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Rationale: Meta-analyses of case series of non-arteritic central retinal artery occlusion (CRAO) indicate beneficial effects of intravenous thrombolysis when initiated early after symptom onset. Randomized data are lacking to address this question., Aims: The REperfusion therapy with intravenous alteplase for recovery of VISION in acute central retinal artery occlusion (REVISION) investigates intravenous alteplase within 4.5 h of monocular vision loss due to acute CRAO., Methods: This study is the randomized (1:1), double-blind, placebo-controlled, multicenter adaptive phase III trial., Study Outcomes: Primary outcome is functional recovery to normal or mildly impaired vision in the affected eye defined as best-corrected visual acuity of the Logarithm of the Minimum Angle of Resolution of 0.5 or less at 30 days (intention-to-treat analysis). Secondary efficacy outcomes include modified Rankin Score at 90 days and quality of life. Safety outcomes include symptomatic intracranial hemorrhage, major bleeding (International Society on Thrombosis and Haemostasis definition) and mortality. Exploratory analyses of optical coherence tomography/angiography, ultrasound and magnetic resonance imaging (MRI) biomarkers will be conducted., Sample Size: Using an adaptive design with interim analysis at 120 patients, up to 422 participants (211 per arm) would be needed for 80% power (one-sided alpha = 0.025) to detect a difference of 15%, assuming functional recovery rates of 10% in the placebo arm and 25% in the alteplase arm., Discussion: By enrolling patients within 4.5 h of CRAO onset, REVISION uses insights from meta-analyses of CRAO case series and randomized thrombolysis trials in acute ischemic stroke. Increased rates of early reperfusion and good neurological outcomes in stroke may translate to CRAO with its similar pathophysiology., Trial Registration: ClinicalTrials.gov: NCT04965038; EU Trial Number: 2023-507388-21-00., Competing Interests: Declaration of conflicting interestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Alteplase/placebo is provided by Boehringer Ingelheim at no costs. Boehringer Ingelheim was given opportunity to review the manuscript for medical/scientific accuracy and intellectual property considerations. The authors did not receive any payment related to trial/manuscript development.

Importance: Cervical artery dissection is the most common cause of stroke in younger adults. To date, there is no conclusive evidence on which antithrombotic therapy should be used to treat patients., Objective: To perform an individual patient data meta-analysis of randomized clinical trials comparing anticoagulants and antiplatelets in prevention of stroke after cervical artery dissection., Data Sources: PubMed.gov, Cochrane database, Embase, and ClinicalTrials.gov were searched from inception to August 1, 2023., Study Selection: Randomized clinical trials that investigated the effectiveness and safety of antithrombotic treatment (antiplatelets vs anticoagulation) in patients with cervical artery dissection were included in the meta-analysis. The primary end point was required to include a composite of (1) any stroke, (2) death, or (3) major bleeding (extracranial or intracranial) at 90 days of follow-up., Data Extraction/synthesis: Two independent investigators performed a systematic review according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, and inconsistencies were resolved by a principal investigator., Main Outcomes and Measures: The primary outcome was a composite of (1) ischemic stroke, (2) death, or (3) major bleeding (extracranial or intracranial) at 90 days of follow-up. The components of the composite outcome were also secondary outcomes. Subgroup analyses based on baseline characteristics with a putative association with the outcome were performed. Logistic regression was performed using the maximum penalized likelihood method including interaction in the subgroup analyses., Results: Two randomized clinical trials, Cervical Artery Dissection in Stroke Study and Cervical Artery Dissection in Stroke Study and the Biomarkers and Antithrombotic Treatment in Cervical Artery Dissection, were identified, of which all participants were eligible. A total of 444 patients were included in the intention-to-treat population and 370 patients were included in the per-protocol population. Baseline characteristics were balanced. There were fewer primary end points in those randomized to anticoagulation vs antiplatelet therapy (3 of 218 [1.4%] vs 10 of 226 [4.4%]; odds ratio [OR], 0.33 [95% CI, 0.08-1.05]; P = .06), but the finding was not statistically significant. In comparison with aspirin, anticoagulation was associated with fewer strokes (1 of 218 [0.5%] vs 10 of 226 [4.0%]; OR, 0.14 [95% CI, 0.02-0.61]; P = .01) and more bleeding events (2 vs 0)., Conclusions and Relevance: This individual patient data meta-analysis of 2 currently available randomized clinical trial data found no significant difference between anticoagulants and antiplatelets in preventing early recurrent events.

