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The therapeutic focus in acute ischemic stroke over the last 2.5 decades has been to balance the benefits of rapid reperfusion therapy with the risks of treatment-related complications. Both intravenous thrombolytics and endovascular thrombectomy are proven to substantially improve outcomes in a time-dependent manner. Each minute saved in achieving successful reperfusion grants an additional week of healthy life and may salvage up to 27 million neurons. The current approach to patient triage is inherited from the preendovascular thrombectomy era of stroke care. Current workflow concentrates on stabilization, diagnosis, and decision-making in the emergency department, followed by thrombolysis if eligible and subsequent transfer to the angiography suite as needed for further treatment. Multiple efforts have been directed toward minimizing the time from first medical contact to reperfusion therapy including prehospital triage and intrahospital workflow. Novel approaches for stroke patient triage such as the direct to angio approach, (also referred to as One Stop Management) are currently in development. The concept was initially introduced as several single-center experiences. In this narrative review article, we will consider various definitions of direct to angio and its variants, discuss its rationale, review its safety and efficacy, assess its feasibility, and delineate its limitations. Further, we will address methods to overcome these limitations and the potential impact of emerging data and new technologies on the direct-to-angio approach.

Background: It is challenging for outcome assessors to remain blinded during outcome assessment in trials with prospective randomized open blinded endpoint (PROBE) design. If assessors are able to guess the correct treatment allocation more often than expected based on chance, the assessors may have been not properly blinded. Aims: We aimed to assess blinding of outcome assessors in a stroke trial with PROBE design and its association with outcome. Methods: We used data of the Interventional Management of Stroke (IMS) III trial. The modified Rankin Scale (mRS) at 90 days was assessed by local assessors who were unaware of treatment allocation. To assess success of blinding, each assessor was asked to guess the patient’s treatment allocation. We assessed whether the percentage of correct guesses was higher than chance (i.e. 50%). The association between correctly guessed treatment allocation and the mRS at 90 days was analyzed with ordinal logistic regression stratified by treatment allocation. We tested for interaction of correctly versus incorrectly guessed treatment allocation with actual treatment allocation on the mRS. Patients with missing data on guessed treatment allocation and patients who died prior to 90-day assessment were excluded. Results: In total, 459 patients were included in this study. The assessors guessed the correct treatment allocation significantly more often than expected (267/459, 58.2%, one-sided p = 0.0003). Correctly guessed treatment allocations were associated with better mRS scores in the intervention group (common odds ratio (cOR): 2.28, 95% confidence interval (CI): 1.50–3.48) and with worse mRS scores in the control group (cOR: 0.47, 95% CI: 0.27–0.83) (pinteraction Conclusions: Assessors may not always be truly blinded for treatment allocation in clinical trials, and their guesses may be associated with outcome. Although causality between the assessors’ guess and patient outcome cannot be determined, future trials with subjective outcome should make efforts to ensure blinding and should report their blinding method and the success of blinding like the IMS III trial. Clinical Trial Registration: URL: https://clinicaltrials.gov . Unique identifier: NCT00359424.

Background and Purpose Intracranial arterial stenosis (ICAS)-related stroke occurs due to three primary mechanisms with distinct infarct patterns: (1) borderzone infarcts (BZI) due to impaired distal perfusion, (2) territorial infarcts due to distal plaque/thrombus embolization, and (3) plaque progression occluding perforators. The objective of the systematic review is to determine whether BZI secondary to ICAS is associated with a higher risk of recurrent stroke or neurological deterioration.Methods As part of this registered systematic review (CRD42021265230), a comprehensive search was performed to identify relevant papers and conference abstracts (with ≥20 patients) reporting initial infarct patterns and recurrence rates in patients with symptomatic ICAS. Subgroup analyses were performed for studies including any BZI versus isolated BZI and those excluding posterior circulation stroke. The study outcome included neurological deterioration or recurrent stroke during follow-up. For all outcome events, corresponding risk ratios (RRs) and 95% confidence intervals (95% CI) were calculated.Results A literature search yielded 4,478 records with 32 selected during the title/abstract triage for full text; 11 met inclusion criteria and 8 studies were included in the analysis (n=1,219 patients; 341 with BZI). The meta-analysis demonstrated that the RR of outcome in the BZI group compared to the no BZI group was 2.10 (95% CI 1.52–2.90). Limiting the analysis to studies including any BZI, the RR was 2.10 (95% CI 1.38–3.18). For isolated BZI, RR was 2.59 (95% CI 1.24–5.41). RR was 2.96 (95% CI 1.71–5.12) for studies only including anterior circulation stroke patients.Conclusion This systematic review and meta-analysis suggests that the presence of BZI secondary to ICAS may be an imaging biomarker that predicts neurological deterioration and/or stroke recurrence.

Background: Clinical trial enrollment and completion is challenging, with nearly half of all trials not being completed or not completed on time. In 2014, the National Institutes of Health StrokeNet in collaboration with stroke epidemiologists from GCNKSS (Greater Cincinnati/Northern Kentucky Stroke Study) began providing proposed clinical trials with formal trial feasibility assessments. Herein, we describe the process of prospective feasibility analyses using epidemiological data that can be used to improve enrollment and increase the likelihood a trial is completed. Methods: In 2014, DEFUSE 3 (Endovascular Therapy Following Imaging Evaluation for Ischemic Stroke 3) trialists, National Institutes of Health StrokeNet, and stroke epidemiologists from GCNKSS collaborated to evaluate the initial inclusion/exclusion criteria for the DEFUSE 3 study. Trial criteria were discussed and an assessment was completed to evaluate the percent of the stroke population that might be eligible for the study. The DEFUSE 3 trial was stopped early with the publication of DAWN (Thrombectomy 6 to 24 Hours After Stroke With a Mismatch Between Deficit and Infarct), and the Wilcoxon rank-sum statistic was used to analyze whether the trial would have been stopped had the proposed changes not been made, following the DEFUSE 3 statistical analysis plan. Results: After initial epidemiological analysis, 2.4% of patients with acute stroke in the GCNKSS population would have been predicted to be eligible for the study. After discussion with primary investigators and modifying 4 key exclusion criteria (upper limit of age increased to 90 years, baseline modified Rankin Scale broadened to 0–2, time since last well expanded to 16 hours, and decreased lower limit of National Institutes of Health Stroke Scale score to Conclusions: Objectively assessing trial inclusion/exclusion criteria using a population-based resource in a collaborative and iterative process including epidemiologists can lead to improved recruitment and can increase the likelihood of successful trial completion.

Background: Our primary objective was to evaluate if disparities in race, sex, age, and socioeconomic status (SES) exist in utilization of advanced neuroimaging in year 2015 in a population-based study. Our secondary objective was to identify the disparity trends and overall imaging utilization as compared with years 2005 and 2010. Methods: This was a retrospective, population-based study that utilized the GCNKSS (Greater Cincinnati/Northern Kentucky Stroke Study) data. Patients with stroke and transient ischemic attack were identified in the years 2005, 2010, and 2015 in a metropolitan population of 1.3 million. The proportion of imaging use within 2 days of stroke/transient ischemic attack onset or hospital admission date was computed. SES determined by the percentage below the poverty level within a given respondent’s US census tract of residence was dichotomized. Multivariable logistic regression was used to determine the odds of advanced neuroimaging use (computed tomography angiogram/magnetic resonance imaging/magnetic resonance angiogram) for age, race, gender, and SES. Results: There was a total of 10 526 stroke/transient ischemic attack events in the combined study year periods of 2005, 2010, and 2015. The utilization of advanced imaging progressively increased (48% in 2005, 63% in 2010, and 75% in 2015 [ P P P 55 years; adjusted odds ratio, 1.34 [95% CI, 1.15–1.57]; P Conclusions: Racial, age, and SES-related disparities exist in the utilization of advanced neuroimaging for patients with acute stroke. There was no evidence of a change in trend of these disparities between the study periods.

