Zealand from May 28, 2010, to December 19, 2017. In this post hoc analysis, patients were divided into 2 groups according to whether they had an acute infarct on index imaging. All POINT trial participants with information available on the presence or absence of acute infarct on index imaging were eligible for this study. Univariable Cox regression models evaluated associations between the presence of an infarct on index imaging and subsequent ischemic stroke and evaluated whether the presence of infarct on index imaging modified the association of clopidogrel-aspirin with subsequent ischemic stroke risk. Data were analyzed from July 2020 to May 2021., Exposures: Presence or absence of acute infarct on index imaging., Main Outcomes and Measures: The primary outcome is whether the presence of infarct on index imaging modified the association of clopidogrel-aspirin with subsequent ischemic stroke risk., Results: Of the 4881 patients enrolled in POINT, 4876 (99.9%) met the inclusion criteria (mean [SD] age, 65 [13] years; 2685 men [55.0%]). A total of 1793 patients (36.8%) had an acute infarct on index imaging. Infarct on index imaging was associated with ischemic stroke during follow-up (hazard ratio [HR], 3.68; 95% CI, 2.73-4.95; P < .001). Clopidogrel-aspirin vs aspirin alone was associated with decreased ischemic stroke risk in patients with an infarct on index imaging (HR, 0.56; 95% CI, 0.41-0.77; P < .001) compared with those without an infarct on index imaging (HR, 1.11; 95% CI, 0.74-1.65; P = .62), with a significant interaction association (P for interaction = .008)., Conclusions and Relevance: In this study, the presence of an acute infarct on index imaging was associated with increased risk of recurrent stroke and a more pronounced benefit from clopidogrel-aspirin. Future work should focus on validating these findings before targeting specific patient populations for acute clopidogrel-aspirin treatment.

Background: A small randomized controlled trial suggested that dabigatran may be as effective as warfarin in the treatment of cerebral venous thrombosis (CVT). We aimed to compare direct oral anticoagulants (DOACs) to warfarin in a real-world CVT cohort., Methods: This multicenter international retrospective study (United States, Europe, New Zealand) included consecutive patients with CVT treated with oral anticoagulation from January 2015 to December 2020. We abstracted demographics and CVT risk factors, hypercoagulable labs, baseline imaging data, and clinical and radiological outcomes from medical records. We used adjusted inverse probability of treatment weighted Cox-regression models to compare recurrent cerebral or systemic venous thrombosis, death, and major hemorrhage in patients treated with warfarin versus DOACs. We performed adjusted inverse probability of treatment weighted logistic regression to compare recanalization rates on follow-up imaging across the 2 treatments groups., Results: Among 1025 CVT patients across 27 centers, 845 patients met our inclusion criteria. Mean age was 44.8 years, 64.7% were women; 33.0% received DOAC only, 51.8% received warfarin only, and 15.1% received both treatments at different times. During a median follow-up of 345 (interquartile range, 140-720) days, there were 5.68 recurrent venous thrombosis, 3.77 major hemorrhages, and 1.84 deaths per 100 patient-years. Among 525 patients who met recanalization analysis inclusion criteria, 36.6% had complete, 48.2% had partial, and 15.2% had no recanalization. When compared with warfarin, DOAC treatment was associated with similar risk of recurrent venous thrombosis (aHR, 0.94 [95% CI, 0.51-1.73]; P =0.84), death (aHR, 0.78 [95% CI, 0.22-2.76]; P =0.70), and rate of partial/complete recanalization (aOR, 0.92 [95% CI, 0.48-1.73]; P =0.79), but a lower risk of major hemorrhage (aHR, 0.35 [95% CI, 0.15-0.82]; P =0.02)., Conclusions: In patients with CVT, treatment with DOACs was associated with similar clinical and radiographic outcomes and favorable safety profile when compared with warfarin treatment. Our findings need confirmation by large prospective or randomized studies.

