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Background: Alteplase (tPA) is the initial treatment for acute ischemic stroke. Current tPA guidelines exclude patients who took direct oral anticoagulants (DOAC) within the prior 48 hours. In this propensity-matched retrospective study we compared acute ischemic stroke patients treated with tPA who had received DOACs within 48 hours of thrombolysis to those not previously treated with DOACs, regarding three outcomes: mortality; intracranial hemorrhage (ICH); and need for acute blood transfusions (as a marker of significant blood loss)., Methods: Using the United States cohort of 54 healthcare organizations in the TriNetx database, we identified 8,582 stroke patients treated with tPA on DOACs within 48 hours of thrombolysis and 46,703 stroke patients treated with tPA not on DOACs since January 1, 2012. We performed propensity score matching on demographic information and seven prior clinical diagnostic groups, resulting in a total of 17,164 acute stroke patients evenly matched between groups. We recorded mortality rates, frequency of ICH, and need for blood transfusions for each group over the ensuing 7- and 30-day periods., Results: Patients treated with tPA on DOACs had reduced mortality (3.3% vs 7.3%; risk ratio [RR] 0.456; P  < 0.001), fewer ICHs (6.8% vs 10.1%; RR 0.678; P  < 0.001), and less risk of major bleeding as measured by frequency of blood transfusions (0.5% vs 1.5%; RR 0.317; p  < 0.001) at 7 days post thrombolytic, than the tPA patients not on DOACS. Findings for 30 days post-thrombolytics were similar/statistically significant with lower mortality rate (7.2% vs 13.1%; RR 0.550; P  < 0.001), fewer ICHs (7.6% vs 10.8%; RR 0.705; P  < 0.001), and fewer blood transfusions (0.9% vs 2.0%; RR 0.448; P  < 0.001)., Conclusion: Acute ischemic stroke patients treated with tPA who received DOACs within 48 hours of thrombolysis had lower mortality rates, reduced incidence of ICH, and less blood loss than those not on DOACs. Our study suggests that prior use of DOACs should not be a contraindication to thrombolysis for ischemic stroke., Competing Interests: Conflicts of Interest: By the WestJEM article submission agreement, all authors are required to disclose all affiliations, funding sources and financial or management relationships that could be perceived as potential sources of bias. This research was supported by the Institute for Translational Sciences at the University of Texas Medical Branch, supported in part by a Clinical and Translational Science Award (UL1 TR001439) from the National Center for Advancing Translational Sciences at the National Institutes of Health (NIH). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. There are no conflicts of interest to declare.

Background and Purpose: Clinical studies have demonstrated that edaravone dexborneol can improve the functional outcomes in patients with acute ischaemic stroke (AIS). The present clinical trial aimed at testing the efficacy and safety of Y-2 sublingual tablet on 90-day functional outcome in patients with AIS., Methods and Design: This is a randomised, double-blind, placebo-controlled, multicentre, parallel-group trial of Y-2 sublingual tablet on patients with AIS.An estimated 914 patients at age of 18-80 years with AIS within 48 hours after symptom onset from 40 hospitals will be randomly assigned to receive Y-2 sublingual tablet or placebo for 14 days. Patients are at score 6-20 points on National Institutes of Health Stroke Scale (NIHSS) and had a modified Rankin Scale (mRS) ≤1 before this stroke, except mechanical thrombectomy and neuroprotective agents treatment., Study Outcomes: The primary outcome is the proportion of patients with mRS ≤1 on day 90 after randomisation. Secondary efficacy outcomes include mRS score on day 90, the proportion of patients with mRS ≤2 on day 90; the change of NIHSS score from baseline to day 14 and the proportion of patients with NIHSS score ≤1 at the days 14, 30 and 90., Discussion: This trial will provide valuable evidence for the efficacy and safety of Y-2 sublingual table for improving 90 days the functional outcomes in patients with AIS., Trial Registration Number: NCT04950920., Competing Interests: Competing interests: RT, JR, SZ and XF are the employees of Simcere Pharmaceutical Group; RC is the employee of Neurodawn Pharmaceutical. Those companies have developed the drug and sponsored the trial. The above-mentioned five authors from companies provided information on the pharmacological mechanism of drugs, gave preclinical experimental data and advised on study design. No other competing interests were reported., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background and Purpose: Recombinant human TNK tissue-type plasminogen activator (rhTNK-tPA) was not inferior to alteplase for ischaemic stroke within 4.5 hours. Our study aimed to investigate the efficacy and safety of rhTNK-tPA in patients who had an ischaemic stroke due to large vessel occlusion (LVO) of anterior circulation beyond 4.5 hours., Methods and Design: Tenecteplase Reperfusion Therapy in Acute Ischaemic Cerebrovascular Events-III (TRACE III) is a multicentre, prospective, randomised, open-label, blind endpoint, controlled clinical trial. Patients who had an ischaemic stroke due to anterior circulation LVO (internal carotid artery, middle cerebral artery M1 and M2 segments) within 4.5-24 hours from last known well (including wake-up stroke and no witness stroke) and with salvageable tissue (ischaemic core volume <70 mL, mismatch ratio ≥1.8 and mismatch volume ≥15 mL) based on CT perfusion or MRI perfusion-weighted imaging (PWI) were included and randomised to rhTNK-tPA 0.25 mg/kg (single bolus) to a maximum of 25 mg or standard medical therapy. Specially, we will exclude patients who are intended for direct thrombectomy. All will be followed up for 90 days., Study Outcomes: Primary efficacy outcome is modified Rankin Scale (mRS) score ≤1 at 90 days. Secondary efficacy outcomes include ordinal distribution of mRS at 90 days, major neurological improvement defined by a decrease ≥8 points compared with the initial deficit or a score ≤1 on the National Institutes of Health Stroke Scale (NIHSS) at 72 hours, mRS score ≤2 at 90 days, the rate of improvement on Tmax >6 s at 24 hours and NIHSS score change from baseline at 7 days. Safety outcomes are symptomatic intracerebral haemorrhage within 36 hours and mortality at 90 days., Discussion: TRACE III will provide evidence for the efficacy and safety of rhTNK-tPA in patients who had an ischaemic strokes due to anterior circulation LVO beyond 4.5 hours., Trial Registration Number: NCT05141305., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Our recent pilot study suggests intra-arterial tenecteplase (TNK) during the first pass of endovascular treatment (EVT) seems safe, may increase first-pass reperfusion and good outcome in acute ischaemic stroke (AIS) patients with large-vessel occlusion (LVO)., Aims: To determine the efficacy and safety of intra-arterial TNK administration during EVT in AIS-LVO patients presenting up to 24 hours from symptom onset., Sample Size Estimates: A maximum of 380 patients are required to test the superiority hypothesis with 80% power according to a two-side 0.05 level of significance, stratified by age, gender, baseline systolic blood pressure, prestroke modified Rankin Scale (mRS), baseline National Institute of Health stroke scale, baseline ASPECTS, time from onset to groin puncture, intravenous thrombolysis before EVT, stroke territory and stroke aetiology., Design: Intra-arterial TNK during thrombectomy for acute stroke (BRETIS-TNK II) study is a prospective, randomised, adaptive enrichment, open-label, blinded end point, multicentre study. Eligible AIS-LVO patients are randomly assigned into the experimental group and control group with a ratio of 1:1. The experimental group will be treated with intra-arterial infusion of TNK during EVT. The control group will be treated with standard EVT., Outcome: The primary end point is a favourable outcome, defined as an mRS score of 0-2 at 90 days. The primary safety end point is symptomatic intracranial haemorrhage within 48 hours, which is defined as an increase in the National Institutes of Health Stroke Scale score of ≥4 points as a result of the intracranial haemorrhage., Conclusions: The results of BRETIS-TNK II will provide evidence for the efficacy and safety of intra-arterial TNK administration during EVT in AIS patients with LVO., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Antagonists of glycoprotein VI-triggered platelet activation used in combination with recanalisation therapies are a promising therapeutic approach in acute ischaemic stroke. Glenzocimab is an antibody fragment that inhibits the action of platelet glycoprotein VI. We aimed to determine and assess the safety and efficacy of the optimal dose of glenzocimab in patients with acute ischaemic stroke eligible to receive alteplase with or without mechanical thrombectomy., Methods: This randomised, double-blind, placebo-controlled study with dose-escalation (1b) and dose-confirmation (2a) phases (ACTIMIS) was done in 26 stroke centres in six European countries. Participants were adults (≥18 years) with disabling acute ischaemic stroke with a National Institutes of Health Stroke Scale score of 6 or higher before alteplase administration. Patients were randomly assigned treatment using a central electronic procedure. Total administered dose at the end of the intravenous administration was 125 mg, 250 mg, 500 mg, and 1000 mg of glenzocimab or placebo in phase 1b and 1000 mg of glenzocimab or placebo in phase 2a. Treatment was initiated 4·5 h or earlier from stroke symptom onset in patients treated with alteplase with or without mechanical thrombectomy. The sponsor, study investigator and study staff, patients, and central laboratories were all masked to study treatment until database lock. Primary endpoints across both phases were safety, mortality, and intracranial haemorrhage (symptomatic, total, and fatal), assessed in all patients who received at least a partial dose of study medication (safety set). The trial is registered on ClinicalTrials.gov, NCT03803007, and is complete., Findings: Between March 6, 2019, and June 27, 2021, 60 recruited patients were randomly assigned to 125 mg, 250 mg, 500 mg, or 1000 mg glenzocimab, or to placebo in phase 1b (n=12 per group) and were included in the safety analysis. Glenzocimab 1000 mg was well tolerated and selected as the phase 2a recommended dose; from Oct 2, 2020, to June 27, 2021, 106 patients were randomly assigned to glenzocimab 1000 mg (n=53) or placebo (n=53). One patient in the placebo group received glenzocimab in error and therefore 54 and 52, respectively, were included in the safety set. In phase 2a, the most frequent treatment-emergent adverse event was non-symptomatic haemorrhagic transformation, which occurred in 17 (31%) of 54 patients treated with glenzocimab and 26 (50%) of 52 patients treated with placebo. Symptomatic intracranial haemorrhage occurred in no patients treated with glenzocimab compared with five (10%) patients in the placebo group. All-cause deaths were lower with glenzocimab 1000 mg (four [7%] patients) than with placebo (11 [21%] patients)., Interpretation: Glenzocimab 1000 mg in addition to alteplase, with or without mechanical thrombectomy, was well tolerated, and might reduce serious adverse events, intracranial haemorrhage, and mortality. These findings support the need for future research into the potential therapeutic inhibition of glycoprotein VI with glenzocimab plus alteplase in patients with acute ischaemic stroke., Funding: Acticor Biotech., Competing Interests: Declaration of interests MM reports consulting fees from Acticor Biotech, Novonordisk, Novartis, and Boehringer Ingelheim. He is a member of the data safety monitoring board for OPTIMIL and MIVAR studies. MK has received speaker's honoraria or compensation for advisory board participation from Boehringer Ingelheim, Bayer, Daiichi Sankyo, Pfizer, Bristol Myers Squibb, AstraZeneca, Sanofi, Novartis, Biogen, and Acticor. MK is member of the supervisory board of CompuGroup Medical. RL reports institutional fees for consultancy from Boehringer Ingelheim and Genentech. PAL has received honoraria for contribution to advisory boards from Boehringer Ingelheim, Bristol Myers Squibb, Bayer, Pfizer, Daiichi Sankyo, and Ricordati; research compensations from Bayer, Sanofi, Acticor; and research grants from the Swiss Heart Foundation, Swiss National Foundation, and the University Hospital Basel Foundation (propatient). SR reports consulting fees from Acticor Biotech and Boerhinger Ingelheim; has received support for attending meetings from Acticor; and is a member of the data safety monitoring board for Pfizer and Bristol Myers Squibb. DT received honoraria from Alexion, AstraZeneca, Pfizer, and Medtronic, and is a member of the advisory board for Alexion and AstraZeneca. JCG is a consultant and a data safety monitoring board member for Acticor, Prolong Pharmaceuticals, and Haemonetics, and an advisory board member for Acticor, Prolong Pharma, and Haemonetics. GA and MJ-P are co-founders of Acticor. GA, SB, and YP are respectively chief executive officer, chief strategy officer, and chief marketing officer of Acticor Biotech. AC, AM, AS, GA, J-MG, MJ-P, SB, and YP are employees or consultants for Acticor. AC, AM, AS, GA, MJ-P, SB, and YP have stock interest in Acticor Biotech. CAM declares no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Objective: This meta-analysis and systematic review were conducted to comprehensively evaluate the efficacy and safety of mesenchymal stem cells in patients with acute ischemic stroke., Method: We conducted a manual search of electronic databases, including PubMed, Embase, the Cochrane Library, and Web of Science, with a search deadline set for February 1, 2023. Data analysis was performed using Stata version 15.0., Result: A total of 9 randomized controlled studies were included, involving a total of 316 people, including 159 mesenchymal stem cells and 147 control groups. Results of meta-analysis: Compared to a placebo group, the administration of mesenchymal stem cells resulted in a significant reduction in the National Institutes of Health Stroke Scale (NIHSS) scores among patients diagnosed with acute ischemic stroke [SMD=-0.99,95% CI (-1.93, -0.05)]. Compared to placebo, barthel index [SMD = 0.48,95% CI (-0.55,1.51)], modified rankin score [SMD = 0.45, 95% CI (1.11, 0.21)], adverse events (RR = 0.68, 95% CI (0.40, 1.17)] the difference was not statistically significant., Conclusion: Based on current studies, mesenchymal stem cell transplantation can ameliorate neurological deficits in patients with ischemic stroke to a certain extent without increasing adverse reactions. However, there was no significant effect on Barthel index and Modified Rankin score., (© 2024. The Author(s).)