Background: Though stroke risk factors such as substance use may vary with age, less is known about trends in substance use over time or about performance of toxicology screens in young adults with stroke. Methods: Using the Greater Cincinnati Northern Kentucky Stroke Study, a population-based study in a 5-county region comprising 1.3 million people, we reported the frequency of documented substance use (cocaine/marijuana/opiates/other) obtained from electronic medical record review, overall and by race/gender subgroups among physician-adjudicated stroke events (ischemic and hemorrhagic) in adults 20 to 54 years of age. Secondary analyses included heavy alcohol use and cigarette smoking. Data were reported for 5 one-year periods spanning 22 years (1993/1994–2015), and trends over time were tested. For 2015, to evaluate factors associated with performance of toxicology screens, multiple logistic regression was performed. Results: Overall, 2152 strokes were included: 74.5% were ischemic, mean age was 45.7±7.6, 50.0% were women, and 35.9% were Black. Substance use was documented in 4.4%, 10.4%, 19.2%, 24.0%, and 28.8% of cases in 1993/1994, 1999, 2005, 2010, and 2015, respectively ( P trend Conclusions: In a population-based study of young adults with stroke, documented substance use increased over time, and documentation of substance use was higher among Black compared with White individuals. Further work is needed to confirm race-based disparities and trends in substance use given the potential for bias in screening and documentation. Findings suggest a need for more standardized toxicology screening.

Background: Asundexian (Bayer AG, Leverkusen, Germany), an oral small molecule factor XIa (FXIa) inhibitor, might prevent thrombosis without increasing bleeding. Asundexian's effect for secondary prevention of recurrent stroke is unknown. Methods: In this randomised, double-blind, placebo-controlled, phase 2b dose-finding trial (PACIFIC-Stroke), patients with acute (within 48 h) non-cardioembolic ischaemic stroke were recruited from 196 hospitals in 23 countries. Patients were eligible if they were aged 45 years or older, to be treated with antiplatelet therapy, and able to have a baseline MRI (either before or within 72 h of randomisation). Eligible participants were randomly assigned (1:1:1:1), using an interactive web-based response system and stratified according to anticipated antiplatelet therapy (single vs dual), to once daily oral asundexian (BAY 2433334) 10 mg, 20 mg, or 50 mg, or placebo in addition to usual antiplatelet therapy, and were followed up during treatment for 26–52 weeks. Brain MRIs were obtained at study entry and at 26 weeks or as soon as possible after treatment discontinuation. The primary efficacy outcome was the dose–response effect on the composite of incident MRI-detected covert brain infarcts and recurrent symptomatic ischaemic stroke at or before 26 weeks after randomisation. The primary safety outcome was major or clinically relevant non-major bleeding as defined by International Society on Thrombosis and Haemostasis criteria. The efficacy outcome was assessed in all participants assigned to treatment, and the safety outcome was assessed in all participants who received at least one dose of study treatment. This study is registered with ClinicalTrials.gov, NCT04304508, and is now complete. Findings: Between June 15, 2020, and July 22, 2021, 1880 patients were screened and 1808 participants were randomly assigned to asundexian 10 mg (n=455), 20 mg (n=450), or 50 mg (n=447), or placebo (n=456). Mean age was 67 years (SD 10) and 615 (34%) participants were women, 1193 (66%) were men, 1505 (83%) were White, and 268 (15%) were Asian. The mean time from index stroke to randomisation was 36 h (SD 10) and median baseline National Institutes of Health Stroke Scale score was 2·0 (IQR 1·0–4·0). 783 (43%) participants received dual antiplatelet treatment for a mean duration of 70·1 days (SD 113·4) after randomisation. At 26 weeks, the primary efficacy outcome was observed in 87 (19%) of 456 participants in the placebo group versus 86 (19%) of 455 in the asundexian 10 mg group (crude incidence ratio 0·99 [90% CI 0·79–1·24]), 99 (22%) of 450 in the asundexian 20 mg group (1·15 [0·93–1·43]), and 90 (20%) of 447 in the asundexian 50 mg group (1·06 [0·85–1·32]; t statistic –0·68; p=0·80). The primary safety outcome was observed in 11 (2%) of 452 participants in the placebo group versus 19 (4%) of 445 in the asundexian 10 mg group, 14 (3%) of 446 in the asundexian 20 mg group, and 19 (4%) of 443 in the asundexian 50 mg group (all asundexian doses pooled vs placebo hazard ratio 1·57 [90% CI 0·91–2·71]). Interpretation: In this phase 2b trial, FXIa inhibition with asundexian did not reduce the composite of covert brain infarction or ischaemic stroke and did not increase the composite of major or clinically relevant non-major bleeding compared with placebo in patients with acute, non-cardioembolic ischaemic stroke. Funding: Bayer AG.

Spontaneous intracerebral hemorrhage (ICH) constitutes 10-15% of all strokes, and is a significant cause of mortality and morbidity. Survivors of ICH, especially those with atrial fibrillation (AF), are at risk for both recurrent hemorrhagic and ischemic cerebrovascular events. A conundrum in the field of vascular neurology, neurosurgery, and cardiology has been the decision to initiate or resume versus withhold anticoagulation in survivors of ICH with AF. To initiate anticoagulation would decrease the risk of ischemic stroke but may increase the risk of hemorrhage. To withhold anticoagulation maintains a lower risk of hemorrhage but does not decrease the risk of ischemic stroke. In this narrative review, we discuss the evidence for and against the use of antithrombotics in ICH survivors with AF, focusing on recently completed and ongoing clinical trials.

Background and ObjectivesThere is a rising incidence of infective endocarditis–related stroke (IERS) in the United States attributed to the opioid epidemic. A contemporary epidemiologic description is necessary to understand the impact of the opioid epidemic on clinical characteristics of IERS. We describe and analyze trends in the demographics, risk factors, and clinical features of IERS.MethodsThis is a retrospective cohort study within a biracial population of 1.3 million in the Greater Cincinnati/Northern Kentucky region. All hospitalized patients with hemorrhagic or ischemic stroke were identified and physician verified from the 2005, 2010, and 2015 calendar years using ICD-9 and ICD-10 codes. IERS was defined as an acute stroke attributed to infective endocarditis meeting modified Duke Criteria for possible or definite endocarditis. Unadjusted comparison of demographics, risk factors, outcome, and clinical characteristics was performed between each study period for IERS and non-IERS. An adjusted model to compare trends used the Cochran-Armitage test for categorical variables and a general linear model or Kruskal-Wallis test for numerical variables. Examination for interaction of endocarditis status in trends was performed using a general linear or logistic model.ResultsA total of 54 patients with IERS and 8,204 without IERS were identified during the study periods. Between 2005 and 2015, there was a decline in rates of hypertension (91.7% vs 36.0%;p= 0.0005) and increased intravenous drug users (8.3% vs 44.0%;p= 0.02) in the IERS cohort. The remainder of the stroke population demonstrated a significant rise in hypertension, diabetes, atrial fibrillation, and perioperative stroke. Infective endocarditis status significantly interacted with the trend in hypertension prevalence (p= 0.001).DiscussionFrom 2005 to 2015, IERS was increasingly associated with intravenous drug use and fewer risk factors, specifically hypertension. These trends likely reflect the demographics of the opioid epidemic, which has affected younger patients with fewer comorbidities.

Background: Major disparities have been reported in recombinant tissue plasminogen activator (rtPA) availability among countries of different socioeconomic status. Aims: To characterize variability of rtPA price, its availability, and its association with and impact on each country’s health expenditure (HE) resources. Methods: We conducted a global survey to obtain information on rtPA price (50 mg vial, 2020 US Dollars) and availability. Country-specific data, including low, lower middle (LMIC), upper middle (UMIC), and high-income country (HIC) classifications, and gross domestic product (GDP) and HE, both nominally and adjusted for purchasing power parity (PPP), were obtained from World Bank Open Data. To assess the impact of rtPA cost, we computed the rtPA price as percentage of per capita GDP and HE and examined its association with the country income classification. Results: rtPA is approved and available in 109 countries. We received surveys from 59 countries: 27 (46%) HIC, 20 (34%) UMIC, and 12 (20%) LMIC. Although HIC have significantly higher per capita GDP and HE compared to UMIC and LMIC (p Conclusion: We documented significant variability in rtPA availability and price among countries. Relative costs are higher in lower income countries, exceeding the available HE. Concerted efforts to improve rtPA affordability in low-income settings are necessary.

