Tenecteplase versus alteplase after acute ischemic stroke at high age.

BACKGROUND: Stroke prevalence is increasing with age. Alteplase is the only agent approved for thrombolytic treatment for patients with ischemic stroke, including patients ≥80 years. In the present study, the aim was to compare efficacy and safety of tenecteplase and alteplase in patients ≥80 years. METHODS: Data from the Norwegian Tenecteplase Stroke Trial, a randomized controlled trial comparing alteplase and tenecteplase, were assessed. RESULTS: Of the 273 patients ≥80 years included, mean age was 85.5 years.In the intention-to-treat analyses, 43.1% receiving tenecteplase and 39.9% receiving alteplase reached excellent functional outcome (modified Rankin Scale score 0-1) after 3 months (odds ratio (OR) 1.14, 95% confidence interval (CI) 0.70-1.85, p=0.59). No significant differences among patients in the two treatment groups regarding frequency of symptomatic intracranial hemorrhage during the first 48 h were identified (11 (8.5%) in the tenecteplase group, 10 (7.0%) in the alteplase group, OR 1.23, 95% CI 0.50-3.00, p 0.65). Death within 3 months occurred in 18 patients (14.3%) in the tenecteplase group and in 21 (15.3%) in the alteplase group (p 0.84). After excluding stroke mimics, the proportion of patients with excellent functional outcome was 44.1% in the tenecteplase group and 34.4% in the alteplase group (OR 1.50 CI 0.90-2.52, p 0.12). CONCLUSION: No differences in the efficacy and safety of tenecteplase versus alteplase in patients ≥80 years were identified. TRIAL REGISTRATION: Clinicaltrials.gov (NCT01949948).

Short-Term Outcome and In-Hospital Complications After Acute Cerebral Infarcts in Multiple Arterial Territories.

Background and Purpose- Patients with acute cerebral infarcts in multiple arterial territories (MACI) represent a substantial portion of the stroke population. There are no data on short-term outcome and in-hospital complications in patients with MACI. We compared patients with MACI with patients having acute cerebral infarct(s) in a single arterial territory. Methods- We analyzed 3343 patients with diffusion-weighted imaging-confirmed acute cerebral infarcts. MACI was defined as at least 2 acute cerebral ischemic lesions in at least 2 arterial cerebral territories. Patients with MACI were compared with patients with acute cerebral infarct(s) in a single arterial territory for relevant in-hospital complications and short-term outcome, namely National Institutes of Health Stroke Scale and modified Rankin Scale at day 7 after admission or at discharge when earlier. Results- A total of 311 patients (9.3%) met the definition of MACI. Both median National Institutes of Health Stroke Scale (2 [1-7] versus 1 [0-4]) and modified Rankin Scale (3 [1-4] versus 2 [1-3]) were higher in patients with MACI. MACI was independently associated with higher National Institutes of Health Stroke Scale and modified Rankin Scale. Deep venous thrombosis, myocardial infarction, and any complications were more frequent in patients with MACI. Conclusions- In-hospital complications were more frequent in patients with MACI, which may adversely affect short-term clinical and functional outcome. Closer follow-up of patients with MACI during hospitalization may prevent such events and negative progression.

Incidence and Etiologies of Stroke Mimics After Incident Stroke or Transient Ischemic Attack.

