IST-3: What are the implications for rt-PA therapy?

Peter SandercockUniversity of Edinburgh

on behalf of the IST-3 collaborative group

ESC Lisbon

23rd May 2012

Disclaimer & disclosures• I will present relevant data from current research

and there may be data or statements not covered by current regulatory approval. This presentation does not suggest clinical use beyond regulatory approval.

• Please always check the most current prescribing information as approved for your country.

• IST-3 was conducted completely independently. BI donated drug and placebo for the first 300 patients in IST-3 and thereafter made no financial contribution, & had no role in data collection, analysis, reporting or the decision to publish.

• IST-3 disclosures in full in Lancet publication

Baseline characteristics1 (n=3035)• 849 (28%) randomised < 3 hours • 1617 (53%) aged > 80 years • 1305 (43%) TACI syndrome• 970 (32%) baseline NIHSS > 16 • 914 (30%) in AF • 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

Time to randomisation and age

0

200

400

600

800

1000

1200

1400

0-3 3-4.5 4.5-6

Time to randomisation (hrs)

Num

ber

<80 yrs>80 yrs

Stroke severity: 970 (32%) NIHSS > 16

0100200300400500600700800900

0 to 5 6 to 10 11 to 15 16 to 20 21 to 35

NIHSS

Num

ber

rt-PA(n=1515)

Control(n=1520)

n (%) n (%)104 (7%) 16 (1%)

Safety: 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

Overall - all patients 0-6 hrs: ‘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

Overall: 6 month OHS

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

Ordinal will be more statistically efficient than primary outcome for subgroup analysis

Focus on early treatmentTime (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: ‘alive and independent’

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 hrs14 more alive and independent (NS)29 more ‘favourable outcome’ (p=0·018) Favourable shift in OHS (p=0.001)No difference in deathsIn patients > 80 years 0-6hrs38 more alive and independentIn patients all ages < 3hrs80 more alive and independent

Stroke 2012; 43; May 3 (online)

One thing that the IST-3 results cannot do is reaffirm or refute

prior trials of thrombolytic therapy…

IST-3 does affirm the benefits of Early treatment < 3hrs

Effect on ‘alive and independent’ (OHS/mRS 0-2) among patients < 3hrs

Implications for practice. IST-3 enables clinicians to:

• Consider thrombolytic treatment for a wider variety of patients, – Particularly those aged over 80 years– With more severe strokes

• Reinforce their efforts to increase the proportion of ischaemic strokes treated < 3 hours

• Have greater confidence that mortality is not increased by treatment

Implications for research• The data strengthen the rationale for the

ongoing trials of thrombolysis among patients presenting more than 4.5 hours after onset

• Need for the planned STTC individual patient data meta-analysis to determine which characteristics (other than age & time) identify who is most likely to benefit

• The imposition of upper age limits on future trials in acute stroke will become harder to justify.

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.

Follow-up at 6 monthsStatus at six months

rt-PA(n=1515)

Placebo(n=1520)

Not known dead/alive 11 13

Alive, disability imputed 31 41

Known disability status 1473 1466

No· for analysis (OHS known or imputed)

1515 1520

Vital status known for 3011/3035 = 99.2%

Kaplan-Meier survival

rt-PAControl