A User's Guide to the NINDS rt-PA Stroke Trial
Contents
1. 1 an analysis of potential baseline imbalances in the NINDS trial and 2 a review of severity adjusted end points 39 40 Both of these studies support the use of rt PA in acute ischemic stroke In a more recent reanalysis of the NINDS data Hoffman and Schriger found similar responses to treatment in the placebo and rt PA treatment groups 41 Contradictory opinions and analyses of the original NINDS data such as these have fueled the controversy regarding the risks and benefits of rt PA therapy in acute ischemic stroke Our report provides researchers with a method to easily access the NINDS database for independent analysis in the hope that further review of this investigation will yield future insights into the risks and or benefits of this intervention Analysis of patients in this trial with elevated blood pressure 15 elevated glucose levels 16 transient ischemic attacks 26 and minor strokes 36 have been performed by the NINDS researchers Other subgroups of patients such as those who received aspirin those with congestive heart failure those with prior strokes and many others can now be analyzed with the understanding that such subgroup analysis should not guide therapeutic decisions but may allow the creation of new hypotheses for future studies While the purchased dataset provides a large amount of data some data appear to be missing Documentation of inclusion and exclusion criteria in the dataset is incomplete2. Seattle Washington United States Ioannidis JPA 2005 Contradicted and initially stronger effects in highly cited clinical research JAMA 294 218 228 Wardlaw JM del Zoppo G Yamaguchi T Berge E 2006 Thrombolysis of acute ischemic stroke Cochrane Review In The Cochrane Library Issue 3 Chichester UK John Wiley and Sons Katzan IL Furlan Aj Lloyd LE Frank JI Harper DL et al 2000 Use of tissue type plasminogen activator for acute ischemic stroke The Cleveland area experience JAMA 283 1151 1158 Bravata DM Kime N Concato J Krumholz HM Brass LM 2002 Thrombolysis for acute stroke in routine clinical practice Arch Intern Med 162 1994 2001 www plosmedicine org May 2008 Volume 5 Issue 5 e113
3. May 2008 Volume 5 Issue 5 e113 Box 1 This will limit any attempt to analyze protocol violations in this study This is unfortunate given that protocol violations have been noted to be problematic in other studies particularly in community hospital settings 44 45 Other baseline data points that were not recorded for example patient s baseline living situation can also potentially hinder future research queries In summary this report describes the process for researchers to acquire and decipher the dataset from the original NINDS rt PA trial A detailed description of the dataset has been provided to assist researchers interested in further evaluating this pivotal trial and for those researchers involved in future trials assessing the role of thrombolytic therapy for acute ischemic stroke m Supporting Information Text S1 Methods of obtaining and deciphering NINDS database Found at doi 10 1371 journal pmed 0050113 sd001 27 KB DOC Text S2 Complete rt PA NINDS database Found at doi 10 1371 journal pmed 0050113 sd002 105 KB DOC Text S3 Results overview Found at doi 10 1371 journal pmed 0050113 sd003 49 KB DOC Text S4 Baseline characteristics minus blood pressure Found at doi 10 1371 journal pmed 0050113 sd004 36 KB DOC Text S5 Patient demographics gender race weight and age Found at doi 10 1371 journal pmed 0050113 sd005 20 KB DOC Text S6 Baseline blood pressures and laboratory values Found at d
4. OM are not in a readable format Multiple conversions are required which can only be accomplished Funding The authors received no specific funding for this article Competing Interests The authors have declared that no competing interests exist Citation Dachs RJ Burton JH Joslin J 2008 A user s guide to the NINDS rt PA Stroke Trial database PLoS Med 5 5 e113 doi 10 1371 journal pmed 0050113 Copyright 2008 Dachs et al This is an open access article distributed under the terms of the Creative Commons Attribution License which permits unrestricted use distribution and reproduction in any medium provided the original author and source are credited Abbreviations NINDS National Institute of Neurological Disorders and Stroke rt PA recombinant tissue plasminogen activator Robert J Dachs is Assistant Director at the Department of Emergency Medicine Saint Clare s and Ellis Hospitals Schenectady New York United States of America John H Burton is Residency Program Director at the Department of Emergency Medicine Albany Medical Center Albany New York United States of America Jeremy Joslin is in the Department of Family Medicine Saint Clare s Hospital Schenectady New York United States of America To whom correspondence should be addressed E mail dachsmd aol com May 2008 Volume 5 Issue 5 e113 with technical assistance from the software company SAS Institute http www sas com Once these c