Patent foramen ovale (PFO) describes a valve in the interatrial septum that permits shunting of blood or thrombotic material between the atria. PFOs are present in approximately 25% of the healthy population and are not associated with any pathology in the vast majority of cases. However, comparisons between patients with stroke and healthy controls suggest that PFOs may be causative of stroke in certain patients whose stroke is otherwise cryptogenic. Options for the diagnosis of PFO include transthoracic echocardiography, transesophageal echocardiography, and transcranial Doppler ultrasonography. PFOs associated with an interatrial septal aneurysm seem to be more strongly linked to risk of recurrent stroke. Therapeutic options for secondary stroke prevention in the setting of a PFO include antiplatelet therapy, anticoagulation, and percutaneous device closure. Recent randomized clinical trials suggest that percutaneous closure reduces the subsequent risk of stroke in appropriately selected patients, with a large relative benefit but small absolute benefit. Referral for percutaneous PFO closure should therefore be considered in certain patients after a multidisciplinary, patient centered discussion. Areas for future study include structural biomarkers to aid in determining the role of PFO closure in older people with possible PFO associated stroke, the role of direct oral anticoagulants, and very long term outcomes after device closure., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Background and Purpose: Clinical fluctuations in ischemic stroke symptoms are common, but fluctuations before hospital arrival have not been previously characterized., Methods: A standardized qualitative assessment of fluctuations before hospital arrival was obtained in an observational study that enrolled patients with mild ischemic stroke symptoms (National Institutes of Health Stroke Scale [NIHSS] score of 0-5) present on arrival to hospital within 4.5 hours of onset, in a subset of 100 hospitals participating in the Get With The Guidelines-Stroke quality improvement program. The number of fluctuations, direction, and the overall improvement or worsening was recorded based on reports from the patient, family, or paramedics. Baseline NIHSS on arrival and at 72 hours (or discharge if before) and final diagnosis and stroke subtype were collected. Outcomes at 90 days included the modified Rankin Scale, Barthel Index, Stroke Impact Scale 16, and European Quality of Life. Prehospital fluctuations were examined in relation to hospital NIHSS change (admission to 72 hours or discharge) and 90-day outcomes., Results: Among 1588 participants, prehospital fluctuations, consisting of improvement, worsening, or both were observed in 35.5%: 25.1% improved once, 5.3% worsened once, and 5.1% had more than 1 fluctuation. Those who improved were less likely and those who worsened were more likely to receive alteplase. Those who improved before hospital arrival had lower change in the hospital NIHSS than those who did not fluctuate. Better adjusted 90-day outcomes were noted in those with prehospital improvement compared to those without any fluctuations., Conclusions: Fluctuations in neurological symptoms and signs are common in the prehospital setting. Prehospital improvement was associated with better 90-day outcomes, controlling for admission NIHSS and alteplase treatment. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02072681.

Background There are multiple tools available to visualize the retinal and choroidal vasculature of the posterior globe. However, there are currently no reliable in vivo imaging techniques that can visualize the entire retrobulbar course of the retinal and ciliary vessels. Purpose To identify and characterize the central retinal artery (CRA) using cone-beam CT (CBCT) images obtained as part of diagnostic cerebral angiography. Materials and Methods In this retrospective study, patients with catheter DSA performed between October 2019 and October 2020 were included if CBCT angiography included the orbit in the field of view. The CBCT angiography data sets were postprocessed with a small field-of-view volume centered in the posterior globe to a maximum resolution of 0.2 mm. The following were evaluated: CRA origin, CRA course, CRA point of penetration into the optic nerve sheath, bifurcation of the CRA at the papilla, visualization of anatomic variants, and visualization of the central retinal vein. Descriptive statistical analysis was performed. Results Twenty-one patients with 24 visualized orbits were included in the analysis (mean age, 55 years ± 15; 14 women). Indications for angiography were as follows: diagnostic angiography ( n = 8), aneurysm treatment ( n = 6), or other ( n = 7). The CRA was identified in all orbits; the origin, course, point of penetration of the CRA into the optic nerve sheath, and termination in the papilla were visualized in all orbits. The average length of the intraneural segment was 10.6 mm (range, 7-18 mm). The central retinal vein was identified in six of 24 orbits. Conclusion Cone-beam CT, performed during diagnostic angiography, consistently demonstrated the in vivo central retinal artery, demonstrating excellent potential for multiple diagnostic and therapeutic applications. © RSNA, 2021 Online supplemental material is available for this article.

