1. UPDATE ON THROMBOLYTIC THERAPY Markku Kaste Department of Neurology Helsinki University Central Hospital (HUCH) University of Helsinki 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 The pooled analysis of ATLANTIS, ECASS and NINDS trials Cochrane systematic review Cochrane systematic review Thrombolysis in clinical practice at HUCH Thrombolysis in clinical practice at HUCH Graham´s meta-analysis of 12 open series Graham´s meta-analysis of 12 open series Ongoing trials Ongoing trials New trials New trials - SITS-MOST - ECASS III The pooled analysis of ATLANTIS, ECASS and NINDS trials The pooled analysis of ATLANTIS, ECASS and NINDS trials Cochrane systematic review Cochrane systematic review Thrombolysis in clinical practice at HUCH Thrombolysis in clinical practice at HUCH Graham´s meta-analysis of 12 open series Graham´s meta-analysis of 12 open series Ongoing trials Ongoing trials New 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. RationaleRationale Quicker administration of IV rtPA improved outcomes in prior individual trials 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 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? We hypothesized that a pooled analysis could suggest whether thrombolysis is beneficial after 3 hours? Quicker administration of IV rtPA improved outcomes in prior individual trials 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 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? We hypothesized that a pooled analysis could suggest whether thrombolysis is beneficial after 3 hours?

5. MethodsMethods Original individual patient data were pooled from 6 randomized controlled trials 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 Method differs from meta-analysis where individual patient data are not generally available and limited adjustment for co-variates is possible Original individual patient data were pooled from 6 randomized controlled trials 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 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 2776 patients Over 300 hospitals Over 300 hospitals 18 countries 18 countries Median age 68 years Median age 68 years Median baseline NIHSSS 12 Median baseline NIHSSS 12 2776 patients 2776 patients Over 300 hospitals Over 300 hospitals 18 countries 18 countries Median age 68 years Median age 68 years Median baseline NIHSSS 12 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 Ratio 95% Conf. Interval TimeOdds Ratio 95% Conf. Interval 0-902.81.8 - 4.5 0-902.81.8 - 4.5 91-1801.51.1 - 2.1 91-1801.51.1 - 2.1 181-2701.41.1 - 1.9 271-3601.20.9 - 1.5 Odds Ratios for Favorable Outcome TimeOdds Ratio 95% Conf. Interval TimeOdds Ratio 95% Conf. Interval 0-902.81.8 - 4.5 0-902.81.8 - 4.5 91-1801.51.1 - 2.1 91-1801.51.1 - 2.1 181-2701.41.1 - 1.9 271-3601.20.9 - 1.5

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

10. ECASS 2 3-4.5 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 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 not associated with onset-to- treatment time PH2 was associated with rtPA treatment (p=.0001) and age (p=.0002) PH2 was associated with rtPA treatment (p=.0001) and age (p=.0002) PH2 occurred in 5.8% of rtPA-treated patients compared to 1.1% of placebo- treated patients (p<.01), median age 72 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 not associated with onset-to- treatment time PH2 was associated with rtPA treatment (p=.0001) and age (p=.0002) 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 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 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 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 A randomized trial is needed to find out whether thrombolysis from 3 to 4 or 4.5 hours improves the outcome of stroke patients Individual studies designed to detect benefit from IV rtPA initiated beyond 3 hours have been negative; our results suggest they were underpowered 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 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 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 Joanna Wardlaw Department of Neurology University of Edinburgh

15. rt-PA : other drugs better thrombolysis worse 0.1 0.66 0.84 1.0 1.33 3.37 10 OR Symptomatic ICH (n = 2955) Dead (n = 2955) Dead or Dependent 0 - 6 hours (n = 2830) Dead or Dependent 0 - 3 hours (n = 957) +62 - 55 -110 +19 (NS) Effect per 1000 = OR for ALL agents (n= ) = n with tPA

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 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 Glenn D. Graham Albuquerque VA and University of New Mexico School of Medicine

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

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

27. 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 AIS Patient suitable for rt-PA SITS- MOST ECASS 3 0-3 hours 3-4 hours 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 The Third European Cooperative Acute Stroke Study

32. HistoryHistory 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 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 ECASS III

33. ObjectiveObjective 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 ECASS III

34. Study Design 1 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 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 ECASS III

35. Study Design 2 ECASS III will be performed in ECASS III will be performed in - 80 study sites in - 80 study sites in - 15 European countries - 15 European countries Patient recruitment will start in the 1st quarter of2003 Patient recruitment will start in the 1st quarter of2003 ECASS III will be performed in ECASS III will be performed in - 80 study sites in - 80 study sites in - 15 European countries - 15 European countries Patient recruitment will start in the 1st quarter of2003 Patient recruitment will start in the 1st quarter of2003 ECASS III

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

37. 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%) 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%) ECASS III

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

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

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

41. ConclusionsConclusions 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 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 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 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 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 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 ECASS III

42. CONCLUSIONSCONCLUSIONS WE HAVE A MAJOR CHALLENGE 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 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) 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 We have now a better treatment for patients with acute ischemic stroke than ever before LET US TAKE THE CHALLENGE ! LET US TAKE THE CHALLENGE ! WE HAVE A MAJOR CHALLENGE 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 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) 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 We have now a better treatment for patients with acute ischemic stroke than ever before LET US TAKE THE CHALLENGE ! LET US TAKE THE CHALLENGE !