Update on the third international stroke trial (IST-3) of thrombolysis for acute ischaemic stroke and baseline features of the 3035 patients recruited

  • Peter Sandercock1Email author,

    Affiliated with

    • Richard Lindley2,

      Affiliated with

      • Joanna Wardlaw1,

        Affiliated with

        • Martin Dennis1,

          Affiliated with

          • Karen Innes1,

            Affiliated with

            • Geoff Cohen1,

              Affiliated with

              • Will Whiteley1,

                Affiliated with

                • David Perry1,

                  Affiliated with

                  • Vera Soosay1,

                    Affiliated with

                    • David Buchanan1,

                      Affiliated with

                      • Graham Venables3,

                        Affiliated with

                        • Anna Czlonkowska4,

                          Affiliated with

                          • Adam Kobayashi4,

                            Affiliated with

                            • Eivind Berge5,

                              Affiliated with

                              • Karsten Bruins Slot5,

                                Affiliated with

                                • Veronica Murray6,

                                  Affiliated with

                                  • Andre Peeters7,

                                    Affiliated with

                                    • Graeme J Hankey8,

                                      Affiliated with

                                      • Karl Matz9,

                                        Affiliated with

                                        • Michael Brainin9,

                                          Affiliated with

                                          • Stefano Ricci10,

                                            Affiliated with

                                            • Teresa A Cantisani11,

                                              Affiliated with

                                              • Gordon Gubitz12,

                                                Affiliated with

                                                • Stephen J Phillips12,

                                                  Affiliated with

                                                  • Arauz Antonio13,

                                                    Affiliated with

                                                    • Manuel Correia14,

                                                      Affiliated with

                                                      • Phillippe Lyrer15,

                                                        Affiliated with

                                                        • Ingrid Kane16,

                                                          Affiliated with

                                                          • Erik Lundstrom17 and

                                                            Affiliated with

                                                            • the IST-3 collaborative group

                                                              Affiliated with


                                                              DOI: 10.1186/1745-6215-12-252

                                                              Received: 14 October 2011

                                                              Accepted: 30 November 2011

                                                              Published: 30 November 2011



                                                              Intravenous recombinant tissue plasminogen activator (rtPA) is approved in Europe for use in patients with acute ischaemic stroke who meet strictly defined criteria. IST-3 sought to improve the external validity and precision of the estimates of the overall treatment effects (efficacy and safety) of rtPA in acute ischaemic stroke, and to determine whether a wider range of patients might benefit.


                                                              International, multi-centre, prospective, randomized, open, blinded endpoint (PROBE) trial of intravenous rtPA in acute ischaemic stroke. Suitable patients had to be assessed and able to start treatment within 6 hours of developing symptoms, and brain imaging must have excluded intracranial haemorrhage and stroke mimics.


                                                              The initial pilot phase was double blind and then, on 01/08/2003, changed to an open design. Recruitment began on 05/05/2000 and closed on 31/07/2011, by which time 3035 patients had been included, only 61 (2%) of whom met the criteria for the 2003 European approval for thrombolysis. 1617 patients were aged over 80 years at trial entry. The analysis plan will be finalised, without reference to the unblinded data, and published before the trial data are unblinded in early 2012. The main trial results will be presented at the European Stroke Conference in Lisbon in May 2012 with the aim to publish simultaneously in a peer-reviewed journal. The trial result will be presented in the context of an updated Cochrane systematic review. We also intend to include the trial data in an individual patient data meta-analysis of all the relevant randomised trials.


                                                              The data from the trial will: improve the external validity and precision of the estimates of the overall treatment effects (efficacy and safety) of iv rtPA in acute ischaemic stroke; provide: new evidence on the balance of risk and benefit of intravenous rtPA among types of patients who do not clearly meet the terms of the current EU approval; and, provide the first large-scale randomised evidence on effects in patients over 80, an age group which had largely been excluded from previous acute stroke trials.

