The International Stroke Trial database

  • Peter AG Sandercock1Email author,

    Affiliated with

    • Maciej Niewada2, 3,

      Affiliated with

      • Anna Członkowska2, 3 and

        Affiliated with

        • the International Stroke Trial Collaborative Group

          Affiliated with

          Trials201112:101

          DOI: 10.1186/1745-6215-12-101

          Received: 22 September 2010

          Accepted: 21 April 2011

          Published: 21 April 2011

          Abstract

          Background

          We aimed to make individual patient data from the International Stroke Trial (IST), one of the largest randomised trials ever conducted in acute stroke, available for public use, to facilitate the planning of future trials and to permit additional secondary analyses.

          Methods

          For each randomised patient, we have extracted data on the variables assessed at randomisation, at the early outcome point (14-days after randomisation or prior discharge) and at 6-months and provide them as an analysable database.

          Results

          The IST dataset includes data on 19 435 patients with acute stroke, with 99% complete follow-up. Over 26.4% patients were aged over 80 years at study entry. Background stroke care was limited and none of the patients received thrombolytic therapy.

          Conclusions

          The IST dataset provides a source of primary data which could be used for planning further trials, for sample size calculations and for novel secondary analyses. Given the age distribution and nature of the background treatment given, the data may be of value in planning trials in older patients and in resource-poor settings.

          Background

          The International Stroke Trial (IST) was conducted between 1991 and 1996 (including the pilot phase between 1991 and 1993). It was a large, prospective, randomised controlled trial, with 100% complete baseline data and over 99% complete follow-up data. The aim of the trial was to establish whether early administration of aspirin, heparin, both or neither influenced the clinical course of acute ischaemic stroke [1].

          Methods

          The study had a prospective, randomised, open treatment, blinded outcome (PROBE) design. The inclusion criteria were: clinical diagnosis of acute ischaemic stroke, with onset within the previous 48 hours and no clear indication for, or clear contraindication to, treatment with aspirin or subcutaneous heparin. Unlike many stroke trials of that era (and subsequently), the study did not set an upper age limit. Patients were to have a CT brain scan to confirm the diagnosis of stroke, and this was to be done before randomisation if at all possible. To enter a patient in the study, the clinician telephoned a central randomisation service (at the Clinical Trial Service Unit, Oxford) during this telephone call, the baseline variables were entered and checked, and once validated, the computer allocated the treatment and the telephonist then informed the clinician. The patients and treating clinicians were not blinded to the treatment given. Early outcome data were collected by the treating physician who completed a follow-up form at 14 days, death or hospital discharge (whichever occurred first). This form recorded data on events in hospital within 14 days, and the doctor's opinion on the final diagnosis of the initial event that led to randomisation. These unblinded data, may therefore be subject to some degree of bias. The primary outcome was the proportion of patients who were either dead or dependent on other people for activities of daily living at six months after randomisation. This outcome was collected by postal questionnaire mailed directly to the patient, or (in Italy) by telephone interview of the patient by a trained researcher, blinded to treatment allocation. The primary outcome was therefore assessed - as far as practicable - blind to treatment allocation and hence should be free from bias. We re-checked the data set for inaccuracies and inconsistencies and extracted data on the variables assessed at randomisation, and at the two outcome assessment points: at 14-days after randomisation, death or prior hospital discharge (whichever occurred first) and at 6-months.

          Results

          Consent for publication of raw data was not obtained from participants. Consent for participation in the trial was obtained from all subjects or from an appropriate proxy, according to the procedures approved by relevant national and local hospital ethics committees (or Institutional Review Boards [IRB]). These patients were treated 15-20 years ago, and many have died. The dataset (see additional file 1 - IST_data.csv) is fully anonymous in a manner that can easily be verified by any user of the dataset. Patients and hospitals are identified only by an anonymous code; there are no identifying data such as name, address or social security numbers; patient age has been rounded to the nearest whole number. In our view, publication of the dataset clearly presents no material risk to confidentiality of study participants.

