Prevention of infections and fever to improve outcome in older patients with acute stroke (PRECIOUS): a randomised, open, phase III, multifactorial, clinical trial with blinded outcome assessment.

Background: Infections and fever after stroke are associated with poor functional outcome or death. We assessed whether prophylactic treatment with anti-emetic, antibiotic, or antipyretic medication would improve functional outcome in older patients with acute stroke. Methods: We conducted an international, 2∗2∗2-factorial, randomised, controlled, open-label trial with blinded outcome assessment in patients aged 66 years or older with acute ischaemic stroke or intracerebral haemorrhage and a score on the National Institutes of Health Stroke Scale ≥ 6. Patients were randomly allocated (1:1) to metoclopramide (oral, rectal, or intravenous; 10 mg thrice daily) vs. no metoclopramide, ceftriaxone (intravenous; 2000 mg once daily) vs. no ceftriaxone, and paracetamol (oral, rectal, or intravenous; 1000 mg four times daily) vs. no paracetamol, started within 24 h after symptom onset and continued for four days. All participants received standard of care. The target sample size was 3800 patients. The primary outcome was the score on the modified Rankin Scale (mRS) at 90 days analysed with ordinal logistic regression and reported as an adjusted common odds ratio (an acOR < 1 suggests benefit and an acOR > 1 harm). This trial is registered (ISRCTN82217627). Findings: From April 2016 through June 2022, 1493 patients from 67 European sites were randomised to metoclopramide (n = 704) or no metoclopramide (n = 709), ceftriaxone (n = 594) or no ceftriaxone (n = 482), and paracetamol (n = 706) or no paracetamol (n = 739), of whom 1471 were included in the intention-to-treat analysis. Prophylactic use of study medication did not significantly alter the primary outcome at 90 days: metoclopramide vs. no metoclopramide (adjusted common odds ratio [acOR], 1.01; 95% CI 0.81-1.25), ceftriaxone vs. no ceftriaxone (acOR 0.99; 95% CI 0.77-1.27), paracetamol vs. no paracetamol (acOR 1.19; 95% CI 0.96-1.47). The study drugs were safe and not associated with an increased incidence of serious adverse events. Interpretation: We observed no sign of benefit of prophylactic use of metoclopramide, ceftriaxone, or paracetamol during four days in older patients with a moderately severe to severe acute stroke. Funding: This project has received funding from the European Union's Horizon 2020 research and innovation programme under grant agreement No: 634809.

Predictors of functional outcome after symptomatic intracranial hemorrhage complicating intravenous thrombolysis: results from the SITS-ISTR.

BACKGROUND AND PURPOSE: Several risk factors of symptomatic intracerebral hemorrhage (SICH) following intravenous thrombolysis for acute ischaemic stroke have been established. However, potential predictors of good functional outcome post-SICH have been less studied. METHODS: Patient data registered in the Safe Implementation of Treatment in Stroke-International Stroke Thrombolysis Register (SITS-ISTR) from 2005 to 2021 were used. Acute ischaemic stroke patients who developed post intravenous thrombolysis SICH according to the SITS Monitoring Study definition were analyzed to identify predictors of functional outcomes. RESULTS: A total of 1679 patients with reported SICH were included, out of which only 2.8% achieved good functional outcome (modified Rankin Scale scores of 0-2), whilst 80.9% died at 3 months. Higher baseline National Institutes of Health Stroke Scale (NIHSS) score and 24-h ΔNIHSS score were independently associated with a lower likelihood of achieving both good and excellent functional outcomes at 3 months. Baseline NIHSS and hematoma location (presence of both SICHs, defined as remote and local SICH concurrently; n = 478) were predictors of early mortality within 24 h. Independent predictors of 3-month mortality were age, baseline NIHSS, 24-h ΔNIHSS, admission serum glucose values and hematoma location (both SICHs). Age, baseline NIHSS score, 24-h ΔNIHSS, hyperlipidemia, prior stroke/transient ischaemic attack, antiplatelet treatment, diastolic blood pressure at admission, glucose values on admission and SICH location (both SICHs) were associated with reduced disability at 3 months (≥1-point reduction across all modified Rankin Scale scores). Patients with remote SICH (n = 219) and local SICH (n = 964) had comparable clinical outcomes, both before and after propensity score matching. CONCLUSIONS: Symptomatic intracerebral hemorrhage presents an alarmingly high prevalence of adverse clinical outcomes, with no difference in clinical outcomes between remote and local SICH.