BackgroundMany acute stroke clinical trials (ASCTs) are underpowered or terminated early due to poor recruitment. A pervasive challenge to ASCT recruitment is the physical separation of patients, their legally authorized representatives, research coordinators, and clinician investigators when trial-eligible patients are identified. Remote research practices (RRPs) can facilitate time-critical ASCT enrollment and follow-up assessments, however, the feasibility and effectiveness are unknown.MethodsThis case-control study retrospectively reviewed ASCT enrollment at two institutions. When conventional in-person clinical research was not possible, completion of study specific essential clinical trial events (ECTEs) were attempted via RRPs utilizing telemedicine evaluation or telephone communication. The primary outcome was successful execution of ECTEs by modality: in-person, telemedicine evaluation, or telephone communication. The secondary outcome was protocol violation rate by modality. We utilized Fisher’s Exact Test for primary and secondary outcomes and descriptive statistics to report RRP utilization.ResultsA total of 1603 individual ECTEs were attempted for 171 subjects. RRPs were utilized for 53.9% of ECTEs (19.3% telemedicine, 34.6% telephone communication). ECTEs were more likely to be completed successfully via telemedicine (100%) than in-person (98.2%) or telephone (92.3%), (pConclusionRemote research practices were effective and doubled randomized ASCT enrollments in comparison to conventional research models that are restricted to in-person interaction alone. Telemedicine was associated with the highest rate of successful ECTE execution and the lowest rate of protocol deviations. These findings may be confounded by indication and further definitive study is indicated.

Introduction: Data on predictors of early stroke recurrence in patients with symptomatic intracranial atherosclerotic disease (sICAD) is limited. We hypothesized that hypoperfusion delay predicts stroke recurrence within 90-days. Methods: We retrospectively collected all patients hospitalized with anterior circulation sICAD over 3 years (April 2019-April 2022) at a comprehensive stroke center. We collected demographics, clinical risk factors, radiological variables, and treatment strategies. Patients with an indication for anticoagulation such as atrial fibrillation and those with intracranial stenting or angioplasty were excluded. The outcome (verified by two independent reviewers) was recurrent stroke within 90 days in the affected artery. We assessed factors associated with stroke recurrence. We measured the effect of hypoperfusion delay volume on stroke recurrence using Cox-regression models. Results: Out of 131 sICAD hospitalizations during the study period, 66 involved the middle cerebral artery (MCA) M1 segment or intracranial internal carotid artery (ICA) and 44 patients met the inclusion criteria. The mean age was 71 years and 41% were women; 75% were treated with best medical management (dual antiplatelet therapy/high intensity statin therapy); and 75% had baseline perfusion imaging performed. Over 90 days, 11/44 (25%) patients had recurrent stroke. Factors associated with recurrence stroke were no best medical management (15.2% vs. 54.5%, p = 0.02), hypoperfusion Tmax>4 sec mismatch volume (p = 0.003), and hypoperfusion delay Tmax>6 sec mismatch volume (p=0.01). Using Youden’s cutoff for Tmax>4 sec mismatch (13 mL) and for Tmax>6 sec mismatch (5 mL), the risk of recurrent stroke at 90 days in separate models was higher in patients with Tmax>4 sec delay mismatch volume > 13 mL (HR 11.98 95% CI 1.48-96.96 p=0.02) and Tmax>6 sec mismatch volume > 5 mL (HR 4.37 95% CI 1.02-18.82, p=0.048). Effect size of the associations did not meaningfully change after adjusting for best medical management. Conclusion: Hypoperfusion delay is associated with an increased recurrent stroke risk within 90 days in patients with sICAD, despite best medical management. Validation by large prospective studies is warranted.

Background: TIAs serve as an opportunity to identify and modify risk factors and to prevent future events. Given known epidemiologic differences in strokes by race and sex, our objective was to investigate the rates of prior TIAs among those with incident ischemic stroke (IS) in the GCNKSS. Methods: We included all physician adjudicated, incident IS among adults age ≥20 years in the GCNKSS, a population-based stroke surveillance study in a 5-county region of southern Ohio/ northern Kentucky, in 2005, 2010, and 2015. We calculated the frequency of cases in which a TIA (sudden onset of focal neurologic symptoms lasting ≤ 24 hours) was documented in the 365 days prior to IS. Frequencies and proportions of prior TIA were compared by sex, race, and age, and location at which patients sought care for their TIA was described. Finally, multivariable logistic regression was performed to investigate demographic and clinical predictors of cases in which TIA preceded stroke; covariates were chosen a priori. Results: We included 5310 IS events; mean age was 69.7 (SD 14.8) years, 54.7% were female, and 20.4% were Black. A total of 351 patients (6.6%) had a documented TIA the year preceding their IS. Overall, 42.2% did not seek care for their TIA, 21.6% called 911 and/or came to the ED, 6.0% saw a PCP, and 6.6% sought other care. In 22.5% of cases, location of care was unknown. In adjusted results, older age, female sex, history of hypertension, and CAD were associated with having had a prior TIA, while Black race was not. NIHSS was inversely associated with prior TIA (Table). Prior TIAs were similar between study years. Conclusions: We conservatively estimate that ≥ 6% of patients with first-ever IS had a TIA in the preceding year, though underreporting is likely. Many patients did not report seeking care for the TIA, suggesting missed opportunities for risk factor modification. Further research is needed to understand the implications of sex and race differences in frequencies of prior TIA.

Background: While optimizing medical treatment contributed to the low recurrence risk seen in SAMMPRIS medical arm, other factors such as delayed enrollment may have contributed to this low event rate. In this study, we aim to determine the 30-day recurrence risk in a real-world setting in patients with symptomatic intracranial atherosclerosis. Methods: We used a stroke registry of a comprehensive stroke center to identify hospitalized patients with acute ischemic stroke in the setting of symptomatic intracranial atherosclerosis of the ICA, M1, vertebral, or basilar with 50-99% luminal narrowing. We excluded patients with a clear indication for anticoagulation and those who received endovascular treatment. The outcome was recurrent stroke attributed to the affected artery within 30-days. We used adjusted Cox regression models to identify factors associated with increased recurrence risk. Results: Among 131 symptomatic 50-99% intracranial stenosis hospitalizations over 3 years, 66 patients met the inclusion criteria. The mean age was 71.9 years and 51.5% were men; 75.8% were treated with best medical management (dual antiplatelet therapy/high intensity stain therapy). Over 30-day follow-up, 21.2 % had recurrent stroke, 57.1% (8/14) occurred within first 7 days. The recurrence risk was similar to another real world ICAD cohort, and higher than that seen in SAMMPRIS (Figure). While maximal medical treatment was the only factor associated with a lower rate of recurrence (OR 0.32 95% CI 0.09-1.12, p = 0.075), the recurrence rate in patients treated with maximal medical therapy (16.0%, 95% CI 8.1-29.3%) and those SAMMPRIS eligible (17.6%, 95% CI 7.9-34.9%) remained elevated. Conclusions: In patients with symptomatic ICAS, the real-world recurrence is higher than that seen in clinical trials, despite optimally using the same medical treatment strategies. This may suggest that the low risk of recurrence achieved in clinical trials may not apply to real world practice.

Background: Monitoring changes in ischemic stroke severity at the population level is important as changes in risk factors and clinical treatments could influence stroke severity. We describe trends in the distribution of NIHSS across 3 time periods in a population-based epidemiologic stroke study. Methods: In 2005, 2010, and 2015 all adult acute ischemic strokes occurring within the Greater Cincinnati area presenting to 15 hospitals were ascertained using discharge codes (ICD-9 433-436; IDC-10 I63-I68, G45-46). Following physician verification, confirmed ischemic stroke cases underwent chart abstraction including estimation of a retrospective (rNIHSS) score at presentation. Descriptive statistics (rNIHSS median, IQR) were generated by survey year, demographics, and medical history. Using a binary definition of stroke severity (median rNIHSS score &gt 4 versus &lt 4), multivariable logistic regression was used to estimate changes in stroke severity over time, adjusting for potential confounders. Random effects were used to account for multiple admissions occurring in the same subject. Results: The number of ischemic stroke admissions in the 2005, 2010, and 2015 surveys was 1778, 1903, and 1933, respectively (Table). The median (IQR) rNIHSS scores were 3 (2-7), 3 (1-6), and 2 (1-6) across the 3 surveys, respectively; the proportion of admissions with rNIHSS &gt 4 was 48%, 39% and 37%, respectively. After adjusting for demographics, medical history and pre-stroke function, compared to 2005, the odds ratio for more severe stroke was 0.69 (95% CI= 0.60-0.79, p=0.001) in 2010 and 0.63 (95% CI= 0.55-0.73, p=0.001) in 2015. Conclusions: In this population- based study there was a statistically significant change in the severity of ischemic stroke hospitalizations with increases in the proportion of milder strokes over time. Potential reasons for this change need to be explored but could include changes in risk factors, clinical treatments or diagnostic approach.