          The dataset includes the following baseline data: age, gender, time from onset to randomisation, presence or absence of atrial fibrillation (AF), aspirin administration within 3 days prior to randomisation, systolic blood pressure at randomisation, level of consciousness and neurological deficit. The deficits were classified as one of the Oxfordshire Community Stroke Project (OCSP) categories: total anterior circulation syndrome (TACS), partial anterior circulation syndrome (PACS), posterior circulation syndrome (POCS) and lacunar syndrome (LACS). We extracted events within 14 days on: the occurrence of recurrent stroke, pulmonary embolism, and death (date and cause of death). At 6 months we extracted: degree of recovery, place of residence and current use of antiplatelet or anticoagulant drugs and death (date and cause of death). The cause of death was classified as: due to initial stroke, recurrent ischaemic stroke, recurrent haemorrhagic stroke, pneumonia, coronary artery disease, pulmonary embolism, other vascular cause or a nonvascular cause. Patients were assigned to one of 6 categories according to the place of residence at 6 months following stroke: own home, relatives home, residential care, nursing home, other hospital departments or unknown. The variables extracted are listed with a brief description of each in Tables 1, 2 and 3. Nineteen thousand four hundred and thirty five patients from 467 hospitals in 36 countries were randomised within 48 hours of symptoms onset, of whom 13020 had a CT before randomisation, 5569 were first scanned after randomisation and 846 were not scanned at all. Five thousand one hundred thirty two (26.4%) were aged over 80 years at study entry. Given that 5569 patients were first scanned after randomisation, and 846 were not scanned at all, the 'final diagnosis' is somewhat imprecise. However, since the analysis was by intention to treat, all participants were retained in the analysis, irrespective of the final diagnosis. The numbers of patients with each final diagnosis are given in Table 4. Whilst the 'final diagnosis variable' is of some interest, it may be influenced by events occurring after randomisation, so for any future analyses, the least biased assessment of the patient characteristics is that recorded at baseline, before randomisation.
          Table 1

          Country codes used in International Stroke Trial.

          Country

          Code

          Albania

          43

          Argentina

          29

          Australia

          01

          Belgium

          03

          Brazil

          42

          Bulgaria

          04

          Canada

          05

          Chile

          06

          Czech Republic

          07

          Denmark

          08

          Ireland

          09

          Finland

          10

          France

          11

          Georgia

          32

          Germany

          12

          Greece

          31

          Hong Kong

          30

          Hungary

          36

          India

          37

          Indonesia

          41

          Israel

          13

          Italy

          14

          Japan

          38

          Latvia

          39

          Malaysia

          40

          Netherlands

          15

          New Zealand

          16

          Norway

          17

          Poland

          18

          Portugal

          19

          Romania

          33

          Singapore

          34

          Slovak Republic

          44

          Slovenia

          20

          South Africa

          21

          Spain

          22

          Sri Lanka

          23

          Sweden

          24

          Switzerland

          25

          Thailand

          26

          Turkey

          35

          UK

          27

          USA

          28

          Table 2

          Variables names and comments.

          Randomisation data

          HOSPNUM

          Hospital number

          RDELAY

          Delay between stroke and randomisation in hours

          RCONSC

          Conscious state at randomisation (F - fully alert, D - drowsy, U - unconscious)

          SEX

          M = male; F = female

          AGE

          Age in years

          RSLEEP

          Symptoms noted on waking (Y/N)

          RATRIAL

          Atrial fibrillation (Y/N); not coded for pilot phase - 984 patients

          RCT

          CT before randomisation (Y/N)

          RVISINF

          Infarct visible on CT (Y/N)

          RHEP24

          Heparin within 24 hours prior to randomisation (Y/N)

          RASP3

          Aspirin within 3 days prior to randomisation (Y/N)

          RSBP

          Systolic blood pressure at randomisation (mmHg)

          RDEF1

          Face deficit (Y/N/C=can't assess)

          RDEF2

          Arm/hand deficit (Y/N/C=can't assess)

          RDEF3

          Leg/foot deficit (Y/N/C=can't assess)

