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The International Stroke Trial database

  • Peter AG Sandercock1Email author,
  • Maciej Niewada2, 3,
  • Anna Członkowska2, 3 and
  • the International Stroke Trial Collaborative Group
Trials201112:101

DOI: 10.1186/1745-6215-12-101

Received: 22 September 2010

Accepted: 21 April 2011

Published: 21 April 2011

The Erratum to this article has been published in Trials 2012 13:24

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).

Notes

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

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Copyright

© Sandercock et al; licensee BioMed Central Ltd. 2011

This article is published under license to BioMed Central Ltd. 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.