                                                              Trial registration


                                                              Progress with the study and modifications to the design

                                                              Planning for the third international stroke trial (IST-3) of thrombolysis for acute ischaemic stroke with intravenous recombinant tissue plasminogen activator (rtPA) began in 1998. At its outset in 2000, the trial was planned as a pragmatic trial which sought to improve the external validity and precision of the estimates of the overall treatment effects (efficacy and safety) of rtPA in acute ischaemic stroke and to determine whether a wider variety of patients than previously thought might benefit from this treatment. After the drug was approved for use in Europe in 2003, the flexible trial eligibility criteria enabled us to continue recruiting patients who did not clearly meet all the criteria set out in the provisional European licence for the drug. With these changes and the need to comply with the increasingly burdensome requirements of research regulation in Europe, some aspects of the trial protocol and its practical procedures have inevitably had to change over the 12 year course of the study. The initial pilot phase of the study, funded by the UK Stroke Association, had a double-blind design, for which Boehringer Ingelheim provided a supply of drug and matching placebo. However, Boehringer Ingelheim did not wish to provide further drug supplies for the expansion phase, funded by The UK Health Foundation, and hence the design of this phase of the study was modified. With appropriate ethical approval, the expansion phase was designed as a prospective, randomised, open blinded endpoint (PROBE) trial and the first patient was recruited in this phase on 1st August 2003. The main phase of the trial was awarded funding by the UK Medical Research Council and began on 1st April 2005. The protocol for the MRC phase of the trial was published in Trials[1].. At each stage, relevant amendments were made to the protocol, and consolidated in an updated protocol (version 1.93) which was approved by appropriate authorities and published on the trial website http://​www.​ist3.​com (additional data file 1). When advanced imaging techniques became more widely available in the participating centres, the study group developed a nested imaging study evaluating the role of CT and MR perfusion and angiography (CTP/CTA/MRP/MRA) in patients with acute ischaemic stroke. The cost-effectiveness of thrombolysis is being investigated in a sub-study in the Scandinavian region cohort.

                                                              Sample size/recruitment target

                                                              In our 2004 application to the MRC for funding of the main phase of the trial we stated: 'Assuming the same event rate as observed in the feasibility phases, the trial could very reliably detect an absolute difference of 10% in the proportion of patients dead or dependent at 6 months after treatment. With a sample size of 6000 patients, the trial would have > 99.9% power to detect such a difference (alpha = 0.001) and sufficient power to permit reliable analyses of the pre-specified subgroups. A trial of this size could detect a smaller, but still clinically worthwhile net benefit of as little as a 3% absolute difference in the primary outcome (80% power, at alpha = 0.05).' The application to the MRC for funding was successful, but by the time the grant was activated, two major changes to research regulation came into force: the European Clinical Trials Directive, the UK Clinical Trials Regulations 2004, and, shortly afterwards, the UK Research Governance Framework. These changes led to a large increase in the time taken to recruit and activate new centres and hence significantly reduced the rate of increase in patient recruitment. By 2007, it was clear that the various factors that had delayed recruitment meant that the original target of 6000 was no longer feasible, and we applied for approval to amend the recruitment target and for additional funding to extend the period of recruitment to mid 2011. These changes were summarised in version 1.93 of the protocol (additional document 1) as follows: "If 3500 patients were recruited, the trial could detect a 4% absolute difference in the primary outcome. A sample size of 1000 patients could detect a 7% absolute difference in the primary outcome, which is consistent with the effect size among patients randomised within 3 hours of stroke in the Cochrane review. Amendment in the light of recruitment by 2007: . The Medical Research Council... awarded an extension to funding to permit recruitment to continue until mid 2011, with a revised recruitment target of 3100 which would yield 80% power to detect an absolute difference of 4.7% in the primary outcome.'


