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Introduction: Scarce data exist about clinical/radiological differences between acute ischemic strokes diagnosed in the emergency room (AISER) and stroke chameleons (SCs). We aimed at describing the differences observed in a comprehensive stroke center in Chile., Methods: Prospective observational study of patients with ischemic stroke syndromes admitted to the emergency room (ER) of Clínica Alemana between December 2014 and October 2023., Results: 1,197 patients were included; of these 63 (5.2%, 95% CI: 4.1-6.6) were SC; these were younger (p < 0.001), less frequently hypertensive (p = 0.03), and they also had lower systolic (SBP) (p < 0.001), diastolic blood pressures (DBP) (p = 0.011), and NIHSS (p < 0.001). Clinically, they presented less frequently gaze (p = 0.008) and campimetry alterations (p = 0.03), facial (p < 0.001) and limb weakness (left arm [p = 0.004], right arm (p = 0.041), left leg (p = 0.001), right leg p = 0.0029), sensory abnormalities (p < 0.001), and dysarthria (p < 0.001). Neuroradiological evaluations included less frequently large vessel occlusions (p = 0.01) and other stroke locations (p = 0.005); they also differed in their etiologies (p < 0.001). Brainstem strokes (p < 0.001) and extinction/inattention symptoms (p < 0.001) were only seen in AISER. In multivariate analysis, younger age (OR: 0.945; 95% CI: 0.93-0.96), DBP (OR: 0.97; 95% CI, 0.95-0.99), facial weakness (OR: 0.39; 95% CI: 0.19-0.78), sensory abnormities (OR: 0.16.18; 95% CI, 0.05-0.4), infratentorial location (OR: 0.36; 95% CI, 0.15-0.78), posterior circulation involvement (OR: 3.02; 95% CI, 1.45-6.3), cardioembolic (OR: 3.5; 95% CI, 1.56-7.99), and undetermined (OR: 2.42; 95% CI, 1.22-4.7; 95%) etiologies, remained statistically significant. A stepwise analysis including only clinical elements present on the patient's arrival to the ER, demonstrates that age (OR: 0.95; 95% CI: 0.94-0.97), DBP (OR: 0.97; 95% CI, 0.95-0.99), the presence of atrial fibrillation (OR: 2.22; 95% CI, 1.04-4.75, NIHSS (OR: 0.88; 95% CI, 0.71-0.89) and the presence in NIHSS of 1a level of consciousness (OR: 5.66; CI: 95% 1.8-16.9), 1b level of consciousness questions (OR: 3.023; 95% CI, 1.35-6.8), facial weakness (OR: 0.3; CI: 95% 0.17-0.8), and sensory abnormalities (OR: 0.27; 95% CI, 0.1-0.72) remained statistically significant., Conclusion: SC had clinical and radiological differences compared to AISER. An additional relevant finding is that neurological symptoms in a patient with atrial fibrillation, even with a negative diffusion-weighted imaging, should be carefully evaluated as a potential stroke until other causes are satisfactorily ruled out., (© 2024 S. Karger AG, Basel.)

Background: People with factor XI deficiency have lower rates of ischaemic stroke than the general population and infrequent spontaneous bleeding, suggesting that factor XI has a more important role in thrombosis than in haemostasis. Milvexian, an oral small-molecule inhibitor of activated factor XI, added to standard antiplatelet therapy, might reduce the risk of non-cardioembolic ischaemic stroke without increasing the risk of bleeding. We aimed to estimate the dose-response of milvexian for recurrent ischaemic cerebral events and major bleeding in patients with recent ischaemic stroke or transient ischaemic attack (TIA)., Methods: AXIOMATIC-SSP was a phase 2, randomised, double-blind, placebo-controlled, dose-finding trial done at 367 hospitals in 27 countries. Eligible participants aged 40 years or older, with acute (<48 h) ischaemic stroke or high-risk TIA, were randomly assigned by a web-based interactive response system in a 1:1:1:1:1:2 ratio to receive one of five doses of milvexian (25 mg once daily, 25 mg twice daily, 50 mg twice daily, 100 mg twice daily, or 200 mg twice daily) or matching placebo twice daily for 90 days. All participants received clopidogrel 75 mg daily for the first 21 days and aspirin 100 mg daily for the first 90 days. Investigators, site staff, and participants were masked to treatment assignment. The primary efficacy endpoint was the composite of ischaemic stroke or incident covert brain infarct on MRI at 90 days, assessed in all participants allocated to treatment who completed a follow-up MRI brain scan, and the primary analysis assessed the dose-response relationship with Multiple Comparison Procedure-Modelling (MCP-MOD). The main safety outcome was major bleeding at 90 days, assessed in all participants who received at least one dose of the study drug. This trial is registered with ClinicalTrials.gov (NCT03766581) and the EU Clinical Trials Register (2017-005029-19)., Findings: Between Jan 27, 2019, and Dec 24, 2021, 2366 participants were randomly allocated to placebo (n=691); milvexian 25 mg once daily (n=328); or twice-daily doses of milvexian 25 mg (n=318), 50 mg (n=328), 100 mg (n=310), or 200 mg (n=351). The median age of participants was 71 (IQR 62-77) years and 859 (36%) were female. At 90 days, the estimates of the percentage of participants with either symptomatic ischaemic stroke or covert brain infarcts were 16·8 (90·2% CI 14·5-19·1) for placebo, 16·7 (14·8-18·6) for 25 mg milvexian once daily, 16·6 (14·8-18·3) for 25 mg twice daily, 15·6 (13·9-17·5) for 50 mg twice daily, 15·4 (13·4-17·6) for 100 mg twice daily, and 15·3 (12·8-19·7) for 200 mg twice daily. No significant dose-response was observed among the five milvexian doses for the primary composite efficacy outcome. Model-based estimates of the relative risk with milvexian compared with placebo were 0·99 (90·2% CI 0·91-1·05) for 25 mg once daily, 0·99 (0·87-1·11) for 25 mg twice daily, 0·93 (0·78-1·11) for 50 mg twice daily, 0·92 (0·75-1·13) for 100 mg twice daily, and 0·91 (0·72-1·26) for 200 mg twice daily. No apparent dose-response was observed for major bleeding (four [1%] of 682 participants with placebo, two [1%] of 325 with milvexian 25 mg once daily, two [1%] of 313 with 25 mg twice daily, five [2%] of 325 with 50 mg twice daily, five [2%] of 306 with 100 mg twice daily, and five [1%] of 344 with 200 mg twice daily). Five treatment-emergent deaths occurred, four of which were considered unrelated to the study drug by the investigator., Interpretation: Factor XIa inhibition with milvexian, added to dual antiplatelet therapy, did not substantially reduce the composite outcome of symptomatic ischaemic stroke or covert brain infarction and did not meaningfully increase the risk of major bleeding. Findings from our study have informed the design of a phase 3 trial of milvexian for the prevention of ischaemic stroke in patients with acute ischaemic stroke or TIA., Funding: Bristol Myers Squibb and Janssen Research & Development., Competing Interests: Declaration of interests MS has received consulting fees from Janssen, HLS Therapeutics, and Bayer; and has served in a leadership or fiduciary role for the Canadian Stroke Consortium. CAM has received honoraria from Bristol Myers Squibb and Boehringer Ingelheim. KT has received honoraria from Bayer, Daiichi Sankyo, Bristol Myers Squibb, Otsuka, Novartis, and Abbott Medical. DB has received consulting fees from Bristol Myers Squibb, Bayer, Ipsen, and Boehringer Ingelheim; and has received honoraria from Novo Nordisk, HUMAN BioPlazma, and Parexel. SEK has received grants or contracts from Bristol Myers Squibb; and has received consulting fees from Bristol Myers Squibb. HL has received consulting fees from Bristol Myers Squibb; has participated on steering committees or advisory boards for Bristol Myers Squibb, the US National Institute of Neurological Disorders and Stroke, and Coherex Medical; and is on the Editorial Board for Medscape Neurology. GT has received consulting fees from Bristol Myers Squibb. GN has received financial support from Bristol Myers Squibb. AC has participated on a steering committee for Bristol Myers Squibb; has received grants or contracts from Bristol Myers Squibb; and has previously served as the President of the Cerebrovascular Section of Polish Neurological Society, honorary president of the Polish Neurological Society, and in a leadership role for the Angels Initiative— Poland. PA has participated on a steering committee for Bristol Myers Squibb and Janssen; has received grants or contracts from Sanofi, Bristol Myers Squibb, AstraZeneca, Pfizer, Merck, AltheraPharm, and the French Government; has received consulting fees from Bayer, Novartis, and Novo Nordisk; has received honoraria from Viatris and Sanofi; and has participated in an advisory board for Novartis. ME has received grants or contracts from Bayer; has received consulting fees from Bayer; has received honoraria from Abbott, Boehringer Ingelheim, Pfizer, Amgen, GSK, Sanofi, and Novartis; has participated on data safety monitoring boards or advisory boards for Bristol Myers Squibb, Bayer, AstraZeneca, Boehringer Ingelheim, Daiichi Sankyo, Amgen, and Covidien; has served in a leadership or fiduciary role for the European Academy of Neurology, German Neurological Society (DGN), International Society for Cerebral Blood Flow and Metabolism, American Heart Association/American Stroke Association, European Stroke Organisation, World Stroke Organization, German Center for Cardiovascular Research (DZHK), and German Center for Neurodegenerative Diseases (DZNE); and has been a recipient of materials from Amgen. DTa has received consulting fees from QuantaIX Neuroscience, Babylink, and Pi-cardia, and for being a national leader in a randomised controlled trial. DTo has received honoraria from Abbott, Alexion, AstraZeneca, Bayer, Boehringer Ingelheim, Medtronic, and Pfizer. LY has participated in steering committees for Bristol Myers Squibb and Janssen Research & Development; has received honoraria from Bayer, Bristol Myers Squibb, Pfizer, Boehringer Ingelheim, and Daiichi Sankyo; and has received support for attendance at the World Stroke Congress from the World Stroke Organization Future Stroke Leaders Program. PvWM has received contracts and support for attending an investigator meeting from Bristol Myers Squibb; and has served as a national leader and member of a steering committee for Bristol Myers Squibb. GSS has received support from and participated on a steering committee for Bristol Myers Squibb; has received grants or contracts from Boehringer Ingelheim; has received consulting fees from Bristol Myers Squibb and Boehringer Ingelheim; and has participated in an advisory board for Bristol Myers Squibb. AAv has received grants and honoraria from Bayer. JD has received support from Bristol Myers Squibb; has received grants from Pfizer; and has received honoraria from Pfizer, Daiichi Sankyo, and AstraZeneca. DS has received contracts, support for attending a steering committee meeting, and materials and drugs for performing the trial from Bristol Myers Squibb. TT has received grants from the University of Gothenburg, Sahlgrenska University Hospital, and Wennerstrom's Foundation; and has received consulting fees from Bayer, Inventiva Pharma, Bristol Myers Squibb, and Portola Pharmaceuticals. JE has received travel support from Bristol Myers Squibb for attending steering committee meetings. SFA has received grants from Bayer and Boehringer Ingelheim; and has received honoraria from Novo Nordisk and Abbott. JRW has served as President Elect of the Austrian Society of Neurology. ECS has received honoraria from Bristol Myers Squibb, Daiichi Sankyo, and Boston Scientific. NGP has served as the President of the Russian National Society of Preventive Cardiology. PML has received grants from Bristol Myers Squibb and Janssen; has received honoraria from Boehringer Ingelheim and Pfizer; has received support for attending the Global Stroke Alliance; has participated on a data safety monitoring board or advisory board for RapidAI; and has served as the President of the Chilean Stroke Association. DG has received grants or contracts, or both, from the US National Heart, Lung and Blood Institute and the US National Institutes of Health; has received consulting fees from Bristol Myers Squibb, Ionis, Janssen, and Anthos Therapeutics; and has participated on a steering committee for Bristol Myers Squibb. HCD has received support from Bristol Myers Squibb; has received grants from Boehringer Ingelheim and AstraZeneca; has received honoraria from Boehringer Ingelheim, Pfizer, Sanofi, and Bristol Myers Squibb; has received support for attending meetings or travel, or both, from Boehringer Ingelheim; and has participated on data safety monitoring boards or advisory boards for Actelion, the German Research Council, and the ELAN Study. RAB has received consulting fees from and has participated on a steering committee for Bristol Myers Squibb. CC has received honoraria from Bristol Myers Squibb and Amgen; and has participated on data safety monitoring boards or advisory boards for AstraZeneca and Biogen. GA, MD, and CP are employees and shareholders of Bristol Myers Squibb. AK and DL are employees and shareholders of Bristol Myers Squibb; and have a pending patent application related to this study. GJH has received consulting fees from Bristol Myers Squibb, Janssen Research & Development, and Bayer; has received honoraria from Janssen Medical Affairs; has received honoraria for participating on a data safety monitoring board for AC Immune; and has received honoraria from the American Heart Association for serving as an Associate Editor for Circulation. SIB, AS, BWY, and AAr declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: The efficacy of intravenous thrombolysis (IVT) is time-dependent., Objective: To compare the door-to-needle (DTN) time of stroke neurologists (SNs) versus non-stroke neurologists (NSNs) and emergency room physicians (EPs). Additionally, we aimed to determine elements associated with DTN ≤ 20 minutes., Methods: Prospective study of patients with IVT treated at Clínica Alemana between June 2016 and September 2021., Results: A total of 301 patients underwent treatment for IVT. The mean DTN time was 43.3 ± 23.6 minutes. One hundred seventy-three (57.4%) patients were evaluated by SNs, 122 (40.5%) by NSNs, and 6 (2.1%) by EPs. The mean DTN times were 40.8 ± 23, 46 ± 24.7, and 58 ± 22.5 minutes, respectively. Door-to-needle time ≤ 20 minutes occurred more frequently when patients were treated by SNs compared to NSNs and EPs: 15%, 4%, and 0%, respectively (odds ratio [OR]: 4.3, 95% confidence interval [95%CI]: 1.66-11.5, p  = 0.004). In univariate analysis DTN time ≤ 20 minutes was associated with treatment by a SN ( p  = 0.002), coronavirus disease 2019 pandemic period ( p  = 0.21), time to emergency room (ER) ( p  = 0.21), presence of diabetes ( p  = 0.142), hypercholesterolemia ( p  = 0.007), atrial fibrillation ( p  < 0.09), score on the National Institutes of Health Stroke Scale (NIHSS) ( p  = 0.001), lower systolic ( p  = 0.143) and diastolic ( p  = 0.21) blood pressures, the Alberta Stroke Program Early CT Score (ASPECTS; p  = 0.09), vessel occlusion ( p  = 0.05), use of tenecteplase ( p  = 0.18), thrombectomy ( p  = 0.13), and years of experience of the physician ( p  < 0.001). After multivariate analysis, being treated by a SN (OR: 3.95; 95%CI: 1.44-10.8; p  = 0.007), NIHSS (OR: 1.07; 95%CI: 1.02-1.12; p  < 0.002) and lower systolic blood pressure (OR: 0.98; 95%CI: 0.96-0.99; p  < 0.003) remained significant., Conclusion: Treatment by a SN resulted in a higher probability of treating the patient in a DTN time within 20 minutes., Competing Interests: AMB, VO, PM: reports research grant from Clínica Alemana; JCN, EM, GC: reports no conflicts of interest; PL: reports research grants from The George Institute and Clínica Alemana de Santiago for ENCHANTED, HAEDPOST, and RECCA studies; personal fees from AstraZeneca and Bayer as SOCRATES and ESUS NAVIGATE trials national leader and a Chilean Government research grant for the ÑANDU project outside the submitted., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution 4.0 International License, permitting copying and reproduction so long as the original work is given appropriate credit (https://creativecommons.org/licenses/by/4.0/).)

