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Background and purpose: In this pooled analysis of seven multicentre cohorts potential differences were investigated in the incidence, characteristics and outcomes between intracranial haemorrhages (ICHs) associated with the use of non‐vitamin K antagonist oral anticoagulants (NOAC‐ICH) or with vitamin K antagonists (VKA‐ICH) in ischaemic stroke patients after oral anticoagulant treatment initiation for atrial fibrillation (AF). Methods: Data from 4912 eligible AF patients who were admitted in a stroke unit with ischaemic stroke or transient ischaemic attack and who were treated with either VKAs or NOACs within 3 months post‐stroke were included. Fatal ICH was defined as death occurring during the first 30 days after ICH onset. A meta‐analysis of available observational studies reporting 30‐day mortality rates from NOAC‐ICH or VKA‐ICH onset was additionally performed. Results: During 5970 patient‐years of follow‐up 71 participants had an ICH, of whom 20 were NOAC‐ICH and 51 VKA‐ICH. Patients in the two groups had comparable baseline characteristics, except for the higher prevalence of kidney disease in VKA‐ICH patients. There was a non‐significant higher number of fatal ICH in patients with VKAs (11 events per 3385 patient‐years) than in those with NOACs (three events per 2623 patient‐years; hazard ratio 0.32, 95% confidence interval 0.09–1.14). Three‐month functional outcomes were similar (P > 0.2) in the two groups. The meta‐analysis showed a lower 30‐day mortality risk for patients with NOAC‐ICH compared to VKA‐ICH (relative risk 0.70, 95% confidence interval 0.51–0.95). Conclusions: Non‐vitamin K oral anticoagulants for intracranial haemorrhages and VKA‐ICH occurring during secondary stroke prevention of AF patients have comparable baseline characteristics and outcomes except for the risk of fatal ICH within 30 days, which might be greater in VKA‐ICH. [ABSTRACT FROM AUTHOR]

BACKGROUND Cryptogenic strokes constitute 20 to 30% of ischemic strokes, and most cryptogenic strokes are considered to be embolic and of undetermined source. An earlier randomized trial showed that rivaroxaban is no more effective than aspirin in preventing recurrent stroke after a presumed embolic stroke from an undetermined source. Whether dabigatran would be effective in preventing recurrent strokes after this type of stroke was unclear. METHODS We conducted a multicenter, randomized, double-blind trial of dabigatran at a dose of 150 mg or 110 mg twice daily as compared with aspirin at a dose of 100 mg once daily in patients who had had an embolic stroke of undetermined source. The primary outcome was recurrent stroke. The primary safety outcome was major bleeding. RESULTS A total of 5390 patients were enrolled at 564 sites and were randomly assigned to receive dabigatran (2695 patients) or aspirin (2695 patients). During a median follow-up of 19 months, recurrent strokes occurred in 177 patients (6.6%) in the dabigatran group (4.1% per year) and in 207 patients (7.7%) in the aspirin group (4.8% per year) (hazard ratio, 0.85; 95% confidence interval [CI], 0.69 to 1.03; P=0.10). Ischemic strokes occurred in 172 patients (4.0% per year) and 203 patients (4.7% per year), respectively (hazard ratio, 0.84; 95% CI, 0.68 to 1.03). Major bleeding occurred in 77 patients (1.7% per year) in the dabigatran group and in 64 patients (1.4% per year) in the aspirin group (hazard ratio, 1.19; 95% CI, 0.85 to 1.66). Clinically relevant nonmajor bleeding occurred in 70 patients (1.6% per year) and 41 patients (0.9% per year), respectively. CONCLUSIONS In patients with a recent history of embolic stroke of undetermined source, dabigatran was not superior to aspirin in preventing recurrent stroke. The incidence of major bleeding was not greater in the dabigatran group than in the aspirin group, but there were more clinically relevant nonmajor bleeding events in the dabigatran group. [ABSTRACT FROM AUTHOR]

Importance: Patients with atrial fibrillation (AF) who have ischemic stroke despite taking oral anticoagulation therapy (OAT) have a very high risk of recurrence. Left atrial appendage occlusion (LAAO) is a mechanical stroke prevention strategy that may provide additional protection in patients with thromboembolic events under OAT., Objective: To compare percutaneous LAAO with continuing OAT alone regarding stroke prevention in patients with AF who had a thromboembolic event despite taking OAT., Design, Setting, and Participants: This cohort study was a propensity score-matched comparison of the STR-OAC LAAO cohort, an international collaboration of 21 sites combining patients from multiple prospective registries of patients who underwent LAAO between 2010 and 2022. STR-OAC LAAO cohort patients who had follow-up longer than 3 months were propensity score-matched to a previously published control cohort comprising patients from an established international collaboration of investigator-initiated prospective studies. This control cohort included patients with nonvalvular AF, recent ischemic stroke or transient ischemic attack, and follow-up longer than 3 months who were taking OAT before the index event. Analyses were adjusted for imbalances in gender, age, hypertension, diabetes, and CHA2 DS2-VASc score., Exposure: Left atrial appendage occlusion vs continuation of oral anticoagulation therapy alone (control group)., Main Outcomes and Measures: The primary outcome was time to first ischemic stroke., Results: Four hundred thirty-three patients from the STR-OAC LAAO cohort (mean [SD] age, 72 [9] years; 171 [39%] females and 262 [61%] males; mean [SD] CHA2 DS2-VASc score, 5.0 [1.6]) were matched to 433 of 1140 patients (38%) from the control group. During 2-year follow-up, 50 patients experienced ischemic stroke: an annualized event rate of 2.8% per patient-year in the STR-OAC LAAO group vs 8.9% per patient-year in the control group. Left atrial appendage occlusion was associated with a lower risk of ischemic stroke (hazard ratio, 0.33; 95% CI, 0.19-0.58; P < .001) compared with the control group. After LAAO, OAT was discontinued in 290 patients (67%), and the remaining 143 patients (33%) continued OAT after LAAO as an adjunctive therapy., Conclusions and Relevance: In patients with nonvalvular AF and a prior thromboembolic event despite taking OAT, LAAO was associated with a lower risk of ischemic stroke compared with continued OAT alone. Randomized clinical trial data are needed to confirm that LAAO may be a promising treatment option for this population with a very high risk of stroke.