Background and Purpose: Acute ischemic stroke treatment with intravenous thrombolysis (IVT) is restricted to a time window of 4.5 h after known or presumed onset. Recently, magnetic resonance imaging-guided treatment decision-making in wake-up stroke (WUS) was shown to be effective. The aim of this study was to determine the safety and outcome of IVT in patients with a time window beyond 4.5 h selected by computed tomography perfusion (CTP) imaging., Methods: We analyzed all consecutive patients last seen well beyond 4.5 h after stroke onset treated with IVT based on CTP between January 2015 and October 2018. CTP was visually assessed to estimate the mismatch between cerebral blood flow and cerebral blood volume maps. Early infarct signs were documented according to Alberta Stroke Program Early CT Score (ASPECTS). Safety data were obtained for mortality and symptomatic intracerebral hemorrhage (sICH). Follow-up was assessed with the modified Rankin Scale (mRS)., Results: A total of 70 patients fulfilled the inclusion criteria (mean age ± SD 77.6 ± 11.5 years, 50.0% female). Median National Institutes of Health Stroke Scale score on admission was 8.0 [interquartile range (IQR), 4-14]. The most frequent reasons for an extended time window were WUS (60.0%) and delayed hospital admission (27.1%). Median time from last seen well to IVT was 11.4 h. Median ASPECTS was 10 (IQR, 9-10) and CTP mismatch 90% (IQR, 80%-100%). A total of 24 patients (34.3%) underwent additional mechanical thrombectomy. sICH occurred in four patients (5.7%). At follow-up, 49.3% had an mRS score of 0-2 and 22.4% had an mRS score of 0-1., Conclusions: In patients presenting in an extended time window beyond 4.5 h, IVT treatment with decision-making based on CTP might be a safe procedure. Further evaluation in clinical trials is needed., (© 2019 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Purpose: The ThRombolysis in Ischemic Stroke Patients (TRISP) collaboration aims to address clinically relevant questions about safety and outcomes of intravenous thrombolysis (IVT) and endovascular thrombectomy. The findings can provide observational information on treatment of patients derived from everyday clinical practice., Participants: TRISP is an open, investigator-driven collaborative research initiative of European stroke centres with expertise in treatment with revascularisation therapies and maintenance of hospital-based registries. All participating centres made a commitment to prospectively collect data on consecutive patients with stroke treated with IVT using standardised definitions of variables and outcomes, to assure accuracy and completeness of the data and to adapt their local databases to answer novel research questions., Findings to Date: Currently, TRISP comprises 18 centres and registers >10 000 IVT-treated patients. Prior TRISP projects provided evidence on the safety and functional outcome in relevant subgroups of patients who were excluded, under-represented or not specifically addressed in randomised controlled trials (ie, pre-existing disability, cervical artery dissections, stroke mimics, prior statin use), demonstrated deficits in organisation of acute stroke care (ie, IVT during non-working hours, effects of onset-to-door time on onset-to-needle time), evaluated the association between laboratory findings on outcome after IVT and served to develop risk estimation tools for prediction of haemorrhagic complications and functional outcome after IVT., Future Plans: Further TRISP projects to increase knowledge of the effect and safety of revascularisation therapies in acute stroke are ongoing. TRISP welcomes participation and project proposals of further centres fulfilling the outlined requirements. In the future, TRISP will be extended to include patients undergoing endovascular thrombectomy., Competing Interests: Competing interests: JFS has received speaker honoraria from W L Gore & Associates GmbH and travel support from Bayer and Boehringer-Ingelheim; HG has received research support from the Swiss National Science Foundation; AZ has received funding for speaker honoraria and consulting fees from Boehringer-Ingelheim and Medtronic-Covidien and consulting fees from Nestec; GK received grants from Swiss Parkinson Association, Swiss Heart Association, Swiss National Science Foundation and served on advisory boards for Boehringer-Ingelheim, Bayer, Daiichi Sankyo (Schweiz) AG, Zambon, Nestle, GE Healthcare within the last two years; YB received honoraria or consulting fees from AstraZeneca France, Daiichi-Sankyo, BMS-Pfizer, Covidiem, Bayer and MSD France; PM received research grants from the Swiss National Science Foundation, the Swiss Heart Foundation; speaker fees from Boehringer-Ingelheim, Bayer, Covidien and Stryker; honoraria from scientific advisory boards from Boehringer-Ingelheim, Bayer, Pfizer, Amgen; consulting fees from Pierre-Fabre and Astra-Zeneca; and travel support from Boehringer-Ingelheim and Bayer. All this support is received by the institution (CHUV) and is used for stroke education and research; DL participated during the last 5 years to 1 advisory boards, symposia or trials sponsored by Sanofi Aventis, BMS, Astrazeneca, Boeringher-Ingelheim, Servier, Ebewe, CoLucid Pharm, Brainsgate, Photothera, Lundbeck, GSK, Bayer, Pfizer et Allergan (honorarium paid to Adrinord or research account of the hospital) and was an associated editor of the Journal of neurology, neurosurgery and psychiatry 2004-2010 (personal financial compensation); CHN has received funding for travel or speaker honoraria from Bayer, Boehringer-Ingelheim, Takeda, and BMS/Pfizer; PJN has received consulting fees from Boehringer-Ingelheim; STE has received funding for travel or speaker honoraria from Bayer and Boehringer-Ingelheim, he has served on scientific advisory boards for Bayer, Boehringer-Ingelheim, BMS/Pfizer and Covidien and on the editorial board of Stroke. He has received an educational grant from Pfizer and research support from the Science Funds (Wissenschaftsfonds) of the University Hospital Basel, the University Basel, the Swiss Heart Foundation and the Swiss National Science Foundation., (© Author(s) (or their employer(s)) 2018. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background and Purpose: We hypothesized that any sex-related difference in outcome poststroke is explained by other prognostic factors and that the response to intravenous recombinant tissue-type plasminogen activator (r-tPA) is equal in males and females after adjustment for such factors., Methods: We accessed an independent collection of randomized clinical trials-the VISTA (Virtual International Stroke Trials Archive). Data were preprocessed by selecting complete cases (n=8028) and matching females to males (coarsened exact matching, n=4575, 24.3% r-tPA). Outcome was assessed by the 7-point modified Rankin Scale (mRS) measured at 90 days after ischemic stroke. Relationship among variables was estimated by adjusted regression analysis., Results: In nonthrombolyzed patients, ordinal analysis of mRS adjusting for stroke- and sex-related prognostic factors suggested comparable outcomes for females and males (odds ratio, 0.96; 95% confidence interval, 0.85-1.06). Females responded comparably to r-tPA as did males, irrespective of the outcome definition of mRS (ordinal: P Interaction =0.46, relative excess risk because of interaction=0). The number needed to treat was 6.8 and 11.2 for 1 female to achieve mRS score of 0 to 2 and 0 to 1, which was highly congruent with males. Analysis for a nonlinear variation of age-by-sex revealed a good outcome for females <45 years with significant disadvantage thereafter (mRS score of 0-2: P Interaction =0.004). No relationship between sex, r-tPA, and bleeding complications was evident., Conclusions: Functional outcome (mRS) without r-tPA was overall similar between the sexes, as was the response to r-tPA. Nonlinear sex-by-age interaction improved estimates of functional independence; this should be considered in sex-related studies in stroke., (© 2016 American Heart Association, Inc.)