Background and Purpose- Stroke mimics (SM) pose a common clinical challenge, but the burden of SM in patients with previous ischemic stroke (IS) or transient ischemic attack is unknown. The objective of this study was to calculate the incidence of SM in IS survivors, compare it with the incidence of recurrent stroke in the same population, and explore the time-dependent patterns of SM etiologies. Methods- This prospective cohort study registered SM events and etiologies among 1872 IS and transient ischemic attack survivors diagnosed with index stroke at Haukeland University Hospital stroke unit from 2007 to 2013 by review of medical records. Cumulative incidences of SM were estimated with a competing risks Cox model and compared with incidence of recurrent stroke in the same population. Results- During 8172 person-years of follow-up, 339 patients had 480 SM events. The cumulative incidence rate of SM during follow-up was 58.7 per 1.000 person-years (95% CI, 53.7-64.2) compared with 34.0 per 1.000 person-years (95% CI, 30.2-38.2) for recurrent stroke in the same time period. The risks of SM and recurrent stroke were highest the first year after index IS or transient ischemic attack. The most frequent SM diagnoses were sequelae of cerebral infarction (19.8%), medical observation, and evaluation for suspected cerebrovascular disease (15.6%) and infections (14.0%). The 2 most frequent and unspecific diagnoses (sequelae of cerebral infarction and medical observation) were clustered in the first months after index stroke. Conclusions- SM after IS or transient ischemic attack are more frequent than recurrent stroke and the risk is especially high in the early period. SMs are multietiological and unspecific diagnoses are most frequent early after index stroke.

Recurrent ischemic stroke: Incidence, predictors, and impact on mortality.

BACKGROUND AND PURPOSE: Recurrent ischemic stroke (IS) or TIA is frequent with a considerable variation in incidence and mortality across populations. Current data on stroke recurrence and mortality are useful to examine trends, risk factors, and treatment effects. In this study, we calculated the incidence of recurrent IS or TIA in a hospital-based stroke population in Western Norway, investigated recurrence factors, and estimated the effect of recurrence on all-cause mortality. METHODS: This prospective cohort study registered recurrence and mortality among 1872 IS and TIA survivors admitted to the stroke unit at Haukeland University Hospital between July 2007 and December 2013. Recurrence and death until September 1, 2016, were identified by medical chart review. Cumulative incidences of recurrence were estimated with a competing risks Cox model. Multivariate Cox models were used to examine recurrence factors and mortality. RESULTS: During follow-up, 220 patients had 277 recurrent IS or TIAs. The cumulative recurrence rate was 5.4% at 1 year, 11.3% at 5 years, and 14.2% at the end of follow-up. Hypertension (HR = 1.65, 95% CI 1.21-2.25), prior symptomatic stroke (HR = 1.63, 95% CI 1.18-2.24), chronic infarcts on MRI (HR = 1.48, 95% CI 1.10-1.99), and age (HR 1.02/year, 95% CI 1.00-1.03) were independently associated with recurrence. A total of 668 (35.7%) patients died during follow-up. Recurrence significantly increased the all-cause mortality (HR = 2.55, 95% CI 2.04-3.18). CONCLUSIONS: The risk of recurrent IS stroke or TIA was modest in our population and was associated with previously established risk factors. Recurrence more than doubled the all-cause mortality.

U-shaped relationship between hemoglobin level and severity of ischemic stroke.

BACKGROUND AND AIM: We aimed to explore the relation between hemoglobin level and ischemic stroke severity and short-term improvement in patients admitted to hospital within 3 hours of stroke onset. METHODS: The relation between stroke severity and hemoglobin was explored by locally weighted scatterplot smoothing (lowess smoother) curves. The effect of hemoglobin on short-term outcome was determined by means of linear regression analyses with NIHSS score day 7 as dependent variable after adjusting for confounders including NIHSS score on admission. Analyses were performed to disclose clinical factor associated with hemoglobin level. RESULTS: This study includes 905 ischemic stroke patients admitted within 3 hours of stroke onset. Lowess smoother curves showed a U-shaped relation between NIHSS score on admission and mRS score day 7 and hemoglobin level. Regression analysis showed low hemoglobin to be independently associated with females, high age, severe stroke, low systolic blood pressure, prior cerebral infarction, not smoking, not atrial fibrillation, and unknown etiology (all P < 0.05). Another regression analysis showed that high NIHSS score day 7 was independently associated with low hemoglobin after adjusting for confounders including NIHSS score on admission. CONCLUSIONS: We found a U-shaped relationship between hemoglobin level on admission and stroke severity. There was no U-shaped relationship between improvement and hemoglobin level. Poor short-term improvement was associated with low hemoglobin levels.

Tenecteplase Versus Alteplase Between 3 and 4.5 Hours in Low National Institutes of Health Stroke Scale.