Background: Knowledge about stroke symptoms, correct decision in front of a stroke case and recognition of stroke risk factors are crucial to fight against stroke burden. We aimed to assess the stroke awareness among a sample of the Chilean population., Methods: A closed-ended questions structured survey was applied in November 2019 using a computer-assisted telephone interviewing system. Probabilistic sample, random selection and stratification for region was used. Multivariate logistic regression model was used to estimate the association between participants' characteristics and responses., Results: Of 706 participants, only 74.4% (95% CI 70.9-77.5) recognized at least one typical stroke symptom. Most (586, 82.4% 95% CI 75.2-89.7) chose to contact the emergency ambulance or directly go to the emergency department in case of a stroke symptom and recognized at least one risk factor (692, 97.9% CI 96.7-98.8). In multivariable analysis, sociodemographic characteristics associated to a worse recognition of at least one stroke symptom were being men (OR 0.67, 95% CI 0.47-0.96), being 55 years old or older (OR 0.59 95% CI 0.37-0.93) and from the lowest socioeconomic level (SES) (OR 0.33 95% CI 0.16-0.67). Female sex was associated with lower stroke risk factor knowledge (OR 0.64 95% IC 0.47-0.87). Participants who recognized at least one typical stroke symptom and would promptly seek care at an emergency department differed significantly between SES (p=0.001) and age groups (p=0.035)., Conclusions: We found insufficient knowledge about stroke symptoms and best decisions making in the Chilean population. We describe gaps that can be targeted in future stroke awareness campaigns. There is a need to strengthen tailored stroke education particularly for underserved populations., Competing Interests: Declarations of interest None., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: It has been reported that acute stroke services were compromised during COVID-19 due to various pandemic-related issues. We aimed to investigate these changes by recruiting centers from different countries., Methods: Eight countries participated in this cross-sectional, observational, retrospective study by providing data from their stroke data base. We compared 1 year before to 1 year during COVID-19 as regards onset to door (OTD), door to needle (DTN), door to groin (DTG), duration of hospital stay, National Institute of Health Stroke Scale (NIHSS) at baseline, 24 h, and at discharge as well as modified Rankin score (mRS) on discharge and at 3 months follow-up., Results: During the pandemic year, there was a reduction in the number of patients, median age was significantly lower, admission NIHSS was higher, hemorrhagic stroke increased, and OTD and DTG showed no difference, while DTN time was longer, rtPA administration was decreased, thrombectomy was more frequent, and hospital stay was shorter. mRS was less favorable on discharge and at 3 months., Conclusion: COVID-19 showed variable effects on stroke services. Some were negatively impacted as the number of patients presenting to hospitals, DTN time, and stroke outcome, while others were marginally affected as the type of management., (© 2022. The Author(s).)

Introduction: The frequency of intravenous thrombolysis (IVT) in acute ischemic stroke (AIS) is lower than it should be in several regions of the world. It is unclear what interventions can produce significant improvements in IVT utilization. We aimed to investigate the temporal trends in IVT in AIS and identify changes in time that could be associated with specific interventions., Methods: We included patients with AIS who were admitted from January 1998 to December 2019 in our institution. To analyze trends in utilization and time points in which they changed, we performed a Joinpoint regression analysis. Interventions were assigned to a specific category according to the Behavior Change Wheel framework intervention function criteria., Results: A total of 3,361 patients with AIS were admitted, among which 538 (16%) received IVT. There were 245 (45.5%) women, and the mean age and median National Institutes of Health Stroke Scale (NIHSS) scores were 68.5 (17.2) years and 8 (interquartile range, 4-15), respectively. Thrombolysis use significantly increased by an average annual 7.6% (95% CI, 5.1-10.2), with one Joinpoint in 2007. The annual percent changes were.45% from 1998 to 2007 and 9.57% from 2007 to 2019, concurring with the stroke code organization, the definition of door-to-needle times as an institutional performance measure quality indicator, and the extension of the therapeutic window., Conclusions: The IVT rates consistently increased due to a continuous process of protocol changes and multiple interventions. The implementation of a complex multidisciplinary intervention such as the stroke code, as well as the definition of a hospital quality control metric, were associated with a significant change in this trend., Competing Interests: VO reports receiving research grants from Clínica Alemana de Santiago, Boehringer-Ingelheim, and ANID. PL reports research support from Clínica Alemana de Santiago and Boehringer Ingelheim, research grants from The George Institute and Clínica Alemana de Santiago during the conduct of the study, unrestricted research grants from Lundbeck and Boehringer Ingelheim, personal fees from AstraZeneca and Bayer as SOCRATES and ESUS NAVIGATE trials national leader, and a Chilean Government research grant for the ÑANDU project outside the submitted work. AB received a research grant from Clínica Alemana de Santiago for the RECCA registry. 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 © 2022 Olavarría, Hoffmeister, Vidal, Brunser, Hoppe and Lavados.)

Background: Topographic patterns may correlate with causes of ischemic stroke., Objective: To investigate the association between diffusion-weighted imaging (DWI) and Trial of Org 10172 in Acute Stroke Treatment (TOAST) classification., Methods: We included 1019 ischemic stroke patients. DWI were classified as: i) negative; ii) DWI single lesion (cortico-subcortical, cortical, subcortical ≥20 mm, or subcortical <20 mm); iii) scattered lesions in one territory (small scattered lesions or confluent with additional lesions); and iv) multiple lesions (multiple unilateral anterior circulation [MAC], multiple posterior circulation [MPC], multiple bilateral anterior circulation [MBAC], and multiple anterior and posterior circulations [MAP])., Results: There was a relationship between DWI patterns and TOAST classification (p<0.001). Large artery atherosclerosis was associated with small, scattered lesions in one vascular territory (Odds Ratio [OR] 4.22, 95% confidence interval [95%CI] 2.61-6.8), MPC (OR 3.52; 95%CI 1.54-8.03), and subcortical lesions <20 mm (OR 3.47; 95%CI 1.76-6.85). Cardioembolic strokes correlated with MAP (OR 4.3; 95%CI 1.64-11.2), cortico-subcortical lesions (OR 3.24; 95%CI 1.9-5.5) and negative DWI (OR 2.46; 95%CI 1.1-5.49). Cryptogenic strokes correlated with negative DWI (OR 4.1; 95%CI 1,84-8.69), cortical strokes (OR 3.3; 95%CI 1.25-8.8), MAP (OR 3.33; 95%CI 1.25-8.81) and subcortical lesion ≥20 mm (OR 2.44; 95%CI 1,04-5.73). Lacunar strokes correlated with subcortical lesions diameter <20 mm (OR 42.9; 95%CI 22.7-81.1) and negative DWI (OR 8.87; 95%CI 4.03-19.5). Finally, MBAC (OR 9.25; 95%CI 1.12-76.2), MAP (OR 5.54; 95%CI 1.94-15.1), and MPC (OR 3.61; 95%CI 1.5-8.7) correlated with stroke of other etiologies., Conclusions: A relationship exists between DWI and stroke subtype.