Background: The 2017 American College of Cardiology/American Heart Association (ACC/AHA) blood pressure (BP) guideline lowered the threshold defining hypertension to 130/80 mmHg. However, how stage 1 hypertension defined using this guideline is associated with cardiovascular events in Chinese adults remains unclear. This study assessed the association between stage 1 hypertension defined by the 2017 ACC/AHA guideline and clinical outcomes in the Chinese population., Methods: Participants with stage 1 hypertension ( n = 69,509) or normal BP ( n = 34,142) were followed in this study from 2006/2007 to 2020. Stage 1 hypertension was defined as a systolic blood pressure of 130-139 mmHg or a diastolic blood pressure of 80-89 mmHg. None were taking antihypertensive medication or had a history of myocardial infarction (MI), stroke, or cancer at baseline. The primary outcome was a composite of MI, stroke, and all-cause mortality. The secondary outcomes were individual components of the primary outcome. Cox proportional hazards models were used for the analysis., Results: During a median follow-up of 11.09 years, we observed 10,479 events (MI, n = 995; stroke, n = 3408; all-cause mortality, n = 7094). After multivariable adjustment, the hazard ratios for stage 1 hypertension vs. normal BP were 1.20 (95% confidence interval [CI], 1.13-1.25) for primary outcome, 1.24 (95% CI, 1.05-1.46) for MI, 1.45 (95% CI, 1.33-1.59) for stroke, and 1.11 (95% CI, 1.04-1.17) for all-cause mortality. The hazard ratios for participants with stage 1 hypertension who were prescribed antihypertensive medications compared with those without antihypertensive treatment during the follow-up was 0.90 (95% CI, 0.85-0.96)., Conclusions: Using the new definition, Chinese adults with untreated stage 1 hypertension are at higher risk for MI, stroke, and all-cause mortality. This finding may help to validate the new BP classification system in China., (Copyright © 2024 The Chinese Medical Association, produced by Wolters Kluwer, Inc. under the CC-BY-NC-ND license.)

Objective: This study aimed to investigate the prognostic impact of serum homocysteine-lowering therapy on patients with hemorrhagic stroke (HS) and its influence on their National Institutes of Health Stroke Scale (NIHSS) and China Stroke Scale (CSS) scores., Methods: A double-blind study involving 120 patients with HS and hyperhomocysteinemia (Hhcy) who were admitted to our hospital was conducted in 2021. They were evenly divided into two groups: the control group (n=60) received low-dose folic acid, methylcobalamin, and vitamin B6 as part of serum homocysteine-lowering therapy, while the study group (n=60) received high-dose folic acid, methylcobalamin, and vitamin B6. The prognosis of each group was compared using the NIHSS and CSS to assess the neurological function of the patients., Results: Before treatment, the levels of oxidative stress markers and vascular endothelial function markers were comparable between the two groups (t = 0.051, 0.015, 0.010, 0.011, 0.013, 0.022, P = .960, .988, .992, 0.991, .989, 0.982). However, after treatment, the study group exhibited higher levels of MDA and ET-1 compared to the control group (t = 3.418, 1.978, P < .001). Additionally, SOD, GSH-Px, and PON1 levels were lower in the study group (t = 3.435, 3.783, 2.735, 3.893, P < .001). The NIHSS scores before treatment were comparable among patients (t = 0.058, P = 0.954), but after treatment, the study group showed significantly lower NIHSS scores (t = 20.105, P < .001). Similarly, the CSS scores before treatment were comparable (t = 0.046, P = .963), but the CSS scores in the study group after treatment were significantly lower (t = 5.027, P < .001)., Conclusions: High-dose folic acid, methylcobalamin, and vitamin B6 as part of serum homocysteine-lowering therapy can improve oxidative stress and vascular endothelial function in HS patients. This treatment also enhances prognosis and ameliorates neurological deficits. Therefore, it holds significant clinical potential and should be considered for broader adoption.

Introduction: Gabapentinoids (GABA) prescribing as a potential and conceivably safer substitute for opioids has substantially increased. Understanding all potential adverse drug events (ADEs) associated with GABA will guide clinical decision-making for pain management., Methods: A 20% sample of Medicare enrollees with new chronic pain diagnoses in 2017-2018 was selected. GABA users were those with >=30 consecutive days prescription in a year without opioid prescription. Opioid users were similarly defined. The control group used neither of these drugs. Propensity score match across three groups based on demographics and comorbidity was performed. We used proportional reporting ratio (PRR), Gamma Poisson Shrinker, and tree-based scan statistic (TBSS) to detect ADEs within 3, 6, and 12 months of follow-up., Results: Immunity disorder was detected within 3 months of follow-up by PRR compared to opioid use (PRR:2.33), and by all three methods compared to controls. Complications of transplanted organs/tissues and schizophrenia spectrum/other psychotic disorders were consistently detected by PRR and TBSS within 3 months. Skin disorders were detected by TBSS; and stroke was detected by PRR within 3 months compared to opioid use (PRR:4.74). Some malignancies were detected by PRR within 12 months. Other signals detected in GABA users were neuropathy and nerve disorders., Conclusions: Our study identified expected and unexpected ADE signals in GABA users. Neurological signals likely related to indications for GABA use. Signals for immunity, mental/behavior, and skin disorders were found in the FDA adverse event reporting system database. Unexpected signals of stroke and cancer require further confirmatory analyses to verify., (© 2023 John Wiley & Sons Ltd.)

Background: Among patients hospitalized for atrial fibrillation, the frequency of off-label direct oral anticoagulant (DOAC) dosing, associated factors, hospital-level variation, and temporal trends in contemporary practice are unknown., Methods: Using the Get With The Guidelines-Atrial Fibrillation registry, patients admitted from January 1, 2014, to March 31, 2020, and discharged on DOACs were stratified according to receipt of underdosing, overdosing, or recommended dosing. Factors associated with off-label dosing (defined as underdosing or overdosing) were identified using logistic regression. Median odds ratio (OR) and time-series analyses were used to assess hospital-level variation and temporal trends, respectively., Results: Of 22 470 patients (70.1±12.1 years, 48.1% female, 82.5% White) prescribed a DOAC at discharge from hospitalization for atrial fibrillation (66% apixaban, 29% rivaroxaban, and 5% dabigatran), underdosing occurred among 2006 (8.9%), overdosing among 511 (2.3%), and recommended dosing among 19 953 (88.8%). The overall rate of off-label dosing was 11.2%. Patient-related factors associated with off-label dose included age (underdosing: OR, 1.06 per 1-year increase [95% CI, 1.06-1.07]; overdosing: OR, 1.07 per 1-year increase [95% CI, 1.06-1.09]), dialysis dependence (underdosing: OR, 5.50 [95% CI, 3.76-8.05]; overdosing: OR, 5.47 [95% CI, 2.74-10.88]), female sex (overdosing: OR, 0.79 [95% CI, 0.63-0.99]), and weight (overdosing: OR, 0.96 per 1-kg increase [95% CI, 0.95-1.00]). Across hospitals, the adjusted median OR for off-label DOAC dose was 1.45 (95% CI, 1.34-1.65; underdosing: OR, 1.52 [95% CI, 1.39-1.76]; overdosing: OR, 1.32 [95% CI, 1.20-1.84]), indicating significant hospital-level variation. Over the study period, recommended dosing significantly increased over time (81.9%-90.9%; P <0.0001 for trend) with a corresponding decline in underdosing (14.4%-6.6%; P <0.0001 for trend) and overdosing (3.8%-2.5%; P =0.001 for trend)., Conclusions: Over 1 in 10 patients hospitalized for atrial fibrillation are discharged on an off-label DOAC dose with significant variation across hospitals. While the proportion of patients receiving recommended dosing has significantly improved over time, opportunities to improve DOAC dosing persist., Competing Interests: Disclosures None.