Introduction: IV thrombolysis (IVT) is established in the unknown or extended time window based on multimodal imaging. Further, increasing evidence exists regarding IVT in patients on oral anticoagulation including direct oral anticoagulants (DOACs). However, data on IVT in ischemic stroke patients on oral anticoagulation with unknown time of stroke onset are sparse., Methods: This study bases on the longitudinal cohort study Stroke Research Consortium in Northern Bavaria (STAMINA; ClinicalTrials.gov Identifier: NCT04357899). Acute ischemic stroke patients treated with IVT in the unknown or extended time window from January 2015 to December 2019 were included. Patient selection was based on multimodal CT or MRI. Patients on oral anticoagulation (vitamin-K antagonist [VKA] or DOAC within 48 h) were eligible for IVT based on INR measurement (VKA) or plasma levels (DOAC) according to an institutional protocol. Primary outcomes were the incidence of any and symptomatic intracranial hemorrhage., Results: Of 170 ischemic stroke patients treated with IVT in the unknown or extended time window, 151 had no oral anticoagulation at stroke onset and 19 were on oral anticoagulation (6 on VKA and 13 on DOAC). The risk of symptomatic ICH according to ECASS II criteria was similar between the patients with and without oral anticoagulation (1 [5.3%] vs. 4 [2.7%], p = 0.453). After adjustment for confounding factors, pre-medication with oral anticoagulation was not associated with symptomatic ICH (aOR 1.02 [0.09-11.02], p = 0.988)., Conclusion: IVT for ischemic stroke with unknown onset appeared safe in selected patients on oral anticoagulation with both DOAC and VKA., (© 2024 S. Karger AG, Basel.)

Background and Aims: General guideline recommendations in patients with intracerebral hemorrhage (ICH) include blood pressure-, temperature- and glucose management. The therapeutic effect of such a "care bundle" (blood pressure lowering, glycemic control, and treatment of pyrexia) on clinical outcomes becomes increasingly established. For the present study, we aimed to investigate associations of strict bundled care treatment (BCT) with clinical outcomes and characterize associations with key outcome effectors such as hematoma enlargement (HE) and peak perihemorrhagic edema (PHE)., Methods: We screened consecutive ICH patients ( n  = 1,322) from the prospective UKER-ICH cohort study. BCT was defined as achieving and maintaining therapeutic ranges for systolic blood pressure (110-160 mmHg), glucose (80-180 mg/dL), and body temperature (35.5-37.5°C) over the first 72 h. The primary outcome was the functional outcome at 12 months (modified Rankin Scale (mRS) 0-3). Secondary outcomes included mortality at 12 months, the occurrence of hematoma enlargement, and the development of peak perihemorrhagic edema. Confounding was addressed by a doubly robust methodology to calculate the absolute treatment effect (ATE) and by calculating e-values., Results: A total of 681 patients remained for analysis, and 182 patients fulfilled all three BCT criteria and were compared to 499 controls. The ATE of BCT to achieve the primary outcome was 9.3%, 95% CI (1.7 to 16.9), p  < 0.001; e-value: 3.1, CI (1.8). Mortality at 12 months was significantly reduced by BCT [ATE: -12.8%, 95% CI (-19.8 to -5.7), p  < 0.001; e-value: 3.8, CI (2.2)], and no association was observed for HE or peak PHE. Significant drivers of BCT effect on the primary outcome were systolic blood pressure control (ATE: 15.9%) and maintenance of normothermia (ATE: 10.9%)., Conclusion: Strict adherence to this "care bundle" over the first 72 h during acute hospital care in patients with ICH was independently associated with improved functional long-term outcome, driven by systolic blood pressure control and maintenance of normothermia. Our findings strongly warrant prospective validation to determine the generalizability especially in Western countries. Clinical trial registration: ClinicalTrials.gov, identifier [ID: NCT03183167]., Competing Interests: AM reports personal fees from Alexion Pharma Germany GmbH, outside the submitted work. BV reports personal fees from Pfizer AG/Bristol-Myers Squibb SA, personal fees from Bayer AG, grants from Institutional grant (Inselspital), personal fees from Ipsen Pharma, personal fees from CSL Behring, outside the submitted work. JK reports personal fees from Beohringer Ingelheim, personal fees from Biogen, personal fees from Boston Scientific, personal fees from Sanofi, personal fees from Bayer AG, personal fees from Alexion, outside the submitted work. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Mrochen, Song, Harders, Sembill, Sprügel, Hock, Lang, Engelhorn, Kallmünzer, Volbers and Kuramatsu.)

Background: Endovascular thrombectomy (EVT) has been proven effective in anterior circulation stroke due to large vessel occlusion (LVO). However, translation from randomized clinical trials (RCTs) with highly selected patients to real-world requires confirmation, particularly to identify associations outside of strict selection criteria., Aims: This study aims to compare functional outcomes after EVT in real-world with those reported in RCTs, and to identify associations with functional outcome after EVT outside RCT-criteria., Methods: This study analyzed longitudinal German real-world data from the Stroke Research Consortium in Northern Bavaria (STAMINA) cohort from January, 2015 to June, 2019. We conducted a trial emulation, comparing patients with anterior circulation stroke and LVO meeting selection criteria for RCTs investigating EVT (1) predominantly within 6 hours with those from HERMES meta-analysis, and (2) within 6-24 hours with those from AURORA meta-analysis. We (3) analyzed treatment effects of EVT and association with functional outcome in patients treated outside RCT criteria., Results: Of 598 patients, 281 (47.0%) met RCT-criteria for treatment within 6 hours (hereinafter STAMINA-HERMES), 74 (12.4%) met RCT-criteria for treatment within 6-24 hours (STAMINA-AURORA), and 277 (46.3%) patients received EVT outside RCT-criteria. We observed no difference in rates of functional independence or mortality, comparing STAMINA-HERMES with HERMES meta-analysis (mRS 0-1: n=120/281 [43%] vs. 291/633 [46%], p=0.36; mortality: n=34/281 [12%] vs. 97/633 [15%], p=0.20), and STAMINA-AURORA with AURORA meta-analysis (mRS 0-1: n=26/74 [35%] vs. 122/266 [46%], p=0.10, mortality: n=10/74 [14%] vs. 45/266 [17%], p=0.48). Patients treated outside RCT-criteria had worse outcome (mRS 0-1: n=38/277 [14%], mortality: n=90/277 [32%], both p<0.001); possibly driven by pre-existing functional dependence (n=172/277 [62%]). Compared to matched controls, EVT outside of RCT-criteria was associated with lower mortality (absolute treatment effect: -14%, 95% Confidence Interval [CI] -23 to -5, p<0.01), but not with recovery to functional independence or premorbid functional status (treatment effect: 4%, CI -4 to 11, p=0.34), which was associated with lower NIHSS (Odds ratio [OR] 0.86, CI 0.80-0.92, p<0.001) and age (OR 0.95, CI 0.93-0.98, p=0.002)., Conclusions: Translation of EVT outcomes reported in RCTs into real-world is possible, however, almost half of patients did not meet trial criteria. Identification of patients who functionally benefit from frequently performed EVT outside RCT-criteria requires further investigation., Trial Registration: Clinicaltrials.gov, NCT04357899., (© 2024. The Author(s).)