5. OPEN 8 ACCESS Freely available online PLOS mepicine A User s Guide to the NINDS rt PA Stroke Trial Database Robert J Dachs John H Burton Jeremy Joslin n December 1995 results from the National Institute for Neurological Disorders NINDS Recombinant Tissue Plasminogen Activator rt PA Stroke Trial were published 1 The implications of this trial have been profound affecting the emergency management of stroke patients as well as any patient with apparent symptoms of an ischemic stroke Based on the NINDS findings the United States Food and Drug Administration approved the use of rt PA for the treatment of acute ischemic stroke Subsequent to this approval both the American Heart Association and the American Academy of Neurology endorsed the use of rt PA for selected stroke patients 2 3 The approval and endorsement of rt PA for stroke therapy has been controversial Since the publication of the NINDS rt PA trial concerns regarding the study s design results and ramifications have been published and disseminated Specific criticisms of the NINDS trial have included 1 lack of early improvement within 24 hours in patients treated with rt PA 2 a trial enrollment policy that required half of the participants to be treated within 0 90 minutes of presentation and the remainder at 91 180 minutes thereby not reflecting a real world setting 3 discrepancies in baseline characteristics of patients favoring t
6. e Can J Emerg Med 3 183 185 Hoffman JR 2000 Should physicians give tPA to patients with acute ischemic stroke Against And just what is the emperor of stroke wearing West J Med 173 149 150 Hoffman JR 2003 Tissue plasminogen activator tPA for acute ischaemic stroke Why so much has been made of so little Med J Aust 179 333 334 Mann J 2002 Truths about the NINDS study Setting the record straight West J Med 176 192 194 Trotter G 2002 Why were the benefits of tPA exaggerated The role of interpretation bias West J Med 176 194 197 PLoS Medicine www plosmedicine org 0707 1 1 no 13 14 15 or 1 a 17 18 24 25 or 26 27 28 2 30 3 par oo NO 34 or 3 jez Haley EC Lewandowski C Tilley B NINDS rt PA Stroke Study Group 1997 Myths regarding the NINDS rt PA Stroke Trial Setting the record straight Ann Emerg Med 30 676 682 Robinson DJ 2000 Should physicians give tPA to patients with acute ischemic stroke For Thrombolytics in stroke Whose risk is it anyway West J Med 173 148 9 Lattimore SU Chalela J Davis L DeGraba T Ezzeddine M et al 2003 Impact of establishing a primary stroke center at a community hospital on the use of thrombolytic therapy The NINDS Suburban Hospital Stroke Center experience Stroke 34 e55 e57 Lenzer J 2002 Alteplase for stroke Money and optimistic claims butt
7. ebral hemorrhage following intravenous t PA therapy for ischemic stroke Stroke 28 2109 2118 5 The NINDS rt PA Stroke Study Group 2005 Recombinant tissue plasminogen activator for minor strokes The National Institute of May 2008 Volume 5 Issue 5 e113 Neurological Disorders and Stroke rt PA Stroke study experience Ann Emerg Med 46 243 252 Tilley BC Marler J Geller N Lu M Legler J et al 1996 Use of a global test for multiple outcomes in stroke trials with application to the NINDS t PA Stroke Trial Stroke 27 2136 2141 38 Woo D Broderick J Kothari R Lu M Brott T et al 1999 Does National Institutes of Health Stroke Scale NIHSS favor left hemisphere stroke Stroke 30 2355 2359 Ingall TJ O Fallen WM Asplud K Goldfrank LR Hertzberg VS et al 2004 Findings from the reanalysis of the NINDS Tissue Plasminogen Activator for Acute Ischemic Stroke Treatment Trial Stroke 35 2418 2424 40 Saver JL Yafeh B 2007 Confirmation of tPA treatment effect by baseline severity adjusted end point reanalysis of the NINDS tPA Stroke Trials Stroke 38 414 416 3 a 3 PLoS Medicine www plosmedicine org 4 jmi 42 43 44 45 Hoffman JR Schriger DL 2007 Impact of treatment on individual patients in the NINDS Trial A graphic representation based on change in NIHSS Score abstract 38th American College of Emergency Physicians Research Forum 8 11 October 2007