Background and Purpose- Thrombolysis with alteplase has beneficial effect on outcome and is safe within 4.5 hours. The present study compares the efficacy and safety of tenecteplase and alteplase in patients treated 3 to 4.5 hours after ischemic stroke. Methods- The data are from a prespecified substudy of patients included in The NOR-TEST (Norwegian Tenecteplase Stroke Trial), a randomized control trial comparing tenecteplase with alteplase. Results- The median admission National Institutes of Health Stroke Scale for this study population was 3 (interquartile range, 2-6). In the intention-to-treat analysis, 57% of patients that received tenecteplase and 53% of patients that received alteplase reached good functional outcome (modified Rankin Scale score of 0-1) at 3 months (odds ratio, 1.19; 95% CI, 0.68-2.10). The rates of intracranial hemorrhage in the first 48 hours were 5.7% in the tenecteplase group and 6.7% in the alteplase group (odds ratio, 0.84; 95% CI, 0.26-2.70). At 3 months, mortality was 5.7% and 4.5%, respectively. After excluding stroke mimics and patients with modified Rankin Scale score of >1 before stroke, the proportion of patients with good functional outcome was 61% in the tenecteplase group and 57% in the alteplase group (odds ratio, 1.24; 95% CI, 0.65-2.37). Conclusions- Tenecteplase is at least as effective as alteplase to achieve a good clinical outcome in patients with mild stroke treated between 3 and 4.5 hours after ischemic stroke. Clinical Trial Registration- URL: https://www.clinicaltrials.gov . Unique identifier: NCT01949948.

High risk of early neurological worsening of lacunar infarction.

BACKGROUND AND PURPOSE: We aimed to evaluate factors associated with neurological worsening among patients with lacunar or non-lacunar infarction admitted within 3 hours and between 3 and 24 hours after stroke onset. METHODS: All patients admitted to Haukeland university hospital between 2006 and 2016 with acute cerebral infarction on MRI and admission within 24 hours were included. Repeated National Institute of Health Stroke Scale (NIHSS) scoring was performed in all patients whenever possible. Neurological worsening during the hospital stay was defined as NIHSS score increase ≥3 compared to NIHSS score on admission. RESULTS: In patients with lacunar infarction admitted within 3 hours of onset, neurological worsening was associated with low NIHSS score on admission, low body temperature, and leukoaraiosis, whereas only internal carotid artery stenosis or occlusion was associated with neurological worsening in non-lacunar infraction. For patients admitted 3-24 hours after onset, neurological worsening was associated with low body temperature, high systolic blood pressure, and short time from onset to admission in patients with lacunar infarction, whereas high systolic blood pressure, high NIHSS score on admission, middle cerebral artery occlusion, and high blood glucose were associated with neurological worsening in patients with non-lacunar infarction (all P < 0.05). CONCLUSIONS: Lacunar infarctions with minor neurological deficits within 3 hours of stroke onset are at high risk of neurological worsening especially if concomitant low body temperature and leukoaraiosis.

Thirty-day recurrence after ischemic stroke or TIA.

BACKGROUND: Incidence of recurrent stroke is highest within 30 days after the initial ischemic stroke (IS) or TIA, but knowledge about early recurrence is lacking. We aimed to identify etiological groups with highest risk of early recurrence and assess how the TOAST classification identified index stroke etiology. METHODS: Medical records of 1874 IS and TIA patients in the Bergen NORSTROKE registry were retrospectively reviewed for identification of recurrent IS or TIA within 30 days after index IS or TIA. Stroke etiology was determined by review of electronical medical journals. Logistic regression was used to calculate odds ratios (OR) for 30-day recurrence. RESULTS: Thirty-three patients (1.8%) were readmitted with recurrent IS or TIA within 30 days after index stroke. By using TOAST, 12 patients were initially classified with stroke of unknown etiology (SUE). Etiologies behind recurrent IS or TIA were after the recurrent episode identified as extracranial large artery atherosclerosis (LAA) in 14 patients (42.4%), intracranial arterial pathology in seven patients (21.2%), active malignancy in six patients (18.2%), and cardio embolism in four patients (12.1%). Small vessel occlusion and SUE were the causes in one patient each. Logistic regression showed that patients with stroke of other determined etiology (SOE) and LAA had increased risk of 30-day recurrence (OR = 9.72, 95% CI 1.84-51.3, p < 0.01 and OR = 4.36, 95% CI 2.01-9.47, p < 0.01, respectively). CONCLUSION: Patients with LAA and SOE had increased risk of recurrent IS or TIA within 30 days. TOAST was inadequate at identifying exact etiologies behind recurrent stroke at index event.

