Update on IST-3 and other trials. Or, ‘how the ECASS-3 results have

helped re-launch IST-3!’

Professor Peter Sandercock, Co-chief investigator

IST-3 collaborator’s webcast10th November 2008

(recruitment data updated post webcast)Note: please feel free to use these slides in presentations and for discussions with colleagues, but please do not cite these data in

publications without prior permission of the Trial management Group

IST-3 funding agencies

OutlineWhat do we know now? • Updated Cochrane Review of all trials• Current usage in clinical practice• Remaining questionsIST-3• Progress with recruitment• Data Monitoring Committee reports• Key messages from Steering Committee• Publications

Cochrane Systematic Review of Thrombolysis Trials

• All randomised controlled trials of any thrombolytic drug versus control

• 2003 version included 18 trials (no. patients =5675)

• Drugs: rt-PA, streptokinase, uro-kinase, rPro-urokinase,

• Time windows: 0-3, 0-6 hrs

• Brain Imaging : CT

• Age over 80 : 42 patientsJM Wardlaw, V Murray (in preparation)

New trials included in 2008 update

• 8 new trials (n=+1477, total: n=7152)

• Drugs: 3 rt-PA; 2 UK; 3 desmoteplase

• Route: 2 intra-arterial, 6 intravenous

• Time windows: 0-6, 3-4.5, 3-9, 0-24 hrs

• Imaging pre randomisation:– CT: 5 – MR: 3 (+1) DWI/PWI mismatch

• Age over 80: ≈42

JM Wardlaw, V Murray (in preparation)

ECASS 3Inclusion:• 3-4.5 hours Age 18-80 yrs

Excluded : • NIHSS>25 or CT infarct signs >1/3MCA• diabetes and prior stroke• stroke in previous 3 months,etc,etc

Outcomes:

Good functional outcome: mRS 0-1 vs 2-6

Baseline

Imbalance in age, NIHSS, prior stroke, DM (all in favour of rt-PA)

IV urokinase

IV streptokinase

IV rt-PA

IV streptokinase+ aspirin

IA pro-urokinase

IA urokinase

IV desmoteplase

Death or dependency at the end of follow-up

Total

0.91 (0.64, 1.42)

0.94 (0.72, 1.24)

0.77 (0.47, 0.89)

1.09 (0.49, 1.72)

0.55 (0.31, 1.00)

0.57 (0.28, 1.14)

0.85 (0.53, 1.38)

0.82 (0.73, 0.91)

Effect of rt-PA on death or dependency

Study or Subgroup

Mori 1992ECASS 1995NINDS 1995ECASS II 1998ATLANTIS B 1999ATLANTIS A 2000Wang 2003ECASS III 2008EPITHET 2008

Total (95% CI)

Total eventsHeterogeneity: Chi² = 21.09, df = 8 (P = 0.007); I² = 62%Test for overall effect: Z = 3.79 (P = 0.0002)

Events

111711551871416429

14029

927

Total

193133124093077167

41851

1967

Events

101851922111355626

15529

999

Total

123073123913067133

40349

1884

Weight

0.7%16.5%16.8%21.8%16.5%2.0%2.4%

20.6%2.7%

100.0%

Peto, Fixed, 95% CI

0.32 [0.07, 1.48]0.79 [0.58, 1.09]0.62 [0.45, 0.85]0.72 [0.55, 0.95]1.08 [0.78, 1.48]2.35 [0.95, 5.82]0.24 [0.10, 0.56]0.81 [0.61, 1.07]0.91 [0.41, 2.01]

0.78 [0.68, 0.89]

Year

199219951995199819992000200320082008

tPA Control Peto Odds Ratio Peto Odds RatioPeto, Fixed, 95% CI

0.01 0.1 1 10 100Favours tPA Favours control

rt-PA trials: 2003 versus 2008 Odds Ratios and 95% CI

SICH Late Death or (incl fatal) Death Dependency

2003 3.1 1.2 * 0.8 * n=2955 2.3 - 4.2 0.9 - 1.5 0.7 - 0.9

p<0.00001 p=0.14 p=0.003

2008 3.1 1.1 0.8 *n=3977 2.3 - 4.0 1.0 - 1.4 0.7 - 0.9

p<0.00001 p=0.16 p<0.0001

* significant heterogeneity confounds interpretation

rt-PA trials: 2008. Absolute effects (no. Events avoided /caused per 1000 treated, 95% CI)

all 0-3 hrs 3-6 hrs

SICH 60 70 60 50, 80 40, 100 50, 80

Death 10 0 2010, 40 50, 50 0, 50

Death or 60 110 40Depend. 100, 30 170, 50 80, 10

X = events avoided (benefit) X = events caused (harm)

Update 2008 conclusions, • Heterogeneity still confounds interpretation• Potential for benefit to at least six hours• Limited new knowledge on latest time windows.• Almost complete lack of randomised evidence

on effects in– older patients; – concomitant antithrombotic use; – stroke severity/subtype, – diabetes

• Outcome following selection on MR mismatch not apparently different to CT.