                                                              The pilot (double blind) phase of the trial began when the first patient was randomised on 5th May 2000; sixteen centres enrolled patients. Recruitment continued without interruption into the open expansion phase (first patient in this phase was randomised on 1st August 2003). In April 2005, recruitment continued with the start of the MRC funded main phase. The independent Data Monitoring Committee (DMC) met regularly throughout the trial, in strict confidence, to review the accumulating trial data and any other relevant external data. Their terms of reference were set out in the protocol, and in the light of the evidence available, the DMC did not recommend any change to the protocol or to recruitment into the study. The trial closed to recruitment on 31st July 2011, with a total of 3035 patients from 156 hospitals in 12 countries (Table 1).
                                                              Table 1

                                                              Recruitment: number of centres and patients in each country


                                                              No. of centres

                                                              No. of patients























































                                                              The eligibility criteria are set out in full in the protocol, but can be summarised in terms of the 'uncertainty principle'[24]. As this was a pragmatic trial, conducted in the ';real world'[5], in order to ensure a wide variety of patients were included, inclusion and exclusion criteria were kept simple [6]. Patients were eligible if: they had symptoms and signs of clinically definite acute stroke; the time of stroke onset was known; treatment could be started within six hours of this onset; and, CT or MRI brain scanning had reliably excluded both intracranial haemorrhage and structural brain lesions which could mimic stroke (e.g cerebral tumour). In addition, if the patient had a clear indication for intravenous thrombolysis with rtPA, they were to be treated in accordance with local guidelines. Equally, if the patient had a clear contraindication to treatment they were not to be entered in the trial. Only if both the clinician and the patient (or a relevant proxy for the patient) felt that the treatment was 'promising but unproven', could the patient be included in the trial after appropriate informed consent. In order to comply with local regulatory and ethical requirements, the form of the consent procedure applied varied somewhat between countries and between centres within each country. Details of the type of consent process applied will be reported separately.

                                                              Baseline data collection and method of treatment allocation

                                                              After informed consent had been obtained, the clinician used either a voice-activated telephone or a secure web-based randomisation system to enter a patient in the study. The systems recorded and checked the baseline characteristics of the patients and allocated the treatment only after all baseline data had been entered and passed range and consistency checks. We used a minimisation program to achieve optimum balance for key prognostic factors (see Table 2a), and from January 2006, the minimisation algorithm was additionally stratified by world region and minimised on everything else within world region. Because simple minimisation within centres can lead to alternation of treatment allocation and thus potential loss of allocation concealment, our system also incorporated a degree of random allocation. Patients were allocated to the treatment group that would minimise the difference between the groups with a probability of 0.80. For 244 patients in the initial phase of the trial, the National Institutes of Health Stroke Score (NIHSS) was not measured directly, but was retrospectively estimated by an algorithm (derived from subsequent patients in the trial based on baseline clinical characteristics). In the initial double-blind phase, the clinician was informed of the treatment allocation in the form of a treatment pack number (which might contain active drug or matching placebo). In the open phase, the investigator was informed of the patient's treatment allocation (either thrombolysis with 0.9 mg/kg i.v. rtPA or control). In both phases, the randomisation system informed the local clinician of the dose (of drug or placebo in the double blind phase, or of the drug dose amongst those allocated thrombolysis in the open phase) to be given as a bolus and as infusion, and the patient's unique trial ID number.
                                                              Table 2a

                                                              Clinical characteristics at randomisation used in the minimisation algorithm





                                                              NW Europe (UK, Austria, Belgium, Switzerland)




                                                              Scandinavia (Norway, Sweden)








                                                              Southern Europe (Italy, Portugal)




                                                              Eastern Europe (Poland)




                                                              Americas (Canada, Mexico)












                                                              < = 70 years




                                                              > 70 years



                                                              Age (more detail)





















                                                              over 90




                                                              0 to 5




                                                              6 to 10




                                                              11 to 15




                                                              16 to 20




                                                              21 to 35



                                                              Stroke syndrome








                                                              Delay in randomisation

                                                              0-3 hours




                                                              > 3 hours



                                                              Delay (more detail)

                                                              0-3 hours




                                                              3-4.5 hours




                                                              4.5-6 hours




                                                              > 6 hours3



                                                              Antiplatelet agents < = 48 hours before randomisation








                                                              1. From January 2006, the randomisation procedure has been stratified by world region and minimises on prognostic factors within world region, using a random element.

                                                              2. For 244 patients in initial phase of the trial, NIHSS was not measured directly, but it was subsequently approximated using an algorithm (derived from subsequent patients in the trial based on clinical characteristics that were measured at baseline).

