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Response to Letter Regarding Article, “Defining Clinically Relevant Cerebral Hemorrhage After Thrombolytic Therapy for Stroke: Analysis of the National Institute of Neurological Disorders and Stroke TissueType Plasminogen Activator Trials” We thank Turc et al1 for their interest in our article2 and their detailed appraisal. The authors raise the concern that the European Cooperative Acute Stroke Study (ECASS) 2 definition may include radiographically minor intracranial hemorrhage (ICH) such as hemorrhagic infarction type 1 or 2.3 In response to their request for additional details on potential competing causes of worsening in patients 22 to 27, we contacted The National Institute of Neurological Disorders and Stroke Tissue-Type Plasminogen Activator (NINDS rt-PA) Stroke Trials Coordinating Center but the individual subject detailed data beyond the elements of the public access data set were not available. Accordingly, the basis of the judgments reached by local site investigators that the hemorrhages in these cases caused the early worsening was not available to be additionally interrogated. We concur that such minor ICHs are generally unlikely to be causative of worse final clinical outcome, but will note that they could indeed do so in some circumstances, for example, by triggering seizures that lead to increased injury in ischemic fields. Furthermore, a definition that does not include hemorrhages such as parenchymal hematoma with intraventricular extension (eg, Safe Implementation of Thrombolysis in Stroke-Monitoring Study [SITS-MOST]) will exclude potentially clinically relevant ICH.4,5 These considerations highlight the importance of distinguishing between expert-based symptomatic ICH classification and algorithm-based symptomatic ICH classification, which is at the crux of the discrepancies between the patients placed in each category. Each method has advantages and disadvantages. Expertbased classification has the advantage of being able to take into account all aspects of a case, including competing causes of worsening and temporal relationship. However, this method is prone to site bias when the expert is the local-treating physician and to dispositional bias when the expert has a disposition to include all possible cases or to include only clearly definitely related cases. In addition, expert classification can only be used practically in formal clinical trials that have the resource for independent adjudication and are not employable in registries and local quality improvement programs. Algorithmic classification has the advantage of being free of rater bias and of being able to be applied automatically in regular practice, in registries, and in quality improvement. However, such classification will mis-assign some cases because of individual case aspects not detected by the algorithm but detectable by an expert. The cases identified by the Turc et al potentially fall into the latter category. We would suggest that algorithm-driven classification be used to provide a first rating in all settings. In clinical trials, the algorithm classifications could be reviewed and revised by independent experts, improving precision. In registry and quality improvement settings, the algorithm classification would be sufficient and practicable.
Disclosures Dr Levine serves on the Scientific Advisory Committee of A Phase IIIB, Double-Blind, Multicenter Study to Evaluate the Efficacy and Safety of Alteplase in Patients With Mild Stroke: Rapidly Improving Symptoms and Neurologic Deficits (PRISMS) and serves as the Independent Medical/Safety Monitor for the National Institute of Neurological Disorders and Stroke–funded The Combined Approach to Lysis Utilizing Eptifibatide and rt-PA in Acute Ischemic Stroke–Full Dose Regimen (CLEAR-FDR). The University of California Regents receive funding for Dr Saver’s services as a scientific consultant on trial design and conduct to Covidien, CoAxia, Stryker, BrainsGate, Genervon, St Jude Medical, and Grifols. Dr Saver has served as an unpaid site investigator in multicenter trials run by Lundbeck and Covidien for which the UC Regents received payments on the basis of clinical trial contracts for the number of subjects enrolled. The UC has patent rights in retrieval devices for stroke. The other author reports no conflicts.
Neal Matsumori Rao, MD Department of Neurology David Geffen School of Medicine at UCLA Los Angeles, CA Steven R. Levine, MD Department of Neurology State University of New York (SUNY), College of Medicine Downstate Medical Center Brooklyn, NY Jeffrey L. Saver, MD Department of Neurology David Geffen School of Medicine at UCLA Los Angeles, CA
References 1. Turc G, Tisserand M, Seners P, Oppenheim C, Baron J-C. Letter by Turc et al regarding article, “Defining clinically relevant cerebral hemorrhage after thrombolytic therapy for stroke: analysis of the National Institute of Neurological Disorders and Stroke Tissue-Type Plasminogen Activator Trials.” Stroke. 2015;46:e43–e44. doi: 10.1161/ STROKEAHA.114.007747. 2. Rao NM, Levine SR, Gornbein JA, Saver JL. Defining clinically relevant cerebral hemorrhage after thrombolytic therapy for stroke: analysis of the National Institute of Neurological Disorders and Stroke tissue-type plasminogen activator trials. Stroke. 2014;45:2728–2733. doi: 10.1161/ STROKEAHA.114.005135. 3. Hacke W, Kaste M, Bluhmki E, Brozman M, Dávalos A, Guidetti D, et al; ECASS Investigators. Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. N Engl J Med. 2008;359:1317–1329. doi: 10.1056/NEJMoa0804656. 4. Wahlgren N, Ahmed N, Dávalos A, Ford GA, Grond M, Hacke W, et al; SITS-MOST Investigators. Thrombolysis with alteplase for acute ischaemic stroke in the Safe Implementation of Thrombolysis in StrokeMonitoring Study (SITS-MOST): an observational study. Lancet. 2007;369:275–282. doi: 10.1016/S0140-6736(07)60149-4. 5. Strbian D, Sairanen T, Meretoja A, Pitkäniemi J, Putaala J, Salonen O, et al; Helsinki Stroke Thrombolysis Registry Group. Patient outcomes from symptomatic intracerebral hemorrhage after stroke thrombolysis. Neurology. 2011;77:341–348. doi: 10.1212/WNL. 0b013e3182267b8c.