Background and Purpose: The best management of acute ischemic stroke patients with a minor stroke and large vessel occlusion is still uncertain. Specific clinical and radiological data may help to select patients who would benefit from endovascular therapy (EVT). We aimed to evaluate the relevance of National Institutes of Health Stroke Scale (NIHSS) subitems for predicting the potential benefit of providing EVT after intravenous thrombolysis (IVT; "bridging treatment") versus IVT alone., Methods: We extracted demographic, clinical, risk factor, radiological, revascularization and outcome data of consecutive patients with M1 or proximal M2 middle cerebral artery occlusion and admission NIHSS scores of 0-5 points, treated with IVT ± EVT between May 2005 and March 2021, from nine prospectively constructed stroke registries at seven French and two Swiss comprehensive stroke centers. Adjusted interaction analyses were performed between admission NIHSS subitems and revascularization modality for two primary outcomes at 3 months: non-excellent functional outcome (modified Rankin Scale score 2-6) and difference in NIHSS score between 3 months and admission., Results: Of the 533 patients included (median age 68.2 years, 46% women, median admission NIHSS score 3), 136 (25.5%) initially received bridging therapy and 397 (74.5%) received IVT alone. Adjusted interaction analysis revealed that only facial palsy on admission was more frequently associated with excellent outcome in patients treated by IVT alone versus bridging therapy (odds ratio 0.47, 95% confidence interval 0.24-0.91; p = 0.013). Regarding NIHSS difference at 3 months, no single NIHSS subitem interacted with type of revascularization., Conclusions: This retrospective multicenter analysis found that NIHSS subitems at admission had little value in predicting patients who might benefit from bridging therapy as opposed to IVT alone. Further research is needed to identify better markers for selecting EVT responders with minor strokes., (© 2023 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Objectives: To investigate the journey to oral anticoagulant (OAC) access following formulary-related rejection of apixaban (Eliquis) and evaluate characteristics associated with failure to achieve OAC access among patients with atrial fibrillation (AF)., Study Design: Retrospective study using the Optum Market Clarity Data from January 2016 through February 2020., Methods: Patients had at least 1 claim rejection for apixaban due to prior authorization (PA), formulary exclusion (FE), or quantity limit (QL) and at least 1 AF diagnosis on or before the rejected claim. Descriptive statistics summarized transaction journeys by type of formulary restriction. Multivariable regression assessed patient characteristics associated with not receiving an OAC within 60 days after initial rejection., Results: Among 18,434 patients in the analytic sample, QL was the most common reason for rejection (68.7%), followed by PA (21.2%) and FE (10.2%). Most patients received a paid OAC claim within 60 days after rejection (82.2%-85.5% across restriction types). Mean time from rejection to paid claim ranged from 5.2 to 10.7 days among patients with a paid OAC claim and 12.4 to 17.6 days among those with multiple attempts before OAC receipt. Characteristics associated with higher odds of not receiving OAC treatment included being male, beingAfrican American, having Medicaid coverage, possessing a high stroke risk score, exhibiting no evidence of prior apixaban treatment, and being prescribed a low dose of apixaban on the initial rejected claim., Conclusions: Most patients with a claim rejection for apixaban received approval for apixaban within 60 days, suggesting that initial rejection merely created a delay in treatment. Vulnerable populations were at greater risk of not receiving a paid OAC claim.

Background: Oral anticoagulants (OACs) are effective in reducing the risk of cardioembolic stroke due to atrial fibrillation. While most nursing home residents with atrial fibrillation qualify for anticoagulation based on clinical guidelines, the net clinical benefits of OACs may diminish as residents approach the end of life., Methods: We conducted a cross-sectional study of 30,503 US nursing home residents with atrial fibrillation (based on Minimum Data Set 3.0 and Medicare Part A records) who used OACs in the year before enrolling in hospice care during 2012-2016. Whether residents discontinued OACs before hospice enrollment was determined using Part D claims and date of hospice enrollment. Modified Poisson models estimated adjusted prevalence ratios (aPR)., Results: Almost half (45.7%) of residents who had recent OAC use discontinued prior to hospice enrollment. Residents who were underweight (aPR: 1.02; 95% confidence interval [CI]: 1.01-1.03), those with high bleeding risk (aPR: 1.04, 95% CI: 1.03-1.05), and those with moderate or severe cognitive impairment (aPR: 1.02, 95% CI: 1.02-1.03) had a higher prevalence of OAC discontinuation before entering hospice. Residents with venous thromboembolism (aPR: 0.94, 95% CI: 0.93-0.96), statin users (aPR: 0.88, 95% CI: 0.87-0.89), and those on polypharmacy (≥10 medications, aPR: 0.72; 95% CI: 0.71-0.73) were less likely to discontinue OACs before enrollment in hospice., Conclusion: Anticoagulants are often discontinued among older nursing home residents with atrial fibrillation before hospice enrollment; it is not clear that these decisions are driven solely by net clinical benefit considerations. Further research is needed on comparative outcomes to inform resident-centered decisions regarding OAC use in older adults entering hospice., (© 2023 The American Geriatrics Society.)

Whether emergency medical service (EMS) improves the outcome of acute ischemic stroke (AIS) patients after intravenous thrombolysis (IVT) is still unknown among the severity of neurologic deficits. This study is to investigate the impact of EMS use on timely treatment and outcomes of AIS with IVT. This is a retrospective observational study. Clinical data after IVT from January 2017 to May 2020 were retrospectively analyzed, including onset-to-needle time (ONT), onset-to-door time (ODT). The patients were divided into EMS and non-EMS groups according to the method of admission. A good outcome was defined as a modified Rankin scale score of ≤2 at 3 months. The severity of neurological deficits was assessed using the national institutes of health stroke scale. A total of 2303 patients were analyzed (906 [(39.3%] female; mean age, 68 ± 13 year), and 1028 (44.6%) patients were transported by EMS and 1418 (67.9%) patients achieved good outcome. Among all patients, compared with non-EMS patients, EMS patients had shorter ONT (148 minutes vs 155 minutes, P = .002) and ODT (95 minutes vs 104 minutes, P < .001), but lower rate of good outcome (61.7% vs 73.0%, P < .001). The multivariate analysis showed that the use of EMS was negatively associated with ONT (ρ = -0.041, P = .048) and ODT (ρ = -0.051, P = .014). Among moderate to severe stroke patients, EMS was related with good outcome independently (OR: 3.101, 95%CI: 1.367-7.038, P = .007). In ischemic stroke, EMS can shorten the pre-hospital delay. Among moderate to severe stroke patients, EMS can further improve the outcome. But the study needs further validation., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background and Objectives: The "weekend effect" describes worse care delivery during off-hours or weekends and has been demonstrated in multiple sub-specialties. Off-hours care for acute ischemic stroke (AIS) has been associated with poorer outcomes. However, there is less data about the "weekend effect" on endovascular thrombectomy (ET) outcomes., Methods: We used Medicare 100% sample datasets and included all AIS admissions from 2018-2019, using validated International Classification of Diseases, 10th Revision, Clinical Modification codes to identify AIS and comorbidities. Medicare provides the date of admission for all hospitalizations, and the day of the week was determined and assigned to weekend (Saturday or Sunday) or weekday (Monday through Friday). We defined 3 major outcomes: inpatient mortality, discharge home (vs. other destination), and 30-day mortality., Results: Among 471427 AIS admissions,13.0% and 12.9% of all AIS admissions occurred on a Saturday and Sunday, respectively, less than the expected 14.3% occurring on any given day (p-value <0.0001). AIS admissions on a weekend were less likely to receive IV thrombolysis (13.6% on Saturday and 12.9% on Sunday) and ET (13.1% on Saturday and 13.2% on Sunday), p-value <0.0001. Among all AIS admissions, weekend admission was associated with worse outcomes, including higher odds of inpatient mortality (adjusted OR 1.04 [95% CI 1.01-1.08, p<0.0001]), lower odds of discharge home (0.94 [0.93-0.96, p<0.0001]), and higher odds of 30-day mortality (1.06 [1.04-1.08, p<0.0001]). However, among AIS patients treated with ET, there was no association of weekend admission with outcomes., Conclusions: In this national and contemporary dataset, we observed that the proportion of thrombolysis and ET cases was less over the weekend, and outcomes (inpatient mortality, 30-day mortality and odds of discharge home) were worse overall. We did not observe this association among AIS patients undergoing ET on a weekend vs. weekday., Competing Interests: Declaration of Competing Interest None., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Introduction: In recent years, the role of intravenous thrombolysis (IVT) before endovascular stroke treatment (EVT) has been discussed intensively. Whether the discussion was accompanied by changing rates of bridging IVT is unknown., Methods: Data were extracted from the prospectively maintained German Stroke Registry, including patients treated with EVT at one of 28 stroke centers in Germany between 2016 and 2021. Primary outcome parameters were the rate of bridging IVT (a) in the entire registry cohort and (b) in patients without formal contraindications to IVT (i.e. recent oral anticoagulants, time window ⩾4.5 h, extensive early ischemic changes) adjusted for demographic and clinical confounders., Results: 10,162 patients (52.8% women, median age 77 years, median National Institutes of Health Stroke Scale score 14) were analyzed. In the entire cohort, the rate of bridging IVT decreased from 63.8% in 2016 to 43.6% in 2021 (average absolute annual decrease 3.1%, 95% CI 2.4%-3.8%), while the proportion of patients with at least one formal contraindication increased by only 1.2% annually (95% CI 0.6%-1.9%). Among 5460 patients without record of formal contraindications, the rate of bridging IVT decreased from 75.5% in 2016 to 63.2% in 2021 and was significantly associated with admission date in a multivariable model (average absolute annual decrease 1.4%, 95% CI 0.6%-2.2%). Clinical factors associated with lower odds of bridging IVT included diabetes mellitus, carotid-T-occlusion, dual antiplatelet therapy, and direct admission to a thrombectomy center., Conclusion: We observed a substantial decline in bridging IVT rates independent of demographic confounders and not explained by an increase in contraindications. This observation deserves further exploration in independent populations.

Cardioembolic stroke from atrial fibrillation causes substantial death and disability in the United States. Treatment with oral anticoagulants provides safe and effective stroke prevention for high-risk patients. This article reviews strategies for the use of anticoagulation and highlights the nurse's role in patient education., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Butylphthalide can improve blood circulation in patients with acute cerebral infarction. Complement 3a receptor 1 (C3aR1) is involved in the regulation of innate immune response and pathogen monitoring, which is closely related to the pathophysiological processes of breast cancer, neurogenesis and lipid catabolism. Our study explored the therapeutic effect of butylphthalide on improving the neurological function of patients with acute anterior circulation cerebral infarction after mechanical thrombectomy, and evaluated the correlation between serum C3aR1 and butylphthalide on improving the neurological function after mechanical thrombectomy. 288 patients with acute anterior circulation cerebral infarction who were admitted to our hospital from January 2019 to November 2022 and were treated with mechanical thrombectomy for the first time were included in this retrospective study and divided into the butylphthalide group and control group that they received treatment methods. The National Institutes of Health Stroke Scale (NIHSS) scale was used to evaluate the patient neurological function treatment efficacy, and the modified Rankin Scale (mRS) scale was used to measure the patient neurological function status 3 months after surgery. Enzyme-linked immunosorbent assay method was used to determine the content of C3aR1 in serum. Two weeks after thrombus removal, the NIHSS efficacy of the butylphthalide group and the control group were 94.44% and 72.22%, respectively. The butylphthalide group was significantly higher than the control group (P < .001). Three months after the operation, the mRS score of the butylphthalide group was significantly lower than that of the control group (P = .001), and the excellent and good rate was significantly higher than that of the control group (P < .001). The serum C3aR1 level of the butylphthalide group was significantly lower than that of the control group 2 weeks after operation and 3 months after operation (P < .001). The serum C3aR1 was positively correlated with the efficacy of NIHSS (R = 0.815, P = .004), which was positively correlated with mRS score (R = 0.774, P = .007). Butylphthalide can improve the therapeutic effect of neurological function in patients with acute anterior circulation cerebral infarction after mechanical thrombus removal. The patient serum C3aR1 is related to the patient neurotherapy efficacy and neurological function status, and its level can reflect the patient neurological function recovery to a certain extent., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc.)