Background: Patients with acute intracerebral hemorrhage who are receiving factor Xa inhibitors have a risk of hematoma expansion. The effect of andexanet alfa, an agent that reverses the effects of factor Xa inhibitors, on hematoma volume expansion has not been well studied., Methods: We randomly assigned, in a 1:1 ratio, patients who had taken factor Xa inhibitors within 15 hours before having an acute intracerebral hemorrhage to receive andexanet or usual care. The primary end point was hemostatic efficacy, defined by expansion of the hematoma volume by 35% or less at 12 hours after baseline, an increase in the score on the National Institutes of Health Stroke Scale of less than 7 points (scores range from 0 to 42, with higher scores indicating worse neurologic deficit) at 12 hours, and no receipt of rescue therapy between 3 hours and 12 hours. Safety end points were thrombotic events and death., Results: A total of 263 patients were assigned to receive andexanet, and 267 to receive usual care. Efficacy was assessed in an interim analysis that included 452 patients, and safety was analyzed in all 530 enrolled patients. Atrial fibrillation was the most common indication for factor Xa inhibitors. Of the patients receiving usual care, 85.5% received prothrombin complex concentrate. Hemostatic efficacy was achieved in 150 of 224 patients (67.0%) receiving andexanet and in 121 of 228 (53.1%) receiving usual care (adjusted difference, 13.4 percentage points; 95% confidence interval [CI], 4.6 to 22.2; P = 0.003). The median reduction from baseline to the 1-to-2-hour nadir in anti-factor Xa activity was 94.5% with andexanet and 26.9% with usual care (P<0.001). Thrombotic events occurred in 27 of 263 patients (10.3%) receiving andexanet and in 15 of 267 (5.6%) receiving usual care (difference, 4.6 percentage points; 95% CI, 0.1 to 9.2; P = 0.048); ischemic stroke occurred in 17 patients (6.5%) and 4 patients (1.5%), respectively. There were no appreciable differences between the groups in the score on the modified Rankin scale or in death within 30 days., Conclusions: Among patients with intracerebral hemorrhage who were receiving factor Xa inhibitors, andexanet resulted in better control of hematoma expansion than usual care but was associated with thrombotic events, including ischemic stroke. (Funded by Alexion AstraZeneca Rare Disease and others; ANNEXA-I ClinicalTrials.gov number, NCT03661528.)., (Copyright © 2024 Massachusetts Medical Society.)

Background: Data on impact of COVID-19 vaccination and outcomes of patients with COVID-19 and acute ischemic stroke undergoing mechanical thrombectomy are scarce. Addressing this subject, we report our multicenter experience., Methods and Results: This was a retrospective analysis of patients with COVID-19 and known vaccination status treated with mechanical thrombectomy for acute ischemic stroke at 20 tertiary care centers between January 2020 and January 2023. Baseline demographics, angiographic outcome, and clinical outcome evaluated by the modified Rankin Scale score at discharge were noted. A multivariate analysis was conducted to test whether these variables were associated with an unfavorable outcome, defined as modified Rankin Scale score >3. A total of 137 patients with acute ischemic stroke (48 vaccinated and 89 unvaccinated) with acute or subsided COVID-19 infection who underwent mechanical thrombectomy attributable to vessel occlusion were included in the study. Angiographic outcomes between vaccinated and unvaccinated patients were similar (modified Thrombolysis in Cerebral Infarction ≥2b: 85.4% in vaccinated patients versus 86.5% in unvaccinated patients; P =0.859). The rate of functional independence (modified Rankin Scale score, ≤2) was 23.3% in the vaccinated group and 20.9% in the unvaccinated group ( P =0.763). The mortality rate was 30% in both groups. In the multivariable analysis, vaccination status was not a significant predictor for an unfavorable outcome ( P =0.957). However, acute COVID-19 infection remained significant (odds ratio, 1.197 [95% CI, 1.007-1.417]; P =0.041)., Conclusions: Our study demonstrated no impact of COVID-19 vaccination on angiographic or clinical outcome of COVID-19-positive patients with acute ischemic stroke undergoing mechanical thrombectomy, whereas worsening attributable to COVID-19 was confirmed.

Telestroke networks aim to improve acute stroke care within their catchment area. Through a teleconsultation service, the network centers provide support to network hospitals that lack continuous neurological expertise for acute stroke management decisions. Although the importance of telemedical treatment in stroke care is steadily increasing, so far no standards exist for the organization of the teleconsultation service in networks.To ensure a high-level of quality for all processes and measures concerning telemedical stroke treatment, the commission for telemedical stroke care of the German Stroke Society (Deutsche Schlaganfall-Gesellschaft, DSG) created the following recommendations on how to organize a teleconsultation service within a telestroke network. The recommendations are the result of an adjustment process between the authors and include guidance on requirements, qualifications, processes and quality management within the teleconsultation service., (© 2024. The Author(s).)

Objective: Hematoma expansion (HE) is the most important therapeutic target during acute care of patients with intracerebral hemorrhage (ICH). Imaging biomarkers such as non-contrast CT (NCCT) markers have been associated with increasing risk for HE. The aim of the present study was to evaluate the influence of NCCT markers with functional long-term outcome and with HE in patients with deep (basal ganglia and thalamus) ICH who represent an important subgroup of patients at the highest risk for functional deterioration with HE due to the eloquence of the affected brain region., Methods: From our prospective institutional database, all patients maximally treated with deep ICH were included and retrospectively analyzed. NCCT markers were recorded at diagnostic imaging, ICH volume characteristics were volumetrically evaluated, and all patients received follow-up imaging within 0-48 h. We explored associations of NCCT makers with unfavorable functional outcome, defined as modified Rankin scale 4-6, after 12 months and with HE. Bias and confounding were addressed by multivariable regression modeling., Results: In 322 patients with deep ICH, NCCT markers were distributed as follows: irregular shape: 69.6%, heterogenous density: 55.9%, hypodensities: 52.5%, island sign: 19.3%, black hole sign: 11.5%, and blend sign: 4.7%. Upon multivariable regression analyses, independent associations were documented with the functional outcome for irregular shape (aOR: 2.73, 95%CI: 1.42-5.22, p  = 0.002), heterogenous density (aOR: 2.62, 95%CI: 1.40-4.90, p  = 0.003) and island sign (aOR: 2.54, 95%CI: 1.05-6.14, p  = 0.038), and with HE for heterogenous density (aOR: 5.01, 95%CI: 1.93-13.05, p  = 0.001) and hypodensities (aOR: 3.75, 95%CI: 1.63-8.62, p  = 0.002)., Conclusion: NCCT markers are frequent in deep ICH patients and provide important clinical implications. Specifically, markers defined by diverging intra-hematomal densities provided associations with a 5-times higher risk for HE and a 2.5-times higher likelihood for unfavorable functional long-term outcome. Hence, these markers allow the identification of patients with deep ICH at high risk for clinical deterioration due to HE., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. JK declared that he was an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Kölbl, Hock, Xu, Sembill, Mrochen, Balk, Lang, Volbers, Engelhorn, Kallmünzer and Kuramatsu.)

