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      Safety and Efficacy of MRI-Based Thrombolysis in Unclear-Onset Stroke

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          Abstract

          Background: Standard selection criteria for thrombolysis typically exclude patients with acute ischemic stroke with unclear onset. Multimodal MRI screening may be able to identify those with a favorable benefit-risk ratio for thrombolysis. We aimed to evaluate the safety and efficacy of MRI-based thrombolysis in unclear-onset stroke (UnCLOS). Methods: We reviewed the thrombolysis database registries from 3 medical centers in Korea. Subjects received thrombolysis with intravenous tissue plasminogen activator (tPA) or combined intravenous tPA and intra-arterial urokinase within 3 h, or intra-arterial urokinase within 6 h from symptom detection. For patients with UnCLOS, MRI-specific eligibility criteria (i.e. positive perfusion-diffusion mismatch and absence of well-developed fluid-attenuated inversion recovery changes of acute diffusion lesions) were applied. Rates of immediate and 5-day recanalization, early neurological improvement and symptomatic intracranial hemorrhage (ICH) within 48 h after treatment and 3-month modified Rankin Scale (mRS) scores were compared between patients with UnCLOS and those with clear-onset stroke (CLOS). Results: 32 patients with UnCLOS and 223 patients with CLOS were included. Baseline characteristics were comparable between the two groups, except that the proportion of MRI screening was higher, and detection-to-door time and door-to-needle time were longer in the UnCLOS group (p < 0.01). Rates of recanalization (immediate, 81.3 vs. 63.1%; delayed, 80.6 vs. 69.1%), early neurological improvement (on day 1, 46.9 vs. 35.9%; on day 7, 50.0 vs. 49.3%), symptomatic ICH (6.3 vs. 5.8%) and 3-month outcome (mRS 0–1, 37.5 vs. 35.0%; mRS 0–2, 50.0 vs. 49.3%) did not differ between the UnCLOS and CLOS groups. Conclusion: These preliminary results suggest that thrombolysis based on MRI criteria may safely be applied to acute stroke patients with unclear onset.

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          Most cited references17

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          The Desmoteplase in Acute Ischemic Stroke Trial (DIAS): a phase II MRI-based 9-hour window acute stroke thrombolysis trial with intravenous desmoteplase.

          Most acute ischemic stroke patients arrive after the 3-hour time window for recombinant tissue plasminogen activator (rtPA) administration. The Desmoteplase In Acute Ischemic Stroke trial (DIAS) was a dose-finding randomized trial designed to evaluate the safety and efficacy of intravenous desmoteplase, a highly fibrin-specific and nonneurotoxic thrombolytic agent, administered within 3 to 9 hours of ischemic stroke onset in patients with perfusion/diffusion mismatch on MRI. DIAS was a placebo-controlled, double-blind, randomized, dose-finding phase II trial. Patients with National Institute of Health Stroke Scale (NIHSS) scores of 4 to 20 and MRI evidence of perfusion/diffusion mismatch were eligible. Of 104 patients, the first 47 (referred to as Part 1) were randomized to fixed doses of desmoteplase (25 mg, 37.5 mg, or 50 mg) or placebo. Because of an excessive rate of symptomatic intracranial hemorrhage (sICH), lower weight-adjusted doses escalating through 62.5 microg/kg, 90 microg/kg, and 125 microg/kg were subsequently investigated in 57 patients (referred to as Part 2). The safety endpoint was the rate of sICH. Efficacy endpoints were the rate of reperfusion on MRI after 4 to 8 hours and clinical outcome as assessed by NIHSS, modified Rankin scale, and Barthel Index at 90 days. Part 1 was terminated prematurely because of high rates of sICH with desmoteplase (26.7%). In Part 2, the sICH rate was 2.2%. No sICH occurred with placebo in either part. Reperfusion rates up to 71.4% (P=0.0012) were observed with desmoteplase (125 microg/kg) compared with 19.2% with placebo. Favorable 90-day clinical outcome was found in 22.2% of placebo-treated patients and between 13.3% (62.5 microg/kg; P=0.757) and 60.0% (125 microg/kg; P=0.0090) of desmoteplase-treated patients. Early reperfusion correlated favorably with clinical outcome (P=0.0028). Favorable outcome occurred in 52.5% of patients experiencing reperfusion versus 24.6% of patients without reperfusion. Intravenous desmoteplase administered 3 to 9 hours after acute ischemic stroke in patients selected with perfusion/diffusion mismatch is associated with a higher rate of reperfusion and better clinical outcome compared with placebo. The sICH rate with desmoteplase was low, using doses up to 125 microg/kg.
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            Early stroke treatment associated with better outcome: the NINDS rt-PA stroke study.

