The SITS Open Study: A Prospective, Open Label Blinded Evaluation Study of Thrombectomy in Clinical Practice.

BACKGROUND AND PURPOSE: We designed SITS (Safe Implementation of Treatment in Stroke) Open to determine benefit and safety of thrombectomy in clinical practice for large artery occlusion stroke, using selected stent retrievers plus standard care versus standard care alone. METHODS: SITS Open was a prospective, open, blinded evaluation, international, multicenter, controlled, nonrandomized registry study. Centers lacking access to thrombectomy contributed controls. Primary end point was categorical shift in modified Rankin Scale score at 3 months in the per protocol (PP) population. Principal secondary outcomes were symptomatic intracranial hemorrhage, functional independency (modified Rankin Scale score 0-2) and death at 3 months. Patients independently evaluated by video-recorded modified Rankin Scale interviews blinded to treatment or center identity by central core laboratory were regarded as PP population. Propensity score matching with covariate adjusted analysis was performed. RESULTS: During 2014 to 2017, 293 patients (257 thrombectomy, 36 control) from 26 centers in 10 countries fulfilled intention-to-treat and 200 (170 thrombectomy, 30 control) PP criteria; enrollment of controls was limited by rapid uptake of thrombectomy. In PP analysis, median age was 71 versus 71 years, and baseline National Institutes of Health Stroke Scale 17 versus 17 in the thrombectomy and control arms, respectively. The propensity score matching analysis for PP showed a significant shift for modified Rankin Scale at 3 months favoring the thrombectomy group (odds ratio, 3.8 [95% CI, 1.61-8.95]; P=0.002). Regarding safety, there were 4 cases of symptomatic intracranial hemorrhage in the thrombectomy group (2.4%) and none in the control group. CONCLUSIONS: In clinical practice, thrombectomy for patients with large artery occlusion stroke is superior to standard of care in our study. Registration: URL: https://www.clinicaltrials.gov. Unique Identifier: NCT02326428.

Intravenous alteplase for stroke with unknown time of onset guided by advanced imaging: systematic review and meta-analysis of individual patient data.

BACKGROUND: Patients who have had a stroke with unknown time of onset have been previously excluded from thrombolysis. We aimed to establish whether intravenous alteplase is safe and effective in such patients when salvageable tissue has been identified with imaging biomarkers. METHODS: We did a systematic review and meta-analysis of individual patient data for trials published before Sept 21, 2020. Randomised trials of intravenous alteplase versus standard of care or placebo in adults with stroke with unknown time of onset with perfusion-diffusion MRI, perfusion CT, or MRI with diffusion weighted imaging-fluid attenuated inversion recovery (DWI-FLAIR) mismatch were eligible. The primary outcome was favourable functional outcome (score of 0-1 on the modified Rankin Scale [mRS]) at 90 days indicating no disability using an unconditional mixed-effect logistic-regression model fitted to estimate the treatment effect. Secondary outcomes were mRS shift towards a better functional outcome and independent outcome (mRS 0-2) at 90 days. Safety outcomes included death, severe disability or death (mRS score 4-6), and symptomatic intracranial haemorrhage. This study is registered with PROSPERO, CRD42020166903. FINDINGS: Of 249 identified abstracts, four trials met our eligibility criteria for inclusion: WAKE-UP, EXTEND, THAWS, and ECASS-4. The four trials provided individual patient data for 843 individuals, of whom 429 (51%) were assigned to alteplase and 414 (49%) to placebo or standard care. A favourable outcome occurred in 199 (47%) of 420 patients with alteplase and in 160 (39%) of 409 patients among controls (adjusted odds ratio [OR] 1·49 [95% CI 1·10-2·03]; p=0·011), with low heterogeneity across studies (I2=27%). Alteplase was associated with a significant shift towards better functional outcome (adjusted common OR 1·38 [95% CI 1·05-1·80]; p=0·019), and a higher odds of independent outcome (adjusted OR 1·50 [1·06-2·12]; p=0·022). In the alteplase group, 90 (21%) patients were severely disabled or died (mRS score 4-6), compared with 102 (25%) patients in the control group (adjusted OR 0·76 [0·52-1·11]; p=0·15). 27 (6%) patients died in the alteplase group and 14 (3%) patients died among controls (adjusted OR 2·06 [1·03-4·09]; p=0·040). The prevalence of symptomatic intracranial haemorrhage was higher in the alteplase group than among controls (11 [3%] vs two [<1%], adjusted OR 5·58 [1·22-25·50]; p=0·024). INTERPRETATION: In patients who have had a stroke with unknown time of onset with a DWI-FLAIR or perfusion mismatch, intravenous alteplase resulted in better functional outcome at 90 days than placebo or standard care. A net benefit was observed for all functional outcomes despite an increased risk of symptomatic intracranial haemorrhage. Although there were more deaths with alteplase than placebo, there were fewer cases of severe disability or death. FUNDING: None.