Background One-quarter of all strokes are subsequent events. It is not known whether higher levels of blood glucose are associated with an increased risk of subsequent stroke after high-risk transient ischemic attack or minor ischemic stroke. Methods and Results We performed a secondary analysis of the POINT (Platelet Oriented Inhibition in New TIA and Minor Ischemic Stroke) trial to evaluate the relationship between serum glucose hyperglycemia (≥180 mg/dL) versus normoglycemia (<180 mg/dL) before enrollment in the trial and outcomes at 90 days. The primary end point was subsequent ischemic stroke modeled by a multivariable Cox model with adjustment for age, sex, race, ethnicity, study treatment assignment, index event, and key comorbidities. Of 4878 patients included in this study, 267 had a recurrent stroke. There was a higher hazard of subsequent stroke in patients with hyperglycemia compared with normoglycemia (adjusted hazard ratio [HR], 1.50 [95% CI, 1.05-2.14]). Treatment with dual antiplatelet therapy was not associated with a reduced hazard of subsequent stroke in patients with hyperglycemia (HR, 1.18 [95% CI, 0.69-2.03]), though the wide confidence interval does not exclude a treatment effect. When modeled as a continuous variable, there was evidence of a nonlinear association between serum glucose and the hazard of subsequent stroke ( P <0.001). Conclusions Hyperglycemia on presentation is associated with an increased risk of subsequent ischemic stroke after high-risk transient ischemic attack or minor stroke. A rapid, simple assay of serum glucose may be a useful biomarker to identify patients at particularly high risk of subsequent ischemic stroke. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT0099102.

Background and Purpose: Dual antiplatelet therapy has been shown to reduce the risk of recurrent stroke in patients with minor stroke or transient ischemic attack. However, whether the effect of dual antiplatelet therapy is modified by pretreatment antiplatelet status is unclear., Methods: This is a post hoc analysis of the POINT trial (Platelet-Oriented Inhibition in New TIA and Minor Ischemic Stroke). Patients were divided into 2 groups based on pretreatment antiplatelet use. The primary outcome was ischemic stroke within 90 days of randomization., Results: We included 4881 patients of whom 41% belonged to the no pretreatment antiplatelet. Ischemic stroke occurred in 6% and 5% in the antiplatelet pretreatment and no antiplatelet pretreatment, respectively. Antiplatelet pretreatment was not associated with the risk of ischemic stroke (adjusted hazard ratio, 1.05 [95% CI, 0.81-137]) or risk of major hemorrhage (hazard ratio, 1.10 [95% CI, 0.55-2.21]; P =0.794). The effect of dual antiplatelet therapy on recurrent ischemic stroke risk was not different in patients who were on antiplatelet before randomization (adjusted hazard ratio, 0.69 [95% CI, 0.50-0.94]) as opposed to those who were not (adjusted hazard ratio, 0.75 [95% CI, 0.50-1.12]), P for interaction = 0.685., Conclusions: In patients with minor stroke and high-risk transient ischemic attack, dual antiplatelet therapy reduces the risk of ischemic stroke regardless of premorbid antiplatelet use.

There are a plethora of cognitive sequelae in addition to neglect and extinction that arise with unilateral right hemispheric stroke (RHS). Cognitive deficits following non-dominant (right) hemisphere stroke are common with unilateral neglect and extinction being the most recognized examples. The severity of RHS is usually underestimated by the National Institutes of Health Stroke Scale (NIHSS), which in terms of lateralized right hemisphere cognitive deficits, tests only for visual inattention/extinction. They account for 2 out of 42 total possible points. Additional neuropsychiatric sequelae include but are not limited to deficiencies in affective prosody comprehension and production (aprosodias), understanding and expressing facial emotions, empathy, recognition of familiar faces, anxiety, mania, apathy, and psychosis. These sequelae have a profound impact on patients' quality of life; affecting communication, interpersonal relationships, and the ability to fulfill social roles. They also pose additional challenges to recovery. There is presently a gap in the literature regarding a cohesive overview of the significant cognitive sequelae following RHS. This paper serves as a narrative survey of the current understanding of the subject, with particular emphasis on neuropsychiatric poststroke syndromes not predominantly associated with left hemisphere lesions (LHL), bilateral lesions, hemiplegia, or paralysis. A more comprehensive understanding of the neuropsychological consequences of RHS extending beyond the typical associations of unilateral neglect and extinction may have important implications for clinical practice, including the ways in which clinicians approach diagnostics, treatment, and rehabilitation., (Copyright © 2021 Elsevier B.V. All rights reserved.)