The Food and Drug Administration requires contemporaneous controls to compare clinical outcomes for participants receiving experimental gene therapy or gene editing clinical trials. However, developing a contemporaneous cohort of rare diseases requires multiple person-hours. In a single referral center for sickle cell disease, we tested the hypothesis that we could create an automated contemporaneous cohort of children and adults with sickle cell anemia (SCA) to predict mortality. Data were obtained between 1 January 2004 and 30 April 2021. We identified 419 individuals with SCA with consistent medical care defined as followed continuously for >0.5 years with no visit gaps >3.0 years. The median age was 10.2 years (IQR, 1-24 years), with a median follow-up of 7.4 years (IQR, 3.6-13.5 years) and 47 deaths. A total of 98% (274 of 277) of the children remained alive at 18 years of age, and 34.3% (94 of 274) of those children were followed into adulthood. For adults, the median age of survival was 49.3 years. Treatment groups were mutually exclusive and in a hierarchical order: hematopoietic stem cell transplant (n = 22)>regular blood transfusion for at least 2 years (n = 56)>hydroxyurea for at least 1 year (n = 243)>no disease-modifying therapy (n = 98). Compared to those receiving no disease-modifying treatment, those treated with hydroxyurea therapy had a significantly lower hazard of mortality (hazard ratio = 0.38; P = 0.016), but no statistical difference for those receiving regular blood transfusions compared to no disease-modifying therapy (hazard ratio = 0.71; P = 0.440). An automated contemporaneous SCA cohort can be generated to estimate mortality in children and adults with SCA., (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Hospital readmissions following stroke are costly and lead to worsened patient outcomes. We examined readmissions rates, diagnoses at readmission, and risk factors associated with readmission following acute ischemic stroke (AIS) in a large United States (US) administrative database. Using the 2019 Nationwide Readmissions Database, we identified adults discharged with AIS (ICD-10-CM I63*) as the principal diagnosis. Survival analysis with Weibull accelerated failure time regression was used to examine variables associated with hospital readmission. In 2019, 273,811 of 285,451 AIS patients survived their initial hospitalization. Of these, 60,831 (22.2%) were readmitted within 2019. Based on Kaplan Meyer analysis, readmission rates were 9.7% within 30 days and 30.5% at 1 year following initial discharge. The most common causes of readmissions were stroke and post stroke sequalae (25.4% of 30-day readmissions, 15.0% of readmissions between 30-364 days), followed by sepsis (10.3% of 30-day readmissions, 9.4% of readmissions between 30-364 days), and acute renal failure (3.2% of 30-day readmissions, 3.0% of readmissions between 30-364 days). After adjusting for multiple patient and hospital-level characteristics, patients at increased risk of readmission were older (71.6 vs. 69.8 years, p<0.001) and had longer initial lengths of stay (7.6 vs. 6.2 day, p<0.001). They more often had modifiable comorbidities, including vascular risk factors (hypertension, diabetes, atrial fibrillation), depression, epilepsy, and drug abuse. Social determinants associated with increased readmission included living in an urban (vs. rural) setting, living in zip-codes with the lowest median income, and having Medicare insurance. All factors were significant at p<0.001. Unplanned hospital readmissions following AIS were high, with the most common reasons for readmission being recurrent stroke and post stroke sequalae, followed by sepsis and acute renal failure. These findings suggest that efforts to reduce readmissions should focus on optimizing secondary stroke and infection prevention, particularly among older socially disadvantaged patients., Competing Interests: Dr. de Havenon 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. This does not alter our adherence to PLOS ONE policies on sharing data and materials., (Copyright: © 2023 Zhou 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: Fluoxetine is one of the selective serotonin reuptake inhibitors that can improve motor and function recovery after a stroke. Several randomized controlled trials (RCTs) have investigated the efficacy and safety of fluoxetine compared to placebo in post-stroke recovery. However, the results are still controversial., Aim: This meta-analysis aimed to provide an updated analysis of the efficacy and safety of fluoxetine versus placebo in post-stroke recovery., Method: RCTs were searched from electronic databases of PubMed, Embase, Clinical Trials, and the Cochrane Central Register of Controlled Trials from inception until July 2022. Google Scholar and the reference lists of included studies were screened to identify additional studies. Outcomes were analyzed using risk ratios (RR) and mean differences (MD) with 95% confidence intervals (CI)., Results: Fourteen RCTs (6584 patients) were included. The fluoxetine group showed a significantly higher Fugl-Meyer motor scale (FMMS) score than the placebo group (MD 15.93, 95%CI 9.76-22.7, P < 0.01). No significant differences were observed in the modified Rankin Scale (mRS) (mRS ≤ 2, RR 1.00, 95%CI 0.88-1.15, P = 0.95), the Barthel index (MD 12.11, 95%CI - 0.71 to 24.92, P = 0.06), and the National Institutes of Health Stroke Scale scores (MD - 0.19, 95%CI - 0.43 to 0.04, P = 0.1) between the two groups. The fluoxetine group showed a lower rate of depression or anxiety than the placebo group (RR 0.67, 95% CI 0.49-0.92, P < 0.05). There were no significant differences between the groups regarding gastrointestinal adverse reactions (P > 0.05), drowsiness (P > 0.05) or insomnia (P > 0.05)., Conclusion: Fluoxetine improved FMMS and reduced anxiety and depression. More well-designed and large sample-size RCTs are required to further analyze the efficacy of fluoxetine in post-stroke recovery., (© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Importance: Ginkgo diterpene lactone meglumine (GDLM) has attracted much attention because of its potential neuroprotective properties in ischemic stroke. The efficacy of GDLM in patients with acute ischemic stroke (AIS) needs to be verified by well-designed randomized clinical trials., Objective: To assess the efficacy and safety of GDLM in patients with AIS., Design, Setting, and Participants: This multicenter, randomized, double-blind, placebo-controlled, parallel-group trial involved 3448 patients who had AIS, were aged 18 to 80 years, had a clinically diagnosed AIS symptom within 48 hours of onset, had a modified Rankin Scale (mRS) score of 0 or 1 prior to onset, and had a National Institutes of Health Stroke Scale score ranging from 4 to 24. The trial took place at 100 centers in China from February 1, 2016, to May 1, 2018. The mRS is a global stroke disability scale with scores ranging from 0 (no symptoms or completely recovered) to 6 (death). The National Institutes of Health Stroke Scale is a tool used by clinicians to quantify impairment caused by stroke (range, 0-42, with higher scores indicating greater severity). Data were analyzed from January 2019 to December 2022., Interventions: Patients were randomized to receive GDLM or placebo once daily via intravenous infusion in a 1:1 ratio. The treatment was dispensed within 48 hours after symptoms and continued for 14 days. Interventions of thrombolysis and thrombectomy were not permitted during the treatment., Main Outcomes and Measures: The primary outcome was the proportion of patients with an mRS of 0 or 1 on day 90 after randomization. Safety outcomes included adverse events and serious adverse events., Results: A total of 3448 patients were randomized, with 1725 patients assigned to the GDLM group and 1723 patients assigned to the placebo group. The median (IQR) age of the patients was 63 (55-71) years, and 1232 (35.7%) were women. The primary outcome on day 90 occurred in 877 patients (50.8%) in the GDLM group, and 759 patients (44.1%) in the placebo group (risk difference, 6.79%; 95% CI, 3.46%-10.10%; odds ratio, 1.31; 95% CI, 1.15-1.50; relative risk, 1.15; 95% CI, 1.08-1.24; P < .001). Adverse events occurred relatively equally between the 2 groups (303 [17.6%] vs 298 [17.3%]; risk difference, 0.27%; 95% CI, -2.26% to 2.80%; odds ratio, 1.02; 95% CI, 0.85-1.21; relative risk, 1.02; 95% CI, 0.88-1.17; P = .83)., Conclusions and Relevance: Among patients with AIS in this randomized clinical trial, GDLM improved the proportion of patients achieving favorable clinical outcomes at 90 days compared with placebo., Trial Registration: ClinicalTrials.gov Identifier: NCT02526225.

Introduction: Blood pressure is not optimally reduced in 3 of 4 patients with hypertension (HTN) in the United States., Aim: We analyzed for factors associations with premorbid non-adherence to HTN medications in acute stroke patients., Methods: This cross-sectional study included 225 acute stroke patients with self-reported adherence to HTM medications in a stroke registry in the Southeastern United States. We defined medication non-adherence as < 90% of prescribed. Logistic regression analyzed demographic and socioeconomic factors for prediction of adherence., Results: There were 145 (64%) patients with adherence and 80 (36%) with non-adherence. The likelihood of adherence to HTN medications was decreased among black patients, OR 0.49 (95% CI 0.26-0.93), p = 0.03, and those without health insurance, OR 0.29 (95% CI 0.13-0.64), p = 0.002. Specific reasons for non-adherence were high medication cost in 26 (33%), side effects in 8 (10%), and other unspecified reasons in 46 (58%) patients., Conclusion: In this study, adherence to HTN medications was significantly lower among black patients and those without health insurance., (© 2023. Italian Society of Hypertension.)

From 2016 to 2021, the National Institutes of Health Stroke Trials Network funded by National Institutes of Health/National Institute of Neurological Disorders and Stroke initiated ten multicenter randomized controlled clinical trials. Optimal subject randomization designs are demanded with 4 critical properties: (1) protection of treatment assignment randomness, (2) achievement of the desired treatment allocation ratio, (3) balancing of baseline covariates, and (4) ease of implementation. For acute stroke trials, it is necessary to minimize the time between eligibility assessment and treatment initiation. This article reviews the randomization designs for 3 trials currently enrolling in Stroke Trials Network funded by National Institutes of Health/National Institute of Neurological Disorders and Stroke, the SATURN (Statins in Intracerebral Hemorrhage Trial), the MOST (Multiarm Optimization of Stroke Thrombolysis Trial), and the FASTEST (Recombinant Factor VIIa for Hemorrhagic Stroke Trial). Randomization methods utilized in these trials include minimal sufficient balance, block urn design, big stick design, and step-forward randomization. Their advantages and limitations are reviewed and compared with traditional stratified permuted block design and minimization., Competing Interests: Disclosures Dr Zhao reports grants from National Institutes of Health. Dr Yeatts reports other intellectual property licensed to American Stroke Association; compensation from C.R. Bard, Inc & Subsidiaries for data and safety monitoring services; employment by Medical University of South Carolina; grants from National Heart, Lung, and Blood Institute; grants from National Institute of Neurological Disorders and Stroke; and compensation from Emory University for data and safety monitoring services. Dr Selim reports grants from NIH/NIA; compensation from MedRhythms, Inc for consultant services; and grants from NIH/NINDS. Dr Adeoye reports service as Chief Medical Officer for sense diagnostics and compensation from NICO Corporation for data and safety monitoring services. Dr Durkalski-Mauldin reports grants from National Institutes of Health. Dr Elm reports grants from National Institutes of Health.

Background and Aims: Although intravenous thrombolysis (IVT) represents standard-of-care treatment for acute ischemic stroke (AIS) in eligible adult patients, definitive evidence-based guidelines and randomized clinical trial data evaluating its safety and efficacy in the pediatric population remain absent from the literature. We aimed to evaluate the utilization and outcomes of IVT for the treatment of pediatric AIS using a large national registry., Methods: Weighted hospitalizations for pediatric (<18 years of age) AIS patients were identified in the National Inpatient Sample during the period of 2001 to 2019. Complex sample statistical methods were performed to assess unadjusted and adjusted outcomes in patients treated with IVT or other medical management., Results: Among 13,901 pediatric AIS patients, 270 (1.9%) were treated with IVT monotherapy (median age 12.8 years). IVT-treated patients developed any intracranial hemorrhage (ICH) at a rate of 5.6% (n = 15), and 71.9% (n = 194) experienced favorable functional outcomes at discharge (to home or to acute rehabilitation). Following propensity-score adjustment for age, acute stroke severity, infarct location, and etiological/comorbid conditions, IVT was not associated with an increased risk of any ICH (5.6% vs 5.4%, p = 0.931; adjusted odds ratio (aOR) = 1.01, 95% confidence interval (CI) = 0.48-2.14, p = 0.971), nor with favorable functional outcome (71.9% vs 74.5%, p = 0.489; aOR = 0.88, 95% CI = 0.60-1.29, p = 0.511) in comparison with other medical therapy., Conclusions: Twenty years of population-level data in the United States demonstrate that pediatric AIS patients treated with IVT experienced high rates of favorable outcomes without an increased risk of hemorrhagic transformation.