Effect of Recanalization on Cerebral Edema in Ischemic Stroke Treated With Thrombolysis and/or Endovascular Therapy.

Background and Purpose- A large infarct and expanding cerebral edema (CED) due to a middle cerebral artery occlusion confers a 70% mortality unless treated surgically. Reperfusion may cause blood-brain barrier disruption and a risk for cerebral edema and secondary parenchymal hemorrhage (PH). We aimed to investigate the effect of recanalization on development of early CED and PH after recanalization therapy. Methods- From the SITS-International Stroke Treatment Registry, we selected patients with signs of artery occlusion at baseline (either Hyperdense Artery Sign or computed tomography/magnetic resonance imaging angiographic occlusion). We defined recanalization as the disappearance of radiological signs of occlusion at 22 to 36 hours. Primary outcome was moderate to severe CED and secondary outcome was PH on 22- to 36-hour imaging scans. We used logistic regression with adjustment for baseline variables and PH. Results- Twenty two thousand one hundred eighty-four patients fulfilled the inclusion criteria (n=18 318 received intravenous thrombolysis, n=3071 received intravenous thrombolysis+thrombectomy, n=795 received thrombectomy). Recanalization occurred in 64.1%. Median age was 71 versus 71 years and National Institutes of Health Stroke Scale score 15 versus 16 in the recanalized versus nonrecanalized patients respectively. Recanalized patients had a lower risk for CED (13.0% versus 23.6%), adjusted odds ratio (aOR), 0.52 (95% CI, 0.46-0.59), and a higher risk for PH (8.9% versus 6.5%), adjusted odds ratio, 1.37 (95% CI, 1.22-1.55), than nonrecanalized patients. Conclusions- In patients with acute ischemic stroke, recanalization was associated with a lower risk for early CED even after adjustment for higher rate for PH in recanalized patients.

Stroke Care and Application of Thrombolysis in Ibero-America: Report From the SITS-SIECV Ibero-American Stroke Register

Background and Purpose: Standardized registries may provide valuable data to further improve stroke care. Our aim was to obtain updated information about characteristics of stroke patients and management of stroke across the Ibero-American countries, using a common in-hospital registry (Safe Implementation of Treatments in Stroke­Sociedad Iberoamericana de Enfermedades Cerebrovasculares) as a basis for further quality improvement. Methods: Data for this study were entered into the Safe Implementation of Treatments in Stroke registry from September 2009 to December 2013 by 58 centers in 14 countries. Data included demographics, risk factors, onset-to-door time, National Institutes of Health Stroke Scale score, stroke subtype, ischemic stroke etiology, treatments, 3-month mortality, and modified Rankin Scale score. Time to treatment was also recorded for patients treated with thrombolysis. Results: Five thousand four hundred one patients were registered; median age, 65 years; 46% women; 3915 (72.5%) ischemic strokes; 686 (13.7%) hemorrhagic strokes; 213 (4.3%) subarachnoid hemorrhages; 414 (8.3%) transient ischemic attacks; and 31 (0.6%) cerebral vein thrombosis. The most prevalent risk factors were hypertension (71.3%), dyslipidemia (35.2%), and diabetes mellitus (23.6%). Atrial fibrillation was present in 15.1%. Three hundred one ischemic strokes were treated with intravenous thrombolysis (IVT; 7.7%). Patients undergoing IVT were more severely affected (median baseline National Institutes of Health Stroke Scale score, 11 versus 6). The rate of symptomatic intracerebral hemorrhages after IVT was 5.7%. At 3 months, 60.3% of IVT-treated patients and 59.1% of untreated patients were independent (modified Rankin Scale score, 0­2). Mortality was 11.4% in treated and 12.8% in untreated patients. Conclusions: Safe Implementation of Treatments in Stroke­Sociedad Iberoamericana de Enfermedades Cerebrovasculares is the largest registry of a general stroke population and the first study to evaluate the level of IVT use in Ibero-America. It provides valuable information that may help to improve the quality of stroke care in the Ibero-American region.

Prehospital exenatide in hyperglycemic stroke-A randomized trial.

