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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

UPDATE ON THROMBOLYTIC THERAPY

Markku Kaste

Department of Neurology

Helsinki University Central Hospital (HUCH)

University of Helsinki

topics of my presentation
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

is there benefit after 3 hours a pooled analysis of the atlantis ecass and ninds rtpa stroke trials

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

rationale
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?
methods
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
results i
Results I
  • 2776 patients
  • Over 300 hospitals
  • 18 countries
  • Median age 68 years
  • Median baseline NIHSSS 12
slide7

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)

results iii
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

slide9
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

results v
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)
conclusions i
Conclusions I
  • The quicker rtPA is given to stroke patients, the greater the benefit
conclusions ii
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
cochrane systematic review

COCHRANE SYSTEMATIC REVIEW

Joanna Wardlaw

Department of Neurology

University of Edinburgh

rt pa other drugs
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

rt pa for acute ischemic hemispheric stroke in clinical practice at huch

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

outcome of dependency after thrombolytic therapy in hemispheric stroke barthel index at 3 months
OUTCOME OF DEPENDENCY AFTER THROMBOLYTIC THERAPY IN HEMISPHERIC STROKE- BARTHEL INDEX AT 3 MONTHS
rt pa for acute ischemic stroke in clinical practice a meta analyasis of safety data

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

slide24

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

ongoing trials
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

eu approval yes but conditional
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)
slide27

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

slide28

SITS-MOST means

Safe Implementation of Thrombolysis in Stroke: The Monitoring Study

sits national coordinators
SITS National Coordinators

SITS National

Coordinators

approve

centres

who apply

for membership

in SITS-MOST

Possible to join also outside Europe

e c a s s iii
E C A S S III

The Third

European Cooperative

Acute Stroke Study

history

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

objective
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

study design 1
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
study design 2
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
endpoints

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
sample size

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%)
inclusion criteria
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
exclusion criteria
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
exclusion criteria1
Exclusion criteria

ECASS III

CT-scan

  • Evidence of ICH on the admission CT
conclusions
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
conclusions1
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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