Thrombolysis for acute ischaemic stroke 1: why do we still need to

do randomised trials & IST3?

Professor Peter SandercockOn behalf of IST-3 Collaborative Group

and for Gruppo Italiano IST-3University of Edinburgh

Who SHOULD get thrombolysis with i.v. rt-PA ‘within licence’?

• Patient MUST be– able to be treated within 3 hours– aged under 80– not have a history of prior stroke + Diabetes– not have any of the standard exclusions– NIHSS < 25– No extensive infarction on CT

• There must be a discussion of risk/consent

Who ACTUALLY gets rt-PA for acute ischaemic stroke ‘within licence’ in Europe?

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rt-P

A f

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FinlandSwedenAustriaNorwayCzech RepublicSloveniaBelgiumDenmarkSpainIcelandGermanyPortugalItalySlovakiaAustraliaNetherlandsUnited KingdomLithuaniaPolandFranceGreeceCroatiaHungaryRussia

SITS-MOST 29/1/2007

Why so much variability in clinical practice?

• Insufficient evidence base

• Licence does not apply to older people

• What to do after 3 hours?

• How to balance risk and benefit?

• No consensus on imaging– Which method: CT or MR?– How should CT or MR appearance influence

decision about thrombolysis?

Compare evidence base! Number of pts in randomised trials of thrombolysis vs control

in acute myocardial infarction

Total no. patients by 1994! 58,600

in acute ischaemic stroke

Total (all agents) 5,675

rt-PA 2,700

rt-PA < 3hrs 930

rt-PA aged > 80 years 42

Number of older patients with acute stroke per year

in UK

87,000 patients aged > 70 years

47,000 patients aged > 80 years

= A big problem for acute medical services!

rt-PA trials meta-analysis. Benefit declines with increasing time to treatment, but scope

for benefit up to 6h?

Benefit

Harm

3 hours 6 hours

Upper and lower 95% confidence limits

Line of no effect

NNT 10 ‘Grey area’NNT 10? > 30? or net

harm?

Risk of treatment: fatal haemorrhage 3%

Risk of NOT treating with rt-PA? Fatal deterioration due to swelling in large infarcts.

CT at 5hrs CT at 72 hrsEarly ischaemic change Swelling and midline shift

‘Area Grigia’ di incertezza: i.v. rt-PA promising but

unproven for patients who:• Present < 3hrs & do not exactly meet NINDS

criteria

• All patients 3-6hours

• Older patients (>75 years)

• Severe stroke, mild stroke…...

• Have subtle, early ischaemic change on CT

• Etc etc …

Current randomised trials of i.v. thrombolysis vs control

Trial Thrombolytic agent

Patient selection trial size & time window

EPITHET rt-PA Clinical, CT (+ DWI/PWI MRI) 3-6 hours 100 patients Results 2008

ECASS III rt-PA Clinical and CT; Age < 80 Stroke onset 3-4.5 hours 800 patients Results mid 2008

IST-3 rt-PA Clinical and CT; Ischaemic stroke 0-6 hours Up to 6000 patients

Thrombolysis for acute ischaemic stroke 2: progress with the trial. Where are we now, what is our

target?

Professor Peter SandercockOn behalf of IST-3 Collaborative Group

and for Gruppo Italiano IST-3University of Edinburgh

Main features of IST - 3

• International, multi-centre, Prospective, Randomised, Open, Blinded Endpoints study of i.v. rt-PA vs control.

• Primary outcome: the proportion of patients alive and independent at six months

• Simple central telephone randomisation with on-line minimisation to balance key prognostic factors.

• Web-based blinded detailed central review of all scans (ASPECTS, 1/3 MCA rule, dense MCA etc)

• Conducted to EU GCP standards.

IST-3 trial: randomisation

If patient fits main eligibility/exclusion criteria,

Clinician/patient/family discuss. If:

• 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

Recruitment by country: coppa del mondo

Country No. centres Pts. %

UK 34 377 38%

Poland 5 172 18%

Norway 12 125 13%

Italy 14 91 9%

Sweden

Australia

Belgium

14

10

3

73

69

56

7%

7%

6%

Austria

Canada

Mexico

1

1

1

8

5

1

1%

1%

-

Gruppo Italiano IST-3 : 2006Serie A (>5 patients)

Milano Ciccone 23

Citta Della Pieve Ricci 17

Aosta Botacchi 6

Serie B (<5 patients)

Citta di Castello Cenciarelli 2

Perugia, Silvestrini Agnelli 1

Gubbio Bigaroni 1

Foligno Brustengi 0

Negrar Adami 0

Vittoria Iemolo 0

Gruppo Italiano IST-3 : 2007

Serie A (>5 patients)Citta Della Pieve*

Niguarda, Milano

Aosta

27

25

13

Citta di Castello

Vibo Valentia*

5

5

Serie B (<5 patients)Foligno 4

Sacro Cuore Negrar Verona

Vittoria

Spoleto

Perugia, Silvestrini

4

3

2

1

Gubbio

Piacenza

1

1

*recruited a patient within last 30 days

Centri che stanno per partire

• Genova

• Modena

• Foggia

• Legnango

• Peschiera

• Verona

• Bologna

• Reggio Emilia

• Bari

Has the ‘area grigia’ changed since IST-3 began?