European Stroke Organisation (ESO) expedited recommendation on tenecteplase for acute ischaemic stroke.

Within the last year, four randomised-controlled clinical trials (RCTs) have been published comparing intravenous thrombolysis (IVT) with tenecteplase and alteplase in acute ischaemic stroke (AIS) patients with a non-inferiority design for three of them. An expedited recommendation process was initiated by the European Stroke Organisation (ESO) and conducted according to ESO standard operating procedure based on the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) framework. We identified three relevant Population, Intervention, Comparator, Outcome (PICO) questions, performed systematic reviews of the literature and meta-analyses, assessed the quality of the available evidence, and wrote evidence-based recommendations. Expert consensus statements were provided if insufficient evidence was available to provide recommendations based on the GRADE approach. For patients with AIS of <4.5 h duration who are eligible for IVT, tenecteplase 0.25 mg/kg can be used as a safe and effective alternative to alteplase 0.9 mg/kg (moderate evidence, strong recommendation). For patients with AIS of <4.5 h duration who are eligible for IVT, we recommend against using tenecteplase at a dose of 0.40 mg/kg (low evidence, strong recommendation). For patients with AIS of <4.5 h duration with prehospital management with a mobile stroke unit who are eligible for IVT, we suggest tenecteplase 0.25 mg/kg over alteplase 0.90 mg/kg (low evidence, weak recommendation). For patients with large vessel occlusion (LVO) AIS of <4.5 h duration who are eligible for IVT, we recommend tenecteplase 0.25 mg/kg over alteplase 0.9 mg/kg (moderate evidence, strong recommendation). For patients with AIS on awakening from sleep or AIS of unknown onset who are selected with non-contrast CT, we recommend against IVT with tenecteplase 0.25 mg/kg (low evidence, strong recommendation). Expert consensus statements are also provided. Tenecteplase 0.25 mg/kg may be favoured over alteplase 0.9 mg/kg for patients with AIS of <4.5 h duration in view of comparable safety and efficacy data and easier administration. For patients with LVO AIS of <4.5 h duration who are IVT-eligible, IVT with tenecteplase 0.25 mg/kg is preferable over skipping IVT before MT, even in the setting of a direct admission to a thrombectomy-capable centre. IVT with tenecteplase 0.25 mg/kg may be a reasonable alternative to alteplase 0.9 mg/kg for patients with AIS on awakening from sleep or AIS of unknown onset and who are IVT-eligible after selection with advanced imaging.

Developments in quality of stroke care in Estonia.

Background: Monitoring and measuring different aspects of stroke care pathway is the cornerstone for improvement of quality. We aim to analyze and give an overview of improvements of stroke care quality in Estonia. Patients and methods: National stroke care quality indicators are collected and reported using reimbursement data and include all adult stroke cases. In Estonia, five stroke-ready hospitals are participating in Registry of Stroke Care Quality (RES-Q), providing data on all stroke patients 1 month every year. Data from the national quality indicators and RES-Q from 2015 to 2021 are presented. Results: The proportion of intravenous thrombolysis for all Estonian hospitalized ischemic stroke cases increased from 16% (95% Confidence Interval, CI 15%-18%) in 2015 to 28% (95% CI 27%-30%) in 2021. Mechanical thrombectomy was provided to 9% (95% CI 8%-10%) in 2021. The 30-day mortality rate has decreased from 21% (95% CI 20%-23%) to 19% (95% CI 18%-20%). More than 90% of patients with cardioembolic stroke are prescribed anticoagulants at discharge, but only 50% are on anticoagulant treatment 1 year after stroke. Also, the availability of inpatient rehabilitation needs improvement, being 21% (95% CI 20%-23%) in 2021. A total of 848 patients are included in the RES-Q. The proportion of patients receiving recanalization therapies was comparable to the national stroke care quality indicators. All stroke-ready hospitals show good onset-to-door times. Conclusion: The overall stroke care quality in Estonia is good, especially the availability of recanalization treatments. However, secondary prevention and the availability of rehabilitation services need improvement in the future.

Health behavior of young patients with ischemic stroke in Estonia: A score of five factors.