            The National Institute of Neurological Disorders and Stroke (NINDS) rt-PA Stroke Study showed a similar percentage of intracranial hemorrhage and good outcome in patients 3 months after stroke treatment given 0 to 90 minutes and 91 to 180 minutes after stroke onset. At 24 hours after stroke onset more patients treated 0 to 90 compared to 91 to 180 minutes after stroke onset had improved by four or more points on the NIH Stroke Scale (NIHSS). The authors performed further analyses to characterize the relationship of onset-to-treatment time (OTT) to outcome at 3 months, early improvement at 24 hours, and intracranial hemorrhage within 36 hours. Univariate analyses identified potentially confounding variables associated with OTT that could mask an OTT-treatment interaction. Tests for OTT-treatment interactions adjusting for potential masking confounders were performed. An OTT-treatment interaction was considered significant if p < or = 0.10, implying that treatment effectiveness was related to OTT. For 24-hour improvement, there were no masking confounders identified and there was an OTT-treatment interaction (p = 0.08). For 3-month favorable outcome, the NIHSS met criteria for a masking confounder. After adjusting for NIHSS as a covariate, an OTT-treatment interaction was detected (p = 0.09): the adjusted OR (95% CI) for a favorable 3-month outcome associated with recombinant tissue-type plasminogen activator (rt-PA) was 2.11 (1.33 to 3.35) in the 0 to 90 minute stratum and 1.69 (1.09 to 2.62) in the 91 to 180 minute stratum. In the group treated with rt-PA, after adjusting for baseline NIHSS, an effect of OTT on the occurrence of intracranial hemorrhage was not detected. If the NINDS rt-PA Stroke Trial treatment protocol is followed, this analysis suggests that patients treated 0 to 90 minutes from stroke onset with rt-PA have an increased odds of improvement at 24 hours and favorable 3-month outcome compared to patients treated later than 90 minutes. No effect of OTT on intracranial hemorrhage was detected within the group treated with rt-PA, possibly due to low power.
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              Combined intravenous and intra-arterial recanalization for acute ischemic stroke: the Interventional Management of Stroke Study.

              (2004)
              To investigate the feasibility and safety of a combined intravenous (IV) and intra-arterial (IA) approach to recanalization in patients with ischemic stroke. Subjects ages 18 to 80 with an NIH Stroke Scale (NIHSS) > or =10 at baseline had IV recombinant tissue plasminogen activator (rt-PA) started (0.6 mg/kg, 60 mg maximum over 30 minutes) within 3 hours of onset. Additional rt-PA was then administered via microcatheter at the site of the thrombus up to a total dose of 22 mg over 2 hours of infusion or until thrombolysis. Primary comparisons were with similar subsets of placebo and rt-PA-treated subjects from the NINDS rt-PA Stroke Trial. The 80 subjects had a median baseline NIHSS score of 18. The median time to initiation of IV rt-PA was 140 minutes as compared with 108 minutes for placebo and 90 minutes for rt-PA-treated subjects in the NINDS rt-PA Stroke Trial. The 3-month mortality in Interventional Management Study (IMS) subjects (16%) was numerically lower but not statistically different than the mortality of placebo (24%) and rt-PA-treated subjects (21%) in the NINDS rt-PA Stroke Trial. The rate of symptomatic intracerebral hemorrhage (6.3%) in IMS subjects was similar to that of rt-PA-treated subjects (6.6%) but higher than the rate in placebo-treated subjects (1.0%, P=0.018) in the NINDS rt-PA Stroke Trial. IMS subjects had a significantly better outcome at 3 months than NINDS placebo-treated subjects for all outcome measures (odds ratios > or =2). A randomized trial of standard IV rt-PA as compared with a combined IV and IA approach is needed.
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                Author and article information

                Journal
                CED
                Cerebrovasc Dis
                10.1159/issn.1015-9770
                Cerebrovascular Diseases
                S. Karger AG
                1015-9770
                1421-9786
                2008
                June 2008
                16 May 2008
                : 25
                : 6
                : 572-579
                Affiliations
                Departments of aNeurology and bRadiology, Asan Medical Center, University of Ulsan College of Medicine, Departments of cNeurology and dRadiology, Keimyung University Dongsan Medical Center, eDepartment of Neurology, Seoul National University Bundang Hospital, and fDepartment of Neurology, Catholic University of Korea, St. Mary’s Hospital, Seoul, Korea
                Article
                132204 Cerebrovasc Dis 2008;25:572–579
                10.1159/000132204
                18483457
                2ece6680-c318-45eb-89b6-b2ed5e2139f1
                © 2008 S. Karger AG, Basel

                Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

                History
                : 12 September 2007
                : 18 December 2007
                Page count
                Figures: 1, Tables: 3, References: 28, Pages: 8
                Categories
                Original Paper

                Geriatric medicine,Neurology,Cardiovascular Medicine,Neurosciences,Clinical Psychology & Psychiatry,Public health
                Thrombolysis, time window,Acute stroke, unclear onset,Magnetic resonance imaging

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