Background: Many acute stroke clinical trials (ASCTs) are underpowered, inconclusive, or terminated early. A pervasive challenge to ASCT recruitment is the physical separation of patients, their legally authorized representatives, research coordinators, and clinician investigators when trial-eligible patients present emergently. Remote research practices (RRPs) may aid time-critical ASCT enrollment and follow-up, however, their feasibility and effectiveness are understudied. Methods: We retrospectively reviewed ASCT enrollment (NCT03785678, NCT03735979, NCT02072681) at two institutions. Essential clinical trial elements (ECTEs) consisted of eligibility screening, informed consent, randomization, study intervention, and inpatient/outpatient follow-up assessments. When conventional in-person clinical research was not possible, ECTEs were attempted via RRPs utilizing either telemedicine evaluation or telephone communication. The primary outcome was the successful execution of accurate, complete ECTEs by research communication modality (in-person, telemedicine, or telephone). The secondary outcome was the protocol violation rate by modality. We utilized Fisher’s Exact Test for primary and secondary outcomes and descriptive statistics to report RRP utilization. Results: A total of 1600 individual ECTEs were attempted on 169 subjects. RRPs were utilized for 53.7% of ECTEs (19.1% telemedicine, 34.6% telephone). ECTEs were more likely to be completed successfully with telemedicine (100%) than in-person (98.5%) or telephone (92.2%), (p Conclusion: RRPs were widely utilized. Telemedicine execution of ECTEs was associated with the highest rate of successful completion and lowest rate of protocol deviations. These findings, while retrospective and confounded by indication, suggest RRPs are effective and require confirmatory study.

Introduction: Stroke secondary to intracranial atherosclerosis (ICAD) results in three distinct infarct patterns: (a) border zone infarcts (BZI) due to impaired distal perfusion (b) territorial infarcts due to distal plaque/thrombus embolization, and (c) perforator infarcts due to plaque progression. Previous studies indicate higher stroke recurrence in ICAD patients with BZI. Methods: This registered systematic review (CRD42021265230) comprised Medline and Web of Science search from inception to March 2022 for keywords (Intracranial Atherosclerosis OR Intracranial Stenosis) AND (Border zone OR Infarct Pattern) to identify papers and conference abstracts reporting initial infarct patterns and recurrence rates in patients with symptomatic ICAD. Sensitivity analyses were performed for studies including any BZI vs isolated BZI and those excluding posterior circulation strokes. The study outcome included neurological deterioration and/or stroke recurrence. For all outcome events, corresponding risk ratios (RR) and 95% confidence intervals (CI) were calculated. Risk of bias assessments will be presented. Results: Literature search yielded 4478 studies,11 met inclusion criteria (n=1315 patients, 354 with BZI, weighted proportions summarized in figure). The meta-analysis of these studies with moderate heterogeneity (I 2 =38.7%) demonstrated that RR of outcomes in BZI group compared to non-BZI group was 2.10 (95% CI 1.52-2.90). Limiting analysis to studies including any BZI, RR (and 95% CI) was 2.32 (1.58-3.40), and 3.25 (2.09-5.07) for studies only including anterior circulation strokes with low heterogeneity for both (I 2 =0%). A non-significantly high outcome rate was seen with isolated BZI (RR 2.29, 95% CI 0.94-5.62) but with moderate heterogeneity across studies (I 2 =70.25%). Conclusion: We demonstrate the presence of BZI secondary to symptomatic ICAD can be imaging biomarker to predict neurological deterioration and/or stroke recurrence.

Background: A hybrid of remote and in-person conduct of research may improve recruitment and retention rates in clinical trials. However, little is known about the current state of remote research practices (RRPs) in stroke trials. Our objective was to characterize the use of telemedicine and RRPs among sites, including Regional Coordinating Centers (RCCs), within NIH StrokeNet. Methods: All NIH StrokeNet clinical sites were sent a standardized questionnaire surveying their voluntary adoption of telemedicine and RRPs in stroke clinical trial recruitment both locally and remotely at affiliated stroke hospitals. The survey was distributed to attendees of the spring StrokeNet conference. The survey results are described using descriptive statistics. Results: Overall, 39 StrokeNet sites (16 RCCs [64.0%]) responded to the survey between April 2022 and July 2022. Thirty-one sites (79.5%) used telemedicine in clinical trials in the following settings: outpatient (66.7%), Emergency Department (46.2%), and inpatient (41.0%). Telemedicine was most commonly utilized for follow-up assessment (51.3%), trial screening (43.6%), obtaining informed consent (43.6%), and guiding the study intervention (33.3%). Reported rates of electronic informed consent use was as follows: 30 sites (76.9%) for acute stroke trials, 22 (56.4%) for secondary stroke prevention trials, and 15 (38.4%) for stroke recovery trials. Only 9 sites (23.1%) reported remotely enrolling patients at affiliated telestroke hospitals and 8 sites (20.5%) initiated study interventions remotely. Conclusions: Telemedicine and e-consent were used at many responding StrokeNet clinical trial sites. Future research is needed to understand the added value of telemedicine and RRPs in clinical research, barriers to adoption, and ideal future state.

Intro: Enrolling women and under-represented minorities into clinical trials is a top priority for the stroke community. Common trial exclusions for medical conditions or demographics may negatively impact enrollment for these groups. We sought to describe the potential impact that various exclusion criteria have on trial eligibility of ischemic stroke (IS) patients by race and sex within the large, biracial Greater Cincinnati/Northern Kentucky Stroke Study (GCNKSS) population. Methods: The GCNKSS is a population-based study of 1.3 million people living in a 5-county area of southern Ohio/ Northern Kentucky. During 7/1/14-12/31/15 for blacks, and 2015 for whites, we captured all hospitalized ischemic strokes by screening ICD-9 codes 430-436 and ICD10 codes I60-I68, and G45-46. Commonly used exclusion criteria from stroke clinical trials were applied to the GCNKSS IS population, and were compared by sex and race. All comparisons were evaluated with chi-square test and corrected for multiple comparisons, as necessary. Results: In 2014-2015, there were 2806 ischemic stroke patients, which were 53% female, and 30% black. Table 1 presents common clinical trial exclusion criteria and the % excluded among IS patients, stratified by sex and race. Every trial exclusion evaluated had significant differences by sex, race, or both. Discussion: Within our population, we found that commonly-used age and disability clinical trial exclusion criteria exclude more women than men, and exclusion of milder strokes affects more men than women. Blood pressure, renal function, and early arrival time criteria exclude more blacks than whites, while older age exclude more whites than blacks. Optimal clinical trial design should be informed by epidemiology data to ensure representation of underrepresented populations in clinical trials. We will continue to provide epidemiology feedback on acute trial exclusion criteria to NIH StrokeNet proposals in the future.

Introduction: Asymptomatic intracerebral hemorrhage (aICH) occurs in ~40% of acute ischemic stroke patients after endovascular thrombectomy (EVT). Unlike symptomatic ICH, which is undoubtedly associated with worse outcomes, studies evaluating the association of aICH on long-term outcomes have been inconclusive. We performed a systematic review and meta-analysis to evaluate the long-term effects of post-EVT aICH. Methods: The meta-analysis protocol was submitted to PROSPERO a priori. PubMed, SCOPUS and Web of Science were searched from inception through April 2022 using database-specific searches with combination of keywords and controlled vocabulary. After deduplication, two authors independently reviewed all abstracts. Included studies contained adult AIS patients undergoing EVT with follow-up imaging assessment of ICH reporting comparative outcomes according to aICH vs no ICH . Meta-analysis was performed using Cochrane Review Manager v5.4. Summary effects were estimated by a fixed-effects model to estimate summary odds ratio (OR) of the effect of aICH vs no ICH on primary outcomes of 90-day modified Rankin score 3-6 and mortality. Results: Systematic review yielded 278 studies; 52 abstracts were fully reviewed ; 8 studies fulfilled inclusion criteria (n=4701 patients total; 1562 with aICH). aICH was associated with 90-day mRS 3-6 (OR 2.11 [95% CI 1.85-2.40]; Figure 1A) and higher mortality (OR 1.66 [95% CI 1.41-1.96]; Figure 1B) compared to no ICH. There was insufficient evidence of difference in 90-day mRS 3-6 when studies were grouped according to Heidelberg (n=2 studies; OR 2.37 [95% CI 0.92, 6.12]) vs ECASS (n=5 studies; OR 2.07 [95%CI 1.62, 2.64]) criteria for ICH. Meta-regression analysis adjusting for covariates will be presented Conclusion: aICH is associated with worse 90-day functional outcomes and higher mortality. Further studies to evaluate the factors predicting aICH and treatments aimed at reducing its occurrence are warranted.