8. f the database is simple the process of gaining access to the information on the CD ROM is convoluted and difficult We have summarized these steps and provided access to the entire database for researchers desiring to analyze the data from this landmark trial for independent research queries Some may suggest that a reanalysis of the NINDS rt PA database is not necessary and that those who review the data are immersed in a futile attempt to topple or tarnish the study s impact However the NINDS rt PA trial has guided the worldwide care of acute ischemic stroke victims since its publication The study has been referenced over 1 900 times 42 and stands alone as the largest randomized control trial to demonstrate rt PA s benefit in patients with acute ischemic stroke The data from this trial have been incorporated into influential pooled analyses 31 and reviews 43 with the salutary results widely promoted by groups such as the American Heart Association and American Stroke Association as the basis of the Brain Attack campaign and the creation of stroke centers Until the results of future prospective trials such as IST 3 The Third International Stroke Trial ECASS 3 The European Cooperative Acute Stroke Study and EPITHET Echoplanar Imaging Thrombolysis Evaluation Trial become available the NINDS rt PA study will likely continue to provide the primary evidence for the use of thrombolytic therapy in the management of acute
9. hose treated with rt PA 4 a small sample size with resulting large confidence intervals and 5 a reported benefit of therapy a finding inconsistent with previous thrombolytic trials in stroke 4 8 Additional concerns have been expressed regarding the generalization of the NINDS results to the community hospital setting the reorientation of emergency medical systems and an unacceptably high risk of harm with limited benefit to patients The NINDS authors have attempted to address many of these concerns 9 and supporters have defended and encouraged the increased use of rt PA in patients with acute stroke 10 11 In hopes of clarifying many of the issues raised researchers who were not involved in the NINDS study have made requests for access to the NINDS rt PA trial data Access to this data was initially denied even after petition to the Food and Drug Administration under the Freedom of Information Act heightening concern and suspicions regarding the trial findings 12 During this period the NINDS authors published no less than 27 reports using various permutations of the NINDS dataset 9 13 38 In October 2003 nearly eight years after the NINDS publication the original data from the NINDS rt PA Stroke Trial were made available to the public Since this time we are aware of only three reports by non NINDS researchers that have used the original dataset 39 41 The Guidelines and Guidance section contains advice on cond
10. ischemic stroke Accessing the database as described in this report can lead to future investigation by interested researchers There have PLoS Medicine www plosmedicine org Box 1 Inclusion and Exclusion Criteria Measurements Available in Dataset Onset of ischemic stroke symptoms Deficit measurable on the National Institutes of Health Stroke Scale Baseline computerized tomography scan of the brain showing no intracranial hemorrhage Systolic blood pressure above 185 mm Hg or diastolic blood pressure above 110 mm Hg e Patients taking heparin within 48 hours Glucose concentration lt 50 mg per deciliter or gt 400 mg per deciliter Measurements Not Available in Dataset History of stroke or serious head trauma in the preceding three months e Major surgery in the past 14 days History of intracranial hemorrhage e Rapidly improving or minor symptoms Symptoms suggestive of subarachnoid hemorrhage Gastrointestinal hemorrhage or urinary tract hemorrhage within the past 21 days Arterial puncture at anoncompressible site in past seven days Seizure at onset of stroke e Patients taking anticoagulants within 48 hours e Elevated partial thromboplastin time or prothrombin time e Platelet counts lt 100 000 e Patients requiring aggressive treatment to reduce their blood pressure to specified limits been few studies by non NINDS researchers using the original NINDS data Published reports include