                                                              3. Protocol violation

                                                              Baseline characteristics of patients

                                                              The characteristics of the patients recorded at baseline are shown, for both treatment groups combined, in Tables 2a and 3 (2b). Patients recruited within 1-2 hours of onset were statistically significantly (p < 0.0001) more likely to have a more severe neurological deficit than those recruited at later time points after onset (Figure 1). Similarly, patients recruited at earlier time points were statistically significantly older than those recruited later (p < 0.0001) (Figure 2). Additionally, the proportion of patients with a visible ischaemic lesion on the baseline imaging rose with time (data not shown).
                                                              Table 2b

                                                              Clinical characteristics at randomisation not used in minimisation algorithm, and recorded at randomisation




                                                              Cardiac rhythm

                                                              Sinus rhythm, not AF




                                                              Atrial fibrillation



                                                              Systolic BP at randomisation

                                                              < = 140 mmHg




                                                              141 to 180 mmHg




                                                              > 180 mmHg




                                                              median (interquartile range)

                                                              155 (140, 170)

                                                              Diastolic BP at randomisation

                                                              < = 80 mmHg




                                                              81 to 110 mmHg




                                                              > 110 mmHg




                                                              median (interquartile range)

                                                              80 (71, 91)

                                                              Blood glucose1

                                                              < 3.5 mmol/l




                                                              3.5-6 mmol/l




                                                              6-8 mmol/l




                                                              > 8 mmol/l




                                                              not measured (old form)




                                                              median (interquartile range)

                                                              7.0 (6.0, 8.0)

                                                              Probability of being alive and independent at 6 m2

                                                              < 0.30




                                                              > = 0.30




                                                              median (interquartile range)

                                                              0.35 (0.12, 0.59)

                                                              Recruited at a centre with pre-trial experience3

                                                              Centres without pre-trial experience




                                                              Centre with pre-trial experience



                                                              Doctor's opinion of scan at randomisation





                                                              Possible evidence of recent ischaemic change




                                                              Definite evidence of recent ischaemic change



                                                              1. For the first 282 patients, glucose was not recorded. After patient 282, it was collected at randomisation. Glucose therefore was not available for those 282 patients

                                                              2. Probability calculated with a validated prognostic model from baseline data [14].

                                                              3. Pre-trial experience of thrombolysis is defined as having had a protocol for open label rtPA and had treated at least 3 people in the 12 months before joining the trial; 76 (49%) centres met this criterion.

                                                              Figure 1

                                                              Baseline stroke severity as assessed by NIHSS among patients randomised at different times after stroke onset. Plot displays median and interquartile range. p value for linear regression on exact time since onset p < 0.0001.

                                                              Figure 2

                                                              Age among patients randomised at different times after stroke onset. Plot displays median and interquartile range. p value for linear regression on exact time since onset p < 0.0001.

                                                              Baseline characteristics of the patients in the context of the prevailing evidence

                                                              The baseline characteristics of the patients recruited into the study changed over the course of the study as clinician's uncertainties about which types of patients should be treated changed. These changes arose from appreciation of the accumulating evidence from randomised controlled trials and consequent changes in the European Licence and clinical guidelines. At the start of the trial in 2000, rtPA was approved for use in the USA and Canada, but was not approved for use in Europe. In 2003, the European Medicines Agency granted provisional approval for the use of rtPA for patients aged less than 80 years who could be treated within three hours (and who also met a number of other criteria). In 2008, when the ECASS-3 study reported evidence of benefit for treatment between 3-4.5 hours [7], guidelines in various European countries suggested that patients aged less than 80 years could benefit even if treated within 3-4.5 hours. We estimated the number of patients in the trial that would have met either the original 2003 approval criteria or the anticipated new 2011 criteria (modified in the light of the ECASS-3 data). If we defined 'meeting the 2003 approval' as: age < 80, delay from onset to randomisation < 3 hoyrs, NIHSS 6 - 25, SBP < = 185, DBP < = 110, 2.7 < = glucose < = 22 and no history of the combination of prior stroke and diabetes mellitus, 61 patients (2%) met the criteria, and if all the same criteria were applied and the time window was extended to 4.5 hours, 350 (12.7%) met the criteria. This clearly demonstrates that the great majority of the patients in IST-3 fall outside the European approval criteria for rtPA., and hence the study will provide valuable new randomised information in many categories of patient - as well the elderly - who are currently not eligible for treatment.