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., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background and Purpose: A subset of ischaemic stroke patients with atrial fibrillation (AF) have ischaemic stroke despite anticoagulation. We sought to determine the association between prestroke anticoagulant therapy and recurrent ischaemic events and symptomatic intracranial haemorrhage (sICH)., Methods: We included consecutive patients with acute ischaemic stroke and AF from the Initiation of Anticoagulation after Cardioembolic stroke (IAC) study from eight comprehensive stroke centres in the USA. We compared recurrent ischaemic events and delayed sICH risk using adjusted Cox regression analyses between patients who were prescribed anticoagulation (ACp) versus patients who were naïve to anticoagulation therapy prior to the ischaemic stroke (anticoagulation naïve)., Results: Among 2084 patients in IAC, 1518 had prior anticoagulation status recorded and were followed for 90 days. In adjusted Cox hazard models, ACp was associated with some evidence of a higher risk higher risk of 90-day recurrent ischaemic events only in the fully adjusted model (adjusted HR 1.50, 95% CI 0.99 to 2.28, p=0.058) but not increased risk of 90-day sICH (adjusted HR 1.08, 95% CI 0.46 to 2.51, p=0.862). In addition, switching anticoagulation class was not associated with reduced risk of recurrent ischaemic events (adjusted HR 0.41, 95% CI 0.12 to 1.33, p=0.136) nor sICH (adjusted HR 1.47, 95% CI 0.29 to 7.50, p=0.641)., Conclusion: AF patients with ischaemic stroke despite anticoagulation may have higher recurrent ischaemic event risk compared with anticoagulation-naïve patients. This suggests differing underlying pathomechanisms requiring different stroke prevention measures and identifying these mechanisms may improve secondary prevention strategies., Competing Interests: Competing interests: SY has a non-funded research collaboration with Medtronic. MEG reports grants from AVID (Eli Lilly), grants from Boston Scientific, and grants from Pfizer outside the submitted work. NH reports grants from NINDS during the conduct of the study; grants from NICHD of the NIH, grants from NINDS of the NIH, grants from CDMRP of the DoD, and personal fees from Astrocyte Pharmaceuticals outside the submitted work. EM reports grants from NIH/NINDS outside the submitted work. AdH reports research support from AMAG and Regeneron., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: The carotid web is a compelling potential mechanism of embolic ischemic stroke. In this study, we aim to determine the prevalence of ipsilateral carotid web in a cohort of ischemic stroke patients and to perform a systematic review and meta-analysis of similar cohorts., Patients & Methods: We performed a retrospective, observational, cohort study of acute ischemic stroke patients admitted to a comprehensive stroke center from June 2012 to September 2017. Carotid web was defined on computed tomography angiography (CTA) as a thin shelf of non-calcified tissue immediately distal to the carotid bifurcation. We described the prevalence of carotid artery webs in our cohort, then performed a systematic review and meta-analysis of similar cohorts in the published literature., Results: We identified 1,435 potentially eligible patients of whom 879 met criteria for inclusion in our analysis. An ipsilateral carotid web was detected in 4 out of 879 (0.45%) patients, of which 4/4 (1.6%) were in 244 patients with cryptogenic stroke and 3/4 were in 66 (4.5%) patients <60 years old with cryptogenic stroke. Our systematic review yielded 3,192 patients. On meta-analysis, the pooled prevalence of ipsilateral carotid web in cryptogenic stroke patients <60 was 13% (95% CI: 7%-22%; I2 = 66.1%). The relative risk (RR) of ipsilateral versus contralateral carotid web in all patients was 2.5 (95% CI 1.5-4.2, p = 0.0009) whereas in patients less than 60 with cryptogenic stroke it was 3.0 (95% CI 1.6-5.8, p = 0.0011)., Discussion: Carotid webs are more common in young patients with cryptogenic stroke than in other stroke subtypes. Future studies concerning the diagnosis and secondary prevention of stroke associated with carotid web should focus on this population., Competing Interests: The authors have declared that no competing interests exist.