BACKGROUND: Behavioral risk factors are common among young patients with stroke. This study aimed to compare the health behavior of patients and healthy controls and develop a combined risk score of health behavior. METHODS: The health behavior of patients aged 18-54 years who suffered an ischemic stroke from 2013 to 2020 in Estonia was compared to the Health Behavior among Estonian Adult Population 2014 study sample. We chose five risk factors for comparison: smoking status, body mass index, physical exercise, diet (salt use and vegetable consumption), alcohol intake (quantity and frequency), and composed a summary score. RESULTS: Comparing 342 patients and 1789 controls, daily smoking (49.0% vs. 22.7%), obesity (33.4% vs. 15.9%), low physical activity (< twice/week) (72.2% vs. 60.5%), excessive salt use (8.6% vs. 4.5%), and frequent alcohol use (≥ weekly) (39.9% vs. 34.0%) were more prevalent among patients. The differences in infrequent vegetable consumption (<6 days/week) and excessive alcohol consumption (7 days, >8 units/females, >16 units/males) were not significant. The observed differences were similar for age groups 18-44 years and 45-54 years. The average Health Behavior Stroke Risk Score (0-10) was 4.6 points (CI 4.4-4.8, SD ± 1.97) for patients and 3.5 points (CI 3.4-3.6, SD ± 1.90) for controls. CONCLUSIONS: Before stroke, young patients displayed significantly worse health behavior than the general population. The largest differences were found for smoking and obesity, and a cumulation of risk factors was observed via the HBSR score.

Safety and efficacy of tenecteplase in patients with wake-up stroke assessed by non-contrast CT (TWIST): a multicentre, open-label, randomised controlled trial.

BACKGROUND: Current evidence supports the use of intravenous thrombolysis with alteplase in patients with wake-up stroke selected with MRI or perfusion imaging and is recommended in clinical guidelines. However, access to advanced imaging techniques is often scarce. We aimed to determine whether thrombolytic treatment with intravenous tenecteplase given within 4·5 h of awakening improves functional outcome in patients with ischaemic wake-up stroke selected using non-contrast CT. METHODS: TWIST was an investigator-initiated, multicentre, open-label, randomised controlled trial with blinded endpoint assessment, conducted at 77 hospitals in ten countries. We included patients aged 18 years or older with acute ischaemic stroke symptoms upon awakening, limb weakness, a National Institutes of Health Stroke Scale (NIHSS) score of 3 or higher or aphasia, a non-contrast CT examination of the head, and the ability to receive tenecteplase within 4·5 h of awakening. Patients were randomly assigned (1:1) to either a single intravenous bolus of tenecteplase 0·25 mg per kg of bodyweight (maximum 25 mg) or control (no thrombolysis) using a central, web-based, computer-generated randomisation schedule. Trained research personnel, who conducted telephone interviews at 90 days (follow-up), were masked to treatment allocation. Clinical assessments were performed on day 1 (at baseline) and day 7 of hospital admission (or at discharge, whichever occurred first). The primary outcome was functional outcome assessed by the modified Rankin Scale (mRS) at 90 days and analysed using ordinal logistic regression in the intention-to-treat population. This trial is registered with EudraCT (2014-000096-80), ClinicalTrials.gov (NCT03181360), and ISRCTN (10601890). FINDINGS: From June 12, 2017, to Sept 30, 2021, 578 of the required 600 patients were enrolled (288 randomly assigned to the tenecteplase group and 290 to the control group [intention-to-treat population]). The median age of participants was 73·7 years (IQR 65·9-81·1). 332 (57%) of 578 participants were male and 246 (43%) were female. Treatment with tenecteplase was not associated with better functional outcome, according to mRS score at 90 days (adjusted OR 1·18, 95% CI 0·88-1·58; p=0·27). Mortality at 90 days did not significantly differ between treatment groups (28 [10%] patients in the tenecteplase group and 23 [8%] in the control group; adjusted HR 1·29, 95% CI 0·74-2·26; p=0·37). Symptomatic intracranial haemorrhage occurred in six (2%) patients in the tenecteplase group versus three (1%) in the control group (adjusted OR 2·17, 95% CI 0·53-8·87; p=0·28), whereas any intracranial haemorrhage occurred in 33 (11%) versus 30 (10%) patients (adjusted OR 1·14, 0·67-1·94; p=0·64). INTERPRETATION: In patients with wake-up stroke selected with non-contrast CT, treatment with tenecteplase was not associated with better functional outcome at 90 days. The number of symptomatic haemorrhages and any intracranial haemorrhages in both treatment groups was similar to findings from previous trials of wake-up stroke patients selected using advanced imaging. Current evidence does not support treatment with tenecteplase in patients selected with non-contrast CT. FUNDING: Norwegian Clinical Research Therapy in the Specialist Health Services Programme, the Swiss Heart Foundation, the British Heart Foundation, and the Norwegian National Association for Public Health.