Clinical Importance of Temporal Bone Features for the Efficacy of Contrast-Enhanced Sonothrombolysis: a Retrospective Analysis of the NOR-SASS Trial.

Contrast-enhanced sonothrombolysis (CEST) seems to be a safe and promising treatment in acute ischemic stroke. It remains unknown if temporal bone features may influence the efficacy of CEST. We investigated the association between different temporal bone features on admission computed tomography (CT) scan and the outcome in acute ischemic stroke patients included in the randomized Norwegian Sonothrombolysis in Acute Stroke Study (NOR-SASS). Patients diagnosed as stroke mimics and those with infratentorial stroke or with incorrect insonation were excluded. We retrospectively assessed temporal bone heterogeneity (presence of diploë), diploë ratio, thickness, and density on admission CT scans. National institute of Health Stroke Scale (NIHSS) at 24 h and modified Rankin Scale (mRS) at 3 months were correlated with CT findings both in CEST and sham CEST patients. A total of 99 patients were included of which 52 were assigned to CEST and 47 to sham CEST. Approximately 20% patients had a heterogeneous temporal bone in both the CEST and sham CEST group. All temporal bone CT features studied were associated with female sex. In the CEST group, temporal bone heterogeneity (p = 0.006) and higher temporal bone diploë ratio (p = 0.002) were associated with higher NIHSS at 24 h. There was no association between temporal bone features and mRS at 3 months. Approximately 20% of acute ischemic stroke patients have heterogeneous temporal bone and may be resistant to standard 2-MHz transcranial Doppler ultrasound treatment. Sonothrombolysis resistance may easily be predicted by admission CT for better selection.

A score for paroxysmal atrial fibrillation in acute ischemic stroke.

Aim Many patients with ischemic stroke have paroxysmal atrial fibrillation that may be difficult to detect. We sought to identify markers of paroxysmal atrial fibrillation and construct a score that may help the clinician to select patients for anticoagulation even if investigations do not disclose atrial fibrillation. Methods A group of patients with acute ischemic stroke and TIA and documented paroxysmal atrial fibrillation was compared to a group of patients with ischemic stroke and TIA and no known paroxysmal atrial fibrillation and sinus rhythm on Holter monitoring. Clinical features, blood tests, ECG, and MRI findings were compared. Sensitivity and specificity of significant markers for paroxysmal atrial fibrillation were calculated. A simple score based on independent markers for paroxysmal atrial fibrillation was constructed. Results Out of 3480 patients with TIA or ischemic stroke, 237 (19%) had paroxysmal atrial fibrillation and 1002 (81%) had sinus rhythm. On univariate analyses, significant markers for paroxysmal atrial fibrillation included increasing age, females, prior ischemic stroke, myocardial infarction, other heart diseases, pathologic troponin, embolic stroke and stroke in different arterial territories (all P < .01). A score including age dichotomized at 75 years, cardiac disease and troponin was constructed. Conclusion We identified many markers for paroxysmal atrial fibrillation and constructed a score that may help the clinician to select patients for anticoagulation even if investigations do not disclose paroxysmal atrial fibrillation.

Tenecteplase versus alteplase for management of acute ischaemic stroke (NOR-TEST): a phase 3, randomised, open-label, blinded endpoint trial.