                                                              Development of the statistical analysis plan

                                                              The statistical analysis plan is being finalised at present, without reference to the unblinded data, and will be published before the code is broken in early 2012. It will take account of external evidence on factors influencing prognosis and response to treatment, the baseline characteristics of patients entering the study and advances in statistical methodology [8, 9]. The SAP will define a small number of 'primary' subgroup analyses, and a larger number of exploratory secondary analyses [8]. During the course of the trial, a number of novel approaches to the analysis of ordered functional outcome data in clinical trials of stroke treatment have been suggested to improve statistical power Statistical tests, which make use of the ordered nature of outcome data, such as ordinal logistic regression and 'shift analysis', may give more reliable results [9]. However, the technique is not universally applicable and it is important that key underlying assumptions are met for the analyses to be valid [10]. The Trial Steering Committee sought statistical advice, and because the underlying assumptions would not necessarily be met in the IST3 dataset, decided an ordinal analysis was not appropriate for the primary analysis of outcome. This decision was also consistent with all the previous trials of intravenous rtPA, none of which had adopted an ordinal approach for the primary analysis. However, an ordinal analysis has been included as one of the secondary exploratory analyses. The trends in Figures 1 &2 demonstrate that the statistical analysis plan will also need to take account of these potentially confounding effects on the assessment of treatment effects overall and in subgroups.

                                                              Reporting of results by allocated treatment

                                                              The trial will be unblinded in early 2012 and the main trial results presented at the European Stroke Conference in Lisbon in May 2012 with the aim of publishing simultaneously in a peer-reviewed journal. The trial primary results will be presented in the context of an updated Cochrane systematic review of all the relevant randomised trials. The imaging sub-study CTP/CTA/MRP/MRA results are due in early 2013. An individual patient data meta-analysis of all trials testing intravenous rtPA, including IST-3, is also being considered.


                                                              With 3035 patients, IST-3 is the largest ever randomised trial of intravenous thrombolysis for the treatment of acute ischaemic stroke (the two largest previous trials each recruited exactly 800 patients [7, 11]. At its outset in 2000, the trial sought to improve the external validity and precision of the estimates of the overall treatment effects (efficacy and safety) of rtPA in acute ischaemic stroke and to determine whether a wider variety of patients than previously thought might benefit from this treatment. With the approval of the treatment for specific types of patients, the trial was able to evaluate the effects of treatment in patients who did not precisely meet the existing European approval for the treatment; in other words, also sought to extend the criteria for treatment. At the start of the trial, when rtPA had not yet received approval from the European regulatory authorities, patients of all ages were recruited within 3 hours. After the provisional approval for the use of rtPA in Europe in 2003 for those patients aged less than 80 years who could be treated within three hours, participating clinicians generally opted to treat patients who met the conditions of the licence, and hence only recruited only those patients in IST3 that did not strictly meet the licence criteria. The elderly have been under-represented in trials of treatments for acute stroke [12], especially thrombolysis with rtPA, where fewer than 100 patients aged over 80 years have been included in randomised trials of this treatment [13]. IST-3 has included 1617 patients aged over 80, so will provide valuable randomised evidence on the balance of risk and benefit in this much under-researched, but increasingly important age-group [12]. IST3 has shown that pragmatic trial designs with broad and flexible entry criteria can recruit large numbers of patients, even in the face of changing and burdensome regulatory regimes; the emergence of new data from other relevant trials and rapidly changing clinical practice.

