The third international stroke trial (IST-3) main results: primary and secondary

outcomes among 3035 patients

The IST3 collaborative group - 156 hospitals in UK, Poland, Italy, Sweden, Norway, Australia, Portugal, Belgium, Austria,

Switzerland, Canada, Mexico

23rd May 2012Lisbon

Disclosures: Boehringer Ingelheim donated rt-PA and placebo for the first 300 patients but had no other part in the study.

Available online at www.thelancet.comFrom 12.00 today

Main features of IST - 3 • Randomised, open study i.v. rt-PA vs control • Target: 3100 acute ischaemic stroke < 6h• Randomised by phone or internet: • Key prognostic factors balanced• Imaging CT or MR• Oxford Handicap Scale (OHS) at 6 months• Primary outcome: % ‘alive and independent’

(OHS 0-2)• Secondary: ordinal ‘shift’ analysis of OHS1

1. Analysis plan. Int J Stroke. 2012;7:186-7

Follow-up

• Monitor clinical state and BP for 24h

• 24-48 hrs repeat CT/MR

• 7 days, death or hospital discharge - if sooner - complete CRF:

• 6 months: follow-up by postal questionnaire to patient or proxy / blinded telephone follow up by national coordinating centre

Adjudication, safety, monitoring• International panel of experts assessed

baseline and follow-up scans blind to clinical details & treatment.

• Clinical and scan data from patients with events / deaths < 7 days adjudicated blind to treatment allocation.

• Independent Data Monitoring Committee

• Site Monitoring Plan agreed with regulators, included targeted source data verification*

*Lancet May 23rd 2012

Eligibility and randomisation

If patient fitted main eligibility/exclusion criteria clinician/patient/family discuss. If there is a:

• Clear INDICATION FOR rt-PA →TREAT (i.e. meets terms of current licence and patient agrees)

• Clear CONTRAINDICATION TO rt-PA → DON’T TREAT

• rt-PA ‘PROMISING BUT UNPROVEN’ → RANDOMISE

Baseline characteristics1 (n=3035)• 849 (28%) randomised < 3 hours

• 1617 (53%) aged > 80 years

• 1305 (43%) TACI syndrome

• 914 (30%) in AF

• 970 (32%) baseline NIHSS > 16

• 95% did not meet EU approval for rt-PA

• Treatment and control groups balanced on all key factors

1.Trials 2011, 12:252. http://www.trialsjournal.com/content/12/1/252

rt-PA(n=1515)

Control(n=1520)

n (%) n (%)

104 (7%) 16 (1%)

Fatal & non-fatal intracranial haemorrhage < 7 days

applying the ‘Cochrane’ definition, of SICH, the 7% IST-3 frequency is comparable with the 7.3% (SITS) registry of 6483

patients treated within licence in routine clinical practice1

1. Wahlgren, Lancet 2007; 369: 275–82

P < 0.0001

Deaths

nrt-PA(%) n

Control(%) p

Within 7 days 163 (11%) 107 (7%) ↑0.001

After 7 days, before 6 mo.

244 (16%) 300 (20%) ↓0.009

All deaths by 6 months.

408 (27%) 407 (27%) 0.6

Primary outcome: ‘alive and independent’ (OHS 0-2)

rt-PA(n=1515)

control(n=1520)

n (%) n (%)

554 (37%) 534 (35%)

Absolute difference/1000 = 14 more alive and independent

(95% CI -20 to 48) NS

Ordinal analysis 6 month OHS

Favourable shift; adjusted common odds ratio 1·27 (95% CI 1·10- 1·47), p=0·001

or, the odds of surviving with less disability were 27% greater for patients treated with rt-PA

SubgroupsTime (hours) from stroke

to randomisation

  0-3h  3-4.5h 4.5-6h

Age  <80 177  558 683

Age >80 672 620 325

 All  849 1178 1008

(interaction)

Subgroups: adjusted effect on primary outcome

The treatment odds ratio in each subgroup has been adjusted for the linear effects of the other

key variables

At six months, for every 1000 patients treated with rt-PA

All ages 0-6 hrs

14 more alive and independent (NS)

29 more ‘favourable outcome’ (p=0·018)

Favourable shift in OHS (p=0.001)

No difference in deaths

In patients > 80 years 0-6hrs

38 more alive and independent

In patients all ages < 3hrs

80 more alive and independent

Summary of evidence

• For the types of patient recruited in IST-3, despite the early hazards, thrombolysis within six hours improved functional outcome.

• Benefit did not appear to be diminished among elderly patients.

• Benefit was greatest among those randomised within 3 hours

Acknowledgements:The 3035 patients, the 156 hospitals in the IST-3 group, the Data

Monitoring Committee, the MRC Steering Committee, Image Reading Panel, Event adjudication panel, International Advisory Board.

Funding: Medical Research Council (managed by NIHR on behalf of the MRC-NIHR partnership), Stroke Association, The Health Foundation,, 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 Swiss National Research Foundation, the Swiss Heart Foundation, the 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, a member of the SINAPSE collaboration, 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.