Background Intravenous alteplase improves outcome after acute ischemic stroke without a benefit in 90-day mortality. There are limited data on whether alteplase is associated with reduced mortality in patients with atrial fibrillation (AF)-related ischemic stroke whose mortality rate is relatively high. We sought to determine the association of alteplase with hemorrhagic transformation and mortality in patients with AF. Methods and Results We retrospectively analyzed consecutive patients with acute ischemic stroke between 2015 and 2018 diagnosed with AF included in the IAC (Initiation of Anticoagulation After Cardioembolic Stroke) study, which pooled data from stroke registries at 8 comprehensive stroke centers across the United States. For our primary analysis, we included patients who did not undergo mechanical thrombectomy (MT), and secondary analyses included patients who underwent MT. We used binary logistic regression to determine whether alteplase use was associated with risk of hemorrhagic transformation and 90-day mortality. There were 1889 patients (90.6%) who had 90-day follow-up data available for analyses and were included; 1367 patients (72.4%) did not receive MT, and 522 patients (27.6%) received MT. In our primary analyses we found that alteplase use was independently associated with an increased risk for hemorrhagic transformation (odds ratio [OR], 2.23; 95% CI, 1.57-3.17) but reduced risk of 90-day mortality (OR, 0.58; 95% CI, 0.39-0.87). Among patients undergoing MT, alteplase use was not associated with a significant reduction in 90-day mortality (OR, 0.68; 95% CI, 0.45-1.04). Conclusions Alteplase reduced 90-day mortality of patients with acute ischemic stroke with AF not undergoing MT. Further study is required to assess the efficacy of alteplase in patients with AF undergoing MT.

Background and Purpose: In patients with acute large vessel occlusion, the natural history of penumbral tissue based on perfusion time-to-maximum (T max ) delay is not well established in relation to late-window endovascular thrombectomy. In this study, we sought to evaluate penumbra consumption rates for T max delays in patients with large vessel occlusion evaluated between 6 and 16 hours from last known normal., Methods: This is a post hoc analysis of the DEFUSE 3 trial (The Endovascular Therapy Following Imaging Evaluation for Ischemic Stroke), which included patients with an acute ischemic stroke due to anterior circulation occlusion within 6 to 16 hours of last known normal. The primary outcome is percentage penumbra consumption, defined as (24-hour magnetic resonance imaging infarct volume-baseline core infarct volume)/(T max 6 or 10 s volume-baseline core volume). We stratified the cohort into 4 categories based on treatment modality and Thrombolysis in Cerebral Infarction (TICI score; untreated, TICI 0-2a, TICI 2b, and TICI3) and calculated penumbral consumption rates in each category., Results: We included 141 patients, among whom 68 were untreated. In the untreated versus TICI 3 patients, a median (interquartile range) of 53.7% (21.2%-87.7%) versus 5.3% (1.1%-14.6%) of penumbral tissue was consumed based on T max >6 s ( P <0.001). In the same comparison for T max >10 s, we saw a difference of 165.4% (interquartile range, 56.1%-479.8%) versus 25.7% (interquartile range, 3.2%-72.1%; P <0.001). Significant differences were not demonstrated between untreated and TICI 0-2a patients for penumbral consumption based on T max >6 s ( P =0.52) or T max >10 s ( P =0.92)., Conclusions: Among extended window endovascular thrombectomy patients, T max >10-s mismatch volume may comprise large volumes of salvageable tissue, whereas nearly half the T max >6-s mismatch volume may remain viable in untreated patients at 24 hours.

