Wake-up stroke and unknown-onset stroke; occurrence and characteristics from the nationwide Norwegian Stroke Register

Introduction: Population-based knowledge of the characteristics of wake-up stroke and unknown-onset stroke is limited. We compared occurrence and characteristics of ischaemic and haemorrhagic wake-up stroke, unknown-onset stroke and known-onset stroke in a nationwide register-based study. Patients and methods: We included patients registered in the Norwegian Stroke Register from 2012 through 2019. Age, sex, risk factors, clinical characteristics, acute stroke treatment and discharge destination were compared according to stroke type and time of onset. Results: Of the 60,320 patients included, 11,451 (19%) had wake-up stroke, 11,098 (18.4%) had unknown time of onset and 37,771 (62.6%) had known symptom onset. The proportion of haemorrhagic stroke was lower among wakeup stroke patients (1107/11,451, 9.7%, 95% CI: 9.1–10.2) than for known-onset stroke (5230/37,771, 13.8%, 95% CI: 13.5–14.2) and for unknown-onset stroke (1850/11,098, 16.7%, 95% CI: 16.0–17.4). Mild stroke (NIHSS Discussion and conclusions: Ischaemic wake-up strokes shared baseline characteristics with known-onset strokes, but tended to be milder. Ischaemic unknown-onset stroke patients differed significantly from wake-up stroke, emphasising the importance of considering them as separate entities

Thrombolytic Treatment in Wake‐Up Stroke: A Propensity Score–Matched Analysis of Treatment Effectiveness in the Norwegian Stroke Registry

Background Previous clinical trials found improved outcome of thrombolytic treatment in patients with ischemic wake‐up stroke (WUS) selected by advanced imaging techniques. The authors assessed the effectiveness of thrombolytic treatment in patients with WUS in a nationwide stroke registry. Methods and Results Using propensity score matching, the authors assessed the effectiveness and safety of thrombolytic treatment versus no thrombolytic treatment in 726 patients (363 matched pairs) with WUS in the Norwegian Stroke Registry in 2014 to 2019. Thrombolytic treatment in WUS versus known‐onset stroke was compared in 730 patients (365 matched pairs). Functional outcomes were assessed by the modified Rankin Scale (mRS) at 3 months. A significant benefit of thrombolytic treatment in WUS was seen in ordinal analysis (odds ratio [OR], 1.48 [95% CI, 1.15–1.91]; P=0.003) and for mRS 0 to 2 (OR, 1.81 [95% CI, 1.29–2.52]; P=0.001) but not for mRS 0 or 1 (OR, 1.32 [95% CI, 1.00–1.74]; P=0.050). The proportion of patients with mRS 0 or 1 was lower in patients with WUS who underwent thrombolysis versus those with known‐onset stroke (50.4% versus 59.5%; OR, 0.69 [95% CI, 0.52–0.93]; P=0.013), while outcomes were similar between groups for mRS 0 to 2 and ordinal analysis. Symptomatic intracranial hemorrhage after thrombolytic treatment occurred in 4.4% of patients with WUS and 3.9% of patients with known‐onset stroke (OR, 1.14 [95% CI, 0.54–2.41]; P=0.726). Conclusions Thrombolytic treatment in patients with WUS was associated with improved functional outcome compared with patients with no thrombolytic treatment and was not associated with increased rates of symptomatic intracranial hemorrhage compared with known‐onset stroke. The results indicate that thrombolytic treatment is effective and safe in WUS in a real‐life setting

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

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.</p