Background and Purpose: In thrombolysis-eligible patients with acute ischemic stroke, there is uncertainty over the most appropriate systolic blood pressure (SBP) lowering profile that provides an optimal balance of potential benefit (functional recovery) and harm (intracranial hemorrhage). We aimed to determine relationships of SBP parameters and outcomes in thrombolyzed acute ischemic stroke patients., Methods: Post hoc analyzes of the ENCHANTED (Enhanced Control of Hypertension and Thrombolysis Stroke Study), a partial-factorial trial of thrombolysis-eligible and treated acute ischemic stroke patients with high SBP (150-180 mm Hg) assigned to low-dose (0.6 mg/kg) or standard-dose (0.9 mg/kg) alteplase and intensive (target SBP, 130-140 mm Hg) or guideline-recommended (target SBP <180 mm Hg) treatment. All patients were followed up for functional status and serious adverse events to 90 days. Logistic regression models were used to analyze 3 SBP summary measures postrandomization: attained (mean), variability (SD) in 1-24 hours, and magnitude of reduction in 1 hour. The primary outcome was a favorable shift on the modified Rankin Scale. The key safety outcome was any intracranial hemorrhage., Results: Among 4511 included participants (mean age 67 years, 38% female, 65% Asian) lower attained SBP and smaller SBP variability were associated with favorable shift on the modified Rankin Scale (per 10 mm Hg increase: odds ratio, 0.76 [95% CI, 0.71-0.82]; P <0.001 and 0.86 [95% CI, 0.76-0.98]; P =0.025) respectively, but not for magnitude of SBP reduction (0.98, [0.93-1.04]; P =0.564). Odds of intracranial hemorrhage was associated with higher attained SBP and greater SBP variability (1.18 [1.06-1.31]; P =0.002 and 1.34 [1.11-1.62]; P =0.002) but not with magnitude of SBP reduction (1.05 [0.98-1.14]; P =0.184)., Conclusions: Attaining early and consistent low levels in SBP <140 mm Hg, even as low as 110 to 120 mm Hg, over 24 hours is associated with better outcomes in thrombolyzed acute ischemic stroke patients. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01422616.

Objectives: Low adherence to a Mediterranean diet (MeDi) is associated with increased incidence, mortality, and severity of acute ischemic strokes (AIS). Nevertheless, the explanatory factors associated with such results are unclear. Our aim was to investigate stroke risk factors associated with adherence to a MeDi in a prospective cohort of AIS patients., Materials and Methods: Patients admitted from February 2017 to February 2020 were included in this study. Adherence was measured using the 14-point Mediterranean Diet Adherence Screener (MEDAS). Demographic and clinical characteristics were compared with adherence with a univariate analysis. A binomial regression was used to investigate the independent association of premorbid factors and MeDi components with adherence., Results: There were 413 patients. Mean age was 68.6 (17.4), 176 (42.6%) women. Median MEDAS score was 6 (IQR 4-7) points. 253 patients (61.2%) had a low adherence (MEDAS ≤ 6). In the univariate analysis, a low MEDAS was associated with lower education, diabetes, sedentary lifestyle, greater body mass index (BMI), lower alcohol consumption, and higher LDLc. In the regression analysis, younger age, lower education, functional disability, hypertension, sedentary lifestyle, and higher BMI were associated with lower MEDAS scores. Six MeDi components had particularly low patient adherence: seafood, legumes, olive oil, nuts, wine, and fruit., Discussion: These data indicate low adherence to MeDi in younger patients who are less educated and have existing cardiovascular risk factors, in particular hypertension, sedentary lifestyle, and higher BMI. Some components of the diet had a particularly low adherence., Conclusions: Tailoring diet prevention interventions to these specific populations, focusing on components with known less adherence, could improve adherence to a MeDi and the opportunity for secondary stroke prevention., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: During the COVID-19 pandemic, decreased volumes of stroke admissions and mechanical thrombectomy were reported. The study's objective was to examine whether subarachnoid haemorrhage (SAH) hospitalisations and ruptured aneurysm coiling interventions demonstrated similar declines., Methods: We conducted a cross-sectional, retrospective, observational study across 6 continents, 37 countries and 140 comprehensive stroke centres. Patients with the diagnosis of SAH, aneurysmal SAH, ruptured aneurysm coiling interventions and COVID-19 were identified by prospective aneurysm databases or by International Classification of Diseases, 10th Revision, codes. The 3-month cumulative volume, monthly volumes for SAH hospitalisations and ruptured aneurysm coiling procedures were compared for the period before (1 year and immediately before) and during the pandemic, defined as 1 March-31 May 2020. The prior 1-year control period (1 March-31 May 2019) was obtained to account for seasonal variation., Findings: There was a significant decline in SAH hospitalisations, with 2044 admissions in the 3 months immediately before and 1585 admissions during the pandemic, representing a relative decline of 22.5% (95% CI -24.3% to -20.7%, p<0.0001). Embolisation of ruptured aneurysms declined with 1170-1035 procedures, respectively, representing an 11.5% (95%CI -13.5% to -9.8%, p=0.002) relative drop. Subgroup analysis was noted for aneurysmal SAH hospitalisation decline from 834 to 626 hospitalisations, a 24.9% relative decline (95% CI -28.0% to -22.1%, p<0.0001). A relative increase in ruptured aneurysm coiling was noted in low coiling volume hospitals of 41.1% (95% CI 32.3% to 50.6%, p=0.008) despite a decrease in SAH admissions in this tertile., Interpretation: There was a relative decrease in the volume of SAH hospitalisations, aneurysmal SAH hospitalisations and ruptured aneurysm embolisations during the COVID-19 pandemic. These findings in SAH are consistent with a decrease in other emergencies, such as stroke and myocardial infarction., Competing Interests: Competing interests: TNN: PI CLEAR study (Medtronic). DCH: Stryker, Vesalio, Cerenovus consultant. AEH: consultant and speaker for Medtronic, Stryker, Microvention, Penumbra, Balt, Scientia, Genentech and GE Healthcare. PJ: Medtronic, Microvention, Balt, Cerenovus consultant. SO-G: Medtronic, Stryker consultant. DSL: Cerenovus, Genentech, Stryker, Medtronic consultant. TGJ: advisor/investor for Anaconda, Route92, FreeOx, and Blockade Medical; Medtronic grants, DAWN, AURORA PI (Stryker). WJM: consultant: Rebound Therapeutics, Viseon Imperative Care, Q’Apel, Stryker, Stream Biomedical, Spartan Micro; Investor: Cerebrotech, Endostream, Q’Apel, Viseon, Rebound, and Spartan Micro. RGN: Stryker; Cerenovus/Neuravi; Anaconda, Cerebrotech, Ceretrieve, Vesalio (Advisory Board); Imperative Care., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: COVID-19 pandemic has forced important changes in health care worldwide. Stroke care networks have been affected, especially during peak periods. We assessed the impact of the pandemic and lockdowns in stroke admissions and care in Latin America., Materials and Methods: A multinational study (7 countries, 18 centers) of patients admitted during the pandemic outbreak (March-June 2020). Comparisons were made with the same period in 2019. Numbers of cases, stroke etiology and severity, acute care and hospitalization outcomes were assessed., Results: Most countries reported mild decreases in stroke admissions compared to the same period of 2019 (1187 vs. 1166, p = 0.03). Among stroke subtypes, there was a reduction in ischemic strokes (IS) admissions (78.3% vs. 73.9%, p = 0.01) compared with 2019, especially in IS with NIHSS 0-5 (50.1% vs. 44.9%, p = 0.03). A substantial increase in the proportion of stroke admissions beyond 48 h from symptoms onset was observed (13.8% vs. 20.5%, p < 0.001). Nevertheless, no differences in total reperfusion treatment rates were observed, with similar door-to-needle, door-to-CT, and door-to-groin times in both periods. Other stroke outcomes, as all-type mortality during hospitalization (4.9% vs. 9.7%, p < 0.001), length of stay (IQR 1-5 days vs. 0-9 days, p < 0.001), and likelihood to be discharged home (91.6% vs. 83.0%, p < 0.001), were compromised during COVID-19 lockdown period., Conclusions: In this Latin America survey, there was a mild decrease in admissions of IS during the COVID-19 lockdown period, with a significant delay in time to consultations and worse hospitalization outcomes., Competing Interests: Declarations of Competing Interest None., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background and Purpose: As studies vary in defining the prognostic significance of smoking in acute ischaemic stroke (AIS), we aimed to determine the relation of smoking and key outcomes in patient participants who had thrombolysed AIS of the international quasi-factorial randomised Enhanced Control of Hypertension and Thrombolysis Stroke Study (ENCHANTED)., Methods: Post-hoc analyses of ENCHANTED, an international quasi-factorial randomised evaluation of intravenous alteplase-dose comparison and levels of blood pressure control in patients who had thrombolysed AIS. Multivariable logistic regression models with inverse probability of treatment weighting (IPTW) propensity scores were used to determine associations of self-reported smoking status and clinical outcomes, according to 90-day modified Rankin Scale (mRS) scores and symptomatic intracerebral haemorrhage (sICH)., Results: Of 4540 patients who had an AIS, there were 1008 (22.2%) current smokers who were younger and predominantly male, with more comorbidities of hypertension, coronary artery disease, atrial fibrillation and diabetes mellitus, and greater baseline neurological impairment, compared with non-smokers. In univariate analysis, current smokers had a higher likelihood of a favourable shift in mRS scores (OR 0.88, 95% CI 0.77 to 0.99; p=0.038) but this association reversed in a fully adjusted model with IPTW (adjusted OR 1.15, 95% CI 1.04 to 1.28; p=0.009). A similar trend was also apparent for dichotomised poor outcome (mRS scores 2-6: OR 1.18, 95% CI 1.05 to 1.33; p=0.007), but not with the risk of sICH across standard criteria., Conclusion: Smoking predicts poor functional recovery in patients who had thrombolysed AIS., Trial Registration Number: NCT01422616., Competing Interests: Competing interests: RTL reports personal fees from Covidien and Pfizer; HA reports lecture fees from Takeda, Daiichi Sankyo, Astellas, and Aska Pharmaceuticals; outside the submitted work; JC reports research grants and lecture fees from Servier for the ADVANCE trial and post-trial follow-up; BO reports receiving fees for service on the data and safety monitoring committee of the THALES (ticagrelor) trial. CA reports personal lecture fees and travel support, and grants paid to his institution, from Takeda China., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: In-hospital acute ischemic stroke (HIS) accounts for 2-17% of all acute ischemic strokes (AIS) seen in hospital and they have worse prognosis. In this study we aimed to identify the frequency of HIS and their characteristics in our center., Materials and Methods: Retrospective analysis of a prospective register of patients with AIS seen at Clínica Alemana de Santiago, between January 2017 and January 2019. HIS and community onset ischemic strokes patients (CIS) were compared, univariate analysis was performed, covariates with p < 0.25 were selected for multivariate analysis. Differences between, proportion of strokes treated with thrombolytic therapy, door to needle time were compared between HIS and CIS patients, as also mortality rates at 90 days., Results: During the study period 369 patients with AIS were seen; of these 20 (5.4%, 95 CI%, 3.5-8.2) corresponded to HIS. In univariate analysis, HIS compared to patients arriving form the community to the emergency room, suffered more frequently from, heart failure (p = 0.04), and active malignancies (p < 0.001). HIS patients had longer times from symptom onset to non-contrast brain tomography (540 ±150 minutes); they were also less frequently treated with intravenous thrombolysis compared to community AIS: 15% versus 30% respectively (p = 0.08). Mortality rates at 90 days were higher in HIS: 30 versus 5% (p = 0.001)., Conclusions: In this cohort, HIS patients suffered delays in their neuroimaging studies and received less intravenous thrombolysis; this underscores the need for a standardized approach to the recognition and management of inhospital acute ischemic stroke., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Objective: Uncertainty exists over the prognostic significance of low arterial oxygen saturation (SaO 2 ) in acute stroke. We aimed to determine the strength of association of SaO 2 and adverse outcomes among participants of the international Head Positioning in acute Stroke Trial (HeadPoST)., Methods: Post-hoc analyzes of HeadPoST, a pragmatic cluster-crossover randomized trial of lying flat versus sitting up head positioning in 11,093 patients (age ≥18 years) with acute stroke at 114 hospitals in 9 countries during 2015-2016. Associations of the lowest recorded SaO 2 level, as a continuous measure and as a cut-point for desaturation (SaO 2 <93%), in the first 24 h and clinical outcomes of death or dependency (modified Rankin scale [mRS] scores 3-6) and any serious adverse event (SAE) at 90 days, were assessed in generalized linear mixed models adjusted for baseline and in-hospital management confounders., Results: There was an inverse J-shaped association between SaO 2 and death or dependency, with a nadir for optimal outcome at 96-97%. Patients with SaO 2 desaturation were older, and had greater neurological impairment, premorbid disability and cardiorespiratory disease. Desaturation was not clearly associated with death or dependency (adjusted odds ratio [aOR] 1.19, 95% confidence interval [CI] 0.95-1.48) but was with SAEs (aOR 1.34, 95% CI 1.07-1.68), without heterogeneity by head position, cardiac-respiratory comorbidity, or other pre-specified subgroups., Conclusions: Any change in SaO 2 outside of 96-97% is associated with poorer outcome after acute stroke., Clinical Trial Registration: HeadPoST is registered at ClinicalTrials.gov (NCT02162017)., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: The COVID-19 pandemic led to profound changes in the organization of health care systems worldwide., Aims: We sought to measure the global impact of the COVID-19 pandemic on the volumes for mechanical thrombectomy, stroke, and intracranial hemorrhage hospitalizations over a three-month period at the height of the pandemic (1 March-31 May 2020) compared with two control three-month periods (immediately preceding and one year prior)., Methods: Retrospective, observational, international study, across 6 continents, 40 countries, and 187 comprehensive stroke centers. The diagnoses were identified by their ICD-10 codes and/or classifications in stroke databases at participating centers., Results: The hospitalization volumes for any stroke, intracranial hemorrhage, and mechanical thrombectomy were 26,699, 4002, and 5191 in the three months immediately before versus 21,576, 3540, and 4533 during the first three pandemic months, representing declines of 19.2% (95%CI, -19.7 to -18.7), 11.5% (95%CI, -12.6 to -10.6), and 12.7% (95%CI, -13.6 to -11.8), respectively. The decreases were noted across centers with high, mid, and low COVID-19 hospitalization burden, and also across high, mid, and low volume stroke/mechanical thrombectomy centers. High-volume COVID-19 centers (-20.5%) had greater declines in mechanical thrombectomy volumes than mid- (-10.1%) and low-volume (-8.7%) centers (p < 0.0001). There was a 1.5% stroke rate across 54,366 COVID-19 hospitalizations. SARS-CoV-2 infection was noted in 3.9% (784/20,250) of all stroke admissions., Conclusion: The COVID-19 pandemic was associated with a global decline in the volume of overall stroke hospitalizations, mechanical thrombectomy procedures, and intracranial hemorrhage admission volumes. Despite geographic variations, these volume reductions were observed regardless of COVID-19 hospitalization burden and pre-pandemic stroke/mechanical thrombectomy volumes.

