The need for trials of i.v. thrombolysis in acute

ischaemic stroke10th January 2008.

Acute stroke & TIA management

• Stroke & TIA = emergencies: ‘Time is brain’• Well-organised acute stroke & TIA system

– Pre-hospital triage. Stroke? -> 999 ambulance– skilled clinical assessment – Re-triage in A&E -> stroke -> admit SU & ?thrombolyse,

TIA -> same-day neurovascular OP1

– immediate CT scan2

• Admit to comprehensive care Stroke Unit – acute care with physiological monitoring – protocols for management of complications– multidisciplinary rehabilitation from day 1 – care until discharge

1. Rothwell EXPRESS Lancet 2007; 2.Wardlaw, Stroke. 2004;35:2477-2483

Current clinical practice

Who should get thrombolysis with i.v. rt-PA?

• 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

Only a small, variable proportion of patients get rt-PA in USA, Germany

Author no. no. % treated hospitals patients rt-PA (range)

USAJohnstone 42 1,195 4.1% (0-12%) Furlan 29 3,948 1.8% (0-10%) Reed 137 23,058 1.6% (0-5%)

GermanyHeuschmann 104 13,440 3.0% (0-18%)

Variation in use of rt-PA for acute ischaemic stroke ‘within licence’ in Europe

recorded in SITS-MOST registry 2007

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FinlandSwedenAustriaNorwayCzech RepublicSloveniaBelgiumDenmarkSpainIcelandGermanyPortugalItalySlovakiaAustraliaNetherlandsUnited KingdomLithuaniaPolandFranceGreeceCroatiaHungaryRussia

SITS register November 2005 SITS-MOST 29/1/2007

Evidence

Randomised trials of thrombolysis vs control in acute myocardial infarction

Total no. patients by 1994! 58,600

Randomised trials of thrombolysis vs control in acute ischaemic stroke

Total (all agents) 5,675

rt-PA 2,700

rt-PA < 3hrs 930

rt-PA aged > 80 years 42

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?

‘Grey areas’ of uncertainty: 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 controlled trials of i.v. thrombolysis

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

IST-3

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

can a wider variety of patients be treated?

Target: up to 6000 patients from > 100 centres in 14 Countries

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 or web 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.

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

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

Progress to date

IST3: Cumulative number of patients randomised

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Randomisation Date

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Recruitment = 1028 patients randomised by 11.1.08.

Recruitment by country (07/01/08)

Country No. centres Pts. %

UK 34 395 38%

Poland 5 172 18%

Norway 12 127 13%

Italy 14 92 9%

Sweden

Australia

Belgium

14

10

3

82

78

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7%

7%

6%

Austria

Canada

Mexico

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1%

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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

Has the ‘grey area’ 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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(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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51-60 61-70 71-80 81-90 91-100 Over100

Age in years at randomisation

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

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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

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

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%)

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.

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

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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

With 3100, we could detect a 4.7%

benefit = NNT 21

New plan: recruit 3,100 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!