Declining first-ever stroke incidence rates in 15- to 54-year-old residents of Tartu, Estonia, from 1991 to 2017.

BACKGROUND: Having a stroke at a young age has a huge socioeconomic impact. Data on the trends of stroke incidence in young adults from prospective population-based studies are scarce. AIMS: The aim of this study was to analyze the trends in stroke incidence in 15- to 54-year-old residents of Tartu, Estonia from 1991 to 2017. METHODS: Three population-based studies with identical study protocols determining the incidence of first-ever stroke have previously been conducted in Tartu, Estonia (1991-1993, 2001-2003, and 2013-2017). All residents of Tartu with first-ever stroke (ischemic stroke, spontaneous intracerebral hemorrhage, and subarachnoid hemorrhage) who were hospitalized to the Department of Neurology, Tartu University Hospital in respective study periods were included prospectively. Overlapping data sources for case ascertainment were used to include both hospitalized and non-hospitalized cases. Trends in first-ever stroke incidence in 15- to 54-year-old residents of Tartu were calculated and compared using rate ratio (RR). RESULTS: Altogether 259 strokes were identified. From 1991 to 2017, the proportion of women increased from 38.3% to 43.6%. Mean age at onset in women decreased from 46.9 (standard deviation (SD): 7.3) to 42.6 (SD: 8.9). Overall crude incidence rates per 100,000 decreased significantly from 1991 to 2003 (from 57.2 (95% confidence interval (CI): 46.9-69.1) to 35.7 (95% CI: 25.7-48.3)); RR: 0.62 (95% CI: 0.44-0.89). While also present in women, the decrease was most notable in 45- to 54-year-old men (RR: 0.55 (95% CI: 0.30-0.99)). In 35- to 44-year-old men, the incidence rates decreased significantly from 2001 to 2017 (RR: 0.37 (95% CI: 0.14-0.99)). CONCLUSION: The overall first-ever stroke incidence rates decreased from 1991 to 2003 and remained stable thereafter.

Trends in traumatic spinal cord injuries in Estonia from 1997 to 2018.

OBJECTIVE: To analyze time trends in incidence, causes and risk factors for traumatic spinal cord injuries (TSCI) in Estonia between 1997-2007 and 2008-2018. DESIGN: Retrospective, population-based cohort study. SETTING: Specialized trauma centres in Estonia. PARTICIPANTS: Medical records of patients with TSCI from 1997 to 2018. INTERVENTION: None. OUTCOME MEASURES: Demographical data, crude and age- and sex-adjusted incidence rates, causes of TSCI, level and extent of injury, associated injuries. RESULTS: A total of 940 new patients with TSCI were identified for the period of 1997-2018. The average annual incidence rate (standardized to the Estonian population by age and sex in 2011) decreased significantly from 37.8 (95% confidence interval (CI) 34.6-41.1) in the first period (1997-2008) to 28.2 per million population (95% CI 25.3-31.0) during the second period (2008-2018) (incidence rate ratio 0.74 (95% CI 0.65-0.85), P < 0.0001). The decrease in incidence was most significant among young men. The mean age at injury increased from 38.7 (±16.7) years to 46.6 (±19.9) years, P < 0.0001. Falls were the leading cause of injury during both periods followed by traffic accidents and sports injuries. Still, traffic accidents as a cause of TSCI decreased significantly (from 30.5% to 20.6%, P = 0.001) and falls increased (from 39.9% to 59.5%, P < 0.0001) during the second period. Alcohol consumption prior to injury also decreased significantly from 66.0% to 55.1% (P = 0.006). CONCLUSION: Estonia has become closer to other European countries regarding TSCI during the last decade; TSCI incidence has significantly decreased, the mean age at injury and the percentage of falls have increased.

Association of statin pre-treatment with baseline stroke severity and outcome in patients with acute ischemic stroke and received reperfusion treatment: An observational study.