OBJECTIVES: Hyperglycemia is a predictor for poor stroke outcome. Hyperglycemic stroke patients treated with thrombolysis have an increased risk of intracranial hemorrhage. Insulin is the gold standard for treating hyperglycemia but comes with a risk of hypoglycemia. Glucagon-like peptide-1 receptor agonists (GLP-1RA) are drugs used in type 2 diabetes that have a low risk of hypoglycemia and have been shown to exert neuroprotective effects. The primary objective was to determine whether prehospital administration of the GLP-1RA exenatide could lower plasma glucose in stroke patients. Secondary objective was to study tolerability and safety. MATERIALS & METHODS: Randomized controlled trial comparing exenatide administrated prehospitally with a control group receiving standard care for hyperglycemia. Patients with Face Arm Speech Test ≥1 and glucose ≥8 mmol/L were randomized. Glucose was monitored for 24 hours. All adverse events were recorded. RESULTS: Nineteen patients were randomized, eight received exenatide. An interim recruitment failure analysis with subsequent changes of the protocol was made. The study was stopped prematurely due to slow inclusion. No difference was observed in the main outcome of plasma glucose at 4 hours, control vs exenatide (mean, SD); 7.0 ± 1.9 vs 7.6 ± 1.6; P = .56). No major adverse events were reported. CONCLUSIONS: We found no evidence that prehospital exenatide had effect on hyperglycemia. However, it was given without adverse events in this study with limited sample size that was prematurely stopped due to slow inclusion.

Predictors for Cerebral Edema in Acute Ischemic Stroke Treated With Intravenous Thrombolysis.

BACKGROUND AND PURPOSE: Cerebral edema (CED) is a severe complication of acute ischemic stroke. There is uncertainty regarding the predictors for the development of CED after cerebral infarction. We aimed to determine which baseline clinical and radiological parameters predict development of CED in patients treated with intravenous thrombolysis. METHODS: We used an image-based classification of CED with 3 degrees of severity (less severe CED 1 and most severe CED 3) on postintravenous thrombolysis imaging scans. We extracted data from 42 187 patients recorded in the SITS International Register (Safe Implementation of Treatments in Stroke) during 2002 to 2011. We did univariate comparisons of baseline data between patients with or without CED. We used backward logistic regression to select a set of predictors for each CED severity. RESULTS: CED was detected in 9579/42 187 patients (22.7%: 12.5% CED 1, 4.9% CED 2, 5.3% CED 3). In patients with CED versus no CED, the baseline National Institutes of Health Stroke Scale score was higher (17 versus 10; P<0.001), signs of acute infarct was more common (27.9% versus 19.2%; P<0.001), hyperdense artery sign was more common (37.6% versus 14.6%; P<0.001), and blood glucose was higher (6.8 versus 6.4 mmol/L; P<0.001). Baseline National Institutes of Health Stroke Scale, hyperdense artery sign, blood glucose, impaired consciousness, and signs of acute infarct on imaging were independent predictors for all edema types. CONCLUSIONS: The most important baseline predictors for early CED are National Institutes of Health Stroke Scale, hyperdense artery sign, higher blood glucose, decreased level of consciousness, and signs of infarct at baseline. The findings can be used to improve selection and monitoring of patients for drug or surgical treatment.

Clinical Selection Strategies to Identify Ischemic Stroke Patients With Large Anterior Vessel Occlusion: Results From SITS-ISTR (Safe Implementation of Thrombolysis in Stroke International Stroke Thrombolysis Registry).

BACKGROUND AND PURPOSE: The National Institutes of Health Stroke Scale (NIHSS) correlates with presence of large anterior vessel occlusion (LAVO). However, the application of the full NIHSS in the prehospital setting to select patients eligible for treatment with thrombectomy is limited. Therefore, we aimed to evaluate the prognostic value of simple clinical selection strategies. METHODS: Data from the Safe Implementation of Thrombolysis in Stroke International Stroke Thrombolysis Registry (January 2012-May 2014) were analyzed retrospectively. Patients with complete breakdown of NIHSS scores and documented vessel status were included. We assessed the association of prehospital stroke scales and NIHSS symptom profiles with LAVO (internal carotid artery, carotid-terminus or M1-segment of the middle cerebral artery). RESULTS: Among 3505 patients, 23.6% (n=827) had LAVO. Pathological finding on the NIHSS item best gaze was strongly associated with LAVO (adjusted odds ratio 4.5, 95% confidence interval 3.8-5.3). All 3 face-arm-speech-time test (FAST) items identified LAVO with high sensitivity. Addition of the item gaze to the original FAST score (G-FAST) or high scores on other simplified stroke scales increased specificity. The NIHSS symptom profiles representing total anterior syndromes showed a 10-fold increased likelihood for LAVO compared with a nonspecific clinical profile. If compared with an NIHSS threshold of ≥6, the prehospital stroke scales performed similarly or even better without losing sensitivity. CONCLUSIONS: Simple modification of the face-arm-speech-time score or evaluating the NIHSS symptom profile may help to stratify patients' risk of LAVO and to identify individuals who deserve rapid transfer to comprehensive stroke centers. Prospective validation in the prehospital setting is required.