          RDEF4

          Dysphasia (Y/N/C=can't assess)

          RDEF5

          Hemianopia (Y/N/C=can't assess)

          RDEF6

          Visuospatial disorder (Y/N/C=can't assess)

          RDEF7

          Brainstem/cerebellar signs (Y/N/C=can't assess)

          RDEF8

          Other deficit (Y/N/C=can't assess)

          STYPE

          Stroke subtype (TACS/PACS/POCS/LACS/OTH=other)

          RDATE

          Year and month of randomisation (yyyy-mm)

          HOURLOCAL

          Local time - hours (99-missing data) of randomisation

          MINLOCAL

          Local time - minutes (99-missing data) of randomisation

          DAYLOCAL

          Estimate of local day of week; 1 - Sunday, 2-Monday, 3-Tuesday, 4-Wednesday, 5-Thursday, 6-Friday, 7-Saturday

          RXASP

          Trial aspirin allocated (Y/N)

          RXHEP

          Trial heparin allocated (M/L/N). The terminology for the allocated dose of unfractioned heparin changed slightly from the pilot to the main study. Patients were allocated either 12500 units subcutaneously twice daily (coded as H in the pilot and M in the main trial), 5000 units twice daily (coded as L throughout) or to 'avoid heparin' (coded as N throughout).

          Data collected on 14 day/discharge form about treatments given in hospital

          DASP14

          Aspirin given for 14 days or till death or discharge (Y/N/U=unknown)

          DASPLT

          Discharged on long term aspirin (Y/N/U=unknown)

          DLH14

          Low dose heparin given for 14 days or till death/discharge (Y/N/U=unknown)

          DMH14

          Medium dose heparin given for 14 days or till death/discharge (Y/N/U=unknown)

          DHH14

          Medium dose heparin given for 14 days etc in pilot (combine with above; Y/N)

          ONDRUG

          Estimate of time in days on trial treatment

          DSCH

          Non trial subcutaneous heparin (Y/N/U=unknown)

          DIVH

          Non trial intravenous heparin (Y/N/U=unknown)

          DAP

          Non trial antiplatelet drug (Y/N/U=unknown)

          DOAC

          Other anticoagulants (Y/N/U=unknown)

          DGORM

          Glycerol or manitol (Y/N/U=unknown)

          DSTER

          Steroids (Y/N/U=unknown)

          DCAA

          Calcium antagonists (Y/N/U=unknown)

          DHAEMD

          Haemodilution (Y/N/U=unknown)

          DCAREND

          Carotid surgery (Y/N/U=unknown)

          DTHROMB

          Thrombolysis (Y/N/U=unknown)

          DMAJNCH

          Major non-cerebral haemorrhage (Y/N/U=unknown)

          DMAJNCHD

          Date of above (days elapsed from randomisation)

          DMAJNCHX

          Comment on above

          DSIDE

          Other side effect (Y/N/U=unknown)

          DSIDED

          Date of above (days elapsed from randomisation)

          DSIDEX

          Comment on above

          Final diagnosis of initial event

          DDIAGISC

          Ischaemic stroke (Y/N/U=unknown)

          DDIAGHA

          Haemorrhagic stroke (Y/N/U=unknown)

          DDIAGUN

          Indeterminate stroke (Y/N/U=unknown)

          DNOSTRK

          Not a stroke (Y/N/U=unknown)

          DNOSTRKX

          Comment on above

          Recurrent stroke within 14 days

          DRSISC

          Ischaemic recurrent stroke (Y/N/U=unknown)

          DRSISCD

          Date of above (days elapsed from randomisation)

          DRSH

          Haemorrhagic stroke (Y/N/U=unknown)

          DRSHD

          Date of above (days elapsed from randomisation)

          DRSUNK

          Unknown type (Y/N/U=unknown)

          DRSUNKD

          Date of above (days elapsed from randomisation)

          Other events within 14 days

          DPE

          Pulmonary embolism; (Y/N/U=unknown)