BACKGROUND: Statins have an important role in stroke prevention, especially in high-risk populations and may also affect the initial stroke severity and outcomes in patients taking them before an ischemic stroke. AIMS: Our aim was to evaluate the association of statin pre-treatment with the severity in acute ischemic stroke (AIS). METHODS: We analyzed AIS patients received intravenous thrombolysis (IVT) and/or endovascular thrombectomy (EVT) and recorded in the SITS International Thrombolysis and Thrombectomy Registry from 2011 to 2017. We identified patients with statin information at baseline. The primary outcome was baseline National Institutes of Health Stroke Scale (NIHSS) score. Secondary outcomes were NIHSS score at 24 h, symptomatic intracerebral hemorrhage (SICH) and functional outcome at 90 days after acute intervention. Multivariable linear and logistic regression and propensity score matching (PSM) was used to quantify the effect of statin pre-treatment. RESULTS: Of 93,849 patients, 23,651 (25.2%) were treated with statins prior the AIS. Statin pre-treatment group was older and had higher comorbidity. Median NIHSS at baseline was similar between groups. In the adjusted and PSM analysis, statin pre-treatment was inversely associated with baseline NIHSS (odds ratio (OR) = 0.77, 95% confidence interval (CI) = 0.6-0.99 and OR for PSM 0.73, 95% CI = 0.54-0.99, p = 0.004) and independently associated with mild stroke defined as NIHSS ⩽8 in adjusted and PSM analysis (OR = 1.21, 95% CI = 1.1-1.34, p < 0.001 and OR for PSM 1.17, 95% CI = 1.05-1.31, p = 0.007). Regarding secondary outcomes, there were no differences in functional outcomes, death nor SICH rates between groups. CONCLUSION: Prior treatment with statins was associated with lower NIHSS at baseline. However, this association did not translate into any difference regarding functional outcome at 90 days. No association was found regarding SICH. These findings indicate the need of further studies to assess the effect on statin pre-treatment on initial stroke severity.

Deceptive Adherence to Anticoagulation in Secondary Stroke Prevention.

Background: Oral anticoagulants (OAC) effectively reduce the risk for ischemic stroke in patients with atrial fibrillation (AF). We aimed to assess OAC treatment adherence in secondary stroke prevention and to find predictors of adherence using individualized patient data. Methods: This retrospective cohort study included patients with a discharge diagnosis of ischemic stroke and AF from Tartu University Hospital from 2017 to 2018. Data from patient charts and the Electronic Hospital Information, Estonian Electronic Prescription, and Estonian Electronic Health Record systems were registered. Results: Of the 353 patients, 237 (67%) were prescribed OAC treatment at discharge and during the first year after stroke, 202 (85%) of them used OAC treatment. The mean adherence was 81%, while only 68% had good adherence. Reduced non-vitamin K antagonist OAC (NOAC) dose was used in 68 patients (39%), which was justified in 23 (34%). First-ever stroke occurrence was the only significant factor for good treatment adherence in logistic regression analysis. There were 47 patients (23%) with complications among the patients on OAC treatment. Majority of the patients (70%) with hemorrhagic complications and 52% of patients with thromboembolic complications had good treatment adherence. Conclusions: Our study showed that OAC treatment adherence following stroke was modest and first-ever stroke was the only predictor of good or full treatment adherence.

Statistical analysis plan for the randomized controlled trial Tenecteplase in Wake-up Ischaemic Stroke Trial (TWIST).

BACKGROUND: Patients with wake-up ischemic stroke are frequently excluded from thrombolytic treatment due to unknown symptom onset time and limited availability of advanced imaging modalities. The Tenecteplase in Wake-up Ischaemic Stroke Trial (TWIST) is a randomized controlled trial of intravenous tenecteplase 0.25 mg/kg and standard care versus standard care alone (no thrombolysis) in patients who wake up with acute ischemic stroke and can be treated within 4.5 h of wakening based on non-contrast CT findings. OBJECTIVE: To publish the detailed statistical analysis plan for TWIST prior to unblinding. METHODS: The TWIST statistical analysis plan is consistent with the Consolidating Standard of Reporting Trials (CONSORT) statement and provides clear and open reporting. DISCUSSION: Publication of the statistical analysis plan serves to reduce potential trial reporting bias and clearly outlines the pre-specified analyses. TRIAL REGISTRATION: ClinicalTrials.gov NCT03181360 . EudraCT Number 2014-000096-80 . WHO ICRTP registry number ISRCTN10601890 .

Obesity and the Risk of Cryptogenic Ischemic Stroke in Young Adults.