Applying openEHR's Guideline Definition Language to the SITS international stroke treatment registry: a European retrospective observational study.

BACKGROUND: Interoperability standards intend to standardise health information, clinical practice guidelines intend to standardise care procedures, and patient data registries are vital for monitoring quality of care and for clinical research. This study combines all three: it uses interoperability specifications to model guideline knowledge and applies the result to registry data. METHODS: We applied the openEHR Guideline Definition Language (GDL) to data from 18,400 European patients in the Safe Implementation of Treatments in Stroke (SITS) registry to retrospectively check their compliance with European recommendations for acute stroke treatment. RESULTS: Comparing compliance rates obtained with GDL to those obtained by conventional statistical data analysis yielded a complete match, suggesting that GDL technology is reliable for guideline compliance checking. CONCLUSIONS: The successful application of a standard guideline formalism to a large patient registry dataset is an important step toward widespread implementation of computer-interpretable guidelines in clinical practice and registry-based research. Application of the methodology gave important results on the evolution of stroke care in Europe, important both for quality of care monitoring and clinical research.

External Validation of the ASTRAL and DRAGON Scores for Prediction of Functional Outcome in Stroke.

BACKGROUND AND PURPOSE: ASTRAL (Acute Stroke Registry and Analysis of Lausanne) and DRAGON (includes dense middle cerebral artery sign, prestroke modified Rankin Scale score, age, glucose, onset to treatment, National Institutes of Health Stroke Scale score) are 2 recently developed scores for predicting functional outcome after acute stroke in unselected acute ischemic stroke patients and in patients treated with intravenous thrombolysis, respectively. We aimed to perform external validation of these scores to assess their predictive performance in the large multicentre Safe Implementation of Thrombolysis in Stroke-International Stroke Thrombolysis Register. METHODS: We calculated the ASTRAL and DRAGON scores in 36 131 and 33 716 patients, respectively, registered in Safe Implementation of Thrombolysis in Stroke-International Stroke Thrombolysis Register between 2003 and 2013. The proportion of patients with 3-month modified Rankin Scale scores of 3 to 6 was observed for each score point and compared with the predicted proportion according to the risk scores. Calibration was assessed using calibration plots, and predictive performance was assessed using area under the curve of the receiver operating characteristic. Multivariate logistic regression coefficients for the variables in the 2 scores were compared with the original derivation cohorts. RESULTS: The ASTRAL showed an area under the curve of 0.790 (95% confidence interval, 0.786-0.795) and the DRAGON an area under the curve of 0.774 (95% confidence interval, 0.769-0.779). All ASTRAL parameters except range of visual fields and all DRAGON parameters were significantly associated with functional outcome in multivariate analysis. CONCLUSIONS: The ASTRAL and DRAGON scores show an acceptable predictive performance. ASTRAL does not require imaging-data and therefore may have an advantage for the use in prehospital patient assessment. Prospective studies of both scores evaluating the impact of their use on patient outcomes after intravenous thrombolysis and endovascular therapy are needed.

Mechanical Thrombectomy in Acute Ischemic Stroke-Patients with Wake-Up Stroke and the Elderly May Benefit as Well.

BACKGROUND: We have assessed to what extent age, sex, preintervention infarct size, time to groin puncture, and stroke severity are associated with outcome of mechanical thrombectomy in patients treated for acute ischemic stroke. METHODS: All 192 patients treated with mechanical thrombectomy for acute ischemic stroke from September 2005 to December 2011 were included in this observational study. Main outcomes were independence, defined as a modified Rankin Scale score of 0-2, an improvement in stroke severity score post-thrombectomy, and the occurrence of symptomatic hemorrhage. Exposure variables were sex, age, intravenous thrombolysis, prethrombectomy stroke severity grading, pretreatment infarct size, time from onset of symptoms to groin puncture, thrombectomy device used, and the angiographic result from the thrombectomy. RESULTS: For patients above 50 years with no neurological symptoms before stroke onset, the proportion gaining independence was unrelated to age group, ranging from 49% to 54%. For patients younger than 50 years of age, the proportion was significantly higher (81%). Patients with wake-up stroke did not differ from other patients with regard to outcome. CONCLUSIONS: Our results emphasize that when patients are selected on the basis of angiographic and perfusion imaging, both older patients and patients with wake-up stroke may experience a favorable outcome after mechanical thrombectomy.