Competing Interests: PC, VV, PvG, CV, PP, BV, PD, AG, GC, EM, MG, and PB report no conflicts of interest.

Background: Stroke is a leading cause of disability and death worldwide. The best estimates of local, national, and global burden of stroke are derived from prospective population-based studies. We aimed to investigate the incidence, risk factors, long-term prognosis, care, and quality of life after stroke in the Ñuble region of Chile., Methods: We did a prospective community-based study with use of multiple overlapping sources of hospitalised, ambulatory, and deceased cases. Standardised diagnostic criteria were used to identify and follow up all cases occurring in the resident population of the Ñuble region, Chile (in a low-income rural-urban population including predominantly people of Indigenous-European heritage), for 1 year. Participants were included if they had a clinical diagnosis of stroke confirmed according to the study criteria. All cases were adjudicated by vascular neurologists. Incidence rates of first-ever stroke were calculated from the population of Ñuble according to the 2017 national census., Findings: From April 1, 2015, to March 31, 2016, we ascertained 1103 stroke cases, of which 890 (80·7%) were first-ever incident cases. The mean age of patients with first-ever stroke was 70·3 years (SD 14·1) and 443 (49·8%) were women. A CT scan was obtained in 801 (90%) of 890 patients (mean time from symptom onset to scan of 13·4 h (SD 29·8). The incidence of first-ever stroke age-adjusted to the world population was 121·7 (95% CI 113·7-130·1) per 100 000. The age-adjusted incidence rates, per 100 000 inhabitants, by main pathological subtypes were as follows: ischaemic stroke (101·5 [95% CI 90·9-113·0]); intracerebral haemorrhage (17·9 [13·5-23·4]), and subarachnoid haemorrhage (4·2 [2·1-7·3]). The 30-day case-fatality rate was 24·6% (21·9-27·6). At 6 months after the stroke, 55·9% (432 of 773) of cases had died or were disabled, which increased to 61·0% (456 of 747) at 12 months. Health-related quality of life in survivors was low at 6 months, improving slightly at 12 months after the stroke., Interpretation: The incidence of stroke in this low-resource population was higher than our previous finding in northern Chile and within the mid-range of most population-based stroke studies. This result was due mainly to a higher incidence of ischaemic stroke, probably associated with increasing age and a high prevalence of cardiometabolic risk factors in the population studied. Our findings suggest that more should be done for the prevention and care of stroke in communities like the Ñuble population., Funding: The National Agency for Research and Development and the Technology-Health Research Fund, Clínica Alemana de Santiago, Boehringer Ingelheim, Bristol Meyers Squibb, The Herminda Martin Clinical Hospital of Chillán, Universidad Mayor, and Universidad de Concepción., (Copyright © 2021 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background and Aims: The structured, simplified modified Rankin scale questionnaire (smRSq) may increase reliability over the interrogative approach to scoring the modified Rankin scale (mRS) in acute stroke research and practice. During the conduct of the alteplase-dose arm of the international ENhanced Control of Hypertension ANd Thrombolysis StrokE stuDy (ENCHANTED), we had an opportunity to compare each of these approaches to outcome measurement., Methods: Baseline demographic data were recorded together with the National Institutes of Health Stroke Scale (NIHSS). Follow-up measures obtained at 90 days included mRS, smRSq, and the 5-Dimension European Quality of life scale (EQ-5D). Agreements between smRSq and mRS were assessed with the Kappa statistic. Multiple logistic regression was used to identify baseline predictors of Day 90 smRSq and mRS scores. Treatment effects, based on Day 90 smRSq/mRS scores, were tested in logistic and ordinal logistic regression models., Results: SmRSq and mRS scores had good agreement (weighted Kappa 0.79, 95% confidence interval (CI) 0.78-0.81), while variables of age, atrial fibrillation, diabetes mellitus, pre-morbid mRS (1 vs. 0), baseline NIHSS scores, and imaging signs of cerebral ischemia, similarly predicted their scores. Odds ratios for death or disability, and ordinal shift, 90-day mRS scores using smRSq were 1.05 (95% CI 0.91-1.20; one-sided P = 0.23 for non-inferiority) and 0.98 (95% CI 0.87-1.11; P = 0.02 for non-inferiority), similar to those using mRS., Conclusions: This study demonstrates the utility of the smRSq in a large, ethnically diverse clinical trial population. Scoring of the smRSq shows adequate agreement with the standard mRS, thus confirming it is a reliable, valid, and useful alternative measure of functional status after acute ischemic stroke., Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01422616.

Background: An indwelling urinary catheter (IUC) is often inserted to manage bladder dysfunction, but its impact on prognosis is uncertain. We aimed to determine the association of IUC use on clinical outcomes after acute stroke in the international, multi-center, cluster crossover, Head Positioning in Acute Stroke Trial (HeadPoST)., Methods: Data were analyzed on HeadPoST participants (n = 11,093) randomly allocated to the lying-flat or sitting-up head position. Binomial, logistic regression, hierarchical mixed models were used to determine associations of early insertion of IUC within seven days post-randomization and outcomes of death or disability (defined as "poor outcome," scores 3-6 on the modified Rankin scale) and any urinary tract infection at 90 days with adjustment of baseline and post-randomization management covariates., Results: Overall, 1167 (12%) patients had an IUC, but the frequency and duration of use varied widely across patients in different regions. IUC use was more frequent in older patients, and those with vascular comorbidity, greater initial neurological impairment (on the National Institutes of Health Stroke Scale), and intracerebral hemorrhage as the underlying stroke type. IUC use was independently associated with poor outcome (adjusted odds ratio (aOR): 1.40, 95% confidence interval (CI): 1.13-1.74), but not with urinary tract infection after adjustment for antibiotic treatment and stroke severity at hospital separation (aOR: 1.13, 95% CI: 0.59-2.18). The number exposed to IUC for poor outcome was 13., Conclusions: IUC use is associated with a poor outcome after acute stroke. Further studies are required to inform appropriate use of IUC.

Objective: As uncertainties exist over underlying causes, we aimed to define the characteristics and prognostic significance of low blood pressure (BP) early after the onset of acute stroke., Methods: Post hoc analyzes of the international Head Positioning in acute Stroke Trial (HeadPoST), a pragmatic cluster-crossover randomized trial of lying flat versus sitting up in stroke patients from nine countries during 2015-2016. Associations of baseline BP and death or dependency [modified Rankin scale (mRS) scores 3-6] and serious adverse events (SAEs) at 90 days were assessed in generalized linear mixed models with adjustment for multiple confounders. SBP and DBP was analysed as continuous measures fitted with a cubic spline, and as categorical measures with low (<10th percentile) and high (≥140 and ≥90 mmHg, respectively) levels compared with a normal range (≥10th percentile; 120-139 and 70-89 mmHg, respectively)., Results: Among 11 083 patients (mean age 68 years, 39.9% women) with baseline BP values, 7.2 and 11.7% had low SBP (<120 mmHg) and DBP (<70 mmHg), respectively. Patients with low SBP were more likely to have preexisting cardiac and ischemic stroke and functional impairment, and to present earlier with more severe neurological impairment than other patients. Nonlinear 'J-shaped' relationships of BP and poor outcome were apparent: compared with normal SBP, those with low SBP had worse functional outcome (adjusted odds ratio 1.27, 95% confidence interval 1.02-1.58) and more SAEs, particularly cardiac events, with adjustment for potential confounders to minimize reverse causation. The findings were consistent for DBP and were stronger for ischemic rather than hemorrhagic stroke., Conclusion: The prognostic significance of low BP on poor outcomes in acute stroke was not explained by reverse causality from preexisting cardiovascular disease, and propensity towards greater neurological deficits and cardiac events. These findings provide support for the hypothesis that low BP exacerbates cardiac and cerebral ischemia in acute ischemic stroke., (Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc.)