Background: Atrial fibrillation (AF) is one of the most frequent causes of stroke. Several randomized trials have shown that prolonged monitoring increases the detection of AF, but the effect on reducing recurrent cardioembolism, ie, ischemic stroke and systemic embolism, remains unknown. We aim to evaluate whether a risk-adapted, intensified heart rhythm monitoring with consequent guideline conform treatment, which implies initiation of oral anticoagulation (OAC), leads to a reduction of recurrent cardioembolism., Methods: Find-AF 2 is a randomized, controlled, open-label parallel multicenter trial with blinded endpoint assessment. 5,200 patients ≥ 60 years of age with symptomatic ischemic stroke within the last 30 days and without known AF will be included at 52 study centers with a specialized stroke unit in Germany. Patients without AF in an additional 24-hour Holter ECG after the qualifying event will be randomized in a 1:1 fashion to either enhanced, prolonged and intensified ECG-monitoring (intervention arm) or standard of care monitoring (control arm). In the intervention arm, patients with a high risk of underlying AF will receive continuous rhythm monitoring using an implantable cardiac monitor (ICM) whereas those without high risk of underlying AF will receive repeated 7-day Holter ECGs. The duration of rhythm monitoring within the control arm is up to the discretion of the participating centers and is allowed for up to 7 days. Patients will be followed for at least 24 months. The primary efficacy endpoint is the time until recurrent ischemic stroke or systemic embolism occur., Conclusions: The Find-AF 2 trial aims to demonstrate that enhanced, prolonged and intensified rhythm monitoring results in a more effective prevention of recurrent ischemic stroke and systemic embolism compared to usual care., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Introduction: Therapeutic hypothermia is a promising candidate for stroke treatment although its efficacy has not yet been demonstrated in patients. Changes in blood molecules could act as surrogate markers to evaluate the efficacy and safety of therapeutic cooling., Methods: Blood samples from 54 patients included in the EuroHYP-1 study (27 treated with hypothermia, and 27 controls) were obtained at baseline, 24 ± 2 h, and 72 ± 4 h. The levels of a panel of 27 biomarkers, including matrix metalloproteinases and cardiac and inflammatory markers, were measured., Results: Metalloproteinase-3 (MMP-3), fatty-acid-binding protein (FABP), and interleukin-8 (IL-8) increased over time in relation to the hypothermia treatment. Statistically significant correlations between the minimum temperature achieved by each patient in the hypothermia group and the MMP-3 level measured at 72 h, FABP level measured at 24 h, and IL-8 levels measured at 24 and 72 h were found. No differential biomarker levels were observed in patients with poor or favorable outcomes according to modified Rankin Scale scores., Conclusion: Although the exact roles of MMP3, FABP, and IL-8 in hypothermia-treated stroke patients are not known, further exploration is needed to confirm their roles in brain ischemia., (© 2023 The Authors. Brain and Behavior published by Wiley Periodicals LLC.)

Introduction: Myocardial injury related to acute ischaemic stroke is common even without primary cardiac disease. We intended to determine associations between values of left ventricular ejection fraction (LVEF) and ischaemic stroke lesion sites., Methods: Of a local database, patients with acute first-ever ischaemic stroke confirmed by brain imaging but without pre-existing heart disease were included. The cardiac morphology and LVEF were obtained from transthoracic or transesophageal echocardiography, and impaired LVEF was categorised as mild (35%-50%), moderate (34%-25%) and severe (<25%). Patient age, stroke severity, ischaemic lesion volume, prevalence of troponin I increase (>0.1 ng/mL), atrial fibrillation and cardiac wall motion abnormalities were assessed and compared between patients with and without impaired LVEF after stroke (significance: p<0.05). A multivariate voxelwise lesion analysis correlated LVEF after stroke with sites of ischaemic lesions., Results: Of 1209 patients who had a stroke, 231 (mean age 66.3±14.0 years) met the inclusion criteria; 40 patients (17.3%) had an impaired LVEF after stroke. Patients with impaired LVEF had higher infarct volumes (53.8 mL vs 30.0 mL, p=0.042), a higher prevalence of troponin increase (17.5% vs 4.2%, p=0.006), cardiac wall motion abnormalities (42.5% vs 5.2%, p<0.001) and atrial fibrillation (60.0% vs 26.2%, p<0.001) than patients with LVEF of >50%. The multivariate voxelwise lesion analysis yielded associations between decreased LVEF and damaged voxels in the insula, amygdala and operculum of the right hemisphere., Conclusion: Our imaging analysis unveils a prominent role of the right hemispheric central autonomic network, especially of the insular cortex, in the brain-heart axis. Our results support preliminary evidence that acute ischaemic stroke in distinct brain regions of the central autonomic network may directly impair cardiac function and thus further supports the concept of a distinct stroke-heart syndrome., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Atrial fibrillation (AF) known before ischemic stroke (KAF) has been postulated to be an independent category with a recurrence risk higher than that of AF detected after stroke (AFDAS). However, it is unknown whether this risk difference is confounded by pre-existing anticoagulation, which is most common in KAF and also indicates a high ischemic stroke recurrence risk., Methods: Individual patient data analysis from 5 prospective cohorts of anticoagulated patients following AF-associated ischemic stroke. We compared the primary (ischemic stroke recurrence) and secondary outcome (all-cause death) among patients with AFDAS versus KAF and among anticoagulation-naïve versus previously anticoagulated patients using multivariable Cox, Fine-Gray models, and goodness-of-fit statistics to investigate the relative independent prognostic importance of AF-category and pre-existing anticoagulation., Results: Of 4,357 patients, 1,889 (43%) had AFDAS and 2,468 (57%) had KAF, while 3,105 (71%) were anticoagulation-naïve before stroke and 1,252 (29%) were previously anticoagulated. During 6,071 patient-years of follow-up, we observed 244 recurrent strokes and 661 deaths. Only pre-existing anticoagulation (but not KAF) was independently associated with a higher hazard for stroke recurrence in both Cox and Fine-Gray models. Models incorporating pre-existing anticoagulation showed better fit than those with AF category; adding AF-category did not result in better model fit. Neither pre-existing anticoagulation nor KAF were independently associated with death., Conclusion: Our findings challenge the notion that KAF and AFDAS are clinically relevant and distinct prognostic entities. Instead of attributing an independently high stroke recurrence risk to KAF, future research should focus on the causes of stroke despite anticoagulation to develop improved preventive treatments. ANN NEUROL 2023;94:43-54., (© 2023 The Authors. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Importance: International guidelines recommend avoiding intravenous thrombolysis (IVT) in patients with ischemic stroke who have a recent intake of a direct oral anticoagulant (DOAC)., Objective: To determine the risk of symptomatic intracranial hemorrhage (sICH) associated with use of IVT in patients with recent DOAC ingestion., Design, Setting, and Participants: This international, multicenter, retrospective cohort study included 64 primary and comprehensive stroke centers across Europe, Asia, Australia, and New Zealand. Consecutive adult patients with ischemic stroke who received IVT (both with and without thrombectomy) were included. Patients whose last known DOAC ingestion was more than 48 hours before stroke onset were excluded. A total of 832 patients with recent DOAC use were compared with 32 375 controls without recent DOAC use. Data were collected from January 2008 to December 2021., Exposures: Prior DOAC therapy (confirmed last ingestion within 48 hours prior to IVT) compared with no prior oral anticoagulation., Main Outcomes and Measures: The main outcome was sICH within 36 hours after IVT, defined as worsening of at least 4 points on the National Institutes of Health Stroke Scale and attributed to radiologically evident intracranial hemorrhage. Outcomes were compared according to different selection strategies (DOAC-level measurements, DOAC reversal treatment, IVT with neither DOAC-level measurement nor idarucizumab). The association of sICH with DOAC plasma levels and very recent ingestions was explored in sensitivity analyses., Results: Of 33 207 included patients, 14 458 (43.5%) were female, and the median (IQR) age was 73 (62-80) years. The median (IQR) National Institutes of Health Stroke Scale score was 9 (5-16). Of the 832 patients taking DOAC, 252 (30.3%) received DOAC reversal before IVT (all idarucizumab), 225 (27.0%) had DOAC-level measurements, and 355 (42.7%) received IVT without measuring DOAC plasma levels or reversal treatment. The unadjusted rate of sICH was 2.5% (95% CI, 1.6-3.8) in patients taking DOACs compared with 4.1% (95% CI, 3.9-4.4) in control patients using no anticoagulants. Recent DOAC ingestion was associated with lower odds of sICH after IVT compared with no anticoagulation (adjusted odds ratio, 0.57; 95% CI, 0.36-0.92). This finding was consistent among the different selection strategies and in sensitivity analyses of patients with detectable plasma levels or very recent ingestion., Conclusions and Relevance: In this study, there was insufficient evidence of excess harm associated with off-label IVT in selected patients after ischemic stroke with recent DOAC ingestion.