Characteristics of patients at baseline

Delay between stroke onset and randomisation

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1 or less 1 to 2 2 to 3 3 to 4 4 to 5 >5Hours between stroke onset and randomisation

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f pat

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.

(Median = 4.1 hours)

0%10%20%30%40%50%60%70%80%90%

100%

1st 224 2nd 224 3rd 224 4th 224

0-3 hrs

3.1-6 hrs

Trends in type of patient recruited since trial began: Time to randomisation

No. patients recruited into trial

Age at randomisation

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50 orunder

51-60 61-70 71-80 81-90 91-100 Over100

Age in years at randomisation

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atie

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Age at randomisation > 330 patients aged > 80 = increased world evidence base 8 x!

0%

10%20%

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100%

1st 224 2nd 224` 3rd 224 4th 224

> 80 years

< 80 years

Trends in type of patient recruited since trial began: age

No. patients recruited into trial

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100%

1st 224 2nd 224` 3rd 224 4th 224

POCI

LACI

PACI

TACI

No. patients recruited into trial

Trends in type of patient recruited since trial began: Infarct subtype

Expert’s opinion of randomisation CT*

• Acute ischaemic change 64%

• Periventricular lucencies 44%

• Normal 6%

*scans may show more than one abnormality

Frequency of hyperdense artery on baseline and follow-up CT

Present on baseline scan 152 (39%)

Present on follow-up scan 102 (26%)

Persisted (seen on 1st & 2nd scan) 88 (23%)

Present on baseline, disappeared by 2nd scan 64 (16%)

Has the ‘area grigia’ changed since IST- began?

NO

2007 report of the IST 3 Data Monitoring Committee

We reviewed analyses based on 896 randomised patients. We should like to commend the investigators for the high quality and completeness of the data, as well as the exemplary conduct of the trial. The DMC did not consider it necessary to recommend any change to the study protocol… we would encourage the investigators to make every effort to recruit all eligible patients so that reliable evidence emerges as rapidly as possible.

Professor Rory Collins, Chairman

Recruitment strategy: the future

• Focus efforts on countries already in trial

• Increase number of centres in these countries

• Work with existing centres to maintain or increase recruitment.

Recruitment strategy: the future. In Italy this means:

• Can your centre recruit enough so you move up (or you can join) Serie A in Gruppo Italiano IST-3?

• Can Italy move up in the coppa del mondo IST-3?

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1 Oct 07: active centres

31 Dec 08: active centres

1 Oct 07: total centres

31 Dec 08: total centres

Projected total number of centres, and number of active centres

Sample size (MRC Protocol)

• with 1000 patients we 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.

• If 3500 patients were recruited, the trial could detect a 4% absolute difference in the primary outcome.

• With 6000 patients, mostly treated between 3 & 6 hours of onset, the trial could detect a 3% absolute difference in the primary outcome

Protocol version 1.92 September 2005

Recruitment IST3: Cumulative number of patients randomised

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Recruitment = 982 patients randomised by 30.11.07. Almost reached 1st target!

Hot news!

• We applied to MRC to extend trial to reach one of our targets

• UK Medical Research Council– Recognised the importance of the trial – agreed to this plan – given extra funds (~ €500,000),

• IST-3 can continue recruitment to mid 2011and report trial in 2012 if needed

Sample size (MRC Protocol)

• with 1000 patients we 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.

• If 3500 patients were recruited, the trial could detect a 4% absolute difference in the primary outcome.

• With 6000 patients, mostly treated between 3 & 6 hours of onset, the trial could detect a 3% absolute difference in the primary outcome

Protocol version 1.92 September 2005

With 3100, we could detect a 4.7%

benefit. NNT 21

New plan: recruit 3,100 by 2011

Third International Stroke Trial. A large randomised trial to answer the question:

can a wider variety of patients be treated?

Target: 3100 patients or more from ~ 100 centres in 14 Countries by 2011

Conclusions

• IST-3 asks very important questions– Who benefits?– By how much?– How to make best use of CT to select patients?

• It is the LAST CHANCE to get these data• We MUST go on• The approval by MRC = recognition of the

scientific importance of our work• Our data will influence clinical practice in the

REAL world!