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UPDATE ON THROMBOLYTIC THERAPY

UPDATE ON THROMBOLYTIC THERAPY. Markku Kaste Department of Neurology Helsinki University Central Hospital (HUCH) University of Helsinki. Topics of my presentation. The pooled analysis of ATLANTIS, ECASS and NINDS trials Cochrane systematic review Thrombolysis in clinical practice at HUCH

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UPDATE ON THROMBOLYTIC THERAPY

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  1. UPDATE ON THROMBOLYTIC THERAPY Markku Kaste Department of Neurology Helsinki University Central Hospital (HUCH) University of Helsinki

  2. Topics of my presentation • The pooled analysis of ATLANTIS, ECASS and NINDS trials • Cochrane systematic review • Thrombolysis in clinical practice at HUCH • Graham´s meta-analysis of 12 open series • Ongoing trials • New trials - SITS-MOST - ECASS III

  3. IS THERE BENEFIT AFTER 3 HOURS? A Pooled Analysis of the ATLANTIS, ECASS, and NINDS rtPA Stroke Trials The ATLANTIS, ECASS, and NINDS Study Group Investigators

  4. Rationale • Quicker administration of IV rtPA improved outcomes in prior individual trials • We hypothesized that combined analysis of those trials would confirm a stroke-onset-to-treatment time effect • We hypothesized that a pooled analysis could suggest whether thrombolysis is beneficial after 3 hours?

  5. Methods • Original individual patient data were pooled from 6 randomized controlled trials • Method differs from meta-analysis where individual patient data are not generally available and limited adjustment for co-variates is possible

  6. Results I • 2776 patients • Over 300 hospitals • 18 countries • Median age 68 years • Median baseline NIHSSS 12

  7. Global Outcome (mRS 0-1, BI 95-100, NIHH 0-1) at Day 90 Adjusted odds ratio with 95% confidence interval by stroke onset to treatment time (OTT) ITT population (N=2776)

  8. Results III Odds Ratios for Favorable Outcome TimeOdds Ratio95% Conf. Interval 0-90 2.8 1.8 - 4.5 91-180 1.5 1.1 - 2.1 181-270 1.4 1.1 - 1.9 271-360 1.2 0.9 - 1.5

  9. mRS 5-6 at Day 90Adjusted odds ratio with 95% confidence interval by stroke onset to treatment time (OTT) ITT population (N=2776) All Studies ECASS 2

  10. ECASS 23-4.5 hour population

  11. Results V • PH2 occurred in 5.8% of rtPA-treated patients compared to 1.1% of placebo-treated patients (p<.01), median age 72 • PH2 was not associated with onset-to-treatment time • PH2 was associated with rtPA treatment (p=.0001) and age (p=.0002)

  12. Conclusions I • The quicker rtPA is given to stroke patients, the greater the benefit

  13. Conclusions II • Individual studies designed to detect benefit from IV rtPA initiated beyond 3 hours have been negative; our results suggest they were underpowered • This pooled analysis suggests a potential for treatment benefit beyond 3 hours • A randomized trial is needed to find out whether thrombolysis from 3 to 4 or 4.5 hours improves the outcome of stroke patients

  14. COCHRANE SYSTEMATIC REVIEW Joanna Wardlaw Department of Neurology University of Edinburgh

  15. rt-PA : other drugs Effect per 1000 Symptomatic ICH (n = 2955) +62 Dead (n = 2955) +19 (NS) Dead or Dependent 0 - 6 hours (n = 2830) - 55 Dead or Dependent 0 - 3 hours (n = 957) -110 0.1 0.66 0.84 1.0 1.333.37 10 OR = OR for ALL agents (n= ) = n with tPA better thrombolysis worse

  16. Rt-PA: time windows: poor functional outcomes

  17. rt-PA for acute ischemic hemispheric stroke in clinical practice at HUCH Markku Kaste Department of Neurology, Helsinki University Central Hospital (HUCH) University of Helsinki

  18. FUNCTIONAL OUTCOME OF THROMBOLYTIC THERAPY IN HEMISPHERIC STROKE- RANKIN SCALE AT 3 MONTHS

  19. OUTCOME OF DEPENDENCY AFTER THROMBOLYTIC THERAPY IN HEMISPHERIC STROKE- BARTHEL INDEX AT 3 MONTHS

  20. FREQUENCY OF HEMORRHAGIC BRAIN LESIONS AFTER THROMBOLYTIC THERAPY IN HEMISPHERIC STROKE

  21. rt-PA for Acute Ischemic Stroke in Clinical Practice:A Meta-Analyasis of Safety Data Glenn D. Graham Albuquerque VA and University of New Mexico School of Medicine