Trends in Door-to-Thrombolysis Time in the Safe Implementation of Stroke Thrombolysis Registry: Effect of Center Volume and Duration of Registry Membership.

BACKGROUND AND PURPOSE: Shorter delays between symptom onset and treatment translate into better outcomes after ischemic stroke thrombolysis. There are considerable intercenter variations in treatment delivery. We analyzed the trends of door-to-needle times (DNTs) in the Safe Implementation of Thrombolysis in Stroke registry between 2003 and 2011. METHODS: We extracted from the Safe Implementation of Thrombolysis in Stroke registry (n=45 079) year of treatment, center code, DNT, sex, age, National Institutes of Health Stroke Scale, and comorbidity. For each center, the year they joined the registry and the annual volume of patients were determined (<5, 5-24, 25-49, 50-74, 75-99, and ≥100 patients/y). RESULTS: DNT was not available for 720 (1.6%) patients. The overall mean (SD) DNT was 73 (37) minutes with a median (interquartile range) of 67 (47-91) minutes. The DNT was 65 (46-90), 68 (50-92), and 72 (51-98) minutes for centers joined early (2003-2005), later (2006-2009), and recently (2009-2011), respectively. Center volume had more robust effect on DNT than year of treatment, and the shortest DNTs were seen in centers with volumes ≥100 patients/y. Earlier enrollment period was also associated with shorter delays. CONCLUSIONS: Centers that joined the registry earlier and those with high annual volume achieved shorter DNT than centers that joined later and low-volume centers. However, in most of the centers, DNT did not change much during the registry period. A multicenter project aiming to reduce DNT is warranted.

Intravenous Thrombolysis for Stroke Recurring Within 3 Months From the Previous Event.

BACKGROUND AND PURPOSE: According to the European license, alteplase can be given no sooner than 3 months after previous stroke. However, it is not known whether past history of stroke influences the effect of treatment. Our aim was to evaluate safety and functional outcome after intravenous thrombolysis administered in everyday practice to patients with previous stroke≤3 months compared with those with first-ever stroke. METHODS: We analyzed consecutive cases treated with alteplase between October 2003 and July 2014 contributed to the Safe Implementation of Thrombolysis for Stroke-Eastern Europe registry from 12 countries. Odds ratios were calculated using unadjusted and adjusted logistic regression. RESULTS: Of 13,007 patients, 11,221 (86%) had no history of stroke and 249 (2%) experienced previous stroke≤3 months before admission. Patients with previous stroke≤3 months had a higher proportion of hypertension and hyperlipidemia. There were no significant differences in outcome, including symptomatic intracerebral hemorrhage according to European Cooperative Acute Stroke Study (unadjusted odds ratio 1.27, 95% confidence interval: 0.74-2.15), and being alive and independent at 3 months (odds ratio 0.81, 95% confidence interval: 0.61-1.09). CONCLUSIONS: Patients currently treated with alteplase, despite a history of previous stroke≤3 months, do not seem to achieve worse outcome than those with first-ever stroke. Although careful patient selection was probably of major importance, our findings provide reassurance that this group of patients may safely benefit from thrombolysis and should not be arbitrarily excluded as a whole. Further studies are needed to identify the shortest safe time lapse from the previous event to treatment with alteplase.

Effect of treatment delay, age, and stroke severity on the effects of intravenous thrombolysis with alteplase for acute ischaemic stroke: a meta-analysis of individual patient data from randomised trials.