Introduction: Door-to-needle time (DNT) has been established as the main indicator in code stroke protocols. According to the 2018 guidelines of the American Heart Association/American Stroke Association, DNT should be less than 45minuts; therefore, effective and revised pre-admission and in-hospital protocols are required., Method: We analysed organisational changes made between 2011 and 2019 and their influence on DNT and the clinical progression of patients treated with fibrinolysis. We collected data from our centre, stored and monitored under the Master Plan for Cerebrovascular Disease of the regional government of Catalonia. Among other measures, we analysed the differences between years and differences derived from the implementation of the Helsinki model., Results: The study included 447 patients, and we observed significant differences in DNT between different years. Pre-hospital code stroke activation, recorded in 315 cases (70.5%), reduced DNT by a median of 14minutes. However, the linear regression model only showed an inversely proportional relationship between the adoption of the Helsinki code stroke model and DNT (beta coefficient, -0.42; P<.001). The removal of vascular neurologists after the adoption of the Helsinki model increased DNT and the 90-day mortality rate., Conclusion: DNT is influenced by the organisational model. In our sample, the application of the Helsinki model, the role of the lead vascular neurologist, and notification of code stroke by pre-hospital emergency services are key factors for the reduction of DNT and the clinical improvement of the patient., (Copyright © 2020 Sociedad Española de Neurología. Published by Elsevier España, S.L.U. All rights reserved.)

Importance: Preclinical and clinical studies have suggested the neuroprotective effect of Panax notoginseng saponins (Xuesaitong soft capsules). However, robust evidence in patients with ischemic stroke is lacking., Objective: To assess the efficacy and safety of Xuesaitong soft capsules in patients with ischemic stroke., Design, Setting, and Participants: This multicenter, double-blind, placebo-controlled randomized clinical trial was conducted at 67 tertiary health centers in China from July 1, 2018, to June 30, 2020. Included patients were aged 18 to 75 years with a diagnosis of ischemic stroke and a National Institutes of Health Stroke Scale score between 4 and 15., Interventions: Eligible patients were randomly assigned within 14 days after symptom onset to receive either treatment with Xuesaitong soft capsules (120 mg orally twice daily) or placebo (120 mg orally twice daily) for 3 months., Main Outcomes and Measures: The primary outcome was functional independence at 3 months, defined as a modified Rankin Scale score of 0 to 2., Results: Among 3072 eligible patients with ischemic stroke who were randomized, 2966 (96.5%) were included in the modified intention-to-treat cohort (median [IQR] age, 62 [55-68] years; 1982 male [66.8%]). The number of patients who achieved functional independence at 3 months was 1328 (89.3%) in the Xuesaitong group and 1218 (82.4%) in the control group (odds ratio, 1.95; 95% CI, 1.56-2.44; P < .001). In the safety cohort, serious adverse events occurred in 15 of 1488 patients (1.0%) in the Xuesaitong group and 16 of 1482 (1.1%) in the control group (P = .85)., Conclusions and Relevance: In this randomized clinical trial, Xuesaitong soft capsules significantly increased the likelihood of functional independence at 3 months in patients with ischemic stroke, indicating that this may be a safe and effective alternative therapy to improve prognosis in this population., Trial Registration: Chinese Clinical Trial Registry Identifier: ChiCTR1800016363.

Objectives: To evaluate current trends in the utilization of intravenous thrombolysis (IV-tPA) and mechanical thrombectomy (MT) in acute ischemic stroke (AIS) in various age groups of children in the United States., Methods: We conducted a serial cross-sectional study using primary AIS admissions in children ⩽ 17 years (weighted n = 2807) contained in the 2009-2019 KIDS Inpatient Database. Age-specific utilization frequency of IV-tPA and MT were calculated. Multivariable-adjusted models were used to evaluate demographic predictors of treatment., Results: From 2009 to 2019, there were 2807 AIS admissions in children in the KID of which 55.9% were in boys and 29.9% were 15-17 years old.128 (4.6%) received IV-tPA. IV-tPA utilization differed by age (5-9 years: 3.1%, 15-17 years 8.1% p value < 0.001). Overall MT usage was 2.3% and this also varied by age (1-4 years: 0.9% and 15-17years 4.0%, p value = 0.006). IV-tPA utilization almost tripled across the study period (2.5% 2009 to 6.5% in 2019, p value =  0.001) while MT use more than doubled over time (1.2% in 2009 and 3.0% in 2019, p value = 0.048). Increased IV-tPA utilization was seen primarily in children 10-14 years (0.8% in 2009 to 7.2% 2019, p value = 0.005) and 15-17 years (5.4% in 2009 to 10.4% in 2019, p value = 0.045). Utilization in younger age groups remained unchanged over time. MT usage was very variable across various age groups over time. IV-tPA and MT utilization increased over time in nonchildren's hospitals (both p values < 0.05) but usage in designated children's hospitals did not change significantly over time. In multivariable models, there was no significant difference in odds of IV-tPA and MT use by sex, race or insurance status., Conclusion: IV-tPA and MT utilization in pediatric AIS increased in the United States over the past decade mainly in older children 10-17 years. Utilization increased mainly in patients hospitalized in nonchildren's hospitals. Usage in children's hospitals did not change significantly over time.

Importance: Youths with sickle cell anemia (SCA) are at risk of pain crises, stroke, and early death. Complications can be reduced by the oral disease-modifying medication hydroxyurea, and in 2014, the National Heart, Lung, and Blood Institute published revised guidelines that hydroxyurea should be offered to youths aged 9 months and older with SCA regardless of disease severity., Objective: To describe changes in hydroxyurea use among youths with SCA before and after release of the National Heart, Lung, and Blood Institute guidelines., Design, Setting, and Participants: This cross-sectional study was conducted using administrative data from 2010 to 2018 from Michigan and New York State (NYS) Medicaid programs. The study population included youths aged 1 to 17 years with SCA enrolled in the Michigan or NYS Medicaid programs for at least 1 year (Michigan: 2010-2018; NYS: 2012-2018). Youths with SCA were identified using validated claims-based definitions. Data were analyzed from June to October 2020., Main Outcomes and Measures: The main outcome was hydroxyurea use characterized as mean annual counts of days' supply of filled hydroxyurea prescriptions. Rates of hydroxyurea use over time were assessed using regression models (Michigan: zero-inflated negative binomial; NYS: negative binomial). Models included indicators for periods before and after guideline release., Results: A total of 4302 youths with SCA (2236 males [52.0%]; 2676 born 2005-2017 [62.2%]; 150 Hispanic [3.5%], 2929 non-Hispanic Black [68.0%], and 389 non-Hispanic White [9.0%]) contributed 12 565 person-years. The mean (SD) annual days' supply of hydroxyurea was 47.2 (93.6) days per youth in Michigan and 97.4 (137.0) days per youth in NYS. In Michigan, there was an increase in the odds of having nonzero days' supply after the guidelines were released (odds ratio, 1.52; 95% CI, 1.07-2.14). In NYS, no change was seen in the mean days' supply of filled hydroxyurea., Conclusions and Relevance: These findings suggest that hydroxyurea was substantially underused among youths with SCA, despite establishment as the primary disease-modifying therapy for SCA, and that there was incomplete clinician or patient uptake of newly released guidelines. Results suggest that expanding use of hydroxyurea may require a multifaceted approach that includes addressing multiple system- and patient-level barriers.

Background: Stroke is a major cause of disability and death. Stroke recovery outcomes range from functional impairment to disability. This study was designed to compare the recovery results of stroke patients treated with fluoxetine to those treated with placebo., Review Summary: Seventeen randomized clinical trials were identified by searching PubMed, Cochrane, Scopus, and Web of Science until June 2021. Fluoxetine enhances the National Institutes of Health Stroke Scale (NIHSS) score [mean difference (MD)=-0.67, 95% confidence interval (CI) (-1.19 to -0.15)] and the Fugl-Meyer Motor Scale (FMMS) score [MD=17.36, 95% CI (12.12-22.61)] at the 3-month follow up. However, the NIHSS score showed no significant difference between the 2 groups at 2 weeks [MD=-0.32, 95% CI (-0.72 to 0.07)] or at 6 months [MD=-0.17, 95% CI (-0.47 to 0.14)]. Fluoxetine-treated and placebo-treated patients had the same overall impact on FMMS scores at 1 month ( P =0.41). Barthel index showed no significant difference between the 2 arms at 3 months ( P =0.21) or 6 months ( P =0.68). Fluoxetine-treated patients were at a higher risk of broken bone [risk ratios (RR)=2.30, 95% CI (1.59-3.32)] and hyponatremia [RR=2.12, 95% CI (1.19-3.76)], and at lower risk of new depression [RR=0.72, 95% CI (0.61-0.84)] in comparison with placebo., Conclusion: The efficacy of fluoxetine on the NIHSS and FMMS is likely to take time to emerge and is expected to be transient. The Barthel index score did not differ between the fluoxetine and placebo groups. The use of fluoxetine increased the incidence of hyponatremia and bone fractures while decreasing the risk of new-onset depression., Competing Interests: The authors declare no conflict of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Depression is a common neuropsychiatric consequence of stroke, but there is little empiric evidence regarding clinical diagnosis and management of poststroke depression., Methods: Retrospective cohort study among 831 471 privately insured patients with first stroke in the USA from 2003 to 2020. We identified diagnoses of poststroke depression using codes from the International Classification of Diseases. We identified treatment based on prescriptions for antidepressants. We used Cox proportional hazards regression analysis to examine rates of poststroke depression diagnosis by gender, age and race/ethnicity. Among individuals who received a diagnosis of poststroke depression, we estimated treatment rates by gender, race/ethnicity and age using negative binomial regression analysis., Results: Annual diagnosis and treatment rates for poststroke depression increased from 2003 to 2020 (both p for trend<0.001). Diagnosis rates were higher in women than men (HR 1.53, 95% CI 1.51 to 1.55), lower among members of racial/ethnic minorities (vs white patients: Asian HR 0.63, 95% CI 0.60 to 0.66; Black HR 0.76, 95% CI 0.74 to 0.78; Hispanic HR 0.88, 95% CI 0.86 to 0.90) and varied by age. Among individuals diagnosed with poststroke depression, 69.8% were prescribed an antidepressant. Rates of treatment were higher in women vs men (rate ratio, RR=1.19, 95% CI: 1.17 to 1.21), lower among members of racial/ethnic minorities (vs white patients: Asian RR 0.85, 95% CI 0.80 to 0.90; Black RR 0.92, 95% CI 0.89 to 0.94; Hispanic RR 0.96, 95% CI 0.93 to 0.99) and higher among older patients., Conclusions: In this insured population, we identify potential inequities in clinical management of poststroke depression by gender, race/ethnicity and age that may reflect barriers other than access to healthcare., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Background and Purpose: Although many stroke centers in United States are using intravenous (IV) tenecteplase (TNK) for acute ischemic stroke patients, there is paucity of comparative data between IV TNK and IV alteplase from real-world settings., Materials and Methods: We analyzed the data from 122 healthcare facilities in Cerner Real World Data and included patients admitted between February 2016 to April 2022 to determine the effect of IV TNK (compared with IV alteplase) on occurrence of two outcomes in acute ischemic stroke patients stratified by use of thrombectomy: non-routine discharge or death, and intracranial hemorrhage after adjusting for potential confounders., Results: Among 30,643 acute ischemic stroke patients analyzed, 29,480 (96.2%) and 1,163 (3.8%) patients received IV alteplase and IV TNK, respectively. The proportion of patients who received thrombectomy was significantly higher among patients who received IV TNK compared with those who received IV alteplase (16.7% versus 11.0%, p<0.001). Occurrence of intracranial hemorrhage was more common among patients treated with IV TNK in acute ischemic stroke patients who did not receive thrombectomy (7.9% versus 5.1%, p<0.001) but not in those who received thrombectomy (20.1% versus 16.8%, p = 0.234). In the logistic regression analysis, patients treated with IV TNK who did not receive thrombectomy were at higher risk of intracranial hemorrhage (OR, 1.34, 95% CI 1.05-1.72, p = 0.02) after adjusting for age (age strata), gender, race/ethnicity, hypertension, diabetes mellitus, atrial fibrillation, hyperlipidemia, malignancy, nicotine dependence, previous ischemic stroke, previous transient ischemic attack, previous intracerebral hemorrhage, previous subarachnoid hemorrhage, previous acute myocardial infarction, atherosclerosis of aorta, previous AKI, congestive heart failure, peripheral vascular disease, and hospital type, aphasia, hemiplegia, neglect, somnolence, stupor and coma, dysphagia, and homonymous hemianopsia. There was no difference in the rate of non-routine discharge or death between patients treated with IV TNK and those treated with IV alteplase in the multivariate analyses., Conclusions: In an analysis of real-world data, IV TNK was associated with higher rates of intracranial hemorrhage compared with IV alteplase in patients with acute ischemic stroke who did not undergo thrombectomy., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Objectives: To investigate whether intravenous thrombolysis (IVT) with alteplase (a recombinant tissue plasminogen activator, rt-PA) before endovascular treatment (EVT) is beneficial for acute ischemic stroke (AIS) patients in different periods., Methods: This study enrolled a total of 140 patients hospitalized between 2019 and 2022 with AIS from large vessel occlusion (LVO) in the anterior circulation. Those patients were divided into the EVT alone group and IVT + EVT group, in which EVT was preceded by intravenous rt-PA. According to the time from onset to femoral artery puncture, the above two groups were divided into the following subgroups: < 4.5 h, between 4.5 and 6 h, between 6 and 8 h, and between 8 and 10 h. There were 78 patients in the EVT alone group and 62 patients in the IVT + EVT group., Results: There was no statistically significant difference in functional independence, recanalization rate, favorable outcome rate, or mortality between the EVT and IVT + EVT groups (P > 0.05). After adjusting for confounding factors, a lower incidence of intracerebral hemorrhage was observed in the EVT group (P < 0.05). A comparison of time-dependent efficacy between the two groups showed that within 6-8 h, there were statistically significant differences between admission and postoperation in the National Institutes of Health Stroke Scale scores at 24 h (P = 0.01) or 7 days (P = 0.02)., Conclusions: Although there was no difference in clinical efficacy and safety between the abovementioned two groups, treatment with IVT + EVT could increase the risk of bleeding compared to EVT. Moreover, in the 6-8 h subgroup, the efficacy of EVT alone was better than that of IVT + EVT., (© 2023. The Author(s).)