OBJECTIVES: We examined the association between obesity and early-onset cryptogenic ischemic stroke (CIS) and whether fat distribution or sex altered this association. MATERIALS AND METHODS: This prospective, multi-center, case-control study included 345 patients, aged 18-49 years, with first-ever, acute CIS. The control group included 345 age- and sex-matched stroke-free individuals. We measured height, weight, waist circumference, and hip circumference. Obesity metrics analyzed included body mass index (BMI), waist-to-hip ratio (WHR), waist-to-stature ratio (WSR), and a body shape index (ABSI). Models were adjusted for age, level of education, vascular risk factors, and migraine with aura. RESULTS: After adjusting for demographics, vascular risk factors, and migraine with aura, the highest tertile of WHR was associated with CIS (OR for highest versus lowest WHR tertile 2.81, 95%CI 1.43-5.51; P=0.003). In sex-specific analyses, WHR tertiles were not associated with CIS. However, using WHO WHR cutoff values (>0.85 for women, >0.90 for men), abdominally obese women were at increased risk of CIS (OR 2.09, 95%CI 1.02-4.27; P=0.045). After adjusting for confounders, WC, BMI, WSR, or ABSI were not associated with CIS. CONCLUSIONS: Abdominal obesity measured with WHR was an independent risk factor for CIS in young adults after rigorous adjustment for concomitant risk factors.

Global Differences in Risk Factors, Etiology, and Outcome of Ischemic Stroke in Young Adults-A Worldwide Meta-analysis: The GOAL Initiative.

BACKGROUND AND OBJECTIVES: There is a worldwide increase in the incidence of stroke in young adults, with major regional and ethnic differences. Advancing knowledge of ethnic and regional variation in causes and outcomes will be beneficial in implementation of regional health care services. We studied the global distribution of risk factors, causes, and 3-month mortality of young patients with ischemic stroke, by performing a patient data meta-analysis from different cohorts worldwide. METHODS: We performed a pooled analysis of individual patient data from cohort studies that included consecutive patients with ischemic stroke aged 18-50 years. We studied differences in prevalence of risk factors and causes of ischemic stroke between different ethnic and racial groups, geographic regions, and countries with different income levels. We investigated differences in 3-month mortality by mixed-effects multivariable logistic regression. RESULTS: We included 17,663 patients from 32 cohorts in 29 countries. Hypertension and diabetes were most prevalent in Black (hypertension, 52.1%; diabetes, 20.7%) and Asian patients (hypertension 46.1%, diabetes, 20.9%). Large vessel atherosclerosis and small vessel disease were more often the cause of stroke in high-income countries (HICs; both p < 0.001), whereas "other determined stroke" and "undetermined stroke" were higher in low and middle-income countries (LMICs; both p < 0.001). Patients in LMICs were younger, had less vascular risk factors, and despite this, more often died within 3 months than those from HICs (odds ratio 2.49; 95% confidence interval 1.42-4.36). DISCUSSION: Ethnoracial and regional differences in risk factors and causes of stroke at young age provide an understanding of ethnic and racial and regional differences in incidence of ischemic stroke. Our results also highlight the dissimilarities in outcome after stroke in young adults that exist between LMICs and HICs, which should serve as call to action to improve health care facilities in LMICs.

Case-Fatality and Functional Outcome after Subarachnoid Hemorrhage (SAH) in INternational STRoke oUtComes sTudy (INSTRUCT).

BACKGROUND: There are few large population-based studies of outcomes after subarachnoid hemorrhage (SAH) than other stroke types. METHODS: We pooled data from 13 population-based stroke incidence studies (10 studies from the INternational STRroke oUtComes sTudy (INSTRUCT) and 3 new studies; N=657). Primary outcomes were case-fatality and functional outcome (modified Rankin scale score 3-5 [poor] vs. 0-2 [good]). Harmonized patient-level factors included age, sex, health behaviours (e.g. current smoking at baseline), comorbidities (e.g.history of hypertension), baseline stroke severity (e.g. NIHSS >7) and year of stroke. We estimated predictors of case-fatality and functional outcome using Poisson regression and generalized estimating equations using log-binomial models respectively at multiple timepoints. RESULTS: Case-fatality rate was 33% at 1 month, 43% at 1 year, and 47% at 5 years. Poor functional outcome was present in 27% of survivors at 1 month and 15% at 1 year. In multivariable analysis, predictors of death at 1-month were age (per decade increase MRR 1.14 [1.07-1.22]) and SAH severity (MRR 1.87 [1.50-2.33]); at 1 year were age (MRR 1.53 [1.34-1.56]), current smoking (MRR 1.82 [1.20-2.72]) and SAH severity (MRR 3.00 [2.06-4.33]) and; at 5 years were age (MRR 1.63 [1.45-1.84]), current smoking (MRR 2.29 [1.54-3.46]) and severity of SAH (MRR 2.10 [1.44-3.05]). Predictors of poor functional outcome at 1 month were age (per decade increase RR 1.32 [1.11-1.56]) and SAH severity (RR 1.85 [1.06-3.23]), and SAH severity (RR 7.09 [3.17-15.85]) at 1 year. CONCLUSION: Although age is a non-modifiable risk factor for poor outcomes after SAH, however, severity of SAH and smoking are potential targets to improve the outcomes.

