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 MedVolume 359(13):1317-1329

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;359:1317-1329

Major Inclusion and Exclusion Criteria

Hacke W et al. N Engl J Med 2008;359:1317-1329

• 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• Yes

• Were pts randomized b/t treatments?

• How was randomization carried out?

• Are outcomes clin relevant

• Double-blind randomized trial

• 1:1Interactive voice randomizBlocks of 4Drug reconstitution sameAll got 10% bolusRem given within 60min• Yes

Demographic and Baseline Characteristics of the Patients

Hacke W et al. N Engl J Med 2008;359:1317-1329

Is it clear what was measured&how?&outcomes?

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;359:1317-1329

Basic data describedWere grps comparable

at baseline?Results clear&objectiveDo numbers add up?Side effects reported?

YesTable 2

YesYesYes

Distribution of Scores on the Modified Rankin Scale

Hacke W et al. N Engl J Med 2008;359:1317-1329

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;359:1317-1329

Prespecified Safety End Points and Other Serious Adverse Events

Hacke W et al. N Engl J Med 2008;359:1317-1329

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.