Objective: The study aimed to assess effects of the simultaneous use of Cerebrolysin and intravenous thrombolysis (Alteplase) on hemorrhagic transformation (HT) and functional outcome as well as to analyze the treatment safety in acute stroke patients., Material and Methods: It was a prospective, randomized, open-label, multicenter, parallel-group, active-controlled pilot study (Trial Registration Number: ISRCTN87656744, https://doi.org/10.1186/ISRCTN87656744, Trial registration date: 16/02/2021). The intervention group ( n =126) was treated with Cerebrolysin infusion (30 mL) started simultaneously with Alteplase (0.9 mg/kg) via a separate IV line. The Cerebrolysin treatment continued for 14 consecutive days with the baseline therapy along. The control group ( n =215) received only Alteplase and the baseline therapy. The primary endpoints were the rate of any and symptomatic hemorrhagic transformation (HT) from admission to day 14. Secondary endpoints were treatment safety and functional outcome measured with the National Institutes of Health stroke scale (NIHSS) in 24 h and on day 14, and with the modified Rankin scale (mRS) on day 90., Results: Treatment with Cerebrolysin resulted in a significant reduction of the symptomatic HT rate with an odds ratio of 0.248 (95% CI: 0.072-0.851; p =0.019). No serious adverse events related to Cerebrolysin were observed. On day 14, the intervention group showed a significant reduction in the NIHSS score ( p =0.045). However, no difference in the mRS score was observed on day 90, but there was a trend towards its improvement., Conclusion: The combination of Cerebrolysin and Alteplase was safe and significantly reduced the rate of symptomatic HT and improved early neurological deficit. However, no difference in functional outcome was found on day 90, but there was a trend towards favorable functional outcome.

Background: The National Institutes of Health Stroke Scale (NIHSS) is the most frequently applied clinical rating scale for standardized assessment of neurological deficits in acute stroke in both clinical and research settings. Notwithstanding this prominent role, important questions regarding its validity remain insufficiently addressed: Investigations of the underlying dimensional structure of the NIHSS yielded inconsistent results that are largely not generalizable across studies. Neurobiological validations by linking measured deficit dimensions to brain anatomy and function are missing., Methods: We, therefore, employ advanced machine learning to identify an optimal representation of the dimensional structure of the NIHSS across two independent and heterogeneous stroke datasets (N = 503 and N = 690). Associated lesion locations are identified by multivariate lesion-deficit mapping (LDM) and their functional relevance is profiled based on a-priori task activation meta-data analysis, to provide an independent link to the behavioural level., Findings: A five-factor structure of the NIHSS was identified as the most robust and generalizable representation of stroke deficit dimensions across study populations, settings, and clinical phenotypes. Specifically, the identified dimensions comprised NIHSS items for (F1) left motor deficits, (F2) right motor deficits, (F3) dysarthria and facial palsy, (F4) language, and (F5) deficits in spatial attention and gaze. LDM linked four of these factors to differentially localized, eloquent neuroanatomical areas. Functional characterization of LDM results aligned with detected deficit dimensions, revealing associations with motor functions, language processing, and various functions in the perception domain., Interpretation: By cross-validating machine learning in heterogeneous multi-site stroke cohorts, we report evidence on the validity of the NIHSS: We identified an overarching structure of the NISHS containing a five-dimensional representation of stroke deficits. We provide an anatomical map of the NIHSS that is of value for future applications of individualized stroke treatment and rehabilitation., Funding: This research was supported by the National Key R&D Program of China (Grant No. 2021YFC2502200), the National Human Brain Project of China (Grant No. 2022ZD0214000)", the German Research Foundation (Deutsche Forschungsgemeinschaft), Project 178316478 (A1, C1, C2), and Project 454012190 of the SPP 2041, the Helmholtz Portfolio Theme "Supercomputing and Modelling for the Human Brain" and Helmholtz Imaging Platform grant NimRLS (ZT-I-PF-4-010)., Competing Interests: Declaration of interests The authors report no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: The effect of sodium glucose cotransporter 2 inhibitors (SGLT2i) on the total (first and recurrent) burden of cardiovascular (CV) hospitalizations, including hospitalization for heart failure, myocardial infarction, and stroke, is poorly understood., Objective: To assess the effect of empagliflozin, an SGLT2i, on total CV hospitalizations among older adults with T2D., Methods: Using data from Medicare fee-for-service (08/2014-09/2017), we identified 1:1 propensity score-matched cohorts of patients with T2D initiating empagliflozin versus sitagliptin or empagliflozin versus glucagon-like peptide-1 receptor agonists (GLP-1RA), balancing >140 baseline covariates. We compared the risk of first and recurrent hospitalizations with any CV condition as the primary discharge diagnosis (ICD-9: 390-459; ICD-10: I00-I99), hospitalizations for heart failure (HHF), and myocardial infarctions (MI) or stroke. We estimated treatment effects based on the Ghosh-Lin semiparametric model for recurrent events as primary and joint frailty model as secondary analysis., Results: We included 11,429 matched-pairs of empagliflozin and sitagliptin initiators and 17,502 matched-pairs of empagliflozin and GLP1-RA initiators with an average age of 72 years. Empagliflozin was associated with a reduced risk of total CV hospitalizations (0.80 [0.69-0.93] vs sitagliptin; 0.88 [0.77-1.00] vs GLP-1RA) and total HHF (0.70 [0.51-0.98] vs sitagliptin; 0.76 [0.56-1.03] vs GLP1-RA) over a mean follow up of 6.3 months. No differences between treatments were observed for MI or stroke. Results were consistent for joint frailty models., Conclusion: Empagliflozin, compared to sitagliptin or to a lesser extent GLP1-RA, was associated with a reduction in the burden of total CV hospitalizations and HHF in older patients with T2D., (Copyright © 2022. Published by Elsevier Inc.)

In recent years, US payers have increased usage of formulary exclusions as a means to help manage costs. Earlier this year, one of the largest pharmacy benefit managers in the country added Eliquis (apixaban), the most widely used anticoagulant, to its list of excluded medicines from its formulary, raising concerns by physicians and patients. In this commentary, we examine the potential impacts of formulary exclusion of a drug like apixaban-a treatment for patients with atrial fibrillation and venous thromboembolism to help prevent stroke and clotting events and which has been demonstrated to have a strong efficacy and safety profile. We discuss the effect of formulary exclusions on patients' ability to access the most clinically appropriate treatment for their health needs, along with possible effects on their health and well-being. We also report descriptive results on apixaban-treated patients with traditional Medicare coverage who faced a formulary exclusion of apixaban in 2017, and these patients' observed behaviors. We found that the majority of these patients remained on apixaban either through pre-emptively switching to a different Part D drug plan with apixaban coverage or applying for formulary exception. Our findings suggest that formulary exclusion did not help to achieve the goal of switching patients to less costly medications but created additional hurdles for patients to access their preferred treatment and increased patient burden. Alternative ways to manage payer costs may be needed to help avoid poor outcomes and reduce the burden placed on patients in their efforts to access life-saving medications.

Aim: To evaluate the association of comparative effectiveness research with Medicare coverage of direct oral anticoagulants. Materials & methods: A literature review for direct oral anticoagulants was conducted from 2011 to 2017. Monthly prescription drug plan and formulary files (n = 28) were used to conduct change-point analysis and assess each outcome variable. Results: Up to 2013, studies showed that dabigatran was more effective than rivaroxaban. In 2015, apixaban was shown to be the safest and most effective drug in comparison with all direct oral anticoagulants. In 2016-2017, dabigatran and apixaban were shown to have similar efficacy. Approximately 75% of plans covered dabigatran under tier 3 until 2015. From 2011 to 2017, less than 30% of plans required prior authorizations, 50% imposed quantity limits and mean copayment was lowest for rivaroxaban. Conclusion: Consistent with comparative effectiveness research, Medicare plans covered apixaban more favorably and edoxaban less favorably. However, discrepancies in comparative effectiveness research translation were found for rivaroxaban and dabigatran.