Estonian young stroke registry: High burden of risk factors and high prevalence of cardiomebolic and large-artery stroke.

BACKGROUND AND AIMS: The aim of the present study was to assess the risk factor burden and stroke etiology of young stroke patients in Estonia and to compare the results with similar cohorts from other countries. METHODS: This study includes ischemic stroke patients aged 18-54 years from the prospective Estonian Young Stroke Registry between 2013 and 2020. All patients were managed in a stroke unit following a prespecified detailed protocol. Data on stroke risk factors, etiology, and stroke severity were analyzed. RESULTS: A total of 437 patients (mean age 44.7 ± 8.3 years; 62% males) were included in the registry during the 8-year study period. A total of 50.2% of patients had ≥ 3 well-documented risk factors (higher for men: odds ratio (OR) 3.8; 95% cardiac index confidence interval (CI) 1.8-8.3; p < .001) and 6.2% of patients had ≥ 3 less well-documented risk factors. While 42% of patients had undetermined cause of stroke (34% of them cryptogenic), the second most frequent etiologies were large-artery atherosclerosis and cardioembolism (both 19%). 60 percent of cardioembolic strokes were due to high-risk causes. Large-artery atherosclerosis was more prevalent in men (OR 1.8; 95% CI 1-3.3; p = .05) and among older patients (OR 6.2; 95% CI 1.8-21.4; p = .008). The median National Institutes of Health Stroke Scale score on admission was 3 (interquartile ranges 2-6), stroke was more severe in men (p = .05). CONCLUSIONS: Our study revealed that young patients with stroke in Estonia have higher burden of well-documented risk factors, higher prevalence of high-risk cardioembolic causes and higher prevalence of large-artery stroke compared to other young stroke cohorts.

ESO guideline for the management of extracranial and intracranial artery dissection.

The aim of the present European Stroke Organisation guideline is to provide clinically useful evidence-based recommendations on the management of extracranial artery dissection (EAD) and intracranial artery dissection (IAD). EAD and IAD represent leading causes of stroke in the young, but are uncommon in the general population, thus making it challenging to conduct clinical trials and large observational studies. The guidelines were prepared following the Standard Operational Procedure for European Stroke Organisation guidelines and according to GRADE methodology. Our four recommendations result from a thorough analysis of the literature comprising two randomized controlled trials (RCTs) comparing anticoagulants to antiplatelets in the acute phase of ischemic stroke and twenty-six comparative observational studies. In EAD patients with acute ischemic stroke, we recommend using intravenous thrombolysis (IVT) with alteplase within 4.5 hours of onset if standard inclusion/exclusion criteria are met, and mechanical thrombectomy in patients with large vessel occlusion of the anterior circulation. We further recommend early endovascular or surgical intervention for IAD patients with subarachnoid hemorrhage (SAH). Based on evidence from two phase 2 RCTs that have shown no difference between the benefits and risks of anticoagulants versus antiplatelets in the acute phase of symptomatic EAD, we strongly recommend that clinicians can prescribe either option. In post-acute EAD patients with residual stenosis or dissecting aneurysms and in symptomatic IAD patients with an intracranial dissecting aneurysm and isolated headache, there is insufficient data to provide a recommendation on the benefits and risks of endovascular/surgical treatment. Finally, nine expert consensus statements, adopted by 8 to 11 of the 11 experts involved, propose guidance for clinicians when the quality of evidence was too low to provide recommendations. Some of these pertain to the management of IAD (use of IVT, endovascular treatment, and antiplatelets versus anticoagulation in IAD with ischemic stroke and use of endovascular or surgical interventions for IAD with headache only). Other expert consensus statements address the use of direct anticoagulants and dual antiplatelet therapy in EAD-related cerebral ischemia, endovascular treatment of the EAD/IAD lesion, and multidisciplinary assessment of the best therapeutic approaches in specific situations.

Regulatory delays in a multinational clinical stroke trial.