Objectives: Opioids are frequently used for analgesia in patients with acute subarachnoid hemorrhage (SAH) due to a high prevalence of headache and neck pain. However, it is unclear if this practice may pose a risk for opioid dependence, as long-term opioid use in this population remains unknown. We sought to determine the prevalence of opioid use in SAH survivors, and to identify potential risk factors for opioid utilization., Methods: We analyzed a cohort of consecutive patients admitted with non-traumatic and suspected aneurysmal SAH to an academic referral center. We included patients who survived hospitalization and excluded those who were not opioid-naïve. Potential risk factors for opioid prescription at discharge, 3 and 12 months post-discharge were assessed., Results: Of 240 SAH patients who met our inclusion criteria (mean age 58.4 years [SD 14.8], 58% women), 233 (97%) received opioids during hospitalization and 152 (63%) received opioid prescription at discharge. Twenty-eight patients (12%) still continued to use opioids at 3 months post-discharge, and 13 patients (6%) at 12-month follow up. Although patients with poor Hunt and Hess grades (odds ratio 0.19, 95% CI 0.06-0.57) and those with intraventricular hemorrhage (odds ratio 0.38, 95% CI 0.18-0.87) were less likely to receive opioid prescriptions at discharge, we did not find significant differences between patients who had long-term opioid use and those who did not., Conclusion: Opioids are regularly used in both the acute SAH setting and immediately after discharge. A considerable number of patients also continue to use opioids in the long-term. Opioid-sparing pain control strategies should be explored in the future., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: Central retinal artery occlusion (CRAO) causes sudden, irreversible blindness and is a form of acute ischemic stroke. In this study, we sought to determine the proportion of patients in whom atrial fibrillation (AF) is detected by extended cardiac monitoring after CRAO., Methods: We performed a retrospective, observational cohort study using data from the Optum deidentified electronic health record of 30.8 million people cross-referenced with the Medtronic CareLink database of 2.7 million people with cardiac monitoring devices in situ. We enrolled patients in 3 groups: (1) CRAO, (2) cerebral ischemic stroke, and (3) age-, sex-, and comorbidity-matched controls. The primary end point was the detection of new AF (defined as ≥2 minutes of AF detected on a cardiac monitoring device)., Results: We reviewed 884 431 patient records in common between the two databases to identify 100 patients with CRAO, 6559 with ischemic stroke, and 1000 matched controls. After CRAO, the cumulative incidence of new AF at 2 years was 49.6% (95% CI, 37.4%–61.7%). Patients with CRAO had a higher rate of AF than controls (hazard ratio, 1.64 [95% CI, 1.17–2.31]) and a comparable rate to patients with stroke (hazard ratio, 1.01 [95% CI, 0.75–1.36]). CRAO was associated with a higher incidence of new stroke compared with matched controls (hazard ratio, 2.85 [95% CI, 1.29–6.29])., Conclusions: The rate of AF detection after CRAO is higher than that seen in age-, sex-, and comorbidity-matched controls and comparable to that seen after ischemic cerebral stroke. Paroxysmal AF should be considered as part of the differential etiology of CRAO, and those patients may benefit from long-term cardiac monitoring.