Background: Sex differences in the structural connectome of the brain are clinically highly relevant, but they have mostly been neglected in stroke trials. We investigated the impact of the interaction sex-by-hemisphere on outcome in stroke patients after intravenous thrombolysis (IVT)., Methods: This is an observational study based on consecutively collected supratentorial stroke patients treated with IVT (n = 1,231). The 3-month modified Rankin scale (mRS) was estimated by adjusted binary (mRS 0-2 for good outcome) and ordinal regression analysis. As baseline characteristics differ substantially between the sexes, we aimed for better covariate balance by employing coarsened exact matching., Results: Sex-by-hemisphere predicted good outcome in the entire cohort (726 left, 505 right hemispheric strokes, p valueinteraction 0.032) and in the matched cohort (338 left, 273 right, p valueinteraction 0.003). Ordinal regression suggested a comparable estimate in the matched cohort (p valueinteraction 0.006). Further investigation revealed relevant between-sex and within-sex risk: right hemispheric strokes in men were 1.54 times (95% confidence intervals (CIs) 1.15-2.01) more likely than in women to achieve mRS 0-2. Women with right hemispheric strokes were 0.72 times (95% CI 0.54-0.92) less likely to reach mRS 0-2 than women with left hemispheric strokes. Conversely, men with right hemispheric strokes were 1.35 times (95% CI 1.06-1.70) more likely to achieve mRS 0-2 than men with left hemispheric strokes., Conclusion: This study suggests that outcomes are different in both sexes after IVT when different hemispheres are affected. Further consideration of this hypothesis in clinical trials might help in guiding individualized, injury-specific treatment approaches for acute ischemic stroke.

