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IST-3 collaborators meeting

IST-3 collaborators meeting. Professor Peter Sandercock University of Edinburgh, UK ISS conference, Capetown, October 2006. Outline. What do we know? Analysis of existing trials of thrombolysis for stroke Overall effects: risks and benefit Subgroups: effect of time & age

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IST-3 collaborators meeting

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  1. IST-3 collaborators meeting Professor Peter Sandercock University of Edinburgh, UK ISS conference, Capetown, October 2006

  2. Outline • What do we know? Analysis of existing trials of thrombolysis for stroke • Overall effects: risks and benefit • Subgroups: effect of time & age • Who is treated? Current use of rt-PA in Europe & USA • Do we need further randomised trials? YES • Randomised trials of IV thrombolysis • IST-3 protocol • Progress with trial • Imaging update

  3. Background

  4. ISIS-2: 17,000 patients with acute MI Percent dead Diff. per Placebo Treated 1000 Streptokinase 12.0% 9.2% 28 Aspirin 11.8% 9.8% 24 P < 0.00001 for both comparisons. NOTE: The 22% reduction in the odds of death observed in ISIS-2 was identical to the estimate of benefit from a meta-analysis of all previous trials

  5. Rapid change in clinical practice. Thrombolysis for MI increased markedly after publication of megatrials in ‘86 & ‘87 Ketley and Woods Lancet 1993: 342: 891-4 GISSI ISIS-2 GISSI AIMS ISIS-2 ASSET

  6. Trials in acute stroke have been far too small “It is still not sufficiently widely appreciated just how large clinical trials need to be to detect reliably the sort of moderate, but important, differences in major outcomes that might exist (especially if effects in different subgroups are to be assessed reliably).” Collins and MacMahon Lancet 2001; 357: 373-380

  7. Randomised trials of thrombolysis vs control in acute myocardial infarction Total no. patients by 1994! 58,600 Randomised trials 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

  8. Previous trials of rt-PA

  9. Review of trials of thrombolysis with rt-PA for acute ischaemic stroke • Risks • Symptomatic cerebral haemorrhage • Death • Benefits • Reduced ‘death or dependency’ • ?reduction in massive cerebral oedema? • Subgroup analyses: effect of • Time to treatment • Age • Risk factors for intracerebral haemorrhage • Appearance of CT scan

  10. rt-PA < 6 hrs RISK: symptomatic intracerebral haemorrhage (SICH) < 3 hours 3 – 6 hours More with control More with rt-PA Cochrane Database of Systematic Reviews 2004

  11. rt-PA < 6hrs RISK: effects on death rt-PA saves lives rt-PA kills Non-significant 16% increase in deaths (95% CI, 6% reduction to 44% increase)

  12. POSSIBLE BENEFIT of rt-PA < 6hrs ? Reduction in symptomatic cerebral oedema

  13. rt-PA <6 hours: BENEFIT = reduction in ‘death or dependency’, despite risk 20% reduction with rt-PA (95% CI 7-23%) BUT thesignificant between- trial heterogeneity (I2=62%) makes result unreliable

  14. Areas of uncertainty

  15. Review of trials of thrombolysis with rt-PA for acute ischaemic stroke • Risks • Symptomatic cerebral haemorrhage • Death • Benefits • Reduced ‘death or dependency’ • ?reduction in massive cerebral oedema? • Subgroup analyses: effect of • Time to treatment • Age • Stroke severity • Risk factors for intracerebral haemorrhage • Appearance of CT scan

  16. rt-PA trials meta-analysis. Benefit declines with increasing time to treatment, but scope for benefit up to 6h (Lancet 2004; 363: 768–74) Benefit Upper and lower 95% confidence limits Line of no effect Harm 3 hours 6 hours

  17. Only a small, variable proportion of patients are treated with rt-PA Country no. no. % treated hospitals patients rt-PA (range) USA 42 1,195 4.1% (0-12%) USA 29 3,948 1.8% (0-10%) USA 137 23,058 1.6% (0-5%) Germany 104 13,440 3.0% (0-18%)

  18. Effect of hospital, age and race, and presence of neurologist on likelihood of receiving thrombolysis for acute ischaemic stroke among 23,058 acute stroke patients from 137 community hospitals in USA • In 35% of hospitals, no patients at all given rt-PA. • Strong trends to LESS rt-PA use: • with increasing age of the patient, • if no neurologist available. Reed et al. Stroke 2001: 32; 1832-44

  19. 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!