                                                              List of abbreviations


                                                              Activated Partial Thromboplastin Time


                                                              Alteplase Thrombolysis for Acute Noninterventional Therapy in Ischemic Stroke


                                                              Blood Pressure in Acute Stroke Collaboration


                                                              Blood pressure


                                                              Computed Tomography


                                                              CT angiography


                                                              CT perfusion


                                                              Digital Imaging and Communications in Medicine standard


                                                              Data Monitoring Committee


                                                              Diffusion Weighted Imaging


                                                              European Cooperative Acute Stroke Study


                                                              Echoplanar Imaging Thrombolytic Evaluation Trial


                                                              Hounsfield Units


                                                              International Committee for Harmonisation


                                                              International Society for Hypertension


                                                              Third International Stroke Trial


                                                              Joint Photographic Experts Group


                                                              Magnetic Resonance


                                                              MR angiography


                                                              MR perfusion


                                                              Medical Research Council


                                                              Magnetic Resonance Imaging


                                                              National Institute of Health Stroke Score


                                                              National Institute of Neurological Disorders and Stroke


                                                              Prothrombin Time


                                                              Odds Ratio


                                                              Prospective randomised open blinded endpoint design


                                                              recombinant tissue plasminogen activator


                                                              Suspected Unexpected Serious Adverse Reaction


                                                              Trial Steering Committee.



                                                              The IST-3 collaborative group wishes chiefly to acknowledge the support of all the patients who participated in the study, and the many individuals not specifically mentioned in the paper who have supported the study. IST-3 is an investigator led trial. The University of Edinburgh and the Lothian Health Board are co-sponsors. The start-up phase was supported by a grant from the Stroke Association, UK. The expansion phase was funded by The Health Foundation UK. The main phase of the trial is funded by: UK MRC and managed by NIHR on behalf of the MRC-NIHR partnership, The Research Council of Norway, AFA Insurances (Sweden), the Swedish Heart Lung Fund, The Foundation of Marianne and Marcus Wallenberg, Stockholm County Council and Karolinska Institute Joint ALF-project grants (Sweden), the Government of Poland, the Australian Heart Foundation, Australian NHMRC, the National Heart Foundation Australia, the Swiss National Research Foundation, the Swiss Heart Foundation, Foundation for health and cardio-/neurovascular research, Basel, Switzerland and the Assessorato alla Sanita, Regione dell'Umbria. Drug and placebo for the 300 patients in the double-blind component of the start-up phase were supplied by Boehringer-Ingelheim GMBh. IST-3 acknowledges the extensive support of the NIHR Stroke Research Network, NHS Research Scotland (NRS), through the Scottish Stroke Research Network, and the National Institute for Social Care and Health Research Clinical Research Centre (NISCHR CRC). The imaging work was undertaken at the Brain Imaging Research Centre http://​www.​bric.​ed.​ac.​uk, a member of the SINAPSE collaboration http://​www.​sinapse.​ac.​uk, at the Division of Clinical Neurosciences, University of Edinburgh. SINAPSE is funded by the Scottish Funding Council (SFC) and the Chief Scientist Office of the Scottish Executive (CSO). Additional support was received from Chest Heart and Stroke Scotland, Desacc, University of Edinburgh, Danderyd Hospital R&D Department, Karolinska Institutet, the Dalhousie University Internal Medicine Research Fund. The study was designed, conducted, analysed and reported independently of all of the sponsors and funding agencies.

                                                              Trial Steering Committee

                                                              Independent Chairman, Professor Colin Baigent (university of Oxford), Professor David Chadwick, (Former Chairman, Retired)): University of Liverpool; Independent members: Dr Pippa Tyrrell (Manchester University), Professor Gordon Lowe (Glasgow University); Co-principal Investigators: Professor Peter Sandercock (Edinburgh University); Professor Richard Lindley (Professor of Geriatric Medicine, University of Sydney); Chief Investigator for Neuroradiology: Professor Joanna Wardlaw (Edinburgh University) Statistician: Geoff Cohen; Trial Manager: Ms Karen Innes. Heather Goodare: lay representative

                                                              CT reading panel

                                                              Joanna Wardlaw, Andrew Farrall, Rüdiger von Kummer, Lesley Cala, Anders von Heijne, Zoe Morris, Alessandro Adami, Andre Peeters, Gillian Potter, Nick Brady.