(Stroke. 2015;46:e45. DOI: 10.1161/STROKEAHA.114.007860.) © 2015 American Heart Association, Inc. Stroke is available at http://stroke.ahajournals.org
DOI: 10.1161/STROKEAHA.114.007860
Downloaded from http://stroke.ahajournals.org/e45 at YALE MEDICAL LIBRARY on June 27, 2015
Response to Letter Regarding Article, ''Defining Clinically Relevant Cerebral Hemorrhage After Thrombolytic Therapy for Stroke: Analysis of the National Institute of Neurological Disorders and Stroke Tissue-Type Plasminogen Activator Trials'' Neal Matsumori Rao, Steven R. Levine and Jeffrey L. Saver Stroke. 2015;46:e45; originally published online January 8, 2015; doi: 10.1161/STROKEAHA.114.007860 Stroke is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231 Copyright © 2015 American Heart Association, Inc. All rights reserved. Print ISSN: 0039-2499. Online ISSN: 1524-4628
The online version of this article, along with updated information and services, is located on the World Wide Web at: http://stroke.ahajournals.org/content/46/2/e45
Permissions: Requests for permissions to reproduce figures, tables, or portions of articles originally published in Stroke can be obtained via RightsLink, a service of the Copyright Clearance Center, not the Editorial Office. Once the online version of the published article for which permission is being requested is located, click Request Permissions in the middle column of the Web page under Services. Further information about this process is available in the Permissions and Rights Question and Answer document. Reprints: Information about reprints can be found online at: http://www.lww.com/reprints Subscriptions: Information about subscribing to Stroke is online at: http://stroke.ahajournals.org//subscriptions/
Downloaded from http://stroke.ahajournals.org/ at YALE MEDICAL LIBRARY on June 27, 2015
Response to Letter Regarding Article, “Defining Clinically Relevant Cerebral Hemorrhage After Thrombolytic Therapy for Stroke: Analysis of the National Institute of Neurological Disorders and Stroke TissueType Plasminogen Activator Trials” We thank Turc et al1 for their interest in our article2 and their detailed appraisal. The authors raise the concern that the European Cooperative Acute Stroke Study (ECASS) 2 definition may include radiographically minor intracranial hemorrhage (ICH) such as hemorrhagic infarction type 1 or 2.3 In response to their request for additional details on potential competing causes of worsening in patients 22 to 27, we contacted The National Institute of Neurological Disorders and Stroke Tissue-Type Plasminogen Activator (NINDS rt-PA) Stroke Trials Coordinating Center but the individual subject detailed data beyond the elements of the public access data set were not available. Accordingly, the basis of the judgments reached by local site investigators that the hemorrhages in these cases caused the early worsening was not available to be additionally interrogated. We concur that such minor ICHs are generally unlikely to be causative of worse final clinical outcome, but will note that they could indeed do so in some circumstances, for example, by triggering seizures that lead to increased injury in ischemic fields. Furthermore, a definition that does not include hemorrhages such as parenchymal hematoma with intraventricular extension (eg, Safe Implementation of Thrombolysis in Stroke-Monitoring Study [SITS-MOST]) will exclude potentially clinically relevant ICH.4,5 These considerations highlight the importance of distinguishing between expert-based symptomatic ICH classification and algorithm-based symptomatic ICH classification, which is at the crux of the discrepancies between the patients placed in each category. Each method has advantages and disadvantages. Expertbased classification has the advantage of being able to take into account all aspects of a case, including competing causes of worsening and temporal relationship. However, this method is prone to site bias when the expert is the local-treating physician and to dispositional bias when the expert has a disposition to include all possible cases or to include only clearly definitely related cases. In addition, expert classification can only be used practically in formal clinical trials that have the resource for independent adjudication and are not employable in registries and local quality improvement programs. Algorithmic classification has the advantage of being free of rater bias and of being able to be applied automatically in regular practice, in registries, and in quality improvement. However, such classification will mis-assign some cases because of individual case aspects not detected by the algorithm but detectable by an expert. The cases identified by the Turc et al potentially fall into the latter category. We would suggest that algorithm-driven classification be used to provide a first rating in all settings. In clinical trials, the algorithm classifications could be reviewed and revised by independent experts, improving precision. In registry and quality improvement settings, the algorithm classification would be sufficient and practicable.
