Randomised doubleblind placebocontrolled trial of thrombolytic therapy with intravenous alteplase in

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Randomised double-blind placebo-controlled trial
of thrombolytic therapy with intravenous
alteplase in acute ischaemic stroke (ECASS II)

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• Lancet 1998 352 1245-51

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Background

• Thrombolysis for acute ischaemic stroke has been
  investigated in several clinical trials, with
  variable results
• There have been several large randomised
  double-blind placebo-controlled trial

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Background (NINDS trial )

• Short maximum interval from symptom onset to
  treatment (180 min)
• A dose of 0.9 mg/kg bodyweight
• strict blood-pressure control
• It found that 11-13 more patients in the
• alteplase group than in the placebo group
  had good functional outcome

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Background (ECASS I)

• ECASS I a European multicenter trial
• used a maximum interval from onset to treatment
  of 6 h
• higher dose of alteplase (1.1 mg/kg)
• Resultmortality and hemorrhage are more common
  in alteplase-treat group

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ECASS II

• A dose of 0.9 mg/kg bodyweight
• strict blood-pressure control
• Alteplase was given within 6 hrs
• Subgroup(0-3 hr ,3-6hr)

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Study setting

• 108 centers in 14 European countries and
  Australia and New Zealand
• within 6 h of symptom onset
• aged 18-80 years clinical diagnosis of moderate
  to severe stroke, who could be treated

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Study setting

• Computed tomography was used to exclude patients
  with signs of major infarction.
• Followed up for the 90-day study period
• endpoint was the modified Rankin scale (mRS) at
  90 days