Original Article Thrombolysis with Alteplase 3 to 4.5 Hours after Acute Ischemic Stroke Werner Hacke, M.D., Markku Kaste, M.D., Erich Bluhmki, Ph.D., Miroslav Brozman, M.D., Antoni Dávalos, M.D., Donata Guidetti, M.D., Vincent Larrue, M.D., Kennedy R. Lees, M.D., Zakaria Medeghri, M.D., Thomas Machnig, M.D., Dietmar Schneider, M.D., Rüdiger von Kummer, M.D., Nils Wahlgren, M.D., Danilo Toni, M.D., for the ECASS Investigators N Engl J Med Volume 359(13): September 25, 2008

T.B.Radzilani

Study Overview Intravenous thrombolysis with alteplase improves the outcomes after acute stroke when alteplase is given within 3 hours after the onset of symptoms In this randomized trial involving patients who presented between 3 and 4.5 hours after the onset of stroke, clinical outcomes were modestly better in patients treated with alteplase than in patients given placebo (favorable outcome in 52% vs. 45% of patients)

1.Test Efficacy of Alteplase given between 3-4,5hrs 2.Test safety 3.Recommend increased use of Alteplase in stroke units 4.ECASS 3

Numbers of Patients Who Were Enrolled, Randomly Assigned to a Study Group, and Included in the Per-Protocol Population Hacke W et al. N Engl J Med 2008;359:

Major Inclusion and Exclusion Criteria Hacke W et al. N Engl J Med 2008;359:

Is design suitable for objectives? Who&What was studied Is the study sample large enough? Were all subjects accounted for? Ethical approval Were all appropriate outcomes considered? Yes Table 1 Sample calculations400pts per grp req for primary endpoint signif Fig 1 Yes

Were pts randomized b/t treatments? How was randomization carried out? Are outcomes clin relevant Double-blind randomized trial 1:1 Interactive voice randomiz Blocks of 4 Drug reconstitution same All got 10% bolus Rem given within 60min Yes

Demographic and Baseline Characteristics of the Patients Hacke W et al. N Engl J Med 2008;359:

 Is it clear what was measured&how?&outco mes?  Validity  Reliability  Pts&Investigaters blinded Table 3 Accuracy;observers were trained to use tools Reproducible:NINDS ‘95,ECASS1&2,Six ran trials analysis System of observation:init,1hr,2hrs,24hrs,d7,d30,d90 Yes

Odds Ratios for Primary End Point and Secondary End Point, Including Components, in the Intention-to-Treat and Per-Protocol Populations at 90 Days Hacke W et al. N Engl J Med 2008;359:

 Basic data described  Were grps comparable at baseline?  Results clear&objective  Do numbers add up?  Side effects reported?  Yes  Table 2  Yes

Distribution of Scores on the Modified Rankin Scale Hacke W et al. N Engl J Med 2008;359:

Odds Ratios for Further Functional End Points at Days 90 and 30 after Treatment in the Intention-to-Treat and Per-Protocol Populations Hacke W et al. N Engl J Med 2008;359:

Prespecified Safety End Points and Other Serious Adverse Events Hacke W et al. N Engl J Med 2008;359:

 Are results related to existing knowledge&objectives?  Is discussion biased?  Second rand trial after NINDS showin sig effects of Alteplase on primary endpoint  ATLANTIS&ECASS2 show no signif >3hhrs  Sympt ICH not incr despite ext time window  Mortality not incr  Selection bias:A&EMEA

Authers’conclusions justified by data Does this paper help me answer my problem? Early treat remains essent Modest but signif improvement in clin outcome usin A>3hrs

Conclusion As compared with placebo, intravenous alteplase administered between 3 and 4.5 hours after the onset of symptoms significantly improved clinical outcomes in patients with acute ischemic stroke; alteplase was more frequently associated with symptomatic intracranial hemorrhage

o Applicability o Aids to implementation? o Barriers to implementation o The necessary changes can be implemented in practice o Stroke units o Ethics committee; Increased vol of pts=staff; Lim resources/beds jourpadizin pt with better chance ; Budget constraints.