Background: Stroke may compromise cardiovascular-autonomic modulation (CAM). The longitudinal post-stroke CAM alterations remain unclear as previous studies excluded patients with cardiovascular medication. This study evaluated whether CAM dysfunction improves after several months in patients under typical clinical conditions, i.e., without excluding patients with cardiovascular medication., Methods: In 82 ischemic stroke patients [33 women, 64.9 ± 8.9 years, NIHSS-scores 2 (interquartile range 1-5)], we evaluated the applications of cardiovascular medication before stroke, during autonomic tests performed within 1 week, 3 and 6 months after stroke onset. We determined resting RR intervals (RRI), systolic, diastolic blood pressures (BPsys), respiration, parameters reflecting total CAM [RRI-standard deviation (RRI-SD), RRI-total powers], sympathetic [RRI-low-frequency powers (RRI-LF), BPsys-LF powers] and parasympathetic CAM [RMSSD, RRI-high-frequency powers (RRI-HF powers)], and baroreflex sensitivity. ANOVA or Friedman tests with post hoc analyses compared patient data with data of 30 healthy controls, significance was assumed for P < 0.05., Results: More patients had antihypertensive medication after than before stroke. First-week CAM testing showed lower RRIs, RMSSD, RRI-SDs, RRI-total powers, RRI-HF powers, and baroreflex sensitivity, but higher BPsys-LF powers in patients than controls. After 3 and 6 months, patients had significantly higher RRIs, RRI-SDs, RRI-total powers, RMSSDs, RRI-HF powers, and baroreflex sensitivity, but lower BPsys-LF powers than in the 1st week; RMSSDs and RRI-HF powers no longer differed between patients and controls. However, 6-month values of RRIs, RRI-SDs, and baroreflex sensitivity were again lower in patients than controls., Conclusions: Even mild strokes compromised cardiovagal modulation and baroreflex sensitivity. After 3 months, CAM had almost completely recovered. Recovery might be related to the mild stroke severity. Presumably, CAM recovery was also promoted by the increased application of cardiovascular medication. Yet, slight CAM dysfunction after 6 months suggests continuing autonomic vulnerability., (© 2022. The Author(s).)