BACKGROUND: Tenecteplase is a newer thrombolytic agent with some pharmacological advantages over alteplase. Previous phase 2 trials of tenecteplase in acute ischaemic stroke have shown promising results. We aimed to investigate the safety and efficacy of tenecteplase versus alteplase in patients with acute stroke who were eligible for intravenous thrombolysis. METHODS: This phase 3, randomised, open-label, blinded endpoint, superiority trial was done in 13 stroke units in Norway. We enrolled adults with suspected acute ischaemic stroke who were eligible for thrombolysis and admitted within 4·5 h of symptom onset or within 4·5 h of awakening with symptoms, or who were eligible for bridging therapy before thrombectomy. Patients were randomly assigned (1:1) to receive intravenous tenecteplase 0·4 mg/kg (to a maximum of 40 mg) or alteplase 0·9 mg/kg (to a maximum of 90 mg), via a block randomisation schedule stratified by centre of inclusion. Patients were not informed of treatment allocation; treating physicians were aware of treatment allocation but those assessing the primary and secondary endpoints were not. The primary outcome was excellent functional outcome defined as modified Rankin Scale (mRS) score 0-1 at 3 months. The primary analysis was an unadjusted and non-stratified intention-to-treat analysis with last observation carried forward for imputation of missing data. This study is registered with ClinicalTrials.gov, number NCT01949948. FINDINGS: Between Sept 1, 2012, and Sept 30, 2016, 1107 patients met the inclusion criteria and seven patients were excluded because informed consent was withdrawn or eligibility for thrombolytic treatment was reconsidered. 1100 patients were randomly assigned to the tenecteplase (n=549) or alteplase (n=551) groups. The median age of participants was 77 years (IQR 64-79) and the median National Institutes of Health Stroke Scale score at baseline was 4 points (IQR 2-8). A final diagnosis other than ischaemic stroke or transient ischaemic attack was found in 99 (18%) patients in the tenecteplase group and 91 (17%) patients in the alteplase group. The primary outcome was achieved by 354 (64%) patients in the tenecteplase group and 345 (63%) patients in the alteplase group (odds ratio 1·08, 95% CI 0·84-1·38; p=0·52). By 3 months, 29 (5%) patients had died in the tenecteplase group compared with 26 (5%) in the alteplase group. The frequency of serious adverse events was similar between groups (145 [26%] in the tenecteplase group vs 141 [26%] in the alteplase group; p=0·74). INTERPRETATION: Tenecteplase was not superior to alteplase and showed a similar safety profile. Most patients enrolled in this study had mild stroke. Further trials are needed to establish the safety and efficacy in patients with severe stroke and whether tenecteplase is non-inferior to alteplase. FUNDING: Research Council of Norway.

NOR-SASS (Norwegian Sonothrombolysis in Acute Stroke Study): Randomized Controlled Contrast-Enhanced Sonothrombolysis in an Unselected Acute Ischemic Stroke Population.

BACKGROUND AND PURPOSE: The NOR-SASS (Norwegian Sonothrombolysis in Acute Stroke Study) aimed to assess effect and safety of contrast-enhanced ultrasound treatment in an unselected acute ischemic stroke population. METHODS: Patients treated with intravenous thrombolysis within 4.5 hours after symptom onset were randomized 1:1 to either contrast-enhanced sonothrombolysis (CEST) or sham CEST. A visible arterial occlusion on baseline computed tomography angiography was not a prerequisite for inclusion. Pulse-wave 2 MHz ultrasound was given for 1 hour and contrast (SonoVue) as an infusion for ≈30 minutes. Magnetic resonance imaging and angiography were performed after 24 to 36 hours. Primary study end points were neurological improvement at 24 hours defined as National Institutes of Health Stroke Scale score 0 or reduction of ≥4 National Institutes of Health Stroke Scale points compared with baseline National Institutes of Health Stroke Scale and favorable functional outcome at 90 days defined as modified Rankin scale score 0 to 1. RESULTS: A total of 183 patients were randomly assigned to either CEST (93 patient) or sham CEST (90 patients). The rates of symptomatic intracerebral hemorrhage, asymptomatic intracerebral hemorrhage, or mortality were not increased in the CEST group. Neurological improvement at 24 hours and functional outcome at 90 days was similar in the 2 groups both in the intention-to-treat analysis and in the per-protocol analysis. CONCLUSIONS: CEST is safe among unselected ischemic stroke patients with or without a visible occlusion on computed tomography angiography and with varying grades of clinical severity. There was, however, statistically no significant clinical effect of sonothrombolysis in this prematurely stopped trial. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01949961.