          DPED

          Date of above (days elapsed from randomisation)

          DALIVE

          Discharged alive from hospital (Y/N/U=unknown)

          DALIVED

          Date of above (days elapsed from randomisation)

          DPLACE

          Discharge destination (A-Home/B-Relatives home/C-Residential care/D-Nursing home/E-Other hospital departments/U-Unknown)

          DDEAD

          Dead on discharge form (Y/N/U=unknown)

          DDEADD

          Date of above (days elapsed from randomisation); NOTE: this death is not necessarily within 14 days of randomisation

          DDEADC

          Cause of death (1-Initial stroke/2-Recurrent stroke (ischaemic or unknown)/3-Recurrent stroke (haemorrhagic)/4-Pneumonia/5-Coronary heart disease/6-Pulmonary embolism/7-Other vascular or unknown/8-Non-vascular/0-unknown)

          DDEADX

          Comment on death

          Data collected at 6 months

          FDEAD

          Dead at six month follow-up (Y/N/U=unknown)

          FLASTD

          Date of last contact (days elapsed from randomisation)

          FDEADD

          Date of death (days elapsed from randomisation); NOTE: this death is not necessarily within 6 months of randomisation

          FDEADC

          Cause of death (1-Initial stroke/2-Recurrent stroke (ischaemic or unknown)/3-Recurrent stroke (haemorrhagic)/4-Pneumonia/5-Coronary heart disease/6-Pulmonary embolism/7-Other vascular or unknown/8-Non-vascular/0-unknown)

          FDEADX

          Comment on death

          FRECOVER

          Fully recovered at 6 month follow-up (Y/N/U=unknown)

          FDENNIS

          Dependent at 6 month follow-up (Y/N/U=unknown)

          FPLACE

          Place of residance at 6 month follow-up (A-Home/B-Relatives home/C-Residential care/D-Nursing home/E-Other hospital departments/U-Unknown)

          FAP

          On antiplatelet drugs at six month follow-up (Y/N/U=unknown)

          FOAC

          On oral anticoagulants at six month follow-up (Y/N/U=unknown)

          Other data and derived variables

          FU1_RECD

          Date discharge form received (days elapsed from randomisation)

          FU2_DONE

          Date 6 month follow-up done (days elapsed from randomisation)

          COUNTRY

          Abbreviated country code

          CNTRYNUM

          Country code (see Table 1)

          FU1_COMP

          Date discharge form completed (days elapsed from randomisation)

          NCCODE

          Coding of compliance (see Table 3)

          CMPLASP

          Compliant for aspirin (N/Y)

          CMPLHEP

          Compliant for heparin (N/Y)

          ID

          Indicator variable for death (1 = died; 0 = did not die)

          TD

          Time of death or censoring in days

          EXPDD

          Predicted probability of death/dependence at 6 month

          EXPD6

          Predicted probability of death at 6 month

          EXPD14

          Predicted probability of death at 14 days

          SET14D

          Know to be dead or alive at 14 days (1 = Yes, 0 = No); this does not necessarily mean that we know outcome at 6 months - see OCCODE for this

          ID14

          Indicator of death at 14 days (1 = Yes, 0 = No)

          OCCODE

          Six month outcome (1-dead/2-dependent/3-not recovered/4-recovered/0 or 9 - missing status

          Indicator variables for specific causes of death

          DEAD1

          Initial stroke (1 = Yes, 0 = No)

          DEAD2

          Reccurent ischaemic/unknown stroke (1 = Yes, 0 = No)

          DEAD3

          Reccurent haemorrhagic stroke (1 = Yes, 0 = No)

          DEAD4

          Pneumonia (1 = Yes, 0 = No)

          DEAD5

          Coronary heart disease (1 = Yes, 0 = No)

          DEAD6

          Pulmonary embolism (1 = Yes, 0 = No)

          DEAD7

          Other vascular or unknown (1 = Yes, 0 = No)

          DEAD8

          Non vascular (1 = Yes, 0 = No)