Background and Purpose: Thrombus length has been reported as an important predictor of successful recanalization by intravenous thrombolysis but its influence on bridging thrombolysis has not been investigated yet. The effect of thrombus length on recanalization rates evaluated by catheter angiography early after intravenous bridging thrombolysis was analyzed., Methods: Ninety-six consecutive patients with acute cerebral artery occlusion were included. Occlusion site and thrombus length on initial computed tomography angiography or magnetic resonance angiography were related to recanalization after intravenous bridging thrombolysis on the initial series of catheter angiography., Results: Eleven of 96 patients (11.5%) showed successful recanalization (TICI 2a, 2b or 3) after intravenous bridging thrombolysis. Mean thrombus length in these patients was 10.8 mm as opposed to 15.6 mm in patients without successful recanalization. No thrombus longer than 16 mm showed complete recanalization. Binary logistic regression demonstrated a significant influence of thrombus length on probability of recanalization (odds ratio 0.78, 95% confidence interval 0.65-0.95; P = 0.014)., Conclusions: Thrombus length is a significant predictor of recanalization rates after bridging thrombolysis. Overall recanalization rate within the time frame until interventional treatment is started was 11.5% after bridging thrombolysis., (© 2014 The Author(s) European Journal of Neurology © 2014 EAN.)

Background: We aimed to investigate the feasibility, preliminary safety, and efficacy of prolonged low-dose intravenous thrombolysis in posterior circulation stroke patients with a thrombus lodged in the basilar artery who were ineligible for standard rtPA administration., Methods: We retrospectively analyzed consecutively collected patients in our stroke database who suffered from a basilar artery thrombosis and were treated with prolonged (>1 h), intravenous, low-dose (≤20 mg) rtPA between 01/2005 and 11/2012., Results: Patients included in this study (n = 14) were 68.5 years (IQR 55.5; 72.75) of age and presented with a median NIHSS of 2 (1; 5.25). Median time from symptom onset to treatment was 63 h (33; 141). A median dose of 5.21 μg/kg h (4.46; 6.25) rtPA was administered over 24 h (min 10; max 48). No patient experienced symptomatic intracerebral hemorrhage, one patient developed a spinal epidural hematoma, and two elderly patients were switched to comfort care and died. In eight patients (57%) a decrease in thrombus size or no thrombus at all was detected on control imaging. Nine patients (64%) had a favorable outcome (mRS 0-2) at day 90., Conclusions: Prolonged low-dose thrombolysis with rtPA may be considered as individual treatment option in selected high-risk patients with basilar artery thrombosis. Presented data may lay the groundwork to further investigate safety and efficacy in a prospective trial.

Background and Purpose: To investigate the relationship between severe bleeding complications and outcome after mechanical thrombectomy with or without glycoprotein-IIb/IIIa inhibitor tirofiban treatment., Methods: The study included prospectively collected data of consecutive patients with acute ischemic stroke in whom mechanical thrombectomy was perfomed in the years 2006 to 2011., Results: Of 162 patients, 128 patients had anterior circulation stroke, and 34 patients had posterior circulation stroke. Additional treatment with tirofiban was given to 30 of 128 patients with anterior circulation stroke and to 20 of 34 patients with posterior circulation stroke. Treatment with tirofiban did not influence recanalization rates. Fatal intracerebral hemorrhage occurred more frequently in tirofiban-treated patients in the entire cohort (12.0% vs 2.7%; P=0.03) and in tirofiban-treated patients with anterior circulation stroke (13.3% vs 3.1%; P=0.05). Logistic regression found age (odds ratio, 1.17; 95% confidence interval, 1.00-1.37; P=0.05) and tirofiban treatment (odds ratio, 3.03; 95% confidence interval, 1.50-4.05; P=0.04) to be independent predictors for fatal intracerebral hemorrhage. Tirofiban treatment was also an independent predictor for poor outcome (odds ratio, 6.60; 95% confidence interval, 1.06-41.52; P=0.04) in addition to National Institute of Health Stroke Scale (odds ratio, 1.08; 95% confidence interval, 1.00-1.17; P=0.05)., Conclusions: In endovascular stroke therapy, additional treatment with the glycoprotein-IIb/IIIa inhibitor tirofiban is associated with increased risk of fatal intracerebral hemorrhage and poor outcome.