BACKGROUND: Alteplase is effective for treatment of acute ischaemic stroke but debate continues about its use after longer times since stroke onset, in older patients, and among patients who have had the least or most severe strokes. We assessed the role of these factors in affecting good stroke outcome in patients given alteplase. METHODS: We did a pre-specified meta-analysis of individual patient data from 6756 patients in nine randomised trials comparing alteplase with placebo or open control. We included all completed randomised phase 3 trials of intravenous alteplase for treatment of acute ischaemic stroke for which data were available. Retrospective checks confirmed that no eligible trials had been omitted. We defined a good stroke outcome as no significant disability at 3-6 months, defined by a modified Rankin Score of 0 or 1. Additional outcomes included symptomatic intracranial haemorrhage (defined by type 2 parenchymal haemorrhage within 7 days and, separately, by the SITS-MOST definition of parenchymal type 2 haemorrhage within 36 h), fatal intracranial haemorrhage within 7 days, and 90-day mortality. FINDINGS: Alteplase increased the odds of a good stroke outcome, with earlier treatment associated with bigger proportional benefit. Treatment within 3·0 h resulted in a good outcome for 259 (32·9%) of 787 patients who received alteplase versus 176 (23·1%) of 762 who received control (OR 1·75, 95% CI 1·35-2·27); delay of greater than 3·0 h, up to 4·5 h, resulted in good outcome for 485 (35·3%) of 1375 versus 432 (30·1%) of 1437 (OR 1·26, 95% CI 1·05-1·51); and delay of more than 4·5 h resulted in good outcome for 401 (32·6%) of 1229 versus 357 (30·6%) of 1166 (OR 1·15, 95% CI 0·95-1·40). Proportional treatment benefits were similar irrespective of age or stroke severity. Alteplase significantly increased the odds of symptomatic intracranial haemorrhage (type 2 parenchymal haemorrhage definition 231 [6·8%] of 3391 vs 44 [1·3%] of 3365, OR 5·55, 95% CI 4·01-7·70, p<0·0001; SITS-MOST definition 124 [3·7%] vs 19 [0·6%], OR 6·67, 95% CI 4·11-10·84, p<0·0001) and of fatal intracranial haemorrhage within 7 days (91 [2·7%] vs 13 [0·4%]; OR 7·14, 95% CI 3·98-12·79, p<0·0001). The relative increase in fatal intracranial haemorrhage from alteplase was similar irrespective of treatment delay, age, or stroke severity, but the absolute excess risk attributable to alteplase was bigger among patients who had more severe strokes. There was no excess in other early causes of death and no significant effect on later causes of death. Consequently, mortality at 90 days was 608 (17·9%) in the alteplase group versus 556 (16·5%) in the control group (hazard ratio 1·11, 95% CI 0·99-1·25, p=0·07). Taken together, therefore, despite an average absolute increased risk of early death from intracranial haemorrhage of about 2%, by 3-6 months this risk was offset by an average absolute increase in disability-free survival of about 10% for patients treated within 3·0 h and about 5% for patients treated after 3·0 h, up to 4·5 h. INTERPRETATION: Irrespective of age or stroke severity, and despite an increased risk of fatal intracranial haemorrhage during the first few days after treatment, alteplase significantly improves the overall odds of a good stroke outcome when delivered within 4·5 h of stroke onset, with earlier treatment associated with bigger proportional benefits. FUNDING: UK Medical Research Council, British Heart Foundation, University of Glasgow, University of Edinburgh.

Remote or extraischemic intracerebral hemorrhage--an uncommon complication of stroke thrombolysis: results from the safe implementation of treatments in stroke-international stroke thrombolysis register.

BACKGROUND AND PURPOSE: Intracerebral hemorrhage after treatment with intravenous recombinant tissue-type plasminogen activator for ischemic stroke can occur in local relation to the infarct, as well as in brain areas remote from infarcted tissue. We aimed to describe risk factors, 3-month mortality, and functional outcome in patients with the poorly understood complication of remote intracerebral hemorrhage, as well as local intracerebral hemorrhage. METHODS: In this study, 43 494 patients treated with intravenous recombinant tissue-type plasminogen activator, with complete imaging data, were enrolled in the Safe Implementation of Treatments in Stroke-International Stroke Thrombolysis Register (SITS-ISTR) during 2002 to 2011. Baseline data were compared among 970 patients (2.2%) with remote parenchymal hemorrhage (PHr), 2325 (5.3%) with PH, 438 (1.0%) with both PH and PHr, and 39 761 (91.4%) without PH or PHr. Independent risk factors for all hemorrhage types were obtained by multivariate logistic regression. RESULTS: Previous stroke (P=0.023) and higher age (P<0.001) were independently associated with PHr, but not with PH. Atrial fibrillation, computed tomographic hyperdense cerebral artery sign, and elevated blood glucose were associated with PH, but not with PHr. Female sex had a stronger association with PHr than with PH. Functional independence at 3 months was more common in PHr than in PH (34% versus 24%; P<0.001), whereas 3-month mortality was lower (34% versus 39%; P<0.001). CONCLUSIONS: Differences between risk factor profiles indicate an influence of previous vascular pathology in PHr and acute large-vessel occlusion in PH. Additional research is needed on the effect of pre-existing cerebrovascular disease on complications of recanalization therapy in acute ischemic stroke.

Within-day and weekly variations of thrombolysis in acute ischemic stroke: results from safe implementation of treatments in stroke-international stroke thrombolysis register.

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.

Role of preexisting disability in patients treated with intravenous thrombolysis for ischemic stroke.