Objective: Limited data exist on the optimum level of SBP in thrombolyzed patients with acute ischemic stroke (AIS). We aimed to determine the effects of intensive blood pressure (BP) lowering, specifically in patients with severe AIS who participated in the international, Enhanced Control of Hypertension and Thrombolysis Stroke Study., Methods: Prespecificed subgroup analyzes of the BP arm of Enhanced Control of Hypertension and Thrombolysis Stroke Study, a multicenter, partial-factorial, open, blinded outcome assessed trial, in which 2227 thrombolysis-eligible and treated AIS patients with elevated SBP (>150 mmHg) were randomized to intensive (target 130-140 mmHg) or guideline-recommended (<180 mmHg) BP management. Severe stroke was defined by computed tomography or magnetic resonance angiogram confirmation of large-vessel occlusion, receipt of endovascular therapy, final diagnosis of large artery atheromatous disease, or high (>10) baseline neurological scores on the National Institutes of Health Stroke Scale. The primary efficacy outcome was death or any disability (modified Rankin scale scores 2-6). The key safety outcome was intracranial hemorrhage (ICH). Treatment effects estimated in logistic regression models are reported as odds ratios (ORs) with 95% confidence intervals (CIs)., Results: There were 1311 patients [mean age 67 years; 37% female; median baseline National Institutes of Health Stroke Scale of 11 (range 6.0-15.0)] with severe AIS. Overall, there was no significant difference in the primary outcome of death or disability. However, intensive BP lowering significantly increased mortality (OR 1.52, 95% CI 1.09-2.13; P = 0.014) compared with guideline BP lowering, despite significantly lowering clinician-reported ICH (OR 0.63, 95% CI 0.43-0.92; P = 0.016)., Conclusion: Intensive BP lowering is associated with increased mortality in patients with severe AIS despite lowering the risk of ICH. Further randomized trials are required to provide reliable evidence over the optimum SBP target in the most serious type of AIS., Trial Registration: ClinicalTrials.gov Identifier: NCT01422616., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Patients with premorbid functional impairment are generally excluded from acute stroke trials. We aimed to determine the impact of including such patients in the Head Positioning in acute Stroke Trial (HeadPoST) and early additional impairment on outcomes., Methods: Post hoc analyses of HeadPoST, an international, cluster-randomized crossover trial of lying-flat versus sitting-up head positioning in acute stroke. Associations of early additional impairment, defined as change in modified Rankin scale (mRS) scores from premorbid levels (estimated at baseline) to Day 7 ("early ΔmRS"), and poor outcome (mRS score 3-6) at Day 90 were determined with generalized linear mixed model. Heterogeneity of the trial treatment effect was tested according to premorbid mRS scores 0-1 versus 2-5., Results: Of 8,285 patients (38.9% female, mean age 68 ± 13 years) with complete data, there were 1,984 (23.9%) with premorbid functional impairment (mRS 2-5). A significant linear association was evident for early ∆mRS and poor outcome (per 1-point increase in ΔmRS, adjusted odds ratio 1.20, 95% confidence interval 1.14-1.27; p < 0.0001). Patients with greater premorbid functional impairment were less likely to develop additional impairment, but their risk of poor 90-day outcome significantly increased with increasing (worse) premorbid mRS scores (linear trend p < 0.0001). There was no heterogeneity of the trial treatment effect by level of premorbid function., Conclusions: Early poststroke functional impairment that exceeded premorbid levels was associated with worse 90-day outcome, and this association increased with greater premorbid functional impairment. Yet, including premorbid impaired patients in the HeadPoST did not materially affect the subsequent treatment effect., Clinical Trial Registration: HeadPoST is registered at http://www.ClinicalTrials.gov (NCT02162017)., (© 2021 S. Karger AG, Basel.)

Objective: Access to acute stroke unit (ASU) care is known to vary worldwide. We aimed to quantify regional variations in the various components of ASU care., Method: Secondary analysis of the Head Positioning in acute Stroke Trial (HeadPoST), an international, multicentre, cluster crossover trial of head-up versus head-down positioning in 11,093 acute stroke patients at 114 hospitals in 9 countries. Patients characteristics and 11 standard components of processes of care were described according to ASU admission within and across four economically-defined regional groups (Australia/UK, China [includes Taiwan], India/Sri Lanka, and South America [Brazil/Chile/Colombia]). Variations in process of ASU care estimates were obtained in hierarchical mixed models, with adjustment for study design and potential patient- and hospital-level confounders., Results: Of 11,086 patients included in analyses, 59.7% (n = 6620) had an ASU admission. In China, India/Sri Lanka and South America, ASU patients were older, had greater neurological severity and more premorbid conditions than non-ASU patients. ASU patients were more likely to receive reperfusion therapy and multidisciplinary care within regions, but the components of care varied across regions. With Australia/UK as reference, patients in other regions had a lower probability of receiving reperfusion therapy, especially in India/Sri Lanka (adjusted odds ratio [aOR] 0.27, 95% confidence interval [CI] 0.12-0.63) and multidisciplinary care (mainly in formal dysphagia assessment, physiotherapy and occupational therapy)., Conclusion: There is significant variation in the components of stroke care across economically-defined regions of the world. Ongoing efforts are required to reduce disparities and optimise health outcomes, especially in resource poor areas., Clinical Trial Registration: HeadPoST is registered at ClinicalTrials.gov (NCT02162017)., (Copyright © 2020 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Although the Head Positioning in acute Stroke Trial (HeadPoST) showed no effect of the flat head position (FP; vs sitting up head position (SUP)) on functional outcome, we hypothesised that it could still offer benefits if commenced early in those with acute ischaemic stroke (AIS) of at least moderate severity., Methods: Subgroup analysis of HeadPoST in participants with National Institutes of Health Stroke Scale (NIHSS) scores ≥7, ≥10 and ≥14, randomised to FP or SUP <4.5 hours of AIS onset on functional outcomes defined by a shift in scores on the modified Rankin scale (mRS) and death/disability (mRS scores 3-6), and any cardiovascular serious adverse event. Logistic regression analyses were undertaken adjusted for study design and baseline risk factors., Results: There was no significant differential treatment effect in patient subgroups defined by increasing baseline NIHSS scores: adjusted OR and 95% CI for ordinal shift and binary (3-6) mRS scores: for NIHSS ≥7 (n=867) 0.92 (0.67 to 1.25) and 0.74 (0.52 to 1.04); NIHSS ≥ 10 (n=606) 0.80 (0.58 to 1.10) and 0.77 (0.49 to 1.19); NIHSS ≥14 (n=378) 0.82 (0.54 to 1.24) and 1.22 (0.69 to 2.14)., Conclusions: Early FP had no significant effect in patients with moderate-severe AIS., Trial Registration Number: NCT02162017., Competing Interests: Competing interests: AB reports research grants from Clínica Alemana de Santiago. PML reports research grants from The George Institute, Clínica Alemana de Santiago, and the Chilean Government, personal fees from Bristol Meyer Squibb, AstraZeneca and Bayer, and an unrestricted research grant from Lundbeck. TR is a National Institutes for Health Research Senior Investigator. VVO reports research grants from Clínica Alemana de Santiago, Boehringer-Ingelheim and Conicyt. PM-V reports research grants from Clínica Alemana de Santiago. MLH holds a National Health and Medical Research Council (NHMRC) of Australia Career Development Fellowship. SM is a member of the NHMRC Research Committee in 2015–2018. OP-N reports research grants for the Brazilian Stroke Research Network from the Brazilian government. CSA holds an NHMRC Senior Principal Research Fellowship, and reports honoraria and travel reimbursement from Takeda, Boehringer Ingelheim and Amgen., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background and Purpose: Transcranial Doppler (TCD) helps identify patients with carotid dissections at risk of ischemic events (IEs). There is paucity of data identifying independent predictors of IE in vertebral arterial dissection (VAD). We sought to investigate the clinical and ultrasound predictors of IE., Methods: Patients with VAD admitted between June 2017 and February 2020 were evaluated clinically and with TCD; sonographic curves, microembolic signals (MES), and the breath-holding index (BHI) test were applied. Covariates found on univariate screen (P < .25) were included in a multivariable linear regression to identify independent predictors of IEs., Results: Of 88 patients with 100 VAD, 75 (85.2%) were females with a mean age 37.9 ± 7.5 years. All patients received antiplatelet treatment. TCD monitoring lasted an average of 21 ± 2.1 minutes. TCD was abnormal in 23 cases (26.1%); 21 patients had abnormal sonographic curves in the vertebral/basilar arteries, while in 4 cases, MES were present and in 5 (4.5%), BHI was abnormal. None of the patients with a normal TCD had an IE. Six strokes occurred during follow up. On univariate analysis, male sex, diabetes, dyslipidemia, a previous myocardial infarct, migraine, time of consultation to the ER, bilateral VAD, MES, BHI abnormalities, post stenotic flow in the basilar artery (PFB), and basilar/vertebral velocities were significantly associated with the risk of IEs. In the multivariate analysis, only the presence of PFB was a significant predictor of IE (OR: 68.6, 95% CI 5-937, <.001)., Conclusions: TCD in VAD predicts patients at high risk of IE., (© 2020 American Society of Neuroimaging.)

Background: Low-dose alteplase (LrtPA) has been shown not to be inferior to the standard-dose (SrtPA) with respect to death/disability., Objective: We aim to evaluate the percentage of patients treated with LrtPA at our center after the ENCHANTED trial and the factors associated with the use of this dosage., Methods: Prospective study in consecutive patients with an acute stroke admitted between June 2016 and November 2018., Results: 160 patients were treated with intravenous thrombolysis, 50% female; mean age 65.4±18.5 years. Of these, 48 patients (30%) received LrtPA. In univariate analysis, LrtPA was associated with patient's age (p=0.000), previous modified Rankin scale scores (mRS) (p<0.000), hypertension (p=0.076), diabetes mellitus (p=0.021), hypercholesterolemia (p=0.19), smoking (p=0.06), atrial fibrillation (p=0.10), history of coronary artery disease (p=0.06), previous treatment with antiplatelet agents (p<0.000), admission International Normalized Ratio-INR (p=0.18), platelet count (p=0.045), leukoaraiosis on neuroimaging (p<0.003), contraindications for thrombolytic treatment (p=0.000) and endovascular treatment (p=0.027). Previous relevant bleedings were determinants for treatment with LrtPA. Final diagnosis on discharge of stroke mimic was significant (p=0.02) for treatment with SrtPA. In multivariate analysis, mRS (OR: 2.21; 95%CI 1.37‒14.19), previous antiplatelet therapy (OR: 11.41; 95%CI 3.98‒32.70), contraindications for thrombolysis (OR: 56.10; 95%CI 8.81‒357.80), leukoaraiosis (OR: 4.41; 95%CI 1.37‒14.10) and diagnosis of SM (OR: 0.22; 95%CI 0.10‒0.40) remained independently associated., Conclusions: Following the ENCHANTED trial, LrtPA was restricted to 30% of our patients. The criteria that clinicians apply are based mostly on clinical variables that may increase the risk of brain or systemic hemorrhage or exclude the patient from treatment with lytic drugs.

Background: Intravenous thrombolysis (IT) in acute ischemic stroke (AIS) is time dependent. The time elapsed from hospital admission to the thrombolytic bolus is named door to needle time (DNT) and is recommend to be of less than 60 min., Aim: To describe the DNT in our center and determine those factors associated with a DNT longer than 60 min., Material and Methods: Prospective analysis of patients treated with IT at a private hospital between June 2016 and June 2019. The percentage of patients with DNT exceeding 60 min, and the causes for this delay were evaluated., Results: IT was used in 205 patients. DNT was 43.6 ± 23.8 min. Forty patients (19.5% (95% CI, 14.4-25.7), had a DNT longer than 60 min. Uni-varied analysis demonstrated that AIS with infratentorial symptomatology (ITS), was significantly associated with DNTs exceeding 60 min. A history of hypertension, a higher NIH Stroke Scale score, the presence of an hyperdense sign in brain tomography (p = 0.001) and the need for endovascular therapy (p = 0.019), were associated with DNT shorter than 60 min. Multivariate analysis ratified the relationship between ITS and DNT longer than 60 min (Odds ratio: 3.19, 95% confidence intervals 1.26-8)., Conclusions: The individual elements that correlated with a DNT longer than 60 min were the failure to detect the AIS during triage and doubts about its diagnosis.

Background: High adherence to a Mediterranean Diet is associated with reduced incidence and mortality of acute ischemic stroke (AIS) but may also be associated with severity. Our purpose was to investigate the association of adherence to a Mediterranean diet and severity in a prospective hospital register of AIS patients., Methods: We included AIS patients admitted from February 2017 to July 2019. All were assessed by a neurologist with a standard stroke protocol, including NIHSS. Adherence to Mediterranean diet was prospectively measured by the 14-point Mediterranean Diet Adherence Screener (MEDAS) and defined as low (0-6 points) or high (7-14 points). Demographic and clinical characteristics were compared by group with univariate analysis. A Generalized Linear Model (GLM) was used to investigate the association of admission NIHSS as a continuous ordinal variable and an ordinal logistic regression (OLR) analysis to determine the independent association of the NIHSS quartiles with adherence to Mediterranean diet., Results: Three hundred sixty-eight patients were included, mean age 68.3 (17.7), 158 (42.9%) females. The median NIHSS score was 3 (IQR 1-9) and the median MEDAS score was 6 (IQR 4.5-8). Patients with high MEDAS scores had significantly lower; admission NIHSS scores, sedentary lifestyle, body mass index, total and LDL cholesterol levels, but higher alcohol consumption. After adjustments, high adherence to Mediterranean diet remained independently associated with lower stroke severity both in the GLM (β coefficient = - 0.19, p = 0.01) and in the OLR model (OR for lower NIHSS quartiles 0.6 (95% CI 0.37-0.98, p = 0.04)., Conclusions: Higher pre-stroke adherence to a Mediterranean diet is independently associated with lower AIS severity.

