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Background and Purpose: Triage tools to identify candidates for thrombectomy are of utmost importance in acute stroke. No prognostic tool has yet gained any widespread use. We compared the predictive value of various models based on National Institutes of Health Stroke Scale (NIHSS) subitems, ranging from simple to more complex models, for predicting large artery occlusion (LAO) in anterior circulation stroke., Methods: Patients registered in the SITS international Stroke Register with available NIHSS and radiological arterial occlusion data were analysed. We compared 2042 patients harbouring an LAO with 2881 patients having no/distal occlusions. Using binary logistic regression, we developed models ranging from simple 1 NIHSS-subitem to full NIHSS-subitems models. Sensitivities and specificities of the models for predicting LAO were examined., Results: The model with highest predictive value included all NIHSS subitems for predicting LAO (area under the curve (AUC) 0.77), yielding a sensitivity and specificity of 69% and 76%, respectively. The second most predictive model (AUC 0.76) included 4-NIHSS-subitems (level of consciousness commands, gaze, facial and arm motor function) yielding a sensitivity and specificity of 67% and 75%, respectively. The simplest model included only deficits in arm motor-function (AUC 0.72) for predicting LAO, yielding a sensitivity and specificity of 67% and 72%, respectively., Conclusions: Although increasingly more complex models yield a higher discriminative performance for predicting LAO, differences between models are not large. Assessing grade of arm dysfunction along with an established stroke-diagnosis model may serve as a surrogate measure of arterial occlusion-status, thereby assisting in triage decisions., Competing Interests: Competing interests: CC was supported by the Stockholm County Council (combined clinical residency and PhD training program). MVM is an employee of SITS International, which receives a grant from Boehringer Ingelheim for the SITS-ISTR. MVM is also supported by the Stockholm County Council (clinical postdoctoral appointment). TPM has received travel and speaker grants from Boehringer Ingelheim for the SITS-ISTR and research grants from Cerevast Inc. NW has received expenses from Boehringer Ingelheim for his role as member of the Steering Committee in relation to the ECASS III trial with alteplase and served as a consultant to Thrombogenics as chairman of the Data and Safety Monitoring Board. SITS International (chaired by NW) receives a grant from Boehringer Ingelheim for the SITS-ISTR. His institution has also received grant support towards administrative expenses for coordination of the ECASS III trial. NW has also received lecture fees from Boehringer Ingelheim and Ferrer. NW is also supported by grants provided by the Stockholm County Council (ALF project). NA is an employee of SITS International, which receives a grant from Boehringer Ingelheim for the SITS-ISTR. NA is also supported by grants provided by the Stockholm County Council (ALF project) and Swedish Heart-lung foundation.

Background The recommended maximum age and time window for intravenous alteplase treatment of acute ischemic stroke differs between the Europe Union and United States. Aims We compared the effects of alteplase in cohorts defined by the current Europe Union or United States marketing approval labels, and by hypothetical revisions of the labels that would remove the Europe Union upper age limit or extend the United States treatment time window to 4.5 h. Methods We assessed outcomes in an individual-patient-data meta-analysis of eight randomized trials of intravenous alteplase (0.9 mg/kg) versus control for acute ischemic stroke. Outcomes included: excellent outcome (modified Rankin score 0-1) at 3-6 months, the distribution of modified Rankin score, symptomatic intracerebral hemorrhage, and 90-day mortality. Results Alteplase increased the odds of modified Rankin score 0-1 among 2449/6136 (40%) patients who met the current European Union label and 3491 (57%) patients who met the age-revised label (odds ratio 1.42, 95% CI 1.21-1.68 and 1.43, 1.23-1.65, respectively), but not in those outside the age-revised label (1.06, 0.90-1.26). By 90 days, there was no increased mortality in the current and age-revised cohorts (hazard ratios 0.98, 95% CI 0.76-1.25 and 1.01, 0.86-1.19, respectively) but mortality remained higher outside the age-revised label (1.19, 0.99-1.42). Similarly, alteplase increased the odds of modified Rankin score 0-1 among 1174/6136 (19%) patients who met the current US approval and 3326 (54%) who met a 4.5-h revised approval (odds ratio 1.55, 1.19-2.01 and 1.37, 1.17-1.59, respectively), but not for those outside the 4.5-h revised approval (1.14, 0.97-1.34). By 90 days, no increased mortality remained for the current and 4.5-h revised label cohorts (hazard ratios 0.99, 0.77-1.26 and 1.02, 0.87-1.20, respectively) but mortality remained higher outside the 4.5-h revised approval (1.17, 0.98-1.41). Conclusions An age-revised European Union label or 4.5-h-revised United States label would each increase the number of patients deriving net benefit from alteplase by 90 days after acute ischemic stroke, without excess mortality.