                                                              Data Monitoring Committee

                                                              Professor Rory Collins, Oxford University, UK (Chairman), Professor Philip Bath (Nottingham University), Professor Jan van Gijn (former member, now retired) (University of Utrecht, The Netherlands), Professor Richard Gray (University of Oxford), Professor Robert Hart (McMaster University, Canada), Professor Salim Yusuf (McMaster University, Canada).

                                                              Event Adjudication Committee

                                                              Keith Muir, Peter Sandercock, Richard Lindley

                                                              National Co-ordinators and Associate National Co-ordinators

                                                              Australia: Richard Lindley, Graeme J. Hankey. Austria: Karl Matz, Michael Brainin. Belgium: Andre Peeters. Canada: Gord Gubitz, Stephen Phillips. Italy: Stefano Ricci. Mexico: Antonio Arauz. Norway: Eivind Berge, Karsten Bruins Slot. Poland: Anna Czlonkowska, Adam Kobayashi. Portugal: Manuel Correia. Switzerland: Phillippe Lyrer. Sweden: Veronica Murray, Andreas Terent, Bo Norrving, Per Wester: UK: Graham Venables

                                                              Trial Coordinating Centre, Edinburgh

                                                              Karen Innes, Alison Clark, David Perry, Vera Soosay, David Buchanan, Sheila Grant, Eleni Sakka, Jonathan Drever, Pauli Hanley, Indee Herath, Ann Leigh Brown, Paul Chmielnik, Christopher Armit, Andrea Walton, Mischa Hautvast, Steff Lewis, Graeme Heron, Sylvia Odusanya, Pam Linksted, Ingrid Kane, Will Whiteley, Robin Sellar, Philip White, Peter Keston, Andrew Farrell, Zoe Morris, Hector Miranda. National Co-ordinating centres: Italy (up to September 2008) Maria Grazia Celani, Enrico Righetti (after September 2008) Silvia Cenciarelli, Tatiana Mazzoli Central Follow up for Italy: Teresa Anna Cantisani. Poland Jan Bembenek Sweden Eva Isaakson. Norway Eivind Berge, Karsten Bruins Slot.

                                                              Centres and countries

                                                              The list of participating centres and the collaborators at each site are listed in additional file 2.

                                                              Authors’ Affiliations

                                                              The IST-3 Co-ordinating Centre, Neurosciences Trial Unit
                                                              Discipline of Medicine, Sydney Medical School - Westmead and The George Institute for Global Health, University of Sydney
                                                              Neurology Department, Sheffield Teaching Hospitals NHS Foundation Trust, Royal Hallamshire Hospital
                                                              2nd Department of Neurology, Institute of Psychiatry and Neurology, Sobieskiego Str. 9, 02- 957 Warsaw, and Department of Experimental and Clinical Pharmacology, Medical University of Warsaw
                                                              Department of Internal Medicine, Oslo University Hospital, Ullevål
                                                              Department of Clinical Sciences, Karolinska Institutet, Danderyd Hospital
                                                              Service de neurologie, Cliniques universitaires Saint-Luc
                                                              Department of Neurology, Royal Perth Hospital
                                                              Neurologische Abteilung, Landesklinikum Donauregion Tulln
                                                              UO Neurologia, ASL 1, Ospedale
                                                              S C di Neurofisiopatologia, Azienda Ospedaliera di Perugia
                                                              Division of Neurology, Dalhousie University and Queen Elizabeth II Health Sciences Centre, Halifax Infirmary
                                                              Instituto Nacional de Neurologia
                                                              Neurology Department, Hospital Geral de Santo Antonio, Largo Prof Abel Salazar
                                                              Department of Neurology, University Hospital Basel
                                                              Stroke Unit, Royal Sussex County Hospital
                                                              Neurology, Institute of Neuroscience, Uppsala University Hospital