Background and Purpose: Randomized trials demonstrated the benefit of dual antiplatelet therapy in patients with minor ischemic stroke or high-risk transient ischemic attack. We sought to determine whether the presence of carotid stenosis was associated with increased risk of ischemic stroke and whether the addition of clopidogrel to aspirin was associated with more benefit in patients with versus without carotid stenosis., Methods: This is a post-hoc analysis of the POINT trial (Platelet-Oriented Inhibition in New TIA and Minor Ischemic Stroke) that randomized patients with minor ischemic stroke or high-risk transient ischemic attack within 12 hours from last known normal to receive either clopidogrel plus aspirin or aspirin alone. The primary predictor was the presence of ≥50% stenosis in either cervical internal carotid artery. The primary outcome was ischemic stroke. We built Cox regression models to determine the association between carotid stenosis and ischemic stroke and whether the effect of clopidogrel was modified by ≥50% carotid stenosis., Results: Among 4881 patients enrolled POINT, 3941 patients met the inclusion criteria. In adjusted models, ≥50% carotid stenosis was associated with ischemic stroke risk (hazard ratio, 2.45 [95% CI, 1.68-3.57], P <0.001). The effect of clopidogrel (versus placebo) on ischemic stroke risk was not significantly different in patients with <50% carotid stenosis (adjusted hazard ratio, 0.68 [95% CI, 0.50-0.93], P =0.014) versus those with ≥50% carotid stenosis (adjusted hazard ratio, 0.88 [95% CI, 0.45-1.72], P =0.703), P value for interaction=0.573., Conclusions: The presence of carotid stenosis was associated with increased risk of ischemic stroke during follow-up. The effect of added clopidogrel was not significantly different in patients with versus without carotid stenosis. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03354429.

Central retinal artery occlusion (CRAO) is a form of acute ischemic stroke which affects the retina. Intravenous thrombolysis is emerging as a compelling therapeutic approach. However, it is not known which patients may benefit from this therapy because there are no imaging modalities that adequately distinguish viable retina from irreversibly infarcted retina. The inner retina receives arterial supply from the central retinal artery and there is robust collateralization between this circulation and the outer retinal circulation, provided by the posterior ciliary circulation. Fundus photography can show canonical changes associated with CRAO including a cherry-red spot, arteriolar boxcarring and retinal pallor. Fluorescein angiography provides 2-dimensional imaging of the retinal circulation and can distinguish a complete from a partial CRAO as well as central versus peripheral retinal non-perfusion. Transorbital ultrasonography may assay flow through the central retinal artery and is useful in the exclusion of other orbital pathology that can mimic CRAO. Optical coherence tomography provides structural information on the different layers of the retina and exploratory work has described its utility in determining the time since onset of ischemia. Two experimental techniques are discussed. 1) Retinal functional imaging permits generation of capillary perfusion maps and can assay retinal oxygenation and blood flow velocity. 2) Photoacoustic imaging combines the principles of optical excitation and ultrasonic detection and - in animal studies - has been used to determine the retinal oxygen metabolic rate. Future techniques to determine retinal viability in clinical practice will require rapid, easily used, and reproducible methods that can be deployed in the emergency setting., Competing Interests: Declaration of Competing Interest None of the authors have conflicts of interest related to this data. This manuscript is not under review at any other journal. There are no redundant publications based on this dataset. All co-authors meet the ICMJE requirements for authorship., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Purpose: Central retinal artery occlusion (CRAO) is a form of acute ischemic stroke that causes severe visual loss and is a harbinger of further cerebrovascular and cardiovascular events. There is a paucity of scientific information on the appropriate management of CRAO, with most strategies based on observational literature and expert opinion. In this scientific statement, we critically appraise the literature on CRAO and provide a framework within which to consider acute treatment and secondary prevention., Methods: We performed a literature review of randomized controlled clinical trials, prospective and retrospective cohort studies, case-control studies, case reports, clinical guidelines, review articles, basic science articles, and editorials concerning the management of CRAO. We assembled a panel comprising experts in the fields of vascular neurology, neuro-ophthalmology, vitreo-retinal surgery, immunology, endovascular neurosurgery, and cardiology, and document sections were divided among the writing group members. Each member received an assignment to perform a literature review, synthesize the data, and offer considerations for practice. Multiple drafts were circulated among the group until consensus was achieved., Results: Acute CRAO is a medical emergency. Systems of care should evolve to prioritize early recognition and triage of CRAO to emergency medical attention. There is considerable variability in management patterns among practitioners, institutions, and subspecialty groups. The current literature suggests that treatment with intravenous tissue plasminogen activator may be effective. Patients should undergo urgent screening and treatment of vascular risk factors. There is a need for high-quality, randomized clinical trials in this field.