Background: Ischemic stroke is the 5 th leading cause of death in the US. As a measure of stroke severity, initial NIHSS has been used to predict clinical outcome. We sought to identify the optimal cut-points of NIHSS at initial presentation that are associated with higher 30-day mortality. Methods: In 2005, 2010, and 2015 all hospitalized, first acute ischemic stroke events occurring within the Greater Cincinnati area were ascertained. Potential ischemic stroke cases underwent chart abstraction and physician adjudication, including retrospective NIHSS score (range 0 - 42) based on clinical findings at initial presentation. Descriptive statistics for NIHSS were estimated by study year, demographics, and medical history. Data regarding mortality was obtained from the National Death Index. The Contal and O’Quigley method based on a modified log-rank test statistic was used to determine cut-points of the NIHSS score associated with 30-day mortality, and hazard ratios were obtained from Cox models with adjustment for sex, race, and age. Results: In 2005, 2010, and 2015 there were 1704, 1818 and 1852 ischemic stroke events with 30-day mortality rates of 10.5%, 9.6% and 9.0%, respectively. Optimal cut-points of NIHSS 16 were identified. Across all 3 periods, 3431 (84.5%) cases had NIHSS 0-8, 352 (8.7%) had NIHSS 9-16 and 274 (6.8%) >16. Kaplan Meier Survival Curves for the 3 NIHSS groups are shown in the Figure. Strokes with NIHSS >16 at initial presentation were associated with a 15-fold (HR with 95% CI: 13, 19) increase in the risk of death at 30-days compared to those with NIHSS Discussion: NIH Stroke Scale scores are a reliable predictor of mortality, with higher NIHSS scores having higher risk of death. The cut points reported identify subgroups of stroke patients with dramatically different prognoses. Future studies should assess if this excess mortality risk among severe strokes persists after the more widespread implementation of thrombectomy beyond 2015.

Background: Previous studies spanning the 1990s-2010s have inconsistently identified a decline in 30-day stroke case-fatality rate (CFR), and little is known about trends in longer term stroke CFR over that period. We studied temporal trends in 30-day and 5-year CFRs in the well-defined Greater Cincinnati/Norther Kentucky (GCNK) stroke population. Methods: The NIH-funded GCNK Stroke Study is a population-based study conducted in a 5-county region that is representative of the USA in terms of Black race, income, and education. The study ascertained all strokes in 1993/4, 1999, 2005, 2010, and 2015 using well-validated methods. All stroke subtypes were included: ischemic strokes (IS), intracerebral hemorrhages (ICH), and subarachnoid hemorrhages (SAHs). Deaths were identified via the National Death Index. Cox proportional hazards models were used to assess all-cause fatality, by subtype, to examine temporal trends adjusting for age, sex, and race. Results: A total of 10372 stroke cases were ascertained over the five study periods (8428 IS, 443 SAH, and 1501 ICH). IS patients did not demonstrate a decline in 30-day CFRs over time, but did show a nonsignificant decrease in 5-year CFR. Among IS patients, female sex was associated with a lower 5-year CFR, whereas Black individuals had a lower 30-day CFR but a higher 5-year CFR. For ICH, there was a small increase in both 30-day and 5-year CFR in later study periods, although this did not reach significance in all years. SAH showed a lower 30-day CFR over time but no change in 5-year CFR. Older age was associated with a higher 30-day and 5-year CFR in all subtypes. Discussion: Despite widespread advances in post-stroke care, adjusted 5-year CFR has not clearly improved for any stroke subtype and may have slightly worsened for ICH. 30-day CFR has shown a modest improvement among SAH patients. Future studies should investigate why Black individuals with IS experience lower early CFR but a higher late CFR.

Background: Intracranial arterial stenosis (ICAS) can cause stroke by different mechanisms: perforator disease, artery to artery embolism, and impaired flow. There is limited data exists on the utility of perfusion imaging in patients with ICAS. We aim to determine associations between perfusion delay volume and 90-day recurrence in patients with anterior circulation ICAS. Methods: This is a two-center study of symptomatic anterior circulation ICAS involving the left M1 or ICA who underwent perfusion imaging (MRP or CTP). The primary predictor was hypoperfusion mismatch volume HPV (T max delay volume - core volume) using Tmax>4 sec or Tmax>6 sec thresholds. The outcome was recurrent cerebrovascular events (RCVE) defined as new or worsening neurological symptoms due to confirmed or suspected new infarct or infarct extension. We used Youden’s index to define the optimal cut-point of Tmax4 and Tmax6 mismatch for predicting recurrent stroke. We fit time-to-event models for RCVE with HPV at dichotomized cut-points, both as a univariate analysis and after adjusting for co-variates. Results: 50 patients met the inclusion criteria and 30% had RCVE. The median T max 4 HPV in mL was higher in patients with vs. without RCVE (121 vs. 19, p < 0.001) and the median T max 6 HPV in mL was higher in patients with vs. without RCVE (33 vs. 0, p = 0.004). We found an association between Tmax> 4 sec hypoperfusion volume (AUC 0.79, p =0.012) and max>6 sec hypoperfusion volume (AUC 0.75, p = 0.008) with RCVE. For Tmax 4 the cut-point was at 94 mL and for Tmax6 the cut-point was at 10 mL. Recurrent stroke was higher in those with vs. without Tmax>4 sec ≥94 mL delay (66.7% vs. 14.3%, (p6 sec≥10 mL delay (68.8% vs. 11.8%, p4 sec HPV ≥ 94 mL was 5.0 (95% CI 1.5-16.4) and that of Tmax>6 sec HPV > 8 ml was 11.3 (95% CI 3.7-116.8). Conclusion: In this two-center study, hypoperfusion delay volume is associated with early recurrence in patients with symptomatic ICAS. Studies are needed to validate our findings and to test endovascular reperfusion in the subset of patients with symptomatic ICAS and perfusion delay.

Randomized clinical trials of acute stroke have led to major advances in acute stroke therapy over the past decade. Despite these successes, recruitment in acute trials is often difficult. We outline challenges in recruitment for acute stroke trials and present potential solutions, which can increase the speed and decrease the cost of identifying new treatments for acute stroke. One of the largest opportunities to increase the speed of enrollment and make trials more generalizable is expansion of inclusion criteria whose impact on expected recruitment can be assessed by epidemiologic and registry databases. Another barrier to recruitment besides the number of eligible patients is availability of study investigators limited to business hours, which may be helped by financial support for after-hours call. The wider use of telemedicine has accelerated quicker stroke treatment at many hospitals and has the potential to accelerate research enrollment but requires training of clinical investigators who are often inexperienced with this approach. Other potential solutions to enhance recruitment include rapid prehospital notification of clinical investigators of potential patients, use of mobile stroke units, advances in the process of emergency informed consent, storage of study medication in the emergency department, simplification of study treatments and data collection, education of physicians to improve equipoise and enthusiasm for randomization of patients within a trial, and clear recruitment plans, and even potentially coenrollment, when there are competing trials at sites. Without successful recruitment, scientific advances and clinical benefit for acute stroke patients will lag.