Background and Purpose: Intravenous thrombolysis (IVT) is the only approved pharmacological treatment for acute ischemic stroke. Off-label IVT for ischemic stroke is common. We aimed to analyse its safety in a large database., Methods: This was a retrospective analysis of the safe implementation of treatments in stroke (SITS) thrombolysis registry with regard to 11 off-label criteria according to the European licence for alteplase. Symptomatic intracranial haemorrhage (SICH) according to SITS was defined as primary safety endpoint and SICH according to the European Cooperative Acute Stroke Study (ECASS II) definition and the National Institute of Neurological Disorders and Stroke definition as secondary safety endpoints. Multivariable logistic regression analyses after replacing missing values using multiple imputations were performed., Results: Patients from 793 centres in 44 countries were included, mainly (95%) in Europe. A total of 56 258 patients who were treated with intravenous alteplase were included. Median age was 71 (IQR 61-78) years and median National Institutes of Health Stroke Scale score was 12 (IQR 7-17). A total of 16 740 (30%) patients received off-label IVT and 1037 (1.8%) patients suffered from SICH according to the SITS definition (SICH SITS). Median percentage of missing values per variable was 0.4%. The only two off-label criteria constituting independent positive and negative predictors for SICH SITS were high blood pressure (odds ratio, 1.39; 95% confidence interval, 1.08-1.80; P = 0.012) and minor stroke (odds ratio, 0.51; 95% confidence interval, 0.33-0.78; P = 0.002). Very severe stroke, previous stroke and diabetes, age and high glucose levels were additional independent predictors of SICH according to the ECASS II and National Institute of Neurological Disorders and Stroke definitions., Conclusions: Thrombolysis appears to be safe with regard to SICH for most of the off-label criteria, especially for minor stroke, but is risky in patients with high blood pressure. Individual risk-benefit evaluation should be performed., (© 2017 EAN.)

In 2008, the recently founded European Stroke Organisation published its guidelines for the management of ischemic stroke and transient ischemic attack. This highly cited document was translated in several languages and was updated in 2009. Since then, the European Stroke Organisation has published guidelines for the management of intracranial aneurysms and subarachnoidal hemorrhage, for the establishment of stroke units and stroke centers, and recently for the management of intracerebral hemorrhage. In recent years, the methodology for the development of guidelines has evolved significantly. To keep pace with this progress and driven by the strong determination of the European Stroke Organisation to further promote stroke management, education, and research, the European Stroke Organisation decided to delineate a detailed standard operating procedure for its guidelines. There are two important cornerstones in this standard operating procedure: The first is the implementation of the Grading of Recommendations Assessment, Development, and Evaluation methodology for the development of its Guideline Documents. The second one is the decision of the European Stroke Organisation to move from the classical model of a single Guideline Document about a major topic (e.g. management of ischemic stroke) to focused modules (i.e. subdivisions of a major topic). This will enable the European Stroke Organisation to react faster when new developments in a specific stroke field occur and update its recommendations on the related module rather swiftly; with the previous approach of a single large Guideline Document, its entire revision had to be completed before an updated publication, delaying the production of up-to-date guidelines. After discussion within the European Stroke Organisation Guidelines Committee and significant input from European Stroke Organisation members as well as methodologists and analysts, this document presents the official standard operating procedure for the development of the Guideline Documents of the European Stroke Organisation., (© 2015 World Stroke Organization.)

Background and Purpose: Temporal variations of thrombolysis delivery and their influence on outcome have been reported with controversial results. In this large cohort study, we evaluated whether thrombolytic treatment has a within-day and weekly variability corresponding to circadian and weekly patterns of ischemic stroke onset, and whether these have impact on clinical outcome., Methods: We retrospectively analyzed patients with acute ischemic stroke receiving intravenous alteplase, prospectively included in the Safe Implementation of Treatments in Stroke-International Stroke Thrombolysis Register. Patients were grouped by treatment on day hours (08:00-19:59) or night hours (20:00-07:59) and treatment on weekdays and weekends. For each subgroup, we analyzed frequency of thrombolytic treatments, time intervals, and outcomes (3-month modified Rankin Scale score 0-2 as good functional outcome, mortality, symptomatic intracerebral hemorrhage)., Results: We included 21 513 patients. Considering the mean expected number of patients treated per hour (0.4) and per day of the week (9.8), if no temporal variations were present, patients were significantly treated more during day hours and weekdays (P<0.0001). Median door-to-needle and onset-to-treatment times were longer for patients treated during night hours and on weekends (P<0.01). After adjustment for confounding variables, treatment during day hours was an independent predictor of good functional outcome (odds ratio, 1.12; 95% confidence interval, 1.04-1.21; P=0.004), and patients treated during weekdays were at risk of higher mortality (odds ratio, 1.15; 95% confidence interval, 1.04-1.28; P=0.008)., Conclusions: Frequency of thrombolytic treatment seems to follow the same circadian pattern of stroke incidence, whereas its correspondence to a weekly pattern is less clear. Time of treatment is an independent predictor of outcome.