Ischemic stroke is one of the leading causes of death and morbidity worldwide, and systemic thrombolytic treatment is still the first-line therapy within 4.5 h from symptom onset. Selecting patients for treatment response is mandatory in any time window but challenging as well. The authors aim to support stroke physicians in their individual decision making. Besides evidence from clinical trials, some suggestions included here exclusively reflect the authors' opinions. This article presents clinical and imaging criteria of selecting patients reasonably, offering causal therapy to a growing number of patients., (© 2012 New York Academy of Sciences.)

Background: The relevance of blood pressure variability (BPV) in the development of intracerebral hemorrhage (ICH) after intravenous thrombolysis (IVT) in acute stroke still remains uncertain., Methods: 427 consecutive patients treated with IVT in the years 2007-2009 were studied. Blood pressure (BP) values were analyzed from admission to follow-up imaging scan and described as mean, maximum, minimum, standard deviation (SD), difference between maximum and minimum, successive variation (SV) and maximum SV. ICH was categorized based on radiologic criteria and symptomatic ICH (sICH) was defined as ICH plus worsening of the National Institute of Health Stroke Scale by ≥4 points or leading to death. Three-month outcome was described by means of the modified Rankin Scale., Results: We observed any ICH in 51 (11.9%) and sICH in 10 (2.3%) patients. Systolic and diastolic BP profiles, including mean, maximum, minimum, SD, difference between maximum and minimum, SV and maximum SV, did not differ between ICH-negative, ICH-positive and sICH patients. In univariate analysis, high systolic BPV was associated with sICH (p = 0.03). A logistic regression model to predict ICH only found early CT findings (OR = 2.74, 95% CI = 1.47-5.11, p < 0.01) as independently associated with ICH. Poor 3-month outcome was independently predicted by age (OR = 0.96, 95% CI = 0.94-0.97, p < 0.001), NIHSS on admission (OR = 0.84, 95% CI = 0.80-0.87, p < 0.001), ICH (OR = 0.29, 95% CI = 0.13-0.66, p < 0.01) and high systolic BPV (OR = 1.68, 95% CI = 1.05-2.69, p < 0.05)., Conclusions: We demonstrate that high BPV in patients receiving IVT leads to poor outcome but does not increase the risk of ICH/sICH., (Copyright © 2011 S. Karger AG, Basel.)

Background and Purpose: Significantly increased blood pressure (BP) is common in patients receiving intravenous thrombolysis (IVT). We aimed to investigate frequency of pre- and post-treatment elevated BP and its relation to intracerebral hemorrhage (ICH) and symptomatic ICH (sICH), respectively., Methods: Data for patients treated with intravenous thrombolysis in the years 2007 to 2009 were retrospectively extracted from our prospectively conducted local stroke database. All documented BP levels from admission to follow-up imaging scan were analyzed. BP protocol violations were defined as systolic BP >185 mm Hg and/or diastolic BP >110 mm Hg. sICH was defined as ICH plus worsening of the National Institute of Health Stroke Scale ≥4 points., Results: BP protocol violation before IVT emerged in 12.6% and during the course of IVT in 40.1% of 427 patients. sICH occurred in 10 (2.3%) and ICH in general occurred in 51 (11.9%) of 427 patients. Proportions of BP protocol violations were similar in patients without ICH, with any ICH, and with sICH (3.1% versus 2.8% versus 3.2%). Systolic BP levels and mean arterial pressure did not differ between patients without ICH, patients with any ICH, and patients with sICH. In the multivariate analysis, only early CT findings independently predicted ICH (OR, 2.39; 95% CI, 1.25-4.61; P=0.009)., Conclusions: BP protocol violations are common before and during the course of IVT, but neither the frequency of BP protocol violations nor the BP levels predicted ICH or sICH in univariate or multivariate analyses.