INTRODUCTION: The initiation and conduct of randomised clinical trials are complicated by multiple barriers, including delays in obtaining regulatory approvals. Quantitative data on the extent of the delays due to national or local review in randomised clinical trials is scarce. MATERIALS AND METHODS: We assessed the times needed to obtain regulatory approval and to initiate a trial site for an academic, EU-funded, phase III, randomised clinical trial of pharmacological prevention of complications in patients with acute stroke in over 80 sites in nine European countries. The primary outcome was the time from the first submission to a regulatory authority to initiation of a trial site. Secondary outcomes included time needed to complete each individual preparatory requirement and the number of patients recruited by each site in the first 6 and 12 months. RESULTS: The median time from the first submission to a regulatory authority to initiation of a trial site was 784 days (IQR: 586-1102). The single most time-consuming step was the conclusion of a clinical trial agreement between the national coordinator and the trial site, which took a median of 194 days (IQR: 93-293). A longer time to site initiation was associated with a lower patient recruitment rate in the first six months after initiation (B = -0.002; p = 0.02). CONCLUSION: In this EU-funded clinical trial, approximately 26 months were needed to initiate a trial site for patient recruitment. The conclusion of a contract with a trial site was the most time-consuming activity. To simplify and speed up the process, we suggest that the level of detail of contracts for academic trials should be proportional to the risks and commercial interests of these trials.

Colchicine for prevention of vascular inflammation in Non-CardioEmbolic stroke (CONVINCE) - study protocol for a randomised controlled trial.

BACKGROUND: Inflammation contributes to unstable atherosclerotic plaque and stroke. In randomised trials in patients with coronary disease, canukinumab (an interleukin-1B antagonist) and colchicine (a tubulin inhibitor with pleiotropic anti-inflammatory effects) reduced recurrent vascular events.Hypothesis: Anti-inflammatory therapy with low-dose colchicine plus usual care will reduce recurrent vascular events in patients with non-severe, non-cardioembolic stroke and TIA compared with usual care alone. DESIGN: CONVINCE is a multi-centre international (in 17 countries) Prospective, Randomised Open-label, Blinded-Endpoint assessment (PROBE) controlled Phase 3 clinical trial in 3154 participants. The intervention is colchicine 0.5 mg/day and usual care versus usual care alone (antiplatelet, lipid-lowering, antihypertensive treatment, lifestyle advice). Included patients are at least 40 years, with non-severe ischaemic stroke (modified Rankin score ≤3) or high-risk TIA (ABCD2 > 3, or positive DWI, or cranio-cervical artery stenosis) within 72 hours-28 days of randomisation, with qualifying stroke/TIA most likely caused by large artery stenosis, lacunar disease, or cryptogenic embolism. Exclusions are stroke/TIA caused by cardio-embolism or other defined cause (e.g. dissection), contra-indication to colchicine (including potential drug interactions), or incapacity for participation in a clinical trial. The anticipated median follow-up will be 36 months. The primary analysis will be by intention-to-treat. OUTCOME: The primary outcome is time to first recurrent ischaemic stroke, myocardial infarction, cardiac arrest, or hospitalisation with unstable angina (non-fatal or fatal). SUMMARY: CONVINCE will provide high-quality randomised data on the efficacy and safety of anti-inflammatory therapy with colchicine for secondary prevention after stroke. SCHEDULE: First-patient first-visit was December 2016. Recruitment to complete in 2021, follow-up to complete in 2023.

Subspecialty training of neurology residents and junior neurologists in the Baltic States.

BACKGROUND: Neurology is a field of increasing subspecialization. There is no published data regarding the proportion of neurology subspecialists in the Baltic States. The aim of this cross-sectional study was to identify factors associated with neurology subspecialty choice, to examine possible differences between neurology residents' and junior neurologists' view of subspecialty, and to assess perceived subspecialty acquisition opportunities and subspecialty attractiveness. METHODS: The research was conducted as an anonymous online survey between December 28, 2020, and January 24, 2021 of neurology residents and neurologists who completed their residency during the last 5 years in the Baltic States. RESULTS: In total, 72 residents and 65 neurologists participated. "Cerebrovascular diseases" and "multiple sclerosis and autoimmune diseases of the nervous system" were rated as the two most attractive subspecialties by residents, whereas "headache" and "clinical neurophysiology" were the most attractive among junior neurologists. "Vertigo and dizziness" and "dementia" were ranked the least attractive among both groups. "Cerebrovascular diseases" were perceived as having the most acquisition opportunities. The two most common determinants of subspecialty choice were "medical content of the subspecialty" and "influence of mentor during undergraduate studies or residency". CONCLUSIONS: Two-thirds of junior neurologists subspecialize in at least one subspecialty, and one-third of residents are already determined to pursue subspecialty training. Junior neurologists rated most outpatient-related subspecialties as more attractive than neurology residents. Between the Baltic States' universities, there was a significant difference in the number of residents who were determined to pursue subspecialty training.