  20. 9 am. This 85 year old man suddenly cannot speak and his right arm is weak. At 3hrs, CT confirms it is an ischaemic stroke: should he be treated? does his age affect his response to thrombolysis? ?

  21. Effect of age on benefit from rt-PA • Analysis of major randomised trials of rt-PA for stroke • Adjustment for age did not modify the relation between benefit and time • No subgroup analysis to answer the simple questions: • Does age alter the balance of risk and benefit? • Should there be an upper age limit for treatment? Lancet 2004; 363: 768–74

  22. Effect of stroke severity (NIHSS) on good outcome with rt-PA 10 2.6 2.5 2.1 2.1 1.9 1.2 Log (OR) good outcome 1 0.1 0-5 6-10 11-15 16-20 > 20 All Patients Baseline NIHSS Score Test for equal OR’s: Chi-square (4 DF) = 1.70; p = 0.79 No evidence of difference in treatment benefit of rt-PA across the five NIHSS severity groups Ingall et al Stroke. 2004;35:2418-2424.

  23. Effect of age on risk? (NINDS trial): factors which predict intracerebral haemorrhage • Baseline NIHSS > 20 • Age > 70 years • Ischaemic changes present on initial CT • Glucose > 16.7 mmol/L Ingall et al Stroke. 2004;35:2418-2424.

  24. Outcome by no. of SICH risk factors, adjusted for co-variates 10 2.6 1.9 1.4 Log (OR) 1 0.1 0 1 >=2 Number of SICH Risk Factors Test for equal OR’s: Chi-square (2 DF) = 1.77; p = 0.41 = no evidence of a difference in risk of SICH in these three groups

  25. NINDS conclusions on SICH. Subgroup analyses suggested that some clinical characteristics were related to the occurrence of SICH However, after adjustment, the differences between subgroups were not statistically significant. Cannot predict reliably who will develop SICH Ingall et al Stroke. 2004;35:2418-2424.

  26. Early ischaemia signs on CT Hypodensity : loss of grey/white differentiation, loss of the lentiform nucleus Swelling : effacement of sulci, compression of ventricle 24 hours 4 hours

  27. ‘Early ischaemia’ signs on CT: effect on response to rt-PA • Two randomised trials, 1,926 patients. • No evidence that ‘early infarct sign’ significantly modifies effect of thrombolysis • But analysis has insufficient statistical power – need larger trials Wardlaw et al, Radiology 2005: 235: 444

  28. What is known: summary • Limited rt-PA trial data (2,100 patients) • Very limited data of effects in older people • Effects on death unclear • ‘Time is brain’; early treatment is best • Clear ~3% risk of fatal brain haemorrhage • Despite risk, potential for net benefit for selected patients up to 6hrs.

  29. Current use of rt-PA in clinical practice

  30. Current rt-PA approval for use in routine clinical practice • 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

  31. Variation in use of rt-PA for acute ischaemic stroke ‘within licence’ in Europe SITS register (2003-5) March 2005

  32. We need further large trials to: • Determine reliably: • whether there are patients outside strict criteria of current approval who benefit < 3hrs • which type of patients benefit 3-6 hours • Balance of risk and benefit in older patients • Contribute further evidence to: • persuade doubting clinicians to change practice • reduce inequalities in patient access to treatment • persuade health authorities to fund: • cost of drug treatment • a well-organised acute stroke service in every acute hospital

  33. Current small scale randomised trials of i.v. thrombolysis

  34. Third International Stroke Trial. A large randomised trial to answer the question: can a wider variety of patients be treated? Target: 6000 patients from 300 centres in 36 Countries