More than 25 years have passed since the US Food and Drug Administration approved IV recombinant tissue plasminogen activator (alteplase) for the treatment of acute ischemic stroke. This landmark decision brought a previously untreatable disease into a new therapeutic landscape, providing inspiration for clinicians and hope to patients. Since that time, the use of alteplase in the clinical setting has become standard of care, continually improving with quality measures such as door-to-needle times and other metrics of specialized stroke unit care. The past decade has seen more widespread use of alteplase in the prehospital setting with mobile stroke units and telestroke and beyond initial time windows via the use of CT perfusion or MRI. Simultaneously, the position of alteplase is being challenged by new lytics and by the concept of its bypass altogether in the era of endovascular therapy. We provide an overview of alteplase, including its earliest trials and how they have shaped the current therapeutic landscape of ischemic stroke treatment, and touch on new frontiers for thrombolytic therapy. We highlight the critical role of thrombolytic therapy in the past, present, and future of ischemic stroke care.

Despite years of basic research and pioneering clinical work, ischemic stroke remains a major public health concern. Prior STAIR (Stroke Treatment Academic Industry Roundtable) conferences identified both failures of clinical trial design and failures in preclinical assessment in developing putative ischemic stroke treatments. At STAIR XI, participants in workshop no. 1 Top Priorities for Neuroprotection sought to redefine the neuroprotection paradigm and given the paucity of evidence underlying preclinical assessment, offer consensus-based recommendations. STAIR proposes the term brain cytoprotection or cerebroprotection to replace the term neuroprotection when the intention of an investigation is to demonstrate that a new, candidate treatment benefits the entire brain. Although “time is still brain,” tissue imaging techniques have been developed to identify patients with both predicted core injury and penumbral, salvageable brain tissue, regardless of time after stroke symptom onset. STAIR XI workshop participants called this imaging approach a tissue window to select patients for recanalization. Elements of the neurovascular unit show differential vulnerability evolving over differing time scales in different brain regions. STAIR proposes the term target window to suggest therapies that target the different elements of the neurovascular unit at different times. Based on contemporary principles of rigor and transparency, the workshop updated, revised, and enhanced the STAIR preclinical recommendations for developing new treatments in 2 phases: an exploratory qualification phase and a definitive validation phase. For new, putative treatments, investigators should carefully characterize the mechanism of action, the pharmacokinetics/pharmacodynamics, demonstrate target engagement, and confirm penetration through the blood-brain barrier. Before clinical trials, testing of candidate molecules in stroke models could proceed in a comprehensive manner using animals of both sexes and to include significant variables such as age and comorbid conditions. Comprehensive preclinical assessment might include multicenter, collaborative testing, for example, network trials. In the absence of a proven cerebroprotective agent to use as a gold standard, however, it remains speculative whether such comprehensive preclinical assessment can effectively predict clinical outcome.

Background and Purpose Recent endovascular trials have spurred a paradigm shift toward routine use of CT perfusion (CTP) for decision-making in acute ischemic stroke. CTP use in the late window, however, remains under evaluation. Our objective was to assess the accuracy of CTP-predicted core in the late window. Methods In a retrospective review of our prospectively identified stroke registry at a single, comprehensive stroke center, we included patients with anterior large vessel occlusions presenting within the 6-24 h window who underwent baseline CTP evaluation and achieved TICI2b or TICI3 reperfusion on endovascular treatment. We recorded baseline CTP-predicted core volumes at relative cerebral blood flow (CBF) thresholds of Results Of the eligible patients, 134 met our inclusion criteria. Mean FIV was 39.5 (SD 49.6). Median CTP to reperfusion time was 93.5 min. Median absolute differences between CTP-predicted core and FIV were 14.7, 14.9, and 16.0 ml at Conclusion CTP cores in the 6–24 h period underestimate FIV, especially with larger infarcts. CTP-predicted core volumes in the late window show moderate positive correlation with FIV.

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 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 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.

Background and Purpose: The National Institutes of Health Stroke Scale (NIHSS) measured at an early time point is an appealing surrogate marker for long-term functional outcome of stroke patients treated with endovascular therapy. However, definitions and analytical methods for an early NIHSS-based outcome measure that optimize power and precision in clinical studies are not well-established. Methods: In this post-hoc analysis of our prospective observational study that enrolled endovascular therapy-treated patients at 12 comprehensive stroke centers across the US, we compared the ability of 24-hour NIHSS, ΔNIHSS (baseline minus 24-hour NIHSS), and percentage change (NIHSS×100/baseline NIHSS), analyzed as continuous and dichotomous measures, to predict 90-day modified Rankin Scale (mRS) using logistic regression (adjusted for age, baseline NIHSS, glucose, hypertension, Alberta Stroke Program Early CT Score, time to recanalization, recanalization status, and intravenous thrombolysis) and Spearman ρ. Results: Of 485 patients in the BEST (Blood Pressure After Endovascular Stroke Therapy) cohort, 446 (92%) with 90-day follow-up data were included. An absolute 24-hour NIHSS, adjusted for baseline in multivariable modeling, had the highest predictive power of all definitions evaluated (aR 2 0.368 and adjusted odds ratio 0.79 [0.75–0.84], P 2 0.444 and adjusted odds ratio 0.84 [0.8–0.86] for ordinal mRS). For predicting mRS score of 0–2 with a cut point, the second most efficient approach, the optimal threshold for 24-hour NIHSS score was ≤7 (sensitivity 80.1%, specificity 80.4%; adjusted odds ratio 12.5 [7.14–20], P P Conclusions: Twenty-four–hour NIHSS, adjusted for baseline, was the strongest predictor of both dichotomous and ordinal 90-day mRS outcomes for endovascular therapy-treated patients. A dichotomous 24-hour NIHSS score of ≤7 was the second-best predictor. Although ΔNIHSS, continuous and dichotomized at ≥4, predicted 90-day outcomes, absolute 24-hour NIHSS definitions performed better.

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 ( 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.

Intracranial stenosis (ICAS) is a common cause of stroke worldwide and patients with symptomatic ICAS exhibit a high rate of recurrence, particularly in the early period after the initial event. In this study, we aimed to study the association between borderzone infarct and recurrent ischemic stroke in patients hospitalized with symptomatic ICAS.This is a retrospective single center study that included patients hospitalized with acute ischemic stroke in the setting of intracranial stenosis (50% or more and an acute ischemic stroke in the territory supplied by the stenosed artery) over a 32-month period. We excluded patients who did not receive a brain MRI or did not have an infarct on brain imaging. The primary predictor is infarct pattern (any borderzone vs. no borderzone infarct) and the primary outcome was recurrent cerebrovascular events (RCVE) within 90 days. We used unadjusted, and age and sex adjusted logistic regression models to determine associations between infarct pattern and RCVE at 90-days.Among 99 patients who met the inclusion criteria (4 tandem), the mean age was 70.1 ± 11.2 years and 41.4% were women; 43 had borderzone infarcts and 19 had RCVE. In adjusted binary logistic regression analysis, borderzone infarct was associated with increased risk of RCVE (adjusted OR 4.00 95% CI 1.33-11.99, p=0.013). The association between borderzone infarction and RCVE was not different among anterior circulation ICAD (adjusted HR 2.85 95% CI 0.64-12.76, p=0.172) vs. posterior circulation ICAD (adjusted HR 6.69 95% CI 1.06-42.11, p=0.043), p-value for interaction = 0.592.In real world post-SAMMPRIS medically treated patients with ICAD, the borderzone infarct pattern was associated with 90-day RCVE. Borderzone infarcts are likely a surrogate marker of impaired distal blood flow, highlighting the importance of targeting stroke mechanisms and developing alternative treatment strategies for high-risk cohorts.

BackgroundIntracerebral hemorrhage (ICH) occurs in ~20%–30% of stroke patients undergoing endovascular therapy (EVT). However, there is conflicting evidence regarding the effect of asymptomatic ICH (aICH) on post-EVT outcomes. We sought to evaluate the effect of aICH on immediate and 90-day post-EVT neurological outcomes.MethodsIn this post-hoc analysis of the multicenter, prospective Blood Pressure after Endovascular Therapy (BEST) study we identified subjects with ICH following EVT. This population was divided into no ICH, aICH, and symptomatic ICH (sICH). Associations with 90-day modified Rankin Scale (mRS) dichotomized by functional independence (0–2 vs 3–6) and early neurological recovery (ENR) were determined using univariate/multivariate logistic regression models.ResultsOf 485 patients enrolled in BEST, 446 had 90-day follow-up data available. 92 (20.6%) developed aICH, and 18 (4%) developed sICH. Compared with those without ICH, aICH was not associated with worse 90-day outcome or lower ENR (OR 0.84 [0.53–1.35], P=0.55, aOR 0.84 [0.48–1.44], P=0.53 for 90-day mRS 0–2; OR 0.77 [0.48–1.23], P=0.34, aOR 0.72 [0.43–1.22] for ENR). aICH was not associated with 90-day outcome or ENR in patients with mTICI ≥2 b (OR 0.78 [0.48–1.26], P=0.33 for 90-day mRS 0–2; OR 0.89 [0.69–1.12], P=0.15 for ENR). A higher proportion of patients with aICH had mTICI ≥2 b than those without ICH (97%vs 87%, P=0.01).ConclusionsaICH was not associated with worse outcomes in patients with large-vessel stroke treated with EVT. aICH was more frequent in patients with successful recanalization. Further validation of our findings in large cohort studies of EVT-treated patients is warranted.