                                                              1. Sandercock P, Lindley R, Wardlaw J, Dennis M, Lewis S, Venables G, Kobayashi A, Czlonkowska A, Berge E, Slot K, Murray V, Peeters A, Hankey G, Matz K, Brainin M, Ricci S, Celani M, Righetti E, Cantisani T, Gubitz G, Phillips S, Arauz A, Prasad K, Correia M, Lyrer P, the IST: The third international stroke trial (IST-3) of thrombolysis for acute ischaemic stroke. Trials 2008,9(1):37.PubMedView Article
                                                              2. Warlow C, D'Hooghe M, Joos F, Lanckneus M, Lecluyse A, Marchau M, Rocher A, Roussel J, Van ZM, Dereume J, Hildebrand J, Ceusters W, De RJ, De RJ, Decoo D, Derom D, Vakaet A, Carton H, Nevelsteen A: MRC European Carotid Surgery Trial: interim results for symptomatic patients with severe (70–99%) or with mild (0–29%) carotid stenosis. Lancet 1991, 337:1235–43.View Article
                                                              3. Peto R, Baigent C: Trials: the next 50 years. BMJ 1998,317(7167):1170–1.PubMedView Article
                                                              4. Collins R, MacMahon S: Reliable assessment of the effects of treatment on mortality and major morbidity, I: clinical trials. Lancet 2001,357(9253):373–80.PubMedView Article
                                                              5. Ware JH, Hamel MB: Pragmatic Trials - Guides to Better Patient Care? NEJM 2011,364(18):1685–7.PubMedView Article
                                                              6. McMahon AD: Study control, violators, inclusion criteria and defining explanatory and pragmatic trials. Statistics in Medicine 2002,21(10):1365–1376.PubMedView Article
                                                              7. Hacke W, Kaste M, Bluhmki E, Brozman M, Davalos A, Guidetti D, Larrue V, Lees KR, Medeghri Z, Machnig T, Schneider D, von Kummer R, Wahlgren N, Toni D, the E, I: Thrombolysis with Alteplase 3 to 4.5 Hours after Acute Ischemic Stroke. The New England Journal of Medicine 2008,359(13):1317–29.PubMedView Article
                                                              8. Kent DM, Rothwell PM, Ioannidis JP, Altman DG, Hayward RA: Assessing and reporting heterogeneity in treatment effects in clinical trials: a proposal. Trials 2010, 11:85.PubMedView Article
                                                              9. Bath PM, Gray LJ, Collier T, Pocock S, Carpenter J: Can we improve the statistical analysis of stroke trials? Statistical reanalysis of functional outcomes in stroke trials. Stroke 2007,38(6):1911–5.PubMedView Article
                                                              10. Saver JL: Novel End Point Analytic Techniques and Interpreting Shifts Across the Entire Range of Outcome Scales in Acute Stroke Trials. Stroke 2007,38(11):3055–62.PubMedView Article
                                                              11. Hacke W, Kaste M, Fieschi C, von Kummer R, Davalos A, Meier D, Larrue V, Bluhmki E, Davis SM, Donnan G, Schneider D, Diez-Tejedor E, Trouillas P, the Second European-Australasian Acute SS, I: Randomised double-blind placebo-controlled trial of thrombolytic therapy with intravenous alteplase in acute ischaemic stroke (ECASS II). Lancet 1998, 352:1245–51.PubMedView Article
                                                              12. Sanossian N, Ovbiagele B: Prevention and management of stroke in very elderly patients. Lancet Neurol 2009,8(11):1031–41.PubMedView Article
                                                              13. Wardlaw JM, Murray V, Berge E, del Zoppo GJ: Thrombolysis for acute ischaemic stroke. Cochrane Database Syst Rev 2009, (4):CD000213.
                                                              14. Konig IR, Ziegler A, Bluhmki E, Hacke W, Bath PMW, Sacco RL, Diener HC, Weimar C, on behalf of the Virtual International Stroke Trials Archive (VISTA) Investigators: Predicting Long-Term Outcome After Acute Ischemic Stroke: A Simple Index Works in Patients From Controlled Clinical Trials. Stroke 2008,39(6):1821–6.PubMedView Article


                                                              © Sandercock et al; licensee BioMed Central Ltd. 2011