Background: Data on the frequency and outcome of mechanical thrombectomy (MT) for large vessel occlusion (LVO) in patients with COVID-19 is limited. Addressing this subject, we report our multicenter experience., Methods: A retrospective cohort study was performed of consecutive acute stroke patients with COVID-19 infection treated with MT at 26 tertiary care centers between January 2020 and November 2021. Baseline demographics, angiographic outcome and clinical outcome evaluated by the modified Rankin Scale (mRS) at discharge and 90 days were noted., Results: We identified 111 out of 11 365 (1%) patients with acute or subsided COVID-19 infection who underwent MT due to LVO. Cardioembolic events were the most common etiology for LVO (38.7%). Median baseline National Institutes of Health Stroke Scale score and Alberta Stroke Program Early CT Score were 16 (IQR 11.5-20) and 9 (IQR 7-10), respectively. Successful reperfusion (mTICI ≥2b) was achieved in 97/111 (87.4%) patients and 46/111 (41.4%) patients were reperfused completely. The procedure-related complication rate was 12.6% (14/111). Functional independence was achieved in 20/108 (18.5%) patients at discharge and 14/66 (21.2%) at 90 days follow-up. The in-hospital mortality rate was 30.6% (33/108). In the subgroup analysis, patients with severe acute COVID-19 infection requiring intubation had a mortality rate twice as high as patients with mild or moderate acute COVID-19 infection. Acute respiratory failure requiring ventilation and time interval from symptom onset to groin puncture were independent predictors for an unfavorable outcome in a logistic regression analysis., Conclusion: Our study showed a poor clinical outcome and high mortality, especially in patients with severe acute COVID-19 infection undergoing MT due to LVO., Competing Interests: Competing interests: MM: Grants or contracts from Balt, Medtronic, MircroVention and Stryker. FD: Consultant for Balt, Cerus Endovascular, Phenox and Cerenovus, honoraria for lectures from Cerenovus, Acandis and Asahi, support for attending meetings from MicroVention, Acandis and Cerus Endovascular, advisory board member for Cerenovus/Johnson & Johnson, associate editor for Journal of NeuroInterventional Surgery. MG: Grants or contracts from Else Kröner Fresenius Stiftung, payment of honoraria for lectures from Phenox, proctoring contract with MircroVention, participation on clinical event committee from MicroVention, chair of ESMINT Examination Committee, received stents from Phenox for research purposes. DK: Grants or contracts from Else Kröner Fresenius Center of Digital Health and Joachim Herz Foundation, spokesman of the “Junge Neuroradiologie” in the German Society of Neuroradiology. CL: Consulting fees, payment of honoraria for lectures and support for attending meetings from Phenox, Penumbra and Acandis. MW: Grants from ab medica, Acandis, Bracco Imaging, Cerenovus, Kaneka Pharmaceuticals, Medtronic, Mentice AB, Microvention, Phenox, Siemens Healthcare and Stryker Neurovascular; Consulting fees from Stryker Healthcare; Payment honoraria for lectures from Stryker Neurovascular. The other authors declare no specific conflict of interest., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Background and Purpose: Ischemic stroke may induce cardiovascular autonomic dysfunction, but most previous studies have included patients with anterior circulation ischemic stroke or brainstem stroke. It remains unclear whether posterior circulation ischemic stroke (PCIS) without brainstem involvement also compromises cardiovascular autonomic modulation (CAM). Therefore, we aimed to assess CAM in PCIS patients with and without brainstem involvement., Methods: In four subgroups of 61 PCIS patients (14 occipital lobe, 16 thalamic, 12 cerebellar, and 19 brainstem strokes) and 30 healthy controls, we recorded RR intervals (RRIs), systolic (SBP) and diastolic blood pressure (DBP), and respiration at supine rest during the first week after stroke onset. We calculated parameters reflecting total CAM (RRI-standard deviation [RRI-SD], RRI-total powers), predominantly sympathetic CAM (RRI-low-frequency [LF] powers and SBP-LF powers] and parasympathetic CAM (root mean square of successive RRI differences [RMSSD], RRI-high-frequency [HF] powers), sympathetic-parasympathetic balance (RRI-LF/HF ratios), and baroreflex sensitivity (BRS). Values were compared among the four PCIS groups and controls using one-way ANOVA Kruskal-Wallis tests, with post-hoc analyses. Significance was assumed for p &lt; 0.05., Results: In each PCIS subgroup, values for RRI, RRI-SD, RMSSD, RRI-HF powers, and BRS were significantly lower, while SBP-LF powers were higher than in the controls. Only in patients with occipital lobe stroke were RRI-LF/HF ratios significantly higher than in controls. Otherwise, autonomic variables did not differ among the four PCIS subgroups., Conclusions: During the first week after stroke onset, our PCIS patients with occipital lobe, thalamic, cerebellar, or brainstem strokes all had reduced cardiovagal modulation, compromised baroreflex, and increased peripheral sympathetic modulation. The RRI-LF/HF ratios suggest that sympathetic predominance is slightly more prominent after occipital lobe stroke. PCIS may trigger cardiovascular autonomic dysfunction even without brainstem involvement., (© 2022 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Background and Purpose: Atrial fibrillation (AF) in stroke patients can be classified as either "known AF" (KAF), defined as AF confirmed before stroke onset, or "AF detected after stroke" (AFDAS), defined as AF diagnosed after stroke onset. While KAF is considered primarily cardiogenic, AFDAS includes patients with stroke-triggered neurogenic arrhythmias. This study aimed to investigate the clinical course of stroke, functional outcomes and the value of oral anticoagulation (OAC) for secondary prevention according to AF subtype., Methods: Acute ischemic stroke patients were consecutively enrolled and AF was classified as AFDAS or KAF. Stroke severity was assessed using the National Institutes of Health Stroke Scale (NIHSS) and 3-month functional outcomes were measured on the modified Rankin scale. Inverse probability weighting was applied to adjust for baseline confounders in patients with AFDAS and KAF. Multivariate logistic regression models were calculated to investigate the value of OAC for secondary prevention., Results: A total of 822 stroke patients with AF were included, of whom 234 patients (28.5%) had AFDAS. AFDAS patients had a lower prevalence of coronary artery disease, heart failure, and sustained AF, but higher rates of large vessel occlusion compared to KAF patients. NIHSS scores were lower in patients on pre-stroke anticoagulation. OAC for secondary prevention was associated with favorable 3-month functional outcome (odds ratio 7.60, 95% confidence interval 3.42-16.88) independently of AF subtype. The rate of stroke recurrence did not differ significantly., Conclusions: Clinical characteristics suggest that AFDAS might comprise a distinct pathophysiological and clinical entity among stroke patients with AF. The benefit of anticoagulation for secondary prevention was not affected by AF subtype., (© 2022 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Objective: This study determined the effect of amantadine treatment on consciousness in patients with non-traumatic brain injury., Methods: We pooled individual patient data of five single-centre observational studies to determine the effect of amantadine treatment among patients with ischaemic stroke, intracerebral haemorrhage, subarachnoid haemorrhage, community-acquired bacterial meningitis and status epilepticus, admitted between January 2012 and December 2015 and ventilated ≥7 days. Patient selection and multivariable regression modelling were used to adjust for differences in intergroup comparison and for parameters associated with consciousness. Improvement of consciousness 5 days after treatment initiation was defined as primary outcome. Secondary outcomes included Glasgow Coma Scale (GCS) at day 5 and GCS at day 10, rate of ICU delirium, epileptic seizures and all-cause mortality at 90 days., Results: Overall, 84 of 294 (28.6%) eligible patients received amantadine. Amantadine treatment was associated with improvement of consciousness at day 5 (amantadine: 86.9% vs control: 54.0%; absolute difference: 32.9 (20.0-44.2); adjusted OR (aOR): 5.71 (2.50-13.05), p<0.001). Secondary outcomes showed differences in GCS 5 days (9 (8-11) vs 6 (3-9), p<0.001) and GCS 10 days (10(8-11) vs 9(6-11),p=0.003) after treatment initiation. There were no significant differences regarding all-cause mortality (aOR: 0.89 (0.44-1.82), p=0.758) and ICU delirium (aOR: 1.39 (0.58-3.31), p=0.462). Rate of epileptic seizures after initiation of amantadine treatment was numerically higher in the amantadine group (amantadine: 10.7% vs control: 3.0%; absolute difference: 7.7 (0.3-16.4); aOR: 3.68 (0.86-15.71), p=0.079)., Conclusions: Amantadine treatment is associated with improved consciousness among patients with different types of non-traumatic brain injury in this observational cohort analysis. Epileptic seizures should be considered as potential side effects and randomised controlled trials are needed to confirm these findings., Competing Interests: Competing interests: JBK reports personal fees from Bayer, personal fees from Bristol-Myers Squibb & Pfizer, personal fees from Sanofi, and personal fees from Boehringer Ingelheim outside the submitted work. BK reports personal fees from Bayer, personal fees from Bristol-Myers Squibb & Pfizer and personal fees from Medtronic outside the submitted work. HBH reports personal fees from Boehringer Ingelheim, personal fees from Bayer AG, personal fees from Daiichi Sankyo, grants and personal fees from Novartis, grants and personal fees from Portola Pharmaceuticals, grants and personal fees from Union Chimique Belge Pharma, and grants and personal fees from Medtronic outside the submitted work. MIS reports grants from IZKF and Marohn Foundation., (© 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.)