11. ler JR Tilley BC Lu M Brott TG Lyden PC et al 2000 Early stroke treatment associated with better outcome Neurology 55 1649 1655 Patel SC Levine SR Tilley BC Grotta JC Lu M et al 2001 Lack of clinical significance of early ischemic changes on computed tomography in acute stroke JAMA 286 2830 2838 Tanne D Levine SR Brey RL Lin H Fagan SC et al 2003 Antiphospholipid protein antibodies and acute ischemic stroke in the NINDS rt PA Stroke Trial Neurology 61 1158 1159 The ATLANTIS ECASS and NINDS rt PA Study Group Investigators 2004 Association of outcome with early stroke treatment Pooled analysis of ATLANTIS ECASS and NINDS rt PA Stroke Trials Lancet 363 768 774 2 The National Institute of Neurological Disorders and Stroke NINDS rt PA Stroke Study Group 1997 A systems approach to immediate evaluation and management of hyperacute stroke Experience at eight centers and implications for community practice and patient care Stroke 28 1530 1540 The National Institute of Neurological Disorders and Stroke NINDS rt PA Stroke Study Group 2000 Effect of intravenous recombinant tissue plasminogen activator on ischemic stroke lesion size measured by computed tomography Stroke 31 2912 2919 The NINDS t Pa Stroke Study Group 1997 Generalized efficacy of t PA for acute stroke Subgroup analysis of the NINDS t PA Stroke Study Stroke 28 2119 2125 The NINDS t Pa Stroke Study Group 1997 Intracer
12. oi 10 1371 journal pmed 0050113 sd006 23 KB DOC Text S7 Computerized tomography results baseline and post intervention Found at doi 10 1371 journal pmed 0050113 sd007 37 KB DOC Text S8 Randomization and timing Found at doi 10 1371 journal pmed 0050113 sd008 30 KB DOC Text S9 Deleterious effects Found at doi 10 1371 journal pmed 0050113 sd009 27 KB DOC Text S10 Neurologic outcomes Found at doi 10 1371 journal pmed 0050113 sd010 32 KB DOC Text S11 Dosing and heparin use Found at doi 10 1371 journal pmed 0050113 sd011 21 KB DOC Text 12 Clinical classification of stroke and clinical outcome Found at doi 10 1371 journal pmed 0050113 sd012 22 KB DOC References 1 The National Institute of Neurological Disorders and Stroke rt PA Stroke Study Group 1995 Tissue plasminogen activator for acute ischemic stroke N Eng J Med 333 1581 1587 American Heart Association in Collaboraton with the International Liason Committee on Rususcitation 2000 Guidelines 2000 for cardiopulmonary resuscitation and emergency cardiovascular care Part 7 The era of reperfusion Section 2 Acute stroke Circulation 102 suppl I 1204 1216 Quality Standards Subcommittee of the American Academy of Neurology Practice Advisory 1996 Thrombolytic therapy for acute ischemic stroke Summary statement Neurology 47 835 839 Hoffman JR 2001 Tissue plasminogen activator for acute ischemic stroke Is the CAEP Position Statement too negativ
13. onversions are completed and the data are placed in an Excel spreadsheet format no key accompanies the dataset to decode the numeric designations given to the variables The steps necessary to obtain the NINDS database software requirements necessary conversions additional instructions incomplete missing data and methods used to decode data variables are documented in Text S1 Patient Results in the Database There are 100 separate variables recorded for the 624 patients enrolled in the NINDS study Text S2 documents each individual variable in the order in which it is displayed in the Excel format Patient results can be divided into nine natural groupings A baseline characteristics B patient demographics C baseline vital signs and laboratory values D head computerized tomography results E treatment randomization and timing of drug delivery F deleterious effects death and hemorrhage G neurological outcomes H dosing of rt PA and use of heparin and I stroke type and clinical outcomes Text S3 summarizes the data for each of the above groups and details the location of missing data inconsistencies with previous reported data and protocol violations not previously reported Texts S4 through S12 present the results of every variable in the groups noted above Discussion This report is intended to demonstrate the process for establishing access and analyzing the NINDS rt PA Stroke Trial dataset While the purchase o