Ischemic stroke represents 87% of all strokes. As global initiatives move forward with stroke care, health care providers and institutions will be called on to deliver the most current evidence-based care. The American Heart Association/American Stroke Association (AHA/ASA) estimates that 795 000 strokes occur each year; 610 000 are new strokes, and 185 000 are recurrent strokes. Eighty-seven percent are ischemic strokes; the overall mortality rate from stroke was 273 000, which makes stroke the fifth leading cause of death and the leading cause of disability in the United States. Stroke costs the United States an estimated $34 billion each year. This article outlines a nursing intervention regarding the use of intravenous thrombolytic therapy for treating acute ischemic stroke, the risk factors related to IV-alteplase, best-practice protocols, and the nursing role in efforts to deliver safe care. The conclusion reveals the need for health care organizations to explore opportunities, continually inspire innovation at the bedside, highlight nursing's essential contribution to acute stroke care, and encourage publishing improvements in patient care and the nurse practice environment., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Background: The incidence of early seizures (occurring within 7 days of stroke onset) after intracerebral haemorrhage reaches 30% when subclinical seizures are diagnosed by continuous EEG. Early seizures might be associated with haematoma expansion and worse neurological outcomes. Current guidelines do not recommend prophylactic antiseizure treatment in this setting. We aimed to assess whether prophylactic levetiracetam would reduce the risk of acute seizures in patients with intracerebral haemorrhage., Methods: The double-blind, randomised, placebo-controlled, phase 3 PEACH trial was conducted at three stroke units in France. Patients (aged 18 years or older) who presented with a non-traumatic intracerebral haemorrhage within 24 h after onset were randomly assigned (1:1) to levetiracetam (intravenous 500 mg every 12 h) or matching placebo. Randomisation was done with a web-based system and stratified by centre and National Institutes of Health Stroke Scale (NIHSS) score at baseline. Treatment was continued for 6 weeks. Continuous EEG was started within 24 h after inclusion and recorded over 48 h. The primary endpoint was the occurrence of at least one clinical seizure within 72 h of inclusion or at least one electrographic seizure recorded on continuous EEG, analysed in the modified intention-to-treat population, which comprised all patients who were randomly assigned to treatment and who had a continuous EEG performed. This trial was registered at ClinicalTrials.gov, NCT02631759, and is now closed. Recruitment was prematurely stopped after 48% of the recruitment target was reached due to a low recruitment rate and cessation of funding., Findings: Between June 1, 2017, and April 14, 2020, 50 patients with mild-to-moderate severity intracerebral haemorrhage were included: 24 were assigned to levetiracetam and 26 to placebo. During the first 72 h, a clinical or electrographic seizure was observed in three (16%) of 19 patients in the levetiracetam group versus ten (43%) of 23 patients in the placebo group (odds ratio 0·16, 95% CI 0·03-0·94, p=0·043). All seizures in the first 72 h were electrographic seizures only. No difference in depression or anxiety reporting was observed between the groups at 1 month or 3 months. Depression was recorded in three (13%) patients who received levetiracetam versus four (15%) patients who received placebo, and anxiety was reported for two (8%) patients versus one (4%) patient. The most common treatment-emergent adverse events in the levetiracetam group versus the placebo group were headache (nine [39%] vs six [24%]), pain (three [13%] vs ten [40%]), and falls (seven [30%] vs four [16%]). The most frequent serious adverse events were neurological deterioration due to the intracerebral haemorrhage (one [4%] vs four [16%]) and severe pneumonia (two [9%] vs two [8%]). No treatment-related death was reported in either group., Interpretation: Levetiracetam might be effective in preventing acute seizures in intracerebral haemorrhage. Larger studies are needed to determine whether seizure prophylaxis improves functional outcome in patients with intracerebral haemorrhage., Funding: French Ministry of Health., Competing Interests: Declarations of interests LP-D reports speaker's honoraria and travel fees from Bioprojet, Jazz Pharmaceuticals, Roche, and UCB. SB reports speaker's honoraria and travel fees from ESAI, Livanona, UCB, and Angelini Pharma. SR reports speaker's honoraria and travel fees from UCB, ESAI, Angelini Pharma, Zogenix, and Gaoma Therapeutics. LD reports speaker's honoraria and travel fees from Alexion, Boehringer Ingelheim, Pfizer, and Servier. All other authors declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background Several studies investigated the role of selective serotonin reuptake inhibitors (SSRIs) in improving poststroke recovery; thus, we have decided to conduct this systematic review and meta-analysis to investigate the efficacy and safety of SSRIs in poststroke recovery. Methods and Results In this meta-analysis we searched the following databases: PubMed, Cochrane, Scopus, and Google Scholar. The studies were included if they were placebo-controlled trials in design and reported SSRIs' effects on poststroke depression, anxiety, disability, dependence, motor abilities, and cognitive functions. The quality of the included studies was assessed using the revised Cochrane risk-of-bias tool for randomized trials. The search yielded 44 articles that included 16 164 patients, and about half of the participants were treated with SSRIs. Our results showed that SSRIs had a significant effect on preventing depression (weighted mean difference [WMD], -7.05 [95% CI, -11.78 to -2.31]), treating depression according to the Hamilton Rating Scale for Depression score (WMD, -1.45 [95% CI, -2.77 to -0.14]), anxiety (relative risk, 0.23 [95% CI, 0.09-0.61]), dependence (WMD, 8.86 [95% CI, 1.23-16.48]), motor abilities according to National Institutes of Health Stroke Scale score (WMD, -0.79 [95% CI, -1.42 to -0.15]), and cognitive functions (WMD, 1.00 [95% CI, 0.12-1.89]). On the other hand, no significant effect of SSRIs on disability was observed. Additionally, we found that treating with SSRIs increased the risk of seizures (relative risk, 1.44 [95% CI, 1.13-1.83]), whereas there was no difference in the incidence of gastrointestinal symptoms or bleeding between SSRIs and a placebo. Conclusions Our study showed that SSRIs are effective in preventing and treating depression, and improving anxiety, motor function, cognitive function, and dependence in patients after stroke. These benefits were only reproducible with the citalopram subanalysis but not fluoxetine. Further well-conducted placebo-controlled trials are needed to investigate the safety and efficacy of citalopram among patients after stroke. Registration URL: www.crd.york.ac.uk/prospero/; Unique identifier: CRD42021285766.

Objective: The purpose of this study was to update trends, investigate sociodemographic disparities, and evaluate the impact on mortality of stroke neuroimaging across the United States from 2012 to 2019., Methods: Retrospective cohort study using CMS Medicare 5% Research Identifiable Files, representing consecutive ischemic stroke emergency department or hospitalized patients aged ≥65 years. A total of 85,547 stroke episodes with demographic and clinical information were analyzed using Cochran-Mantel-Haenszel tests and logistic regression. Outcome measures were neuroimaging (CT angiography [CTA], CT perfusion [CTP], MRI, MR angiography [MRA]) utilization, acute treatment (endovascular thrombectomy [EVT] and intravenous thrombolysis [IVT]), and mortality while in the hospital and at 30 days and 1 year post discharge., Results: Significantly increasing utilization trends for CTA (250%), CTP (428%) and MRI (18%), and a decreasing trend for MRA (-33%) were observed from 2012 to 2019 (P < .0001). Controlling for covariates in the logistic regression models, CTA and CTP were significantly associated with higher EVT and IVT utilization. Although CTA, MRI, and MRA were associated with lower mortality, CTP was associated with higher mortality post discharge. Less neuroimaging was performed in rural patients; older patients (≥80 years) had lower utilization of CTA, MRI, and MRA; female patients had lower rates of CTA; and Black patients had lower utilization of CTA and CTP., Conclusions: CTA and CTP utilization increased in the Medicare ischemic stroke population from 2012 to 2019 and both were associated with greater EVT and IVT use. However, disparities exist in neuroimaging utilization across all demographic groups, and further understanding of the root causes of these disparities will be crucial to achieving equity in stroke care., (Copyright © 2022 American College of Radiology. Published by Elsevier Inc. All rights reserved.)

There is conflicting information regarding the impact of chronic atrial fibrillation (AF) on the outcomes of thrombolyzed patients with stroke. This study was designed to identify high-risk patients with chronic AF who had undergone thrombolysis treatment and to explore whether the baseline National Institutes of Health Stroke Scale (NIHSS) could be used to distinguish poor clinical outcomes in thrombolyzed patients. A total of 164 acute ischemic stroke patients with chronic AF were enrolled in this study. The patients were categorized as having poor or favorable outcomes. A favorable 90-day outcome was defined as a modified Rankin Scale (mRS) score ≤2. Our study showed that the baseline NIHSS score of patients with poor functional recovery (mRS >2) was significantly higher than that of patients with favorable outcomes (median 16 vs 12). Receiver operating characteristic (ROC) curve analysis of mRS score showed that a baseline NIHSS score of 14 was the optimal threshold for predicting unfavorable outcomes in patients with chronic AF. Multivariate logistic regression analysis showed that baseline NIHSS score >14 was independently associated with poor outcomes (odds ratio = 4.182, 95% confidence interval 2.092-8.361). Our study showed that stroke severity modified the effect of chronic AF on the outcome of thrombolytic therapy. The approach of stratifying stroke severity may be used to evaluate treatment strategies for decision making in intravenous thrombolytic therapy for acute stroke with chronic AF., (Copyright © 2022 the Author(s). Published by Wolters Kluwer Health, Inc.)

Objectives: The NINDS rt-PA Stroke Study is frequently cited in support of alteplase for acute ischemic stroke within 3 h of symptom onset. Multiple post-hoc reanalyses of this trial have been published to adjust for a baseline imbalance in stroke severity. We performed a risk of selection bias assessment and reanalyzed trial data to determine if the etiology of this baseline imbalance was more likely due to random chance or randomization errors., Methods: A risk of selection bias assessment was conducted using signaling questions from the Cochrane Risk of Bias 2 (ROB 2) tool. Four sensitivity analyses were conducted on the trial data based on the randomization process: assessment of imbalances in allocation in unique strata; adherence to a pre-specified restriction on randomization between time strata at each randomization center; assessment of differences in baseline computed tomography (CT) results in unique strata; and comparison of baseline characteristics between allocation groups within each time strata. A multivariable logistic regression model was used to compare reported treatment effects with revised treatment effects after adjustment of baseline imbalances identified in the sensitivity analyses., Results: Based on criteria from the ROB 2 tool, the risk of bias arising from the randomization process was high. Sensitivity analyses found 11 of 16 unique strata deviated from the expected 1:1 allocation ratio. Three randomization centers violated an apriori rule regarding a maximum difference in allocation between the time strata. Three unique strata had imbalances in baseline CT results that prognostically favored alteplase. Four imbalances in baseline characteristics were identified in the 91-180-min time stratum that all prognostically favored alteplase and were consistent with a larger alteplase treatment effect size compared to the 0-90-min time stratum. After adjustments for baseline imbalances, all reported treatment effects were reduced. Three out of seven originally positive reported results were revised to non-significant., Conclusion: This risk of selection bias assessment revealed a high risk of selection bias in the NINDS rt-PA Stroke Study. Sensitivity analyses conducted based on the randomization process supported this assessment. Baseline imbalances in the trial were more likely due to randomization errors than random chance. Adjusted analyses accounting for baseline imbalances revealed a reduction in reported treatment effects supporting the presence of selection bias in the trial. Treatment decisions and guideline recommendations based on the original treatment effect reported in the NINDS rt-PA Stroke Study should be done cautiously., (© 2022. The Author(s).)