          H14

          Cerebral bleed/heamorrhagic stroke within 14 days; this is slightly wider definition than DRSH and is used for analysis of cerebral bleeds; (1 = Yes, 0 = No)

          ISC14

          Indicator of ischaemic stroke within 14 days (1 = Yes, 0 = No)

          NK14

          Indicator of indeterminate stroke within 14 days (1 = Yes, 0 = No)

          STRK14

          Indicator of any stroke within 14 days (1 = Yes, 0 = No)

          HTI14

          Indicator of haemorrhagic transformation within 14 days (1 = Yes, 0 = No)

          PE14

          Indicator of pulmonary embolism within 14 days (1 = Yes, 0 = No)

          DVT14

          Indicator of deep vein thrombosis on discharge form (1 = Yes, 0 = No)

          TRAN14

          Indicator of major non-cerebral bleed within 14 days (1 = Yes, 0 = No)

          NCB14

          Indicator of any non-cerebral bleed within 14 days (1 = Yes, 0 = No)

          Table 3

          Provisional categories for non compliance (NCCODE).

          1.

          Should not have been randomised

          2.

          Refused treatment

          3.

          Initial event not a stroke

          4.

          Haemorrhagic stroke

          5.

          Non compliers

          6.

          Discharged after 14 days

          7.

          Discharged up to 14 days

          8.

          Died prior to receiving the study drug(s)

          9.

          Died after receiving the study drug(s)

          10.

          Recurrent stroke/pulmonary embolism

          11.

          Clinical decision

             11a.

          Suspected abnormality

             11b.

          Withdrawn as dying

             11c.

          Pre-existing condition

             11d.

          Stated abnormal PTT

             11e.

          Stated surgery

             11f.

          Stated atrial fibrillation

          12.

          Administration problem

          13.

          Missed out more than 3 doses

          14.

          Side effect

             14a.

          Refused treatment

             14b.

          Discharged

             14c.

          Administration problem

             14d.

          Clinical decision

             14e.

          Recurrent stroke

             14f.

          Haemorrhagic stroke

          Table 4

          Final diagnosis of initial event.

           

          Number

          Ischaemic stroke

          17398

          Haemorrhagic stroke

          599

          Definite stroke, pathological type unknown

          992

          Not a stroke

          420

          Uncertain diagnosis

          26

          Total

          19435

          To restrict analyses to cases of definite ischaemic stroke, confirmed at the time of trial entry, the variable denoting whether CT had been performed before entry (RCT) should = Y and the final diagnosis should also be ischaemic (DDIAGISC=Y).

          Please note that, in the original 1997 Lancet report on the trial [1], figures two a and two b reported the effects of allocation to aspirin and to heparin on the primary outcome, subdivided by various baseline characteristics and by the final diagnosis. The numbers of patients with each pathological type of stroke are somewhat different to the numbers above, because they relate to the number of patients with complete 6 month follow-up data, whereas the numbers above relate to all randomised patients.

          Anonymisation

          As recommended by Hrynaszkiewicz et al. [2] we have removed all direct and indirect identifiers from the database. We therefore present patient's age rounded to the nearest whole number of years. Time of admission to hospital (a potential identifier) was not recorded. Dates of events occurring post randomisation have been converted to the number of days from randomisation. The time variables that were recorded (see below) referred to time of randomisation in the trial (i.e. the time at which the system generated the treatment allocation), not time of admission to hospital, a variable, that - in our view - would not help identify the patient.

          Discussion

          This large data set, with very complete follow-up, includes a very broad range of acute stroke patients with a uniquely large number of very elderly patients, and so may be useful to researchers planning future research studies. Users of the dataset should be aware that the study was conducted at a time when stroke unit care was not widely available and thrombolytic therapy was used rarely (and none of the included patients received it) [3]. Thus, the background stroke care for the included subjects, while not typical of present-day acute stroke care [4], is perhaps more typical of current stroke care in resource poor settings [5]. Given that the developing world faces a future epidemic of non-communicable diseases, including stroke [5], these data may therefore prove particularly valuable for planning future trials in resource-poor settings. In the developed world, the proportion of the general population who are 'very elderly' is rapidly increasing. Older people have been substantially under-represented in stroke trials to date [6], so we hope the large number of patients aged over 80 in this data set could also facilitate planning of trials in the 'older old'.