Novel Thrombolytics for Acute Ischemic Stroke: Challenges and Opportunities.

Progress in finding a better alternative to alteplase has been slow. Tenecteplase and desmoteplase have better pharmacological profiles compared with alteplase, but definite clinical evidence of their superiority is lacking. The two major phase III studies that have tested the efficacy and safety of desmoteplase in ischemic stroke patients have shown neutral results and a promising safety profile, but the trials compared desmoteplase with placebo only in late admitted patients. Future trials should focus on testing novel thrombolytics in the early time window either as the sole acute recanalizing treatment or combined with thrombectomy.

Therapeutic Potential of Tenecteplase in the Management of Acute Ischemic Stroke.

Given that alteplase has been the only approved thrombolytic agent for acute ischemic stroke for almost two decades, there has been intense interest in more potent and safer agents over the last few years. Tenecteplase is a bioengineered mutation of alteplase with advantageous pharmacodynamics and pharmacokinetics. The superiority of tenecteplase over alteplase has been proven by in vitro and animal studies, and it was approved for use in myocardial infarction more than a decade ago. In patients with acute ischemic stroke, tenecteplase has shown promise in randomized phase II trials and the drug is currently being tested in four phase III clinical trials that will start delivering definite results in the near future: NOR-TEST (NCT01949948), TASTE (ACTRN12613000243718), TEMPO-2 (NCT02398656), and TALISMAN (NCT02180204).

A pragmatic approach to sonothrombolysis in acute ischaemic stroke: the Norwegian randomised controlled sonothrombolysis in acute stroke study (NOR-SASS).

BACKGROUND: Ultrasound accelerates thrombolysis with tPA (sonothrombolysis). Ultrasound in the absence of tPA also accelerates clot break-up (sonolysis). Adding intravenous gaseous microbubbles may potentiate the effect of ultrasound in both sonothrombolysis and sonolysis. The Norwegian Sonothrombolysis in Acute Stroke Study aims in a pragmatic approach to assess the effect and safety of contrast enhanced ultrasound treatment in unselected acute ischaemic stroke patients. METHODS/DESIGN: Acute ischaemic stroke patients ≥ 18 years, with or without visible arterial occlusion on computed tomography angiography (CTA) and treatable ≤ 4(½) hours after symptom onset, are included in NOR-SASS. NOR-SASS is superimposed on a separate trial randomising patients with acute ischemic stroke to either tenecteplase or alteplase (The Norwegian Tenecteplase Stroke Trial NOR-TEST). The NOR-SASS trial has two arms: 1) the thrombolysis-arms (NOR-SASS A and B) includes patients given intravenous thrombolysis (tenecteplase or alteplase), and 2) the no-thrombolysis-arm (NOR-SASS C) includes patients with contraindications to thrombolysis. First step randomisation of NOR-SASS A is embedded in NOR-TEST as a 1:1 randomisation to either tenecteplase or alteplase. Second step NOR-SASS randomisation is 1:1 to either contrast enhanced sonothrombolysis (CEST) or sham CEST. Randomisation in NOR-SASS B (routine alteplase group) is 1:1 to either CEST or sham CEST. Randomisation of NOR-SASS C is 1:1 to either contrast enhanced sonolysis (CES) or sham CES. Ultrasound is given for one hour using a 2-MHz pulsed-wave diagnostic ultrasound probe. Microbubble contrast (SonoVue®) is given as a continuous infusion for ~30 min. Recanalisation is assessed at 60 min after start of CEST/CES. Magnetic resonance imaging and angiography is performed after 24 h of stroke onset. Primary study endpoints are 1) major neurological improvement measured with NIHSS score at 24 h and 2) favourable functional outcome defined as mRS 0-1 at 90 days. DISCUSSION: NOR-SASS is the first randomised controlled trial designed to test the superiority of contrast enhanced ultrasound treatment given ≤ 4(½) hours after stroke onset in an unselected acute ischaemic stroke population eligible or not eligible for intravenous thrombolysis, with or without a defined arterial occlusion on CTA. If a positive effect and safety can be proven, contrast enhanced ultrasound treatment will be an option for all acute ischaemic stroke patients. EudraCT No 201200032341; www.clinicaltrials.gov NCT01949961.