Background: Dysphagia is associated with aspiration pneumonia after stroke. Data are limited on the influences of dysphagia screen and assessment in clinical practice., Aims: To determine associations between a "brief" screen and "detailed" assessment of dysphagia on clinical outcomes in acute stroke patients., Methods: A prospective cohort study analyzed retrospectively using data from a multicenter, cluster cross-over, randomized controlled trial (Head Positioning in Acute Stroke Trial [HeadPoST]) from 114 hospitals in nine countries. HeadPoST included 11,093 acute stroke patients randomized to lying-flat or sitting-up head positioning. Herein, we report predefined secondary analyses of the association of dysphagia screening and assessment and clinical outcomes of pneumonia and death or disability (modified Rankin scale 3-6) at 90 days., Results: Overall, 8784 (79.2%) and 3917 (35.3%) patients were screened and assessed for dysphagia, respectively, but the frequency and timing for each varied widely across regions. Neither use of a screen nor an assessment for dysphagia was associated with the outcomes, but their results were compared to "screen-pass" patients, those who failed had higher risks of pneumonia (adjusted odds ratio [aOR] = 3.00, 95% confidence interval [CI] = 2.18-4.10) and death or disability (aOR = 1.66, 95% CI = 1.41-1.95). Similar results were evidence for the results of an assessment for dysphagia. Subsequent feeding restrictions were related to higher risk of pneumonia in patients failed dysphagia screen or assessment (aOR = 4.06, 95% CI = 1.72-9.54)., Conclusions: Failing a dysphagia screen is associated with increased risks of pneumonia and poor clinical outcome after acute stroke. Further studies concentrate on determining the effective subsequent feeding actions are needed to improve patient outcomes.

Background and Purpose- Patient-centered outcomes are important. We aimed to determine predictors of health-related quality of life (HRQoL) and develop utility-weighted modified Rankin Scale (mRS) scores in thrombolyzed acute ischemic stroke patients from both arms of ENCHANTED (Enhanced Control of Hypertension and Thrombolysis Stroke Study). Methods- ENCHANTED was an international quasi-factorial clinical trial of different doses of intravenous alteplase and intensities of blood pressure control in acute ischemic stroke patients, with outcomes on the 5-Dimensional European Quality of Life Scale and mRS assessed at 90 days post-randomization. Logistic regression models were used to identify baseline predictors of poor HRQoL (≤mean 5-Dimensional European Quality of Life Scale utility scores). Ordinary least squares regression derived utility-weighted mRS scores. Results- In 4016 acute ischemic stroke patients with complete 5-Dimensional European Quality of Life Scale and mRS data, independent predictors of poor HRQoL were older age (odds ratio, 1.19 [95% CI, 1.12-1.27], per 10-year increase), non-Asian ethnicity (1.91 [1.61-2.27]), greater stroke severity on the National Institutes of Health Stroke Scale (1.11 [1.09-1.12]), diabetes mellitus (1.41 [1.18-1.69]), premorbid disability (mRS score 1 versus 0; 1.62 [1.33-1.97]), large vessel atheromatous pathogenesis (1.32 [1.12-1.54]), and proxy respondent (2.35 [2.01-2.74]). Sensitivity analyses indicate the ethnicity influence on HRQoL was driven by the high proportion of Chinese (62.9% of Asian) participants with better HRQoL compared with non-Chinese or other Asian groups. Derived utility values across mRS scores 0 to 5 were 0.977, 0.885, 0.748, 0.576, 0.194, and -0.174, respectively. Correlations between mRS and 5-Dimensional European Quality of Life Scale scores were stronger in Asians. Conclusions- HRQoL is worse after thrombolyzed acute ischemic stroke in the elderly, non-Asians, with greater initial severity, diabetes mellitus, premorbid disability, due to large vessel atheroma, and proxy assessment. The broader significance of better HRQoL in Asians is tempered by Chinese participants dominating analyses. From utility-weighted mRS scores indicating the greatest steps in mRS scores are between 5 and 3, treatments to avoid major disability provide the greatest benefits for patients. Registration- URL: https://www.clinicaltrials.gov. Unique identifier: NCT01422616.

Background: Randomized controlled trials provide high-level evidence, but the necessity to include selected patients may limit the generalisability of their results., Methods: Comparisons were made of baseline and outcome data between patients with acute ischemic stroke (AIS) recruited into the alteplase-dose arm of the international, multi-center, Enhanced Control of Hypertension and Thrombolysis Stroke study (ENCHANTED) in the United Kingdom (UK), and alteplase-treated AIS patients registered in the UK Sentinel Stroke National Audit Programme (SSNAP) registry, over the study period June 2012 to October 2015., Results: There were 770 AIS patients (41.2% female; mean age 72 years) included in ENCHANTED at sites in England and Wales, which was 19.5% of alteplase-treated AIS patients registered in the SSNAP registry. Trial participants were significantly older, had lower baseline neurological severity, less likely Asian, and had more premorbid symptoms, hypertension and atrial fibrillation. Although ENCHANTED participants had higher rates of symptomatic intracerebral hemorrhage than those in SSNAP, there were no differences in onset-to-treatment time, levels of disability (assessed by the modified Rankin scale) at hospital discharge, and mortality over 90 days between groups., Conclusions: Despite the high level of participation, equipoise over the dose of alteplase among UK clinician investigators favored the inclusion of older, frailer, milder AIS patients in the ENCHANTED trial., Clinical Trial Registration: Clinical Trial Registration-URL: http://www.clinicaltrials.gov . Unique identifier: NCT01422616.

Background The uptake of proven stroke treatments varies widely. We aimed to determine the association of evidence-based processes of care for acute ischemic stroke ( AIS ) and clinical outcome of patients who participated in the HEADPOST (Head Positioning in Acute Stroke Trial), a multicenter cluster crossover trial of lying flat versus sitting up, head positioning in acute stroke. Methods and Results Use of 8 AIS processes of care were considered: reperfusion therapy in eligible patients; acute stroke unit care; antihypertensive, antiplatelet, statin, and anticoagulation for atrial fibrillation; dysphagia assessment; and physiotherapist review. Hierarchical, mixed, logistic regression models were performed to determine associations with good outcome (modified Rankin Scale scores 0-2) at 90 days, adjusted for patient and hospital variables. Among 9485 patients with AIS, implementation of all processes of care in eligible patients, or "defect-free" care, was associated with improved outcome (odds ratio, 1.40; 95% CI, 1.18-1.65) and better survival (odds ratio, 2.23; 95% CI , 1.62-3.09). Defect-free stroke care was also significantly associated with excellent outcome (modified Rankin Scale score 0-1) (odds ratio, 1.22; 95% CI , 1.04-1.43). No hospital characteristic was independently predictive of outcome. Only 1445 (15%) of eligible patients with AIS received all processes of care, with significant regional variations in overall and individual rates. Conclusions Use of evidence-based care is associated with improved clinical outcome in AIS . Strategies are required to address regional variation in the use of proven AIS treatments. Clinical Trial Registration URL : https://www.clinicaltrials.gov . Unique Identifier: NCT02162017.

The Head Positioning in Acute Stroke Trial (HeadPoST) is a pragmatic, international, cluster crossover randomized trial of 11,093 patients with acute stroke assigned to a lying-flat (0°) or sitting-up (head elevated ≥30°) position. This post hoc analysis aimed to determine the association between blood pressure variability (BPV) and outcomes for patients from a wide range of international clinical settings and how the association was modified by randomized head position. BPV was defined according to the standard criteria, with the key parameter considered the coefficient of variation (CV) of systolic BP (SBP) over 24 h. Outcome was ordinal 90-day Modified Rankin Scale (mRS) score. The association was analyzed by ordinal, logistic regression, hierarchical, mixed models with fixed intervention (lying flat vs. sitting up), and fixed period, random cluster, and random cluster-period, effects. Nine thousand one hundred and fifty six (8324 acute ischemic stroke and 817 intracerebral hemorrhage; mean age 68.1 years; 39.2% women) were included in the analysis. CV of SBP had a significant linear association with unfavorable shift of mRS at 90 days (adjusted odds ratio 1.06, 95% confidence interval 1.02-1.11; P = 0.01). There was no heterogeneity of the association by randomized head positioning. In addition, CV of diastolic BP (DBP) (1.08, 1.03-1.12; P = 0.001) over 24 h post stroke was significantly associated with 3-month poor outcome. The association was more apparent in sitting-up position (1.12, 1.06-1.19) compared with lying-flat position (1.03, 0.98-1.09) (P interaction = 0.005). BPV was associated with adverse stroke outcome, and the magnitude of the association was greater with sitting-up head positioning in terms of DBP variability.

Background and Purpose- Infratentorial intracerebral hemorrhage (ICH) has a poor outcome but is rarely analyzed by cerebellar versus brain stem location. We evaluated this relationship and clinical outcomes among participants of the INTERACT 1 and 2 (Intensive Blood Pressure Reduction in Acute Cerebral Hemorrhage Trials). Methods- Participants with brain stem and cerebellar ICH were compared. Logistic regression models were used to compare outcomes of death or major disability and quality of life. Results- Of 195 included patients, 92 (47%) and 103 (53%) had brain stem and cerebellar ICH, respectively. Patients with brain stem ICH were younger (mean [SD] age, 59±13 versus 70±11 years), less female (28.3% versus 50.5%), with higher admission National Institutes of Health Stroke Scale scores (median [interquartile range], 6 [4-10) versus 3 [2-8]), less prior ICH (3% versus 17%), smaller ICH volumes (1.6 mL [1.0-2.8 mL] versus 5.1 mL [2.6-10.7 mL]), and less intraventricular extension (3% versus 39%) than those with cerebellar ICH. Brain stem ICH had higher mortality (odds ratio, 37.1; 95% CI, 1.99-692.27) and worse scores in the European Quality of Life Scale (EQ-5D) pain domain (odds ratio, 3.36; 95% CI, 1.38-8.20). Conclusions- Cerebellar and brain stem ICH differ in their clinical characteristics and prognosis, with the latter being associated with higher case fatality and worse EQ-5D scores in the pain domain. Clinical Trial Registration- URL: https://www.clinicaltrials.gov . Unique identifiers: NCT00226096 and NCT00716079.