          The publication of raw datasets such as the IST's may offer wholly unanticipated benefits to the wider research community. For example, the dataset was licensed to an independent statistical group who used the data to estimate the size and direction of biases introduced when non-randomised comparisons were made and the differences between direct and indirect comparisons. This empirical work led to two important publications on the topic [7, 8]. Such additional benefits, realised long after the original trial was completed, are a further clear indication of the value of opening access to such datasets.

          Note for users of the data set

          The authors ask that any publications arising from the use of this dataset acknowledges the source of the dataset, its funding and the collaborative group that collected the data.

          Sources of Funding

          The study was principally funded by the UK Medical Research Council, the UK Stroke Association, and the European Union BIOMED-1 program. Limited support for collaborators' meetings and travel was provided by Eli Lilly, Sterling Winthrop (now Bayer USA), Sanofi, and Bayer UK. Follow-up in Australia was supported by a grant from the National Heart Foundation and in Canada by a Nova Scotia Heart and Stroke Foundation grant. Czech Republic IST was supported by a grant from the IGA Ministry of Health. India IST was supported by the McMaster INCLEN program and the All India Institute of Medical Sciences. The IST in New Zealand was funded by the Julius Brendel Trust and the Lottery Grants Board. In Norway, the IST was supported by the Norwegian Council on Cardiovascular Disease and Nycomed (for insurance).

          Declarations

          Acknowledgements

          The chief acknowledgement is to the thousands of stroke patients who joined the IST and to their doctors. The staff of the Neurosciences Trials Unit coordinated the study, and randomization was provided by staff at the Clinical Trial Service Unit in Oxford.

          Authors’ Affiliations

          (1)
          Department of Clinical Neurosciences, University of Edinburgh, Department of Clinical Neurosciences, Western General Hospital
          (2)
          Department of Clinical and Experimental Pharmacology, Warsaw Medical University, Poland
          (3)
          2nd Department of Neurology, Institute of Psychiatry and Neurology

          References

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          2. Hrynaszkiewicz I, Norton ML, Vickers AJ, Altman DG: Preparing raw clinical data for publication: guidance for journal editors, authors, and peer reviewers. [http://​www.​trialsjournal.​com/​content/​11/​1/​9] Trials 2010, 11:9.PubMedView Article
          3. Weir NU, Sandercock P, Lewis SC, Signorini D, Warlow CP, on behalf of the IST Collaborative Group: Variations between countries in outcome after stroke in the International Stroke Trial (IST). Stroke 2001, 32:1370–1377.PubMed
          4. Irwin P, Hoffman A, Lowe D, Pearson M, Rudd AG: Improving clinical practice in stroke through audit: results of three rounds of National Stroke Audit. J Eval Clin Pract 2005, 11:306–314.PubMedView Article
          5. Kengne AP, Anderson CS: The neglected burden of stroke in Sub-Saharan Africa. International Journal of Stroke 2006, 1:180–190.PubMedView Article
          6. Sanossian N, Ovbiagele B: Prevention and management of stroke in very elderly patients. Lancet Neurol 2009, 8:1031–1041.PubMedView Article
          7. Deeks JJ, Dinnes J, D'Amico RA, Sowden AJ, Sakarovitch C, Song F, Petticrew M, Altman DG: Evaluating non-randomised intervention studies. Health Technology Assessment 2003, 7:1–173.
          8. Glenny AM, Altman DG, Song F, Sakarovitch C, Deeks JJ, D'Amico R, Bradburn M, Eastwood AJ: Indirect comparisons of competing interventions. Health Technology Assessment 2005, 9:1–148.PubMed

          Copyright

          © Sandercock et al; licensee BioMed Central Ltd. 2011

          This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://​creativecommons.​org/​licenses/​by/​2.​0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.