Background and Purpose: The Alberta Stroke Program Early Computed Tomography (CT) Score (ASPECTS) and CT perfusion (CTP) are commonly used to predict the ischemic core in acute ischemic strokes. CT angiography source images (CTA-SI) can also provide additional information to identify the extent of ischemia. Our objective was to investigate the correlation of noncontrast CT (NCCT) ASPECTS and CTA-SI ASPECTS with CTP core volumes. Methods: We utilized a single institutional, retrospective registry of consecutive patients with acute ischemic stroke with large vessel occlusion between May 2016 and May 2018. We graded ASPECTS both on baseline NCCT and CTA-SI and measured CTP core using automated RAPID software (cerebral blood flow Results: A total of 52 patients fit the inclusion criteria of large vessel occlusion in 6 to 24 hours and baseline imaging work up of NCCT, CTA, and CTP. The median age was 63 (interquartile range=53.5–75) and 38.46% were female. The median NCCT ASPECTS was 7 (interquartile range=6–9), CTA-SI ASPECTS was 5 (interquartile range=4–7), and CTP core was 14.5 mL (interquartile range=0–46 mL). There was a moderate correlation between NCCT ASPECTS and CTP core (r s =−0.55, P s =−0.50, P =0.0002). The optimal NCCT ASPECTS cutoff score to detect CTP core ≤70 mL was ≥6 (sensitivity, 0.84; specificity, 0.57; positive predictive value, 0.93; negative predictive value, 0.36) and the optimal CTA-SI ASPECTS was ≥5 (sensitivity, 0.76; specificity, 0.71; positive predictive value, 0.94; negative predictive value, 0.31). Conclusions: There was a moderate correlation between NCCT and CTA-SI ASPECTS in predicting CTP defined ischemic core in delayed time windows. Further studies are needed to determine if NCCT and CTA imaging could be used for image-based patient selection when CTP imaging is not available.

Background and Purpose: Accumulating evidence from randomized controlled clinical trials suggests that tenecteplase may represent an effective treatment alternative to alteplase for acute ischemic stroke. In the present systematic review and meta-analysis, we sought to compare the efficacy and safety outcomes of intravenous tenecteplase to intravenous alteplase administration for acute ischemic stroke patients with large vessel occlusions (LVOs). Methods: We searched MEDLINE (Medical Literature Analysis and Retrieval System Online) and Scopus for published randomized controlled clinical trials providing outcomes of acute ischemic stroke with confirmed LVO receiving intravenous thrombolysis with either tenecteplase at different doses or alteplase at a standard dose of 0.9 mg/kg. The primary outcome was the odds of modified Rankin Scale score of 0 to 2 at 3 months. Results: We included 4 randomized controlled clinical trials including a total of 433 patients. Patients with confirmed LVO receiving tenecteplase had higher odds of modified Rankin Scale scores of 0 to 2 (odds ratio, 2.06 [95% CI, 1.15–3.69]), successful recanalization (odds ratio, 3.05 [95% CI, 1.73–5.40]), and functional improvement defined as 1-point decrease across all modified Rankin Scale grades (common odds ratio, 1.84 [95% CI, 1.18–2.87]) at 3 months compared with patients with confirmed LVO receiving alteplase. There was little or no heterogeneity between the results provided from included studies regarding the aforementioned outcomes (I 2 ≤20%). No difference in the outcomes of early neurological improvement, symptomatic intracranial hemorrhage, any intracranial hemorrhage, and the rates of modified Rankin Scale score 0 to 1 or all-cause mortality at 3 months was detected between patients with LVO receiving intravenous thrombolysis with either tenecteplase or alteplase. Conclusions: Acute ischemic stroke patients with LVO receiving intravenous thrombolysis with tenecteplase have significantly better recanalization and clinical outcomes compared with patients receiving intravenous alteplase.

Background Intravenous recombinant tissue plasminogen activator is the only proven effective medication for the treatment of acute ischemic stroke. Two approaches that may augment recombinant tissue plasminogen activator thrombolysis and prevent arterial reocclusion are direct thrombin inhibition with argatroban and inhibition of the glycoprotein 2b/3a receptor with eptifibatide. Aim The multi-arm optimization of stroke thrombolysis trial aims to determine the safety and efficacy of intravenous therapy with argatroban or eptifibatide as compared with placebo in acute ischemic stroke patients treated with intravenous recombinant tissue plasminogen activator within 3 h of symptom onset. Sample size estimate A maximum of 1200 randomized subjects to test the superiority of argatroban or eptifibatide to placebo in improving 90-day modified Rankin scores. Methods and design Multiarm optimization of stroke thrombolysis is a multicenter, multiarm, adaptive, single blind, randomized controlled phase 3 clinical trial conducted within the National Institutes of Health StrokeNet clinical trial network. Patients treated with 0.9 mg/kg intravenous recombinant tissue plasminogen activator within 3 h of stroke symptom onset are randomized to receive intravenous argatroban (100 µg/kg bolus followed by 3 µg/kg/min for 12 h), intravenous eptifibatide (135 µg/kg bolus followed by 0.75 µg/kg/min infusion for 2 h) or IV placebo. Patients may receive endovascular thrombectomy per usual care. Study outcomes The primary efficacy outcome is improved modified Rankin score assessed at 90 days post-randomization. Discussion Multiarm optimization of stroke thrombolysis is an innovative and collaborative project that is the culmination of many years of dedicated efforts to improve outcomes for stroke patients.

SUMMARY: Small vessel disease, a disorder of cerebral microvessels, is an expanding epidemic and a common cause of stroke and dementia. Despite being almost ubiquitous in brain imaging, the clinicoradiologic association of small vessel disease is weak, and the underlying pathogenesis is poorly understood. The STandards for ReportIng Vascular changes on nEuroimaging (STRIVE) criteria have standardized the nomenclature. These include white matter hyperintensities of presumed vascular origin, recent small subcortical infarcts, lacunes of presumed vascular origin, prominent perivascular spaces, cerebral microbleeds, superficial siderosis, cortical microinfarcts, and brain atrophy. Recently, the rigid categories among cognitive impairment, vascular dementia, stroke, and small vessel disease have become outdated, with a greater emphasis on brain health. Conventional and advanced small vessel disease imaging markers allow a comprehensive assessment of global brain heath. In this review, we discuss the pathophysiology of small vessel disease neuroimaging nomenclature by means of the STRIVE criteria, clinical implications, the role of advanced imaging, and future directions.