  22. Glenn D. Graham 2002

  23. Glenn D. Graham 2002

  24. Table. Meta-analysis. Summary statistics are weighted by the number of patients in each study. Symptomatic ICH percentages are for bleeding with the first 36 hours or the closes reported time point. Deaths and other outcome measures are at 90 days or the closest time. NINDS trial data are from Part 1 and 2 combined, except for the percentage of very favorable outcomes, which is from Part 2 only. Glenn D. Graham 2002

  25. ONGOING TRIALS • Bridging trial: iv followed by ia • DEFUSE(US) andEPITETH(AUS) • 3-6h, MRI based • IST 3 (0-6h) • Placebo within first 3h • Uncertainity principle • In-experienced centers - learning curve 54

  26. EU approval, yes, but conditional • Actilyse approved within 3 h after stroke, but conditional approval • After 3 years reconsideration based on: • Safety monitoring of treated patients (SITS-MOST) • RCT within 3-4 h interval (ECASS III)

  27. AIS Patient suitable for rt-PA 0-3 hours 3-4 hours SITS-MOST ECASS 3 Observational study of safety and efficacy within 3 hours of symptom onset in acute ischaemic stroke > 1500 patients per year, 3years International, multicentre trial 100 - 200 centres Primary safety variables:- symptomatic ICH at 36 hours- mortality at 3 months Secondary efficacy variables:- Independence for activities of daily living at 3 months In-/exclusion criteria: strictly according to SPC Double-blind, placebo-controlled study in the 3 - 4 h time window after Double-blind, placebo-controlled study 2  400 patients Study duration: from 1.Q 2003 to 4.Q 2005 Primary endpoint: mRS 0 - 1 Secondary endpoint: Global outcome In-/exclusion criteria: strictly according to the SPC, except time window

  28. SITS-MOST means Safe Implementation of Thrombolysis in Stroke: The Monitoring Study

  29. www.acutestroke.org

  30. SITS National Coordinators SITS National Coordinators approve centres who apply for membership in SITS-MOST Possible to join also outside Europe

  31. E C A S S III The Third European Cooperative Acute Stroke Study

  32. ECASS III History Most stroke patients do not arrive at hospital within a 3 h time window EU Health Authorities wanted to extend the time window from 3 to 4 hours The scientific society wanted to know whether there is benefit beyond 3 hours

  33. Objective ECASS III The aim of ECASS III is to confirm the superiority of rt-PA over placebo for patients with ischemic stroke when administered within a time window from 3 to 4 hours from the onset of symptoms

  34. Study Design 1 ECASS III • ECASS III is a double-blind, placebo- controlled, randomized study to determine the safety and efficacy of 0.9mg/kg rt-PA in acute ischemic stroke when administered within a 3-4 hour time window

  35. Study Design 2 ECASS III • ECASS III will be performed in - 80 study sites in - 15 European countries • Patient recruitment will start in the 1st quarter of 2003

  36. ECASS III Endpoints PRIMARY ENDPOINT • Modified Rankin Scale 0-1 at day 90 • SECONDARY ENDPOINTS • Global outcome (mRS 0-1, Barthel Index 100-95, Glasgow Outcome Scale 0-1) at day 90 • Modified Rankin Scale 0-1 at day 90 stratified by admission NIHSS

  37. ECASS III Sample size • The size of 400 patients per group will allow to detect or disapprove a 10% difference in the primary endpoint between the treatment groups (two-sided alfa = 5% and power probability of about 90%)

  38. Inclusion Criteria ECASS III • Age : 18-80 • Clinical diagnosis of ischemic stroke causing a measurable neurological deficit (NIHSS < 24), no significant improvement • Treatment possible within a time window from 3 to 4 hours • Informed consent

  39. Exclusion criteria ECASS III Clinical • Severe stroke (NIHSS >24 on admission) • Diabetes and earlier clinical stroke • Usual thrombolysis exclusion criteria such as trauma, malignancy, pre- existing handicap, recent surgery and puncture, pregnancy, and others

  40. Exclusion criteria ECASS III CT-scan • Evidence of ICH on the admission CT

  41. Conclusions ECASS III • ECASS III is not going to be an easy trial but if it is positive the time and effort it takes to perform it is well spent • If the hypothesis that rt-PA is safe and effective up to 4 hours, proves to be correct, the therapy will be available for a larger European stroke population

  42. CONCLUSIONS • WE HAVE A MAJOR CHALLENGE • If we are not able to treat stroke patients more effectively in the future than we have done in the past we do not have resources to treat all stroke patients properly • Thrombolysis in stroke is safe and effective, evidence-based medicine (EBM) • We have now a better treatment for patients with acute ischemic stroke than ever before • LET US TAKE THE CHALLENGE !

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