BACKGROUND AND PURPOSE: Little is known about the effect of thrombolysis in patients with preexisting disability. Our aim was to evaluate the impact of different levels of prestroke disability on patients' profile and outcome after intravenous thrombolysis. METHODS: We analyzed the data of all stroke patients admitted between October 2003 and December 2011 that were contributed to the Safe Implementation of Treatments in Stroke-Eastern Europe (SITS-EAST) registry. Patients with no prestroke disability at all (modified Rankin Scale [mRS] score, 0) were used as a reference in multivariable logistic regression. RESULTS: Of 7250 patients, 5995 (82%) had prestroke mRS 0, 791 (11%) had prestroke mRS 1, 293 (4%) had prestroke mRS 2, and 171 (2%) had prestroke mRS≥3. Compared with patients with mRS 0, all other groups were older, had more comorbidities, and more severe neurological deficit on admission. There was no clear association between preexisting disability and the risk of symptomatic intracranial hemorrhage. Prestroke mRS 1, 2, and ≥3 were associated with increased risk of death at 3 months (odds ratio, 1.3, 2.0, and 2.6, respectively) and lower chance of achieving favorable outcome (achieving mRS 0-2 or returning to the prestroke mRS; 0.80, 0.41, 0.59, respectively). Patients with mRS≥3 and 2 had similar vascular profile and favorable outcome (34% versus 29%), despite higher mortality (48% versus 39%). CONCLUSIONS: Prestroke disability does not seem to independently increase the risk of symptomatic intracranial hemorrhage after thrombolysis. Despite higher mortality, 1 in 3 previously disabled patients may return to his/her prestroke mRS. Therefore, they should not be routinely excluded from thrombolytic therapy.

Predictors of functional dependence despite successful revascularization in large-vessel occlusion strokes.

BACKGROUND AND PURPOSE: High revascularization rates in large-vessel occlusion strokes treated by mechanical thrombectomy are not always associated with good clinical outcomes. We evaluated predictors of functional dependence despite successful revascularization among patients with acute ischemic stroke treated with thrombectomy. METHODS: We analyzed the pooled data from the Multi Mechanical Embolus Removal in Cerebral Ischemia (MERCI), Thrombectomy Revascularization of Large Vessel Occlusions in Acute Ischemic Stroke (TREVO), and TREVO 2 trials. Successful revascularization was defined as thrombolysis in cerebral infarction score 2b or 3. Functional dependence was defined as a score of 3 to 6 on the modified Rankin Scale at 3 months. We assessed relationship of demographic, clinical, angiographic characteristics, and hemorrhage with functional dependence despite successful revascularization. RESULTS: Two hundred and twenty-eight patients with successful revascularization had clinical outcome follow-up. The rates of functional dependence with endovascular success were 48.6% for Trevo thrombectomy and 58.0% for Merci thrombectomy. Age (odds ratio, 1.04; 95% confidence interval, 1.02-1.06 per 1-year increase), National Institutes of Health Stroke Scale score (odds ratio, 1.08; 95% confidence interval, 1.02-1.15 per 1-point increase), and symptom onset to endovascular treatment time (odds ratio, 1.11; 95% confidence interval, 1.01-1.22 per 30-minute delay) were predictors of functional dependence despite successful revascularization. Symptom onset to reperfusion time beyond 5 hours was associated with functional dependence. All subjects with symptomatic intracranial hemorrhage had functional dependence. CONCLUSIONS: One half of patients with successful mechanical thrombectomy do not have good outcomes. Age, severe neurological deficits, and delayed endovascular treatment were associated with functional dependence despite successful revascularization. Our data support efforts to minimize delays to endovascular therapy in patients with acute ischemic stroke to improve outcomes. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT00318071, NCT01088672, and NCT01270867.

Safety of intravenous thrombolysis for ischemic stroke in patients treated with warfarin.