14. ress the brain attack campaign BMJ 324 723 729 Broderick J Lu M Jackson C Pancioli A Tilley B et al 2001 Apolipoprotein E phenotype and the efficacy of intravenous tissue plasminogen activator in acute ischemic stroke Ann Neurol 49 736 744 Broderick JP Lu M Kothari R Levine SR Lyden PD et al 2000 Finding the most powerful measures of t PA s effectiveness in the NINDS t PA Stroke Trial Stroke 31 2335 2341 Brott T Lu M Kothari R Fagan SC Frankel M et al 1998 Hypertension and its treatment in the NINDS rt PA Stroke Trial Stroke 29 1504 1509 5 Bruno A Levine SR Frankel MR Brott TG Lin Y et al 2002 Admission glucose level and clinical outcomes in the NINDS rt PA Stroke Trial Neurology 59 669 674 Fagan SC Morgenstern LB Petitta A Ward RE Tilley BC et al 1998 Cost effectiveness of tissue plasminogen activator for acute ischemic stroke Neurology 50 883 890 Frankel M Morgenstern LB Kwiatkowski T Lu M Tilley BC et al 2000 Predicting prognosis after stroke A placebo group analysis from the National Institute of Neurological Disorders and Stroke rt PA Stroke Trial Neurology 55 952 959 Grotta J Welch KMA Fagan S Lu M Frankel M et al 2001 Clinical deterioration following improvement in the NINDS rt PA Stroke Trial Stroke 32 661 668 Kwiatkowski TG Libman RB Frankel M Tilley BC Morgenstern LB et al 1999 Effects of tissue plasminogen activator for acu
15. te ischemic stroke at one year N Eng J Med 340 1781 1787 Kwiatkowski T Libman R Tilley BC Lewandowski C Grotta J et al 2005 The impact of imbalances in baseline stroke severity on outcome in the NINDS rt PA Stroke Study Ann Emerg Med 45 377 384 Lu M Lyden PD Brott TG Hamilton S Broderick JP et al 2005 Beyond subgroup analysis Improving the clinical interpretation of treatment effects in stroke research J Neurosci Methods143 209 216 3 Lu M Tilley BC the NINDS t PA Stroke Trial Study Group 2001 Use of odds ratio or relative risk to measure a treatment effect in clinical trials with multiple correlated binary outcomes Data from the NINDS t PA Stroke Trial Stat Med 20 1891 1901 Lu M Tilley BC Li S 1998 Issues on permutation tests Applications in analysis of CT lesion volume in the NINDS T PA Stroke Trial In ASA Proceedings of the Biopharmaceutical Section pp 27 32 Alexandria VA American Statistical Association Lyden L Lu M Jackson C Marler J Kothari R et al 1999 Underlying structure of the NIH Stroke Scale Results of factor analysis Stroke 30 2347 2354 Lyden P Lu M Kwiatkowski T Frankel M Levine S et al 2001 Thrombolysis in patients with transient neurologic deficits Neurology 57 2125 2128 Lyden P Lu M Levine S Brott T Broderick J et al 2001 A modified National Institutes of Health Stroke Scale for use in stroke clinical trials Stroke 32 1310 1317 Mar
16. ucting and reporting medical research PLoS Medicine www plosmedicine org Summary Points In 1995 the NINDS rt PA study documented an improvement in neurologic outcomes at three months for those patients given rt PA within 3 hours of onset of an acute ischemic stroke This trial has become the sentinel study supporting the use of rt PA in acute ischemic stroke Questions raised regarding this trial have been difficult to answer since the raw data have been unavailable to non NINDS researchers e In October 2003 the data from this trial became available for purchase e In this report we describe the process of acquiring and deciphering the dataset from the original trial provide a detailed description of the dataset and discuss the implications for potential future research We document our efforts to access and decipher the NINDS rt PA Stroke Trial dataset By documenting the steps necessary to obtain and organize the data along with a description of each data point we hope to assist future researchers and clinicians who desire to further analyze this landmark trial Obtaining the NINDS rt PA Database A CD ROM containing the NINDS rt PA database can be purchased from the National Technical Information Service http www ntis gov 1 888 584 8332 The cost is US 79 00 plus US 5 00 for shipping and handling and delivery can be expected within seven to ten business days However the data on the CD R
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