  35. Main features of IST - 3 • International, multi-centre, Prospective, Randomised, Open, Blinded Endpoints study of i.v. rt-PA vs control. Independent. Investigator-led • Primary outcome: the proportion of patients alive and independent at six months (Modified Rankin 0,1 or 2) • Randomisation by telephone or internet with on-line minimisation to balance key prognostic factors. • Blinded central review of all scans

  36. Recruitment Recruitment at 28.10.06: 648 patients from 65 centres in 9 countries.

  37. Recruitment by country

  38. In process Czech Republic Hungary India Mexico Portugal Seeking to join Argentina Belarus Brazil Chile South Africa Switzerland Taiwan Thailand Ukraine Countries in process of joining/seeking to join trial

  39. 192 patients aged > 80 = increased world evidence base 5 x! 120 patients aged over 80

  40. Median = 4.1 hours

  41. Report of the IST 3 Data Monitoring Committee The Data Monitoring Committee for the IST-3 trial reviewed the interim outcome data on 26 September 2006, and had no safety concerns. We would encourage all collaborators to support this important trial and the study organisers to explore all appropriate ways to achieve the required rate of recruitment as rapidly as possible. Professor Rory Collins, Chairman

  42. Summary • IST-3 is obtaining very important data about thrombolysis, outside the current licence • It has already increased the world randomised evidence base on the effect of rt-PA in patients aged > 80, by 5 times! • It is encouraging new centres to use thrombolysis in a randomised trial • Closely monitored • Adds to the randomised evidence • It will provide uniquely useful data on the impact of clinical and CT findings on response to rt-PA

  43. Persisting hyperdense artery sign, ASPECTS score and risk of developing mass effect: an analysis based on the first 389 patients from the IST-3 Trial. Kobayashi A,1,2 Skowronska M1,2, Bembenek J3, Sandercock P4, Kane I4, Czlonkowska A1,2, Lewis S4, Wardlaw J4, for the IST-3 Collaborative Group 1 Medical Univerity of Warsaw, Poland, 2 Institute of Psychiatry and Neurology, Warsaw, Poland, 3 Wolski Hospital, Warsaw, Poland, 4 University of Edinburgh, United Kingdom

  44. Background • In patients with acute ischaemic stroke, the hyperdense artery sign is a marker of fresh thrombus occluding the vessel • The hyperdense artery sign • is associated with greater stroke severity • can disappear with reperfusion, • can persist if the artery remains occluded • If persistent, may predict infarct swelling • No evidence that hyperdense artery on baseline CT influenced response to rt-PA in NINDS trial

  45. Hyperdense artery

  46. Aims of this analysis • In patients randomised in IST3, to assess how often the hyperdense artery sign: • is seen on baseline CT scan • disappears by the time of second scan • is associated with ‘early ischaemic change’ and mass effect on baseline and follow-up CT • Assess associations with a persistent hyperdense artery

  47. IST-3 image assessment protocol • Design: • randomised controlled trial of rt-PA vs control in 6000 patients with acute ischaemic stroke < 6 hrs of onset • Eligibility for the trial • No clear indication for, or contraindication to, thrombolysis with iv rt-PA. • CT scan • Before randomisation (MR permitted) • Repeat CT at 24-48 hrs after randomisation • All scans read centrally • blinded to clinical details, treatment allocation, and later events • Detailed assessment of • site, size, location of early ischaemic change & swelling • ASPECTS score • presence of of hyperdense artery • haemorrhage, non stroke lesions etc.

  48. Scale to assess swelling and mass effect Wardlaw AJNR 1994

  49. ASPECTS Score Each of 10 MCA territory regions scored normal/ abnormal for hypodensity , and total no. abnormal areas subtracted from 10, so most extensive visible MCA ischaemia score = 0 (worst), no visible ischaemic change = 10 (best)

  50. Material and methods • We included in this analysis data from all patients randomised, for whom we had on 15.12.05: • Digitised copies of baseline and follow-up CT * (we excluded patients with MR as baseline scan, or who had no follow-up CT) • The (blinded) assessment by the expert central reader of both scans entered in database • Analyses presented are based on the 389 patients who met these criteria

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