Background and Purpose- Low ankle-brachial index (ABI) identifies a stroke subgroup with high risk of recurrent stroke, cardiovascular events, and death. However, limited data exist on the relationship between low ABI and stroke in low and middle-income countries. Therefore, we evaluated the prevalence of ABI ≤0.90 (which is diagnostic of peripheral artery disease) in nonembolic stroke patients or transient ischemic attack and assessed the correlation of low ABI with stroke risk, factors, and recurrent vascular events and death. Methods- Patients ≥45 years with acute transient ischemic attack or minor ischemic strokes were recruited consecutively from over 17 low-income and middle-income countries (Latin America [1543 patients], Middle East [1041 patients], North Africa [834 patients], and South Africa [217 patients]). The ABI measurement was performed at a single visit. Stroke recurrence and risk of new vascular events were assessed after 24 months of follow-up. Results- Among 3487 enrolled patients, abnormal ABI (<0.9) was present in 22.3 %. Patients with an ABI of ≤0.9 were more likely ( P<0.05) to be male, older, and have a history of peripheral artery disease, hypertension, and diabetes mellitus. During 2-year follow-up, the rate of major cardiovascular event was higher in patients with ABI <0.9 than those with ABI ≥0.9 (Kaplan-Meier estimates, 22.5%; 95% CI, 19.6-25.8 versus 13.7%; 21.4-15.1; P<0.001), and when ABI was categorized into 4 groups (≤0.6; 95% CI, 0.6-0.9; 0.9-1; 1-1.4), the rate of major cardiovascular event was higher in those with ABI ≤0.6 than the other groups (Kaplan-Meier estimates, 32.6%; 95% CI, 21.0-48.3 for ABI≤0.6 versus 21.7%; 95% CI, 18.8-25.0 for ABI 0.6-0.9 versus 14.3%; 95% CI, 12.4-16.6 for ABI 0.9-1 versus 13.3%; 95% CI, 11.6-15.2 for ABI 1-1.4; P<0.001). Conclusions- Among patients with nonembolic ischemic stroke or transient ischemic attack, those with low ABI had a higher rate of vascular events and death in this population. Screening for ABI in stroke patients may help identify patients at high risk of future events.

Background: Systolic blood pressure of more than 185 mm Hg is a contraindication to thrombolytic treatment with intravenous alteplase in patients with acute ischaemic stroke, but the target systolic blood pressure for optimal outcome is uncertain. We assessed intensive blood pressure lowering compared with guideline-recommended blood pressure lowering in patients treated with alteplase for acute ischaemic stroke., Methods: We did an international, partial-factorial, open-label, blinded-endpoint trial of thrombolysis-eligible patients (age ≥18 years) with acute ischaemic stroke and systolic blood pressure 150 mm Hg or more, who were screened at 110 sites in 15 countries. Eligible patients were randomly assigned (1:1, by means of a central, web-based program) within 6 h of stroke onset to receive intensive (target systolic blood pressure 130-140 mm Hg within 1 h) or guideline (target systolic blood pressure <180 mm Hg) blood pressure lowering treatment over 72 h. The primary outcome was functional status at 90 days measured by shift in modified Rankin scale scores, analysed with unadjusted ordinal logistic regression. The key safety outcome was any intracranial haemorrhage. Primary and safety outcome assessments were done in a blinded manner. Analyses were done on intention-to-treat basis. This trial is registered with ClinicalTrials.gov, number NCT01422616., Findings: Between March 3, 2012, and April 30, 2018, 2227 patients were randomly allocated to treatment groups. After exclusion of 31 patients because of missing consent or mistaken or duplicate randomisation, 2196 alteplase-eligible patients with acute ischaemic stroke were included: 1081 in the intensive group and 1115 in the guideline group, with 1466 (67·4%) administered a standard dose among the 2175 actually given intravenous alteplase. Median time from stroke onset to randomisation was 3·3 h (IQR 2·6-4·1). Mean systolic blood pressure over 24 h was 144·3 mm Hg (SD 10·2) in the intensive group and 149·8 mm Hg (12·0) in the guideline group (p<0·0001). Primary outcome data were available for 1072 patients in the intensive group and 1108 in the guideline group. Functional status (mRS score distribution) at 90 days did not differ between groups (unadjusted odds ratio [OR] 1·01, 95% CI 0·87-1·17, p=0·8702). Fewer patients in the intensive group (160 [14·8%] of 1081) than in the guideline group (209 [18·7%] of 1115) had any intracranial haemorrhage (OR 0·75, 0·60-0·94, p=0·0137). The number of patients with any serious adverse event did not differ significantly between the intensive group (210 [19·4%] of 1081) and the guideline group (245 [22·0%] of 1115; OR 0·86, 0·70-1·05, p=0·1412). There was no evidence of an interaction of intensive blood pressure lowering with dose (low vs standard) of alteplase with regard to the primary outcome., Interpretation: Although intensive blood pressure lowering is safe, the observed reduction in intracranial haemorrhage did not lead to improved clinical outcome compared with guideline treatment. These results might not support a major shift towards this treatment being applied in those receiving alteplase for mild-to-moderate acute ischaemic stroke. Further research is required to define the underlying mechanisms of benefit and harm resulting from early intensive blood pressure lowering in this patient group., Funding: National Health and Medical Research Council of Australia; UK Stroke Association; Ministry of Health and the National Council for Scientific and Technological Development of Brazil; Ministry for Health, Welfare, and Family Affairs of South Korea; Takeda., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: Echocardiography (ECO) is frequently used as a screening test in patients with acute ischemic brain disease. We aimed to evaluate the additional information and therapeutic impact resulting from ECO in these patients., Methods: We conducted a prospective study performing ECO on consecutive patients with ischemic stroke or transient ischemic attacks, admitted to our centre between February 2013 and May 2017., Results: A total of 696 patients were included (female, 57.3%; mean age, 70 ± 15.3 years). Seven hundred thirty two echocardiographic examinations were performed (696 transthoracic and 36 transesophageal). Echocardiography yielded findings judged of clinical importance in 142 patients (20.4%, 95% CI 17.5-23.5). The most frequent of these were left atrial volume enlargement or a normal evaluation. Echocardiography findings resulted in changes in the management of 76 patients (10.7% 95% CI 8.8-13.4); initiation of anticoagulation therapy, administration of IV antibiotic therapy, cardiac surgeries, or other pharmacological therapies occurring in 42 cases (6%). The presence of coronary heart disease (OR: 2.64 95% CI 1.34-5.25), atrial fibrillation (OR: 0.24; 95% CI, 0.2-0.69), and admission NIHSS (OR: 1.04; 95% CI, 1.01-1.09), were the variables associated with changes in management., Conclusions: In unselected patients with acute ischemic stroke ECO had a low yield of additional information, and it changed management in a small percentage of patients., (Copyright © 2018. Published by Elsevier Inc.)

Objective: To determine the extent to which the effects of intensive blood pressure (BP) lowering are modified by doses of alteplase in thrombolysis-eligible acute ischemic stroke (AIS) patients., Methods: Prespecified analyses of the Enhanced Control of Hypertension and Thrombolysis Stroke Study for patients enrolled in both arms: (i) low-dose (0.6 mg/kg body weight) or standard-dose (0.9 mg/kg) alteplase and (ii) intensive (target systolic BP [SBP] 130-140 mm Hg) or guideline-recommended (target SBP <180 mm Hg) BP management. The primary outcome was functional recovery, measured by a shift in scores on modified Rankin scale at 90 days. The safety outcome was any intracranial hemorrhage (ICH)., Results: There were 925 participants (mean age 67 years, 39% female, 77% Asian) randomized to both arms: 242 randomly assigned to guideline/standard-dose (GS); 234 to guideline/low-dose (GL); 227 to intensive/standard-dose (IS); and 222 to intensive/low-dose (IL). Overall, average SBP levels within 24 h were lower in the low-dose compared to standard-dose alteplase group (146 and 144 vs. 151 and 150 mm Hg, for GS and GL vs. IS and IL, respectively, p < 0.0001). There was no heterogeneity of the effects of BP lowering (intensive vs. guideline) on functional recovery between standard-dose (OR 0.81, 95% CI 0.59-1.12) and low-dose alteplase (1.06, 0.77-1.47; p = 0.25 for interaction). Similar results were observed for ICH (p = 0.50 for interaction)., Conclusions: In thrombolysis-treated patients with predominantly mild-to-moderate severity AIS, intensive BP lowering neither improve functional recovery, either with low- or standard-dose intravenous alteplase, nor beneficially interact with low-dose alteplase in reducing ICH., Trial Registration: The trial is registered with ClinicalTrials.gov (NCT01422616)., (© 2019 S. Karger AG, Basel.)

Background: The lifetime risk of stroke has been calculated in a limited number of selected populations. We sought to estimate the lifetime risk of stroke at the regional, country, and global level using data from a comprehensive study of the prevalence of major diseases., Methods: We used the Global Burden of Disease (GBD) Study 2016 estimates of stroke incidence and the competing risks of death from any cause other than stroke to calculate the cumulative lifetime risks of first stroke, ischemic stroke, or hemorrhagic stroke among adults 25 years of age or older. Estimates of the lifetime risks in the years 1990 and 2016 were compared. Countries were categorized into quintiles of the sociodemographic index (SDI) used in the GBD Study, and the risks were compared across quintiles. Comparisons were made with the use of point estimates and uncertainty intervals representing the 2.5th and 97.5th percentiles around the estimate., Results: The estimated global lifetime risk of stroke from the age of 25 years onward was 24.9% (95% uncertainty interval, 23.5 to 26.2); the risk among men was 24.7% (95% uncertainty interval, 23.3 to 26.0), and the risk among women was 25.1% (95% uncertainty interval, 23.7 to 26.5). The risk of ischemic stroke was 18.3%, and the risk of hemorrhagic stroke was 8.2%. In high-SDI, high-middle-SDI, and low-SDI countries, the estimated lifetime risk of stroke was 23.5%, 31.1% (highest risk), and 13.2% (lowest risk), respectively; the 95% uncertainty intervals did not overlap between these categories. The highest estimated lifetime risks of stroke according to GBD region were in East Asia (38.8%), Central Europe (31.7%), and Eastern Europe (31.6%), and the lowest risk was in eastern sub-Saharan Africa (11.8%). The mean global lifetime risk of stroke increased from 22.8% in 1990 to 24.9% in 2016, a relative increase of 8.9% (95% uncertainty interval, 6.2 to 11.5); the competing risk of death from any cause other than stroke was considered in this calculation., Conclusions: In 2016, the global lifetime risk of stroke from the age of 25 years onward was approximately 25% among both men and women. There was geographic variation in the lifetime risk of stroke, with the highest risks in East Asia, Central Europe, and Eastern Europe. (Funded by the Bill and Melinda Gates Foundation.).

Along with the rising global burden of disability attributed to stroke, costs of stroke care are rising, providing the impetus to direct our research focus towards effective measures of stroke prevention. In this Series paper, we discuss strategies for reducing the risk of the emergence of disease (primordial prevention), preventing the onset of disease (primary prevention), and preventing the recurrence of disease (secondary prevention). Our focus includes global strategies and campaigns, and measurements of the effectiveness of worldwide preventive interventions, with an emphasis on low-income and middle-income countries. Our findings reveal that effective tobacco control, adequate nutrition, and development of healthy cities are important strategies for primordial prevention, whereas polypill strategies, use of mobile technology (mHealth), along with salt reduction and other dietary interventions, are effective in the primary prevention of stroke. An effective collaboration between various health-care sectors, government policies, and campaigns can successfully implement secondary prevention strategies, through surveillance and registries, such as the WHO's non-communicable diseases programmes, across high-income and low-income countries., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background Whether lying-flat improves blood flow in patients with acute ischemic stroke is unknown. Our aim was to investigate if lying-flat "changes" cerebral blood flow velocities assessed by transcranial Doppler in acute ischemic stroke patients. Methods In a multicenter cluster clinical trial, we randomly assigned patients within 12 h from onset of a neurological deficit due to cerebral ischemia of the anterior circulation to lying-flat or upright head positioning. The primary outcome was a change of 8 cm/s or more in mean cerebral blood flow velocities on transcranial Doppler to the middle cerebral artery at 1 and 24 h post-randomization, adjusted for imbalance in baseline variables. Secondary outcomes included serious adverse events and physical functioning at 90 days. Results Ninety-four of 304 patients screened were recruited. The primary outcome occurred in 11 (26%) of 43 patients in the lying-flat group and in 6 (12%) of 51 in the upright group at 1 h (adjusted odds ratio, 3.81; 95% CI, 1.07 to 13.54), and in 23 (53%) and 18 (36%) patients in these respective groups at 24 h (adjusted odds ratio, 3.04; 95% CI, 1.08 to 8.53). There were no between-group differences in serious adverse events, including pneumonia, heart failure or mortality, nor in functional outcome at 3 months (adjusted common odds ratio, 1.38; 95% CI 0.64 to 3.00). Conclusion The lying-flat head position was associated with a significant increase in cerebral blood flow velocities at one and 24 h within the ipsilateral hemisphere of anterior circulation acute ischemic stroke, without serious safety concerns. Clinical trial registration-URL: http://www.clinicaltrials.gov . Unique identifier: NCT01706094.