Background: Patients with atrial fibrillation have a relevant risk for ischemic stroke despite the recommended use of direct oral anticoagulants (DOAC). The risk correlates with the functional DOAC plasma levels in clinical trials, but the value of their measurement in community use remains undetermined., Objectives: We aim to investigate the clinical implications and the prognostic value of DOAC plasma level measurement during steady state., Methods: In this observational clinical cohort study among patients with ischemic stroke and atrial fibrillation, 397 individuals on oral anticoagulants for secondary stroke prevention were included between 2016 and 2020. The functional DOAC plasma levels were measured during steady state. Early stroke recurrence within 3 months was recorded as the main outcome parameter., Results: Three hundred ninety-seven patients (201 female, mean age 78 [±9] years, median CHA 2 DS 2 VASc-Score 6 [interquartile range 5-7]) were included. Mean DOAC plasma trough level was 95.9 (±66.9) ng/ml. A high glomerular filtration rate (GFR) was an independent predictor of lower levels in a multivariate model (R coefficient: -0.174, P = .014). During follow-up, 10 patients (3%) suffered from early ischemic stroke recurrence despite the use of DOAC, while 10 clinically relevant bleeding complications occurred (3%). Ischemic stroke recurrence was associated with numerical lower plasma levels for patients on apixaban and dabigatran after propensity score matching., Conclusions: Monitoring of DOAC plasma levels could help to identify patients with increased risk for stroke recurrence and should be considered for certain subgroups, including patients with high GFR., (© 2022 The Authors. Journal of Thrombosis and Haemostasis published by Wiley Periodicals LLC on behalf of International Society on Thrombosis and Haemostasis.)

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: Several automated computed tomography perfusion software applications have been developed to provide support in the definition of ischemic core and penumbra in acute ischemic stroke. However, the degree of interchangeability between software packages is not yet clear. Our study aimed to evaluate 2 commonly used automated perfusion software applications (Syngo.via and RAPID) for the indication of ischemic core with respect to the follow-up infarct volume (FIV) after successful recanalization and with consideration of the clinical impact., Methods: Retrospectively, 154 patients with large vessel occlusion of the middle cerebral artery or the internal carotid artery, who underwent endovascular therapy with a consequent Thrombolysis in Cerebral Infarction 3 result within 2 hours after computed tomography perfusion, were included. Computed tomography perfusion core volumes were assessed with both software applications with different thresholds for relative cerebral blood flow (rCBF). The results were compared with the FIV on computed tomography within 24 to 36 hours after recanalization. Bland-Altman was applied to display the levels of agreement and to evaluate systematic differences., Results: Highest correlation between ischemic core volume and FIV without significant differences was found at a threshold of rCBF<38% for the RAPID software ( r =0.89, P <0.001) and rCBF<25% for the Syngo software ( r =0.87, P <0.001). Bland-Altman analysis revealed best agreement in these settings. In the vendor default settings (rCBF<30% for RAPID and rCBF<20% for Syngo) correlation between ischemic core volume and FIV was also high (RAPID: r =0.88, Syngo: r =0.86, P <0.001), but mean differences were significant ( P <0.001). The risk of critical overestimation of the FIV was higher with rCBF<38% (RAPID) and rCBF<25% (Syngo) than in the default settings., Conclusions: By adjusting the rCBF thresholds, comparable results with reliable information on the FIV after complete recanalization can be obtained both with the RAPID and Syngo software. Keeping the software specific default settings means being more inclusive in patient selection, but forgo the highest possible accuracy in the estimation of the FIV.

Objective: The optimal timing to start direct oral anticoagulants (DOACs) after an acute ischaemic stroke (AIS) related to atrial fibrillation (AF) remains unclear. We aimed to compare early (≤5 days of AIS) versus late (>5 days of AIS) DOAC-start., Methods: This is an individual patient data pooled analysis of eight prospective European and Japanese cohort studies. We included patients with AIS related to non-valvular AF where a DOAC was started within 30 days. Primary endpoints were 30-day rates of recurrent AIS and ICH., Results: A total of 2550 patients were included. DOACs were started early in 1362 (53%) patients, late in 1188 (47%). During 212 patient-years, 37 patients had a recurrent AIS (1.5%), 16 (43%) before a DOAC was started; 6 patients (0.2%) had an ICH, all after DOAC-start. In the early DOAC-start group, 23 patients (1.7%) suffered from a recurrent AIS, while 2 patients (0.1%) had an ICH. In the late DOAC-start group, 14 patients (1.2%) suffered from a recurrent AIS; 4 patients (0.3%) suffered from ICH. In the propensity score-adjusted comparison of late versus early DOAC-start groups, there was no statistically significant difference in the hazard of recurrent AIS (aHR=1.2, 95% CI 0.5 to 2.9, p=0.69), ICH (aHR=6.0, 95% CI 0.6 to 56.3, p=0.12) or any stroke., Conclusions: Our results do not corroborate concerns that an early DOAC-start might excessively increase the risk of ICH. The sevenfold higher risk of recurrent AIS than ICH suggests that an early DOAC-start might be reasonable, supporting enrolment into randomised trials comparing an early versus late DOAC-start., Competing Interests: Competing interests: The following companies manufacture drugs involved in this study: Bayer (BY, rivaroxaban), Boehringer Ingelheim (BI, dabigatran), Pfizer/Bristol Meyer Squibb (PB, apixaban) and Daiichi Sankyo (DS, edoxaban). GMDM: scientific advisory boards and travel honoraria: BY; speaker honoraria: PB. DJS: scientific advisory boards: BY and PB. GT: scientific advisory boards: BY, DS and BI. MK: speaker honoraria from DS, BY and PB. KT: speaker honoraria from DS, BY, BI and PB. KM: speaker honoraria from BY, travel grant from PB. PL: scientific advisory boards: BY, DS and BI; funding for travel or speaker honoraria: BY and BI; research funding: BI. LHB: consultancy or advisory board fees or speaker’s honoraria from BY and PB. MP: honoraria as a member of the speaker bureau of BI, BY and PB. SE: funding for travel or speaker honoraria: BY, BI, PB and DS; scientific advisory boards: BY, BI and PB; educational grant from PB; research grant from DS. DJW: speaking honoraria: BY., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: To investigate the safety and effectiveness of direct oral anticoagulants (DOAC) versus vitamin K antagonists (VKA) after recent stroke in patients with atrial fibrillation (AF) aged ≥85 years., Methods: Individual patient data analysis from seven prospective stroke cohorts. We compared DOAC versus VKA treatment among patients with AF and recent stroke (<3 months) aged ≥85 versus <85 years. Primary outcome was the composite of recurrent stroke, intracranial hemorrhage (ICH) and all-cause death. We used simple, adjusted, and weighted Cox regression to account for confounders. We calculated the net benefit of DOAC versus VKA by balancing stroke reduction against the weighted ICH risk., Results: In total, 5,984 of 6,267 (95.5%) patients were eligible for analysis. Of those, 1,380 (23%) were aged ≥85 years and 3,688 (62%) received a DOAC. During 6,874 patient-years follow-up, the impact of anticoagulant type (DOAC versus VKA) on the hazard for the composite outcome did not differ between patients aged ≥85 (HR ≥85y  = 0.65, 95%-CI [0.52, 0.81]) and < 85 years (HR <85y  = 0.79, 95%-CI [0.66, 0.95]) in simple (p interaction  = 0.129), adjusted (p interaction  = 0.094) or weighted (p interaction  = 0.512) models. Analyses on recurrent stroke, ICH and death separately were consistent with the primary analysis, as were sensitivity analyses using age dichotomized at 90 years and as a continuous variable. DOAC had a similar net clinical benefit in patients aged ≥85 (+1.73 to +2.66) and < 85 years (+1.90 to +3.36 events/100 patient-years for ICH-weights 1.5 to 3.1)., Interpretation: The favorable profile of DOAC over VKA in patients with AF and recent stroke was maintained in the oldest old. ANN NEUROL 2022;91:78-88., (© 2021 The Authors. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Purpose: Endovascular therapy (EVT) of large-vessel occlusion in acute ischemic stroke (AIS) may be performed in general anesthesia (GA) or conscious sedation (CS). We intended to determine the contribution of ischemic cerebral lesion sites on the physician's decision between GA and CS using voxel-based lesion symptom mapping (VLSM)., Methods: In a prospective local database, we sought patients with documented AIS and EVT. Age, stroke severity, lesion volume, vigilance, and aphasia scores were compared between EVT patients with GA and CS. The ischemic lesions were analyzed on CT or MRI scans and transformed into stereotaxic space. We determined the lesion overlap and assessed whether GA or CS is associated with specific cerebral lesion sites using the voxel-wise Liebermeister test., Results: One hundred seventy-nine patients with AIS and EVT were included in the analysis. The VLSM analysis yielded associations between GA and ischemic lesions in the left hemispheric middle cerebral artery territory and posterior circulation areas. Stroke severity and lesion volume were significantly higher in the GA group. The prevalence of aphasia and aphasia severity was significantly higher and parameters of vigilance lower in the GA group., Conclusions: The VLSM analysis showed associations between GA and ischemic lesions in the left hemispheric middle cerebral artery territory and posterior circulation areas including the thalamus that are known to cause neurologic deficits, such as aphasia or compromised vigilance, in AIS-patients with EVT. Our data suggest that higher disability, clinical impairment due to neurological deficits like aphasia, or reduced alertness of affected patients may influence the physician's decision on using GA in EVT., (© 2021. The Author(s).)