The Norwegian tenecteplase stroke trial (NOR-TEST): randomised controlled trial of tenecteplase vs. alteplase in acute ischaemic stroke.

BACKGROUND: Alteplase is the only approved thrombolytic agent for acute ischaemic stroke. The overall benefit from alteplase is substantial, but some evidence indicates that alteplase also has negative effects on the ischaemic brain. Tenecteplase may be more effective and less harmfull than alteplase, but large randomised controlled phase 3 trials are lacking. The Norwegian Tenecteplase Stroke Trial (NOR-TEST) aims to compare efficacy and safety of tenecteplase vs. alteplase. METHODS/DESIGN: NOR-TEST is a multi-centre PROBE (prospective randomised, open-label, blinded endpoint) trial designed to establish superiority of tenecteplase 0.4 mg/kg (single bolus) as compared with alteplase 0.9 mg/kg (10% bolus + 90% infusion/60 minutes) for consecutively admitted patients with acute ischaemic stroke eligible for thrombolytic therapy, i.e. patients a) admitted <4½ hours after symptoms onset; b) admitted <4½ hours after awakening with stroke symptoms c) receiving bridging therapy before embolectomy.Randomisation tenecteplase:alteplase is 1:1. The primary study endpoint is favourable functional outcome defined as modified Rankin Scale 0-1 at 90 days. Secondary study endpoints are: 1) haemorrhagic transformation (haemorrhagic infarct/haematoma); 2) symptomatic cerebral haemorrhage on CT 24-48 hours; 3) major neurological improvement at 24 hours; 4) recanalisation at 24-36 hours; 5) death. DISCUSSION: NOR-TEST may establish a novel approach to acute ischaemic stroke treatment. A positive result will lead to a more effective, safer and easier treatment for all acute ischaemic stroke pasients.NOR-TEST is reviewed and approved by the Regional Committee for Medical and Health Research Ethics (2011/2435), and The Norwegian Medicines Agency (12/01402). NOR-TEST is registered with EudraCT No 2011-005793-33 and in ClinicalTrials.gov (NCT01949948).

Low body temperature associated with severe ischemic stroke within 6 hours of onset: The Bergen NORSTROKE Study.

BACKGROUND: Hypothermia is considered neuroprotective and a potential treatment in cerebral ischemia. Some studies suggest that hyperthermia may promote clot lysis. We hypothesized that low body temperature would prolong time to spontaneous clot lysis resulting in an association between low body temperature and severe neurological deficits in the early phase of ischemic stroke. METHODS: In this prospective study, patients (n = 516) exhibiting ischemic stroke with symptom onset within 6 hours were included. Body temperature and National Institute of Health Stroke Scale (NIHSS) score were registered on admission. Because low body temperature on admission may be secondary to immobilization due to large stroke, separate analyses were performed on patients with cerebral hemorrhage admitted within 6 hours (n = 85). RESULTS: Linear regression showed that low body temperature on admission was independently associated with a high NIHSS score within 6 hours of stroke onset in patients with ischemic stroke (P < 0.001). The association persisted when NIHSS was measured at 24 hours after admission. No such associations were found in patients with cerebral hemorrhage admitted within 6 hours of stroke onset. CONCLUSION: Our study suggests that low body temperature within 6 hours of symptom onset is associated with severe ischemic stroke. This is in support of our hypothesis, although other contributing mechanisms cannot be excluded.