Disclosures Dr Levine serves on the Scientific Advisory Committee of A Phase IIIB, Double-Blind, Multicenter Study to Evaluate the Efficacy and Safety of Alteplase in Patients With Mild Stroke: Rapidly Improving Symptoms and Neurologic Deficits (PRISMS) and serves as the Independent Medical/Safety Monitor for the National Institute of Neurological Disorders and Stroke–funded The Combined Approach to Lysis Utilizing Eptifibatide and rt-PA in Acute Ischemic Stroke–Full Dose Regimen (CLEAR-FDR). The University of California Regents receive funding for Dr Saver’s services as a scientific consultant on trial design and conduct to Covidien, CoAxia, Stryker, BrainsGate, Genervon, St Jude Medical, and Grifols. Dr Saver has served as an unpaid site investigator in multicenter trials run by Lundbeck and Covidien for which the UC Regents received payments on the basis of clinical trial contracts for the number of subjects enrolled. The UC has patent rights in retrieval devices for stroke. The other author reports no conflicts.
Neal Matsumori Rao, MD Department of Neurology David Geffen School of Medicine at UCLA Los Angeles, CA Steven R. Levine, MD Department of Neurology State University of New York (SUNY), College of Medicine Downstate Medical Center Brooklyn, NY Jeffrey L. Saver, MD Department of Neurology David Geffen School of Medicine at UCLA Los Angeles, CA
References 1. Turc G, Tisserand M, Seners P, Oppenheim C, Baron J-C. Letter by Turc et al regarding article, “Defining clinically relevant cerebral hemorrhage after thrombolytic therapy for stroke: analysis of the National Institute of Neurological Disorders and Stroke Tissue-Type Plasminogen Activator Trials.” Stroke. 2015;46:e43–e44. doi: 10.1161/ STROKEAHA.114.007747. 2. Rao NM, Levine SR, Gornbein JA, Saver JL. Defining clinically relevant cerebral hemorrhage after thrombolytic therapy for stroke: analysis of the National Institute of Neurological Disorders and Stroke tissue-type plasminogen activator trials. Stroke. 2014;45:2728–2733. doi: 10.1161/ STROKEAHA.114.005135. 3. Hacke W, Kaste M, Bluhmki E, Brozman M, Dávalos A, Guidetti D, et al; ECASS Investigators. Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. N Engl J Med. 2008;359:1317–1329. doi: 10.1056/NEJMoa0804656. 4. Wahlgren N, Ahmed N, Dávalos A, Ford GA, Grond M, Hacke W, et al; SITS-MOST Investigators. Thrombolysis with alteplase for acute ischaemic stroke in the Safe Implementation of Thrombolysis in StrokeMonitoring Study (SITS-MOST): an observational study. Lancet. 2007;369:275–282. doi: 10.1016/S0140-6736(07)60149-4. 5. Strbian D, Sairanen T, Meretoja A, Pitkäniemi J, Putaala J, Salonen O, et al; Helsinki Stroke Thrombolysis Registry Group. Patient outcomes from symptomatic intracerebral hemorrhage after stroke thrombolysis. Neurology. 2011;77:341–348. doi: 10.1212/WNL. 0b013e3182267b8c.
(Stroke. 2015;46:e45. DOI: 10.1161/STROKEAHA.114.007860.) © 2015 American Heart Association, Inc. Stroke is available at http://stroke.ahajournals.org
DOI: 10.1161/STROKEAHA.114.007860
Downloaded from http://stroke.ahajournals.org/e45 at YALE MEDICAL LIBRARY on June 27, 2015
Response to Letter Regarding Article, ''Defining Clinically Relevant Cerebral Hemorrhage After Thrombolytic Therapy for Stroke: Analysis of the National Institute of Neurological Disorders and Stroke Tissue-Type Plasminogen Activator Trials'' Neal Matsumori Rao, Steven R. Levine and Jeffrey L. Saver Stroke. 2015;46:e45; originally published online January 8, 2015; doi: 10.1161/STROKEAHA.114.007860 Stroke is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231 Copyright © 2015 American Heart Association, Inc. All rights reserved. Print ISSN: 0039-2499. Online ISSN: 1524-4628
The online version of this article, along with updated information and services, is located on the World Wide Web at: http://stroke.ahajournals.org/content/46/2/e45
Permissions: Requests for permissions to reproduce figures, tables, or portions of articles originally published in Stroke can be obtained via RightsLink, a service of the Copyright Clearance Center, not the Editorial Office. Once the online version of the published article for which permission is being requested is located, click Request Permissions in the middle column of the Web page under Services. Further information about this process is available in the Permissions and Rights Question and Answer document. Reprints: Information about reprints can be found online at: http://www.lww.com/reprints Subscriptions: Information about subscribing to Stroke is online at: http://stroke.ahajournals.org//subscriptions/
Downloaded from http://stroke.ahajournals.org/ at YALE MEDICAL LIBRARY on June 27, 2015