Background: In the European Cooperative Acute Stroke Study III (ECASS III), alteplase administered 3.0-4.5 h after the onset of stroke symptoms resulted in a significant benefit in the primary endpoint (modified Rankin scale [mRS] score 0-1) versus placebo, with no difference in mortality between the treatment groups. Compared with the 0-3 h window, there was no excess risk of symptomatic intracranial haemorrhage. We assessed the usefulness of additional endpoints and did subgroup and sensitivity analyses to further investigate the benefit of alteplase., Methods: In a double-blind, multicentre study in Europe, patients with acute ischaemic stroke were randomly assigned to intravenous alteplase (0.9 mg/kg bodyweight) or placebo. Additional outcome analyses included functional endpoints at day 90 or day 30 (mRS 0-1 [day 30], mRS 0-2, Barthel index > or =85, and global outcome statistic [day 30]) and treatment response (8-point improvement from baseline or 0-1 score on the National Institutes of Health stroke scale [NIHSS], and a stratified responder analysis by baseline NIHSS score). The subgroup analyses were based on the mRS 0-1 at day 90, symptomatic intracranial haemorrhage, and death. Analyses were by intention to treat and per protocol. This study is registered with ClinicalTrials.gov, number NCT00153036., Findings: 418 patients were assigned to alteplase and 403 to placebo. Although not significant in every case, all additional endpoints showed at least a clear trend in favour of alteplase. Alteplase was effective in various subgroups, including older patients (<65 years: odds ratio 1.61, 95% CI 1.05-2.48; > or =65 years: 1.15, 0.80-1.64; p=0.230), and the effectiveness was independent of the severity of stroke at baseline (NIHSS 0-9: 1.28, 0.84-1.96; NIHSS 10-19: 1.16, 0.73-1.84; NIHSS > or =20: 2.32, 0.61-8.90; p=0.631). The incidence of symptomatic intracranial haemorrhage seemed to be independent of previous antiplatelet drug use (no: 2.41, 1.09-5.33; yes: 2.33, 0.79-6.90; p=0.962) and time from onset of symptoms to treatment (181-210 min: 1.62, 0.26-10.25; 211-240 min: 1.97, 0.82-4.76; 241-270 min: 3.15, 1.01-9.79; p=0.761), but not of age dichotomised at 65 years (<65 years: 0.74, 0.28-1.96; > or =65 years: 5.79, 2.18-15.39; p=0.004)., Interpretation: Our results support the use of alteplase up to 4.5 h after the onset of stroke symptoms across a broad range of subgroups of patients who meet the requirements of the European product label but miss the approved treatment window of 0-3 h., Funding: Boehringer Ingelheim.

Background: The aim of the Safe Implementation of Thrombolysis in Stroke-Monitoring Study (SITS-MOST) was to assess the safety and efficacy of intravenous alteplase as thrombolytic therapy within the first 3 h of onset of acute ischaemic stroke. Under European Union regulations, SITS-MOST was required to assess the safety profile of alteplase in clinical practice by comparison with results in randomised controlled trials., Methods: 6483 patients were recruited from 285 centres (50% with little previous experience in stroke thrombolysis) in 14 countries between 2002 and 2006 for this prospective, open, monitored, observational study. Primary outcomes were symptomatic (a deterioration in National Institutes of Health stroke scale score of >or=4) intracerebral haemorrhage type 2 within 24 h and mortality at 3 months. We compared mortality, the proportion of patients with symptomatic intracerebral haemorrhage as per the Cochrane definition, and functional outcome at 3 months with relevant pooled results from randomised controlled trials., Findings: Baseline characteristics of patients in SITS-MOST were much the same as those in the pooled randomised controlled trials. At 24 h, the proportion of patients with symptomatic intracerebral haemorrhage (per the SITS-MOST protocol) was 1.7% (107/6444; 95% CI 1.4-2.0); at 7 days, the proportion with the same condition as per the Cochrane definition was 7.3% (468/6438; 6.7-7.9) compared with 8.6% (40/465; 6.3-11.6) in the pooled randomised controlled trials. The mortality rate at 3 months in SITS-MOST was 11.3% (701/6218; 10.5-12.1) compared with 17.3% (83/479; 14.1-21.1) in the pooled randomised controlled trials., Interpretation: These data confirm that intravenous alteplase is safe and effective in routine clinical use when used within 3 h of stroke onset, even by centres with little previous experience of thrombolytic therapy for acute stroke. The findings should encourage wider use of thrombolytic therapy for suitable patients treated in stroke centres.