• No material change in main outcomes since 2003.

Estimated % of all ischaemic strokes treated with thrombolysis

• USA: 1-7%1 • Canada 3%2

• Germany 3%3

• Sweden 5.5%4

1. Cocho et al.,Qureshi et al., 2.Kapral et al,3. Heuschmann et al, 4. (http://www.riks-stroke.org).

How many stroke patients per year in UK* might avoid being ‘dead or dependent’ with

each treatment?

  % treated with this

intervention

Number treated per

year

Benefit per 1000

treated

Number who avoid death or dependency

Aspirin 80% 104000 13 1350

Stroke Unit 60% 78000 56 4370

Thrombolysis 2% 2080 63 163

Thrombolysis 30% 31200 47 1470*130,000 strokes per year

Even if the EU approval for thrombolysis is extended to 4.5 hrs, this will still exclude patients who

• Are aged > 80 years

• Either ‘very mild stroke’ or NIHSS > 25

• Prior stroke within the last 3 months

• Have a history of prior stroke + Diabetes

• Arrive at 4.5 to 6.0 hours

• Other relative contraindications specified in the licence (e.g. ‘extensive infarction’, which is not defined in any way)

Stroke patients > 80 years

• Patients over 80 have been excluded from randomised trials and the licence

• In the UK 30% of all strokes are aged > 80 = 31,000 ischaemic stroke patients each year automatically excluded from thrombolysis

Severe stroke (NIHSS > 25)

• This man had a large MCA infarct

• NIHSS > 25,

• rt-PA not approved for him

• He spent many months in hospital

• He was very disabled

• He was no longer able to care for his wife

Mild, or rapidly improving strokes (NIHSS < 4)

• 2 hours ago, this man developed right hemiparesis, now rapidly improving.

• NIHSS < 4, so rt-PA not approved

• Many such patients recover without rt-PA,

• BUT 15-30% later deteriorate suddenly -> disabling stroke

• Should we treat them to prevent deterioration?

Vertebro-basilar territory ischaemic strokes

• Acute cerebellar infarct

• Excluded from previous trials of iv rt-PA

• Time window for treatment unclear

• Is there benefit from iv thrombolysis for such patients?

‘Extensive infarction’• Does this patient

have ‘extensive infarction?’

• Not defined in EU approval

• Much debate about definition

• Should this patient be excluded from thrombolysis?

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

can a wider variety of patients be treated?

Target: up to 3100 patients from > 100 centres in 12 Countries by mid 2011

IST 3 Sample size• 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 3100 patients were recruited, the trial could detect a 4.7% absolute difference in the primary outcome. (remarkably close to the 4% difference seen in the updated Cochrane review)

• 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 by 31 March 2008 = 1104

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Recruitment by 10.11.2008 = 1343 patients

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46 patients in past month = increased

recruitment rate after ECASS-3 results

released!

ECASS-3results

Projected numbers of patients by mid 2011

MRC target = 3100

At 46 per month = 2806

If we can recruit an extra 9 patients per

month, we’ll reach our target!

Recruitment by country in IST-3Country No. centres Pts. %

UK 44 534 40%

Poland 5 197 15%

Norway 13 151 12%

Sweden 14 137 10%

Italy 20 124 9%

Australia 10 107 8%

Belgium 3 61 5%

Austria 2 17 1%

Canada 1 8 1%

Mexico 1 3 0%

Portugal 3 3 0%

Total 119 1343  

Analyses of data on the 1281 patients recruited by 24.9.2008

Type of patient recruited

• Age: IST-3 largest randomised controlled trial in ‘older’ hyper-acute stroke – 893 patients > 70 years, – 564 patients > 80 years.

• Severity & subtype: – Wide range of severity– Subtypes not much recruited in previous trials:

153 Lacunar infarcts

77 Posterior circulation infarcts

Age and time to randomisation

stroke onset to randomisation

(hrs)< 80 years >80 Years

0-3 89 (12%) 186 (33%)

3-4.5 323 (45%) 249 (44%)

>4.5 305 (43%) 129 (23%)

Age

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

100%

1st 320 2nd 320 3rd 320 4th 322

POCI

LACI

PACI

TACI

No. patients recruited into trial

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

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

100%

1st 320 2nd 320 3rd 320 4th322

0 - 3 hrs

3 - 4.5 hrs

4.5 - 6 hrs

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

No. patients recruited into trial

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Randomisation quarter and year

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>80, 4.5-6

>80, 3-4.5

>80, 0-3

<80, 4.5-6

<80, 3-4.5

<80, 0-3

Type of patient recruited in main phase

Perfusion imaging in IST3• The trial imaging system can store and analyse CT

and MR perfusion data from patients recruited in IST-3

• We have been collecting these perfusion data • If you have CT or MR perfusion and angiography

data on your IST-3 patients, please send the data with the routine plain (non-contrast) images to the trial office.