OBJECTIVE: Controversy surrounds the safety of intravenous (IV) tissue plasminogen activator (tPA) in ischemic stroke patients treated with warfarin. The European tPA license precludes its use in anticoagulated patients altogether. American guidelines accept IV tPA use with an international normalized ratio (INR) ≤ 1.7. The influence of warfarin on symptomatic intracerebral hemorrhage (SICH), arterial recanalization, and long-term functional outcome in stroke thrombolysis remains unclear. METHODS: We analyzed data from 45,074 patients treated with IV tPA enrolled in the Safe Implementation of Thrombolysis in Stroke (SITS) International Stroke Thrombolysis Register. A total of 768 patients had baseline warfarin treatment with INR ≤ 1.7. Outcome measures were SICH, arterial recanalization, mortality, and functional independence at 3 months. RESULTS: Patients on warfarin with INR ≤ 1.7 were older, had more comorbidities, and had more severe strokes compared to patients without warfarin. There were no significant differences between patients with and without warfarin in SICH rates (adjusted odds ratio [aOR] = 1.23, 95% confidence interval [CI] = 0.72-2.11 per SITS-MOST; aOR = 1.26, 95% CI = 0.82-1.70 per European Cooperative Acute Stroke Study II) after adjustment for age, stroke severity, and comorbidities. Neither did warfarin independently influence mortality (aOR = 1.05, 95% CI = 0.83-1.35) or functional independence at 3 months (aOR = 1.01, 95% CI = 0.81-1.24). Arterial recanalization by computed tomography/magnetic resonance angiography trended higher in warfarin patients (62% [37 of 59] vs 55% [776/1,475], p = 0.066). Recanalization approximated by disappearance at 22 to 36 hours of a baseline hyperdense middle cerebral artery sign was increased (63% [124 of 196] vs 55% [3,901 of 7,099], p = 0.022). INTERPRETATION: Warfarin treatment with INR ≤ 1.7 did not increase the risk for SICH or death, and had no impact on long-term functional outcome in patients treated with IV tPA for acute ischemic stroke.

Face Arm Speech Time Test use in the prehospital setting, better in the ambulance than in the emergency medical communication center.

BACKGROUND: Prehospital identification of acute stroke increases the possibility of early treatment and good outcome. To increase identification of stroke, the Face Arm Speech Time (FAST) test was introduced in the Emergency Medical Communication Center (EMCC). This substudy aims to evaluate the implementation of the FAST test in the EMCC and the ambulance service. METHODS: The study was conducted in the region of Stockholm, Sweden during 6 months. The study population consisted of all calls to the EMCC concerning patients presenting at least one FAST symptom or a history/finding making the EMCC or ambulance personnel to suspect stroke within 6 h. Positive FAST was compared to diagnosis at discharge. Positive predictive values (PPV) for a stroke diagnosis at discharge were calculated. RESULTS: In all, 900 patients with a median age of 71 years were enrolled, 667 (74%) by the EMCC and 233 (26%) by the ambulances. At discharge, 472 patients (52%) were diagnosed with stroke/transient ischemic attack (TIA), 337 identified by the EMCC (71%) and 135 (29%) by the ambulances. The PPV for a discharge diagnosis of stroke/TIA was 51% (CI 47-54%) in EMCC-enrolled and 58% (CI 52-64%) in ambulance-enrolled patients. With a positive FAST the PPV of a correct stroke/TIA diagnosis increased to 56% (CI 52-61%) and 73% (CI 66-80%) in EMCC- and ambulance-enrolled patients, respectively. Positive FAST from EMCC was also found in 44% of patients with a nonstroke diagnosis at discharge. A stroke/TIA diagnosis at discharge but negative FAST was found in 58 and 27 patients enrolled by the EMCC and ambulances, respectively. CONCLUSIONS: The PPV of FAST is higher when used on the scene by ambulance than by EMCC. FAST may be a useful prehospital tool to identify stroke/TIA but has limitations as the test can be negative in true strokes, can be positive in nonstrokes, and FAST symptoms may be present but not identified in the emergency call. For the prehospital care situation better identification tools are needed.

Mechanical thrombectomy in acute ischemic stroke-experience from 6 years of practice.

INTRODUCTION: We present our results from the first 6 years with mechanical thrombectomy in the treatment of ischemic stroke. METHODS: Every patient treated with mechanical thrombectomy for acute ischemic stroke from September 2005 to December 2011 was consecutively included in this retrospective analysis. Baseline and outcome data were retrieved from computerized records at the hospital. National Institute of Health Stroke Scale (NIHSS) score and the modified Rankin Scale (mRS) score were used as outcome parameters. Favorable outcome was defined as a mRS score of 0-2, corresponding to independence in activities of daily living. We also evaluated revascularization and severe adverse events, with focus on symptomatic intracranial hemorrhage. RESULTS: Good functional outcome (mRS 0-2) was achieved in 50 % (120/240) of all patients. For patients with no neurological deficit prior to stroke onset (i.e., mRS = 0 before stroke), the proportion with good functional outcome was 54 %. Symptomatic hemorrhages occurred in 4.6 % of the cases (5.7 % in the anterior circulation). CONCLUSION: In summary, our results supports that mechanical thrombectomy is a safe and effective method to restore blood flow in selected patients suffering from an acute ischemic stroke.