Background and Purpose: The optimal acute management of patients with large vessel occlusion (LVO) and minor clinical deficits on admission [National Institutes of Health Stroke Scale (NIHSS) ≤ 4] remains to be elucidated. The aim of the present study was to investigate the prognostic factors and therapeutic management of those patients. Methods: In this retrospective cohort study, we investigated (1) all patients with acute ischemic stroke due to an LVO who underwent mechanical thrombectomy (MT) and (2) all patients with minor clinical deficits (NIHSS ≤ 4) on admission due to an LVO between January 2013 and December 2016 at the University Medical Center Erlangen. We dichotomized management of patients with minor deficits treated with MT for analysis according to immediate mechanical thrombectomy (IT) and initial medical management with rescue intervention (MM) in case of secondary deterioration. Primary endpoints were secondary deterioration, in-hospital mortality, and functional outcome on day 90 (dichotomized modified Rankin Scale 0-2: favorable, 3-6: poor). Results: Two hundred twenty-three patients (83% with anterior circulation stroke, 13 (6%) with minor deficits) treated with MT and 88 patients with minor deficits due to LVO [13 (15%) treated with MT] were included. Secondary deterioration ( n = 19) was independently associated with poor outcome in patients with minor deficits and LVO [odds ratio (OR), 0.060; 95% confidence interval (CI), 0.013-0.280], which in turn was associated with the occlusion site [especially M1 occlusion: 11 (58%) vs. 3 (4%) in patients without secondary deterioration, p < 0.0001]. IT ( n = 8) was associated with a lower intrahospital mortality compared to MM ( n = 5; 13 vs. 80%; OR, 0.036; 95% CI, 0.002-0.741). Seven of eight patients with IT survived until discharge, with 29% showing a favorable functional outcome on day 90. Conclusions: Secondary deterioration is associated with poor outcome in patients with LVO and minor deficits, which in turn was associated with occlusion site. Future randomized controlled trials should assess whether selected patients, depending on occlusion site and associated characteristics, may benefit from MT., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Volbers, Gröger, Engelhorn, Marsch, Macha, Schwab, Dörfler, Lang and Kallmünzer.)

Background: rt-PA for ischemic stroke in the unknown or extended time window beyond the first 4. 5 h after symptom onset is safe and effective for certain patients after selection by multimodal neuroimaging. However, the evidence for this approach comes mainly from patients with anterior circulation stroke (ACS), while the data on posterior circulation stroke (PCS) are scarce. Methods: Ischemic stroke patients treated with IV-thrombolysis in the unknown or extended time window between January 2011 and May 2019 were identified from an institutional registry. The patients were categorized into PCS or ACS based on clinico-radiological findings. We analyzed the hemorrhagic complications, clinical and imaging efficacy outcomes, and mortality rates by comparing the PCS and ACS patient groups. Adjusted outcome analyses were performed after propensity score matching for the relevant factors. Results: Of the 182 patients included, 38 (20.9%) had PCS and 144 (79.1%) had ACS. Symptomatic acute large vessel occlusion (LVO) was present in 123 patients on admission [27 (22.0%) PCS and 96 (78.0%) ACS]. The score on the National Institutes of Health Stroke Scale (NIHSS), the time from last seen normal, and the door-to-needle times were similar in PCS and ACS. In patients with LVO, the NIHSS score was lower [8 (5-15) vs. 14 (9-18), p = 0.005], and infarction visible on follow-up imaging was less common [70.4 vs. 87.5%; aRD, -18.9% (-39.8 to -2.2%)] in the PCS patient group. There was a trend toward a lower risk for intracranial hemorrhage (ICH) following intravenous thrombolysis in PCS vs. ACS, without reaching a statistical significance [5.3 vs. 16.9%; aRD, -10.4% (-20.4 to 4.0%)]. The incidence of symptomatic ICH [according to the ECASS III criteria: 2.6 vs. 3.5%; aRD, -2.9% (-10.3 to 9.2%)], efficacy outcomes, and mortality rates were similar in PCS and ACS patients. Conclusions: In this real-world clinical cohort, the safety and the efficacy of rt-PA for ischemic stroke in the unknown or extended time window did not show relevant differences between PCS and ACS, with a trend toward less hemorrhagic complications in PCS. The findings reconfirm the clinician in the usage of rt-PA beyond the first 4.5 h also in selected patients with PCS., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Macha, Hoelter, Siedler, Wang, Knott, Stoll, Engelhorn, Doerfler, Schwab, Mühlen and Kallmünzer.)