Background and Purpose: According to evidence-based clinical practice guidelines, patients presenting with disabling stroke symptoms should be treated with intravenous tissue plasminogen activator (IV tPA) within 4.5 h of time last known well. However, 25% of strokes are detected upon awakening (i.e., wake-up stroke [WUS]), which renders patients ineligible for IV tPA administered via time-based treatment algorithms, because it is impossible to establish a reliable time of symptom onset. We performed a systematic review and meta-analysis of the efficacy and safety of IV tPA compared with normal saline, placebo, or no treatment in patients with WUS using imaging-based treatment algorithms., Methods: We searched MEDLINE, Web of Science, and Scopus between January 1, 2006 and April 30, 2020. We included controlled trials (randomized or nonrandomized), observational cohort studies (prospective or retrospective), and single-arm studies in which adults with WUS were administered IV tPA after magnetic resonance imaging (MRI)- or computed tomography (CT)-based imaging. Our primary outcome was recovery at 90 days (defined as a modified Rankin Scale [mRS] score of 0-2), and our secondary outcomes were symptomatic intracranial hemorrhage (sICH) within 36 h, mortality, and other adverse effects., Results: We included 16 studies that enrolled a total of 14,017 patients. Most studies were conducted in Europe (37.5%) or North America (37.5%), and 1757 patients (12.5%) received IV tPA. All studies used MRI-based (five studies) or CT-based (10 studies) imaging selection, and one study used a combination of modalities. Sixty-one percent of patients receiving IV tPA achieved an mRS score of 0 to 2 at 90 days (95% confidence interval [CI]: 51%-70%, 12 studies), with a relative risk (RR) of 1.21 compared with patients not receiving IV tPA (95% CI: 1.01-1.46, four studies). Three percent of patients receiving IV tPA experienced sICH within 36 h (95% CI: 2.5%-4.1%; 16 studies), which is an RR of 4.00 compared with patients not receiving IV tPA (95% CI: 2.85-5.61, seven studies)., Conclusions: This systematic review and meta-analysis suggests that IV tPA is associated with a better functional outcome at 90 days despite the increased but acceptable risk of sICH. Based on these results, IV tPA should be offered as a treatment for WUS patients with favorable neuroimaging findings., (© 2021 European Academy of Neurology.)

Background and Purpose: Although most strokes present with mild symptoms, these have been poorly represented in clinical trials. The objective of this study is to describe multidimensional outcomes, identify predictors of worse outcomes, and explore the effect of thrombolysis in this population., Methods: This prospective observational study included patients with ischemic stroke or transient ischemic attack, a baseline National Institutes of Health Stroke Scale (NIHSS) score 0 to 5, presenting within 4.5 hours from symptom onset. The primary outcome was a 90-day modified Rankin Scale score of 0 to 1; secondary outcomes included good outcomes in the Barthel Index, Stroke Impact Scale-16, and European Quality of Life. Multivariable models were created to determine predictors of outcomes and the effect of alteplase., Results: A total of 1765 participants were included from 100 Get With The Guidelines-Stroke participating hospitals (age, 65±14; 42% women; final diagnosis of ischemic stroke, 90%; transient ischemic attack, 10%; 57% received alteplase). At 90 days, 37% were disabled and 25% not independent. Worse outcomes were noted for older individuals, women, non-Hispanic Blacks and Hispanics, Medicaid recipients, smokers, those with diabetes, atrial fibrillation, prior stroke, higher baseline NIHSS, visual field defects, and extremity weakness. Similar outcomes were noted for the alteplase-treated and untreated groups. Alteplase-treated patients were younger (64±13 versus 67±1.4) with higher NIHSS (2.9±1.4 versus 1.7±1.4). After adjusting for age, sex, race/ethnicity, and baseline NIHSS, we did not identify an effect of alteplase on the primary outcome but did find an association with Stroke Impact Scale-16 in the restricted sample of baseline NIHSS score 3–5. Few symptomatic intracerebral hemorrhages were recorded (<1%)., Conclusions: A large proportion of stroke patients presenting with low NIHSS have a disabled outcome. Baseline predictors of worse outcomes are described. An effect of alteplase on outcomes was not identified in the overall cohort, but a suggestion of efficacy was noted in the NIHSS 3–5 subgroup., Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02072681.