Background: Debate exists as to whether statin pretreatment confers an increased risk of 90-day mortality and symptomatic intracranial haemorrhage (sICH) in acute ischaemic stroke (AIS) patients treated with intravenous thrombolysis. We assessed the effects of undifferentiated lipid-lowering pretreatment on outcomes and interaction with low-dose versus standard-dose alteplase in a post hoc subgroup -analysis of the Enhanced Control of Hypertension and Thrombolysis Stroke Study., Methods: In all, 3,284 thrombolysis-eligible AIS patients (mean age 66.6 years; 38% women), with information on lipid-lowering pretreatment, were randomly assigned to low-dose (0.6 mg/kg) or standard-dose (0.9 mg/kg) intravenous alteplase within 4.5 h of symptom onset. Of the total number of patients, 615 (19%) received statin or other lipid-lowering pretreatment. The primary clinical outcome was combined endpoint of death or disability (modified Rankin Scale scores 2-6) at 90 days., Results: Compared with patients with no lipid-lowering pretreatment, those with lipid-lowering pretreatment were significantly older, more likely to be non-Asian and more likely to have a medical history including vascular co-morbidity. After propensity analysis assessment and adjustment for important baseline variables at the time of randomisation, as well as imbalances in management during the first 7 days of hospital admission, there were no significant differences in mortality (OR 0.85; 95% CI 0.58-1.25, p = 0.42), or in overall -90-day death and disability (OR 0.85, 95% CI 0.67-1.09, p = 0.19), despite a significant decrease in sICH among those with -lipid-lowering pretreatment according to the European Co-operative Acute Stroke Study 2 definition (OR 0.49, 95% CI 0.28-0.83, p = 0.009). No differences in key efficacy or safety outcomes were seen in patients with and without lipid-lowering pretreatment between low- and standard-dose alteplase arms., Conclusions: Lipid-lowering pretreatment is not associated with adverse outcome in AIS patients treated with intravenous alteplase, whether assessed by 90-day death and disability or death alone., (© 2018 S. Karger AG, Basel.)

Background: The prognosis in acute spontaneous intracerebral hemorrhage (ICH) is related to hematoma volume, where >30 mL is commonly used to define large ICH as a threshold for neurosurgical decompression but without clear supporting evidence., Objectives: To determine the factors associated with large ICH and neurosurgical intervention among participants of the Intensive Blood Pressure Reduction in Acute Cerebral Hemorrhage Trials (INTERACT)., Methods: We performed pooled analysis of the pilot INTERACT1 (n = 404) and main INTERACT2 (n = 2839) studies of ICH patients (<6 h of onset) with elevated systolic blood pressure (SBP, 150-220 mm Hg) who were randomized to intensive (target SBP < 140 mm Hg) or contemporaneous guideline-recommended (target SBP < 180 mm Hg) management. Neurosurgical intervention data were collected at 7 d postrandomization. Multivariable logistic regression was used to determine associations., Results: There were 372 (13%) patients with large ICH volume (>30 mL), which was associated with nonresiding in China, nondiabetic status, severe neurological deficit (National Institutes of Health stroke scale [NIHSS] score ≥ 15), lobar location, intraventricular hemorrhage extension, raised leucocyte count, and hyponatremia. Significant predictors of those patients who underwent surgery (226 of 3233 patients overall; 83 of 372 patients with large ICH) were younger age, severe neurological deficit (lower Glasgow coma scale score, and NIHSS score ≥ 15), baseline ICH volume > 30 mL, and intraventricular hemorrhage., Conclusions: Early identification of severe ICH, based on age and clinical and imaging parameters, may facilitate neurosurgery and intensive monitoring of patients., (Copyright © 2017 by the Congress of Neurological Surgeons)

Background and Purpose: Renal dysfunction (RD) is associated with poor prognosis after stroke. We assessed the effects of RD on outcomes and interaction with low- versus standard-dose alteplase in a post hoc subgroup analysis of the ENCHANTED (Enhanced Control of Hypertension and Thrombolysis Stroke Study)., Methods: A total of 3220 thrombolysis-eligible patients with acute ischemic stroke (mean age, 66.5 years; 37.8% women) were randomly assigned to low-dose (0.6 mg/kg) or standard-dose (0.9 mg/kg) intravenous alteplase within 4.5 hours of symptom onset. Six hundred and fifty-nine (19.8%) patients had moderate-to-severe RD (estimated glomerular filtration rate, <60 mL/min per 1.73 m 2 ) at baseline. The impact of RD on death or disability (modified Rankin Scale scores, 2-6) at 90 days, and symptomatic intracerebral hemorrhage, was assessed in logistic regression models., Results: Compared with patients with normal renal function (>90 mL/min per 1.73 m 2 ), those with severe RD (<30 mL/min per 1.73 m 2 ) had increased mortality (adjusted odds ratio, 2.07; 95% confidence interval, 0.89-4.82; P =0.04 for trend); every 10 mL/min per 1.73 m 2 lower estimated glomerular filtration rate was associated with an adjusted 9% increased odds of death from thrombolysis-treated acute ischemic stroke. There was no significant association with modified Rankin Scale scores 2 to 6 (adjusted odds ratio, 1.03; 95% confidence interval, 0.62-1.70; P =0.81 for trend), modified Rankin Scale 3 to 6 (adjusted odds ratio, 1.20; 95% confidence interval, 0.72-2.01; P =0.44 for trend), or symptomatic intracerebral hemorrhage, or any heterogeneity in comparative treatment effects between low-dose and standard-dose alteplase by RD grades., Conclusions: RD is associated with increased mortality but not disability or symptomatic intracerebral hemorrhage in thrombolysis-eligible and treated acute ischemic stroke patients. Uncertainty persists as to whether low-dose alteplase confers benefits over standard-dose alteplase in acute ischemic stroke patients with RD., Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01422616., (© 2017 American Heart Association, Inc.)

Background: Seizures after ischemic stroke have not been well-studied. We aim to determine the frequency, determinants, and significance of early seizures after thrombolysis for acute ischemic stroke., Methods: Data are from the Enhanced Control of Hypertension and Thrombolysis Stroke Study (ENCHANTED), an international, multicenter, randomized controlled trial where patients with acute ischemic stroke were randomized to low-dose (0.6 mg/kg) or standard-dose (0.9 mg/kg) IV alteplase. The protocol prespecified prospective data collection on in-hospital seizures over 7 days postrandomization. Logistic regression models were used to determine variables associated with seizures and their significance on poor outcomes of death or disability (modified Rankin scale scores 3-6), symptomatic intracerebral hemorrhage (sICH), and European Quality of Life 5-Dimensions questionnaire [EQ-5D] over 90 days., Results: Data were available for 3,139 acute ischemic stroke participants, of whom 42 (1.3%) had seizures at a median 22.7 hours after the onset of symptoms. Baseline variables associated with seizures were male sex (odds ratio [OR] 2.19, 95% confidence interval [CI] 1.07-4.50), severe neurologic impairment (NIH Stroke Scale score ≥10; OR 2.16, 95% CI 1.06-4.40), and fever (OR 4.55, 95% CI 2.37-8.71). Seizures independently predicted poor recovery: death or major disability (OR 2.88, 95% CI 1.28-6.47), unfavorable ordinal shift of mRS scores (OR 1.94, 95% CI 1.10-3.39), and lower than median EQ-5D health utility index score (OR 3.50, 95% CI 1.37-8.91). There was no association of seizures with sICH in adjusted analysis., Conclusions: In thrombolysis-treated patients with acute ischemic stroke, seizures are uncommon, occur early, and predict poor recovery., Clinicaltrialsgov Identifier: NCT01422616.

Background There is evidence to indicate that the lying flat head position increases cerebral blood flow and oxygenation in patients with acute ischemic stroke, but how these physiological effects translate into clinical outcomes is uncertain. The Head Position in Stroke Trial aims to determine the comparative effectiveness of lying flat (0°) compared to sitting up (≥30°) head positioning, initiated within 24 h of hospital admission for patients with acute stroke. Design An international, pragmatic, cluster-randomized, crossover, open, blinded outcome assessed clinical trial. Each hospital with an established acute stroke unit (cluster) site was required to recruit up to 140 consecutive cases of acute stroke (one phase of head positioning before immediately crossing over to the other phase of head positioning), including both acute ischemic stroke and intracerebral hemorrhage, in each randomized head position as a 'business as usual' policy. Objective To outline in detail the predetermined statistical analysis plan for the study. Methods All accumulated data will be reviewed and formally assessed. Information regarding baseline characteristics of patients, their process of care and management will be outlined, and for each item, statistically relevant descriptive elements will be described. For the trial outcomes, the most appropriate statistical comparisons are described. Results A statistical analysis plan was developed that is transparent, verifiable, and predetermined before completion of data collection. Conclusions We developed a predetermined statistical analysis plan for Head Position in Stroke Trial to avoid analysis bias arising from prior knowledge of the findings, in order to reliably quantify the benefits and harms of lying flat versus sitting up early after the onset of acute stroke. Trial registration ClinicalTrials.gov identifier NCT02162017; ANZCTR identifier ACTRN12614000483651.

Background and Purpose: Many patients receiving thrombolysis for acute ischemic stroke are on prior antiplatelet therapy (APT), which may increase symptomatic intracerebral hemorrhage risk. In a prespecified subgroup analysis, we report comparative effects of different doses of intravenous alteplase according to prior APT use among participants of the international multicenter ENCHANTED study (Enhanced Control of Hypertension and Thrombolysis Stroke Study)., Methods: Among 3285 alteplase-treated patients (mean age, 66.6 years; 38% women) randomly assigned to low-dose (0.6 mg/kg) or standard-dose (0.9 mg/kg) intravenous alteplase within 4.5 hours of symptom onset, 752 (22.9%) reported prior APT use. Primary outcome at 90 days was the combined end point of death or disability (modified Rankin Scale [mRS] scores, 2-6). Other outcomes included mRS scores 3 to 6, ordinal mRS shift, and symptomatic intracerebral hemorrhage by various standard criteria., Results: There were no significant differences in outcome between patients with and without prior APT after adjustment for baseline characteristics and management factors during the first week; defined by mRS scores 2 to 6 (adjusted odds ratio [OR], 1.01; 95% confidence interval [CI], 0.81-1.26; P =0.953), 3 to 6 (OR, 0.95; 95% CI, 0.75-1.20; P =0.662), or ordinal mRS shift (OR, 1.03; 95% CI, 0.87-1.21; P =0.770). Alteplase-treated patients on prior APT had higher symptomatic intracerebral hemorrhage (OR, 1.82; 95% CI, 1.00-3.30; P =0.051) according to the safe implementation of thrombolysis in stroke-monitoring study definition. Although not significant ( P -trend, 0.053), low-dose alteplase tended to have better outcomes than standard-dose alteplase in those on prior APT compared with those not using APT (mRS scores of 2-6; OR, 0.84; 95% CI, 0.62-1.12 versus OR, 1.16; 95% CI, 0.99-1.36)., Conclusions: Low-dose alteplase may improve outcomes in thrombolysis-treated acute ischemic stroke patients on prior APT, but this requires further evaluation in a randomized controlled trial., Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01422616., (© 2017 American Heart Association, Inc.)