Background Prior observational studies indicate that lower systolic blood pressure (SBP) after successful endovascular treatment (EVT) is associated with better functional outcomes in patients with acute ischemic stroke. However, whether targeting SBP to levels below the guideline‐recommended target of ≤180 mm Hg is safe and efficacious remains to be determined. Methods The BEST (Blood Pressure After Endovascular Stroke Therapy)‐II trial (NCT04116112) is a pragmatic, phase 2, multisite, prospective, randomized, open‐label trial with blinded end‐point assessment designed to (1) compare the safety of lower SBP targets with higher SBP targets in successfully EVT‐treated patients with stroke and (2) inform the design and estimate the probability of success of a future phase 3 trial. A total of 120 patients with acute ischemic stroke who undergo successful EVT (final modified Thrombolysis in Cerebral Infarction score ≥2b) for intracranial internal carotid artery or M1 or M2 segment of the middle cerebral artery will be randomized to the SBP targets of ≤180, Results Enrollment in the BEST‐II trial began in January 2020, with 90 patients enrolled as of October 13, 2021. The trial is progressing ahead of target, with an anticipated enrollment completion date before January 2023. Conclusions The BEST‐II trial results will inform the stroke community of the safety of lower SBP targets in patients with acute ischemic stroke who are successfully treated with EVT and will demonstrate the feasibility of both achieving lower blood pressure targets as well as conducting an efficacy trial. Trial enrollment is on target despite the COVID‐19 pandemic. Clinical Trial Registration Information NCT04116112 ( https://clinicaltrials.gov/ct2/show/NCT04116112 )

National Institutes of Health Stroke Scale (NIHSS), measured a few hours to days after stroke onset, is an attractive outcome measure for stroke research. NIHSS at the time of presentation (baseline NIHSS) strongly predicts the follow-up NIHSS. Because of the need to account for the baseline NIHSS in the analysis of follow-up NIHSS as an outcome measure, a common and intuitive approach is to define study outcome as the change in NIHSS from baseline to follow-up (ΔNIHSS). However, this approach has important limitations. Analyzing ΔNIHSS implies a very strong assumption about the relationship between baseline and follow-up NIHSS that is unlikely to be satisfied, drawing into question the validity of the resulting statistical analysis. This reduces the precision of the estimates of treatment effects and the power of clinical trials that use this approach to analysis. ANCOVA allows for the analysis of follow-up NIHSS as the dependent variable while adjusting for baseline NIHSS as a covariate in the model and addresses several challenges of using ΔNIHSS outcome using simple bivariate comparisons (eg, a t test, Wilcoxon rank-sum, linear regression without adjustment for baseline) for stroke research. In this article, we use clinical trial simulations to illustrate that variability in NIHSS outcome is less when follow-up NIHSS is adjusted for baseline compared to ΔNIHSS and how a reduction in this variability improves the power. We outline additional, important clinical and statistical arguments to support the superiority of ANCOVA using the final measurement of the NIHSS adjusted for baseline over, and caution against using, the simple bivariate comparison of absolute NIHSS change (ie, delta).

Stroke is a major cause of death and disability globally. Diagnosis depends on clinical features and brain imaging to differentiate between ischaemic stroke and intracerebral haemorrhage. Non-contrast CT can exclude haemorrhage, but the addition of CT perfusion imaging and angiography allows a positive diagnosis of ischaemic stroke versus mimics and can identify a large vessel occlusion target for endovascular thrombectomy. Management of ischaemic stroke has greatly advanced, with rapid reperfusion by use of intravenous thrombolysis and endovascular thrombectomy shown to reduce disability. These therapies can now be applied in selected patients who present late to medical care if there is imaging evidence of salvageable brain tissue. Both haemostatic agents and surgical interventions are investigational for intracerebral haemorrhage. Prevention of recurrent stroke requires an understanding of the mechanism of stroke to target interventions, such as carotid endarterectomy, anticoagulation for atrial fibrillation, and patent foramen ovale closure. However, interventions such as lowering blood pressure, smoking cessation, and lifestyle optimisation are common to all stroke subtypes.

Background and Purpose— The first of the 2 NINDS (National Institute of Neurological Disorders and Stroke) Study trials did not show a significant increase in early neurological improvement, defined as National Institutes of Health Stroke Scale (NIHSS) improvement by ≥4, with alteplase treatment. We hypothesized that early neurological improvement defined as a percentage change in NIHSS (percent change NIHSS) at 24 hours is superior to other definitions in predicting 3-month functional outcomes and using this definition there would be treatment benefit of alteplase over placebo at 24 hours. Methods— We analyzed the NINDS rt-PA Stroke Study (Parts 1 and 2) trial data. Percent change NIHSS was defined as ([admission NIHSS score−24-hour NIHSS score]×100/admission NIHSS score] and delta NIHSS as (admission NIHSS score−24-hour NIHSS score). We compared early neurological improvement using these definitions between alteplase versus placebo patients. We also used receiver operating characteristic curve to determine the predictive association of early neurological improvement with excellent 3-month functional outcomes (Barthel Index score of 95–100 and modified Rankin Scale score of 0–1), good 3-month functional outcome (modified Rankin Scale score of 0–2), and 3-month infarct volume. Results— There was a significantly greater improvement in the 24-hour median percent change NIHSS among patients treated with alteplase compared with the placebo group (28% versus 15%; P =0.045) but not median delta NIHSS (3 versus 2; P =0.471). Receiver operating characteristic curve comparison showed that percent change NIHSS (ROC percent ) was better than delta NIHSS (ROC delta ) and admission NIHSS (ROC admission ) with regards to excellent 3-month Barthel Index (ROC percent , 0.83; ROC delta , 0.76; ROC admission , 0.75), excellent 3-month modified Rankin Scale (ROC percent , 0.83; ROC delta , 0.74; ROC admission , 0.78), and good 3-month modified Rankin Scale (ROC percent , 0.83; ROC delta , 0.76; ROC admission , 0.78). Conclusions— In the NINDS rt-PA trial, alteplase was associated with a significant percent change improvement in NIHSS at 24 hours. Percent change in NIHSS may be a better surrogate marker of thrombolytic activity and 3-month outcomes.

BACKGROUND AND PURPOSE: The increased severity of white matter disease is associated with worse outcomes and an increased rate of intracerebral hemorrhage in patients with ischemic stroke undergoing thrombolytic treatment. However, whether white matter disease is associated with outcomes in patients undergoing endovascular treatment remains unclear. MATERIALS AND METHODS: In this prespecified exploratory analysis of our prospective multi-institutional study that enrolled consecutive adult patients with anterior circulation ischemic stroke undergoing endovascular treatment from November 2017 to September 2018, we compared the following outcomes between patients with none-to-minimal (van Swieten score, 0–2) and moderate-to-severe (van Swieten score, 3–4) white matter disease using logistic regression: 90-day mRS 3–6, death, intracerebral hemorrhage, successful recanalization, and early neurologic recovery. RESULTS: Of the 485 patients enrolled in the Blood Pressure after Endovascular Stroke Therapy (BEST) study, 389 had white matter disease graded (50% women; median age, 68 years; range, 58–79 years). A van Swieten score of 3–4 (n = 74/389, 19%) was associated with a higher rate of 90-day mRS of 3–6 (45% versus 18%; adjusted OR, 2.73; 95% CI, 1.34–5.93; P = .008). Although the death rate was higher in patients with van Swieten scores of 3–4 (26% versus 15%), the adjusted likelihood was not significantly different (adjusted OR, 1.14; 95% CI, 0.56–2.26; P = .710). Ordered regression revealed a shift toward worse mRS scores with increasing van Swieten scores (adjusted common OR, 3.04; 95% CI, 1.93–4.84; P

Limited data exist evaluating the effect of blood pressure (BP) on clinical outcomes among patients with acute ischemic stroke with large vessel occlusion treated with mechanical thrombectomy (MT). We sought to evaluate the association of BP levels on clinical outcomes among patients with acute ischemic stroke with large vessel occlusion treated with MT. Studies were identified that reported the association of systolic BP (SBP) or diastolic BP levels before, during, or after MT on the outcomes of patients with acute ischemic stroke treated with MT. Unadjusted and adjusted analyses of studies reporting odds ratios (OR adj ) per 10 mm Hg BP increment were performed. Our analysis included 25 studies comprising 6474 patients. Higher pre-MT mean SBP ( P =0.008) and post-MT maximum SBP ( P =0.009) levels were observed in patients who died within 3 months. Patients with 3-month functional independence were noted to have lower pre-MT ( P P adj , 1.19 [95% CI,1.00–1.43]; I 2 =78%, P value for Cochran Q test: 0.001) and symptomatic intracranial hemorrhage (OR adj , 1.65 [95% CI, 1.11–2.44]; I 2 =0%, P value for Cochran Q test: 0.80), respectively. Increasing pre- and post-MT mean SBP levels were associated with lower odds of 3-month functional independence (OR adj , 0.86 [95% CI, 0.77–0.96]; I 2 =18%, P value for Cochran Q test: 0.30) and (OR adj , 0.80 [95% CI, 0.72–0.89]; I 2 =0%, P value for Cochran Q test: 0.51), respectively. In conclusion, elevated BP levels before and after MT are associated with adverse outcomes among patients with acute ischemic stroke with large vessel occlusion.