• IST-3 will be able to add greatly to the evidence base on perfusion/diffusion mismatch and response to rt-PA.

Impact of ECASS-3 on IST-3• No evidence of a decline in IST-3 recruitment

since results released, in fact recruitment has increased from ~30/month to 44 in the past month!

• Recruitment of patients < 80 yrs, 3-4.5 hrs with NIHSS < 25 is only 15% of those recruited since ECASS-3 published

• Many centres will be assessing more patients for thrombolysis up to 4.5 now, and so more may be considered for entry in IST-3

Data Monitoring Committee and MRC Steering Committee

• Data Monitoring Committee (DMC) meeting 23rd September, rapid review of ECASS3 data, updated Cochrane review, and IST3 data to inform discussions at collaborators meeting 26th Sept, Vienna

• Full DMC meeting 30th October to consider above data in detail

• MRC trial Steering Committee: review of progress of trial and plans for future

Letter from IST-3 Data Monitoring Committee 23rd September

• Dear Peter• In preparation for the release of the ECASS-III results (and

blind to those results), the IST-3 Data Monitoring Committee had arranged a teleconference for today (23 September 2008). Our review of the available data from IST-3 and the other trials, including safety information from ECASS-III, does not lead us to consider there to be any need for a change to IST-3. We would encourage the IST-3 collaborators to maintain the increase in the rate of recruitment. The DMC will continue to monitor interim results from IST-3 as planned.

• Yours sincerely

• Professor Rory Collins• Chair, IST-3 DMC

Letter from IST-3 Data Monitoring Committee 3rd November

The IST-3 Data Monitoring Committee held its scheduled interim review of the unblinded data from IST-3 on 30 October 2008. Based on our review of these data, as well as the safety and efficacy data from the other trials of tPA in acute stroke (including recently reported ECASS-III among patients treated 3 and 4.5 hours after symptom onset), the DMC concluded there was no need for any change to IST-3. We would encourage the IST-3 collaborators to maintain the increase in the rate of recruitment, and in particular, to consider all eligible patients for randomisation (irrespective of the presenting time from symptom onset).

Professor Rory Collins Chair, IST-3 DMC

Summary• Current EU approval is very strict and

permits treatment of only small numbers of patients; public health impact is small

• ECASS3 results help widen the time window a bit, but will not increase randomised evidence of effects in older people, or the many other categories excluded from treatment by EU approval

• If IST-3 results confirm benefits in a wider range, more could be treated and public health impact greatly increased

Key Messages from Professor Colin Baigent, Chairman of IST-3 Steering Committee

• There are encouraging signs that recruitment in IST-3 is continuing to accelerate, reflecting encouragement from the results of ECASS-3

• This increased rate is likely to be maintained, since new centres continue to join the trial

• The revised target of 3100 by mid 2011 now appears eminently feasible

• The Steering Committee was reassured and encouraged by the very positive report from the DMC

IST-3 Papers in peer-reviewed journals 2007/8

1. Wardlaw JM, Bath P, Sandercock P, Perry D, Palmer J, Watson G, Lloyd S, Geddes J, Farrall A. The NeuroGrid stroke exemplar clinical trial protocol. International Journal of Stroke. 2007;2:63-9

2. Sandercock P, Lindley R, Wardlaw J, Dennis M, Lewis S, Venables G, et al. The Third International Stroke Trial (IST) of thrombolysis for acute ischaemic stroke.. Trials 2008;9(37) http://www.trialsjournal.com/content/9/1/37

3. SCOPE (Stroke Complications and Outcomes Prediction Engine) Collaborations and IST. Predicting outcome in hyper-acute stroke: validation of a prognostic model in the Third International Stroke Trial (IST3).. Journal of Neurology Neurosurgery and Psychiatry 2008;79:397-400

4. Adam Kobayashi, et al, on behalf of the IST-3 Collaborative Group. Oxfordshire Community Stroke Project clinical stroke syndrome and appearances of tissue and vascular lesions on pre-treatment CT in hyperacute ischaemic stroke among the first 510 patients in the Third International Stroke Trial (IST-3). Stroke (in Press)