Importance: Bayesian adaptive trial design has the potential to create more efficient clinical trials. However, a barrier to the uptake of bayesian adaptive designs for confirmatory trials is limited experience with how they may perform compared with a frequentist design., Objective: To compare the performance of a bayesian and a frequentist adaptive clinical trial design., Design, Setting, and Participants: This prospective cohort study compared 2 trial designs for a completed multicenter acute stroke trial conducted within a National Institutes of Health neurologic emergencies clinical trials network, with individual patient-level data, including the timing and order of enrollments and outcome ascertainment, from 1151 patients with acute stroke and hyperglycemia randomized to receive intensive or standard insulin therapy. The implemented frequentist design had group sequential boundaries for efficacy and futility interim analyses at 90 days after randomization for 500, 700, 900, and 1100 patients. The bayesian alternative used predictive probability of trial success to govern early termination for efficacy and futility with a first interim analysis at 500 randomized patients and subsequent interims after every 100 randomizations., Main Outcomes and Measures: The main outcome was the sample size at end of study, which was defined as the sample size at which each of the studies stopped accrual of patients., Results: Data were collected from 1151 patients. As conducted, the frequentist design passed the futility boundary after 936 participants were randomized. Using the same sequence and timing of randomization and outcome data, the bayesian alternative crossed the futility boundary approximately 3 months earlier after 800 participants were randomized., Conclusions and Relevance: Both trial designs stopped for futility before reaching the planned maximum sample size. In both cases, the clinical community and patients would benefit from learning the answer to the trial's primary question earlier. The common feature across the 2 designs was frequent interim analyses to stop early for efficacy or for futility. Differences between how these analyses were implemented between the 2 trials resulted in the differences in early stopping.

Background: Prior studies have investigated the clinical and imaging factors for hemorrhagic transformation (HT), especially symptomatic intracranial hemorrhage (sICH); however, whether alteplase increases the risk of HT after endovascular thrombectomy (EVT) is unknown. This study aimed to assess clinical and imaging features associated with HT, sICH, and parenchymal hematoma (PH) in patients with acute ischemic stroke after EVT, with and without intravenous alteplase in DIRECT-MT (Direct Intraarterial Thrombectomy to Revascularize Acute Ischemic Stroke Patients with Large Vessel Occlusion Efficiently in Chinese Tertiary Hospitals: a Multicenter Randomized Clinical Trial)., Methods: The DIRECT-MT trial is a randomized trial of EVT alone versus intravenous thrombolysis combined with EVT. HT, sICH, and PH was evaluated on follow-up computed tomography. Multivariable ordinal logistic regression analysis was used to test the association of stepwise selected determinants with HT, sICH, and PH., Results: In total, 633 patients were analyzed; 261 (41.2%) had HT; 34 (5.4%) had sICH; and 85 (13.4%) had PH. The median age was 69, and 56.7% were men. The median National Institutes of Health Stroke Scale score was 18, and 320 patients were in combination-therapy group. Symptomatic intracranial hemorrhage was associated with higher baseline National Institutes of Health Stroke Scale score (adjusted odds ratio [OR], 1.06 [95% CI, 1.10-1.12]) and higher glucose level at hospital arrival (adjusted OR, 1.14 [95% CI, 1.00-1.29]). No association was found between alteplase treatment and HT, sICH, or PH. The independent predictor of sICH was higher baseline National Institutes of Health Stroke Scale score (adjusted OR, 1.09 [95% CI, 1.01-1.18]) in EVT alone group, and history of anticoagulant drugs (adjusted OR, 3.75 [95% CI, 1.07-13.06]), higher glucose level at hospital arrival (adjusted OR, 1.19 [95% CI, 1.03-1.38]), >3 passes of device (adjusted OR, 4.42 [95% CI, 1.36-14.32]) in combination-therapy group., Conclusions: In DIRECT-MT, independent predictors of sICH were baseline National Institutes of Health Stroke Scale score and glucose level at hospital arrival. Alteplase treatment did not increase the risk of HT, sICH, or PH after EVT. The independent predictor of sICH was different in EVT alone group and combination-therapy group., Registration: URL: https://www., Clinicaltrials: gov; Unique identifier: NCT03469206.

Background: The "1-3-6-12-day rule" for starting direct oral anticoagulants (DOACs) in patients with nonvalvular atrial fibrillation after acute ischemic stroke or transient ischemic attack recommends timings that may be later than used in clinical practice. We investigated more practical optimal timing of DOAC initiation according to stroke severity., Methods: The combined data of prospective registries in Japan, Stroke Acute Management with Urgent Risk-factor Assessment and Improvement-nonvalvular atrial fibrillation (September 2011 to March 2014) and RELAXED (February 2014 to April 2016) were used. Patients were divided into transient ischemic attack and 3 stroke subgroups by the National Institutes of Health Stroke Scale score: mild (0-7), moderate (8-15), and severe (≥16). The early treatment group was defined as patients starting DOACs earlier than the median initiation day in each subgroup. Outcomes included a composite of recurrent stroke or systemic embolism, ischemic stroke, and severe bleeding within 90 days. Six European prospective registries were used for validation., Results: In the 1797 derivation cohort patients, DOACs were started at median 2 days after transient ischemic attack and 3, 4, and 5 days after mild, moderate, and severe strokes, respectively. Stroke or systemic embolism was less common in Early Group (n=785)-initiating DOACS within 1, 2, 3, and 4 days, respectively-than Late Group (n=1012) (1.9% versus 3.9%; adjusted hazard ratio, 0.50 [95% CI, 0.27-0.89]), as was ischemic stroke (1.7% versus 3.2%, 0.54 [0.27-0.999]). Major bleeding was similarly common in the 2 groups (0.8% versus 1.0%). On validation, both ischemic stroke (2.4% versus 2.2%) and intracranial hemorrhage (0.2% versus 0.6%) were similarly common in Early (n=547) and Late (n=1483) Groups defined using derivation data., Conclusions: In Japanese and European populations, early DOAC initiation within 1, 2, 3, or 4 days according to stroke severity seemed to be feasible to decrease the risk of recurrent stroke or systemic embolism and no increase in major bleeding. These findings support ongoing randomized trials to better establish the optimal timing of DOAC initiation.

Background: Intracerebral hemorrhage (ICH) is the deadliest form of stroke. In observational studies, lower serum magnesium has been linked to more hematoma expansion (HE) and intracranial hemorrhage, implying that supplemental magnesium sulfate is a potential acute treatment for patients with ICH and could reduce HE. FAST-MAG (Field Administration of Stroke Therapy - Magnesium) was a clinical trial of magnesium sulfate started prehospital in patients with acute stroke within 2 hours of last known well enrolled. CT was not required prior to enrollment, and several hundred patients with acute ICH were enrolled. In this ancillary analysis, we assessed the effect of magnesium sulfate treatment upon HE in patients with acute ICH., Methods: We retrospectively analyzed data that were prospectively collected in the FAST-MAG study. Patients received intravenous magnesium sulfate or matched placebo within 2 hours of onset. We compared HE among patients allocated to intravenous magnesium sulfate or placebo with a Mann-Whitney U . We used the same method to compare neurological deficit severity (National Institutes of Health Stroke Scale) and global disability (modified Rankin Scale) at 3 months., Results: Among 268 patients with ICH meeting study entry criteria, mean 65.4±13/4 years, 33% were female, and 211 (79%) had a history of hypertension. Initial deficit severities were median (interquartile range) of 4 (3-5) on the Los Angeles Motor Scale in the field and National Institutes of Health Stroke Scale score of 16 (9.5-25.5) early after hospital arrival. Follow-up brain imaging was performed a median of 17.1 (11.3-22.7) hours after first scan. The magnesium and placebo groups did not statistically differ in hematoma volume on arrival, 10.1 (5.6-28.7) versus 12.4 (5.6-28.7) mL ( P =0.6), or HE, 2.0 (0.1-7.4) versus 1.5 (-0.2 to 8) mL ( P =0.5). There was no difference in functional outcomes (modified Rankin Scale score of 3-6), 59% versus 50% ( P =0.5)., Conclusions: Magnesium sulfate did not reduce HE or improve functional outcomes at 90 days. A benefit for patients with initial hypomagnesemia was not addressed., Registration: URL: https://www., Clinicaltrials: gov; Unique identifier: NCT00059332.

Background: Non-interventional large-scale research on real-world patients who had a stroke requires the use of multiple data sources ensuring access to longitudinal data from large populations with clinically-detailed information. We sought to establish a framework for longitudinal research on patients hospitalised with stroke by linking information-rich, deidentified inpatient data from the Paul Coverdell National Acute Stroke Program (PCNASP) to commercial and Medicare Advantage longitudinal claims data., Methods: All stroke admissions in PCNASP between 2008 and 2015 were evaluated for linkage to longitudinal claims from a commercial insurer using an algorithm based on six available common data fields (patient age, gender, admission date, discharge date, discharge diagnosis and state) and a hospital match. We evaluated the linkage quality (via the percentage of unique records in the linked dataset) and the representativeness of the linked population. We also described medical history, stroke severity and patterns of medication use among the PCNASP-claims linked cohort., Results: The linkage produced uniqueness equal to 99.1%. We identified 5644 linked and 98 896 unlinked patients who had an ischaemic stroke hospitalisation in claims data. Linked patients were younger than unlinked (69.7 vs 72.5 years), but otherwise similar by medical history, prestroke medication use or lab values. Stroke severity was mild and most patients were discharged home. Prestroke and discharge use of antihypertensive and statins in the PCNASP were greater than their use as measured by filled prescriptions in claims., Conclusions: High-quality linkage between the PCNASP and commercial claims data is feasible. This linkage identified differences between reported or recommended versus actual out-of-hospital medication utilisation, highlighting the importance of longitudinal data availability for research aimed to improve the care of patients who had a stroke., Competing Interests: Competing interests: EP is co-investigator of an investigator-initiated grant to the Brigham and Women’s Hospital from Boehringer-Ingelheim, not related to the topic of the submitted work. SS is the principal investigator of investigator-initiated grants to the Brigham and Women’s Hospital from Bayer, Vertex, and Boehringer Ingelheim unrelated to the topic of this study. He is a consultant to WHISCON and to Aetion, a software manufacturer of which he owns equity. His interests were declared, reviewed, and approved by the Brigham and Women’s Hospital and Partners HealthCare System in accordance with their institutional compliance policies. LHS is principal investigator of NIH-NINDS grants (U24NS107243), co-investigator of other grants (PCORI R-1609-35995, NIH-NINDS R01NS111952, NIH R01AG062770), and reports the following relationships relevant to research grants or companies that manufacture products for thrombolysis or thrombectomy even if the interaction involves non-thrombolysis products: scientific consultant regarding trial design and conduct to Genentech (late window thrombolysis) and Member of steering committee (TIMELESS NCT03785678); consultant on user interface design and usability to LifeImage; stroke systems of care consultant to the Massachusetts Dept of Public Health; member of a Data Safety Monitoring Boards (DSMB) for Penumbra (MIND NCT03342664); Serving as National PI for Medtronic (Stroke AF NCT02700945); National Co-PI, late window thrombolysis trial, NINDS (P50NS051343, MR WITNESS NCT01282242. LMVRM reports is principal investigator of a NIH-NIA grant (5K08AG053380-02), principal investigator of an investigator-initiated grant sponsored by the Epilepsy Foundation of America (60300-EFA-PCO-000-19-01), co-principal investigator of a CDC grant (SIP 20-007), co-investigator of other grants (NIH-NIA 5R01AG062282-02, NIH-NIA 2P01AG032952-11, NIH- NIA 3R01AG062282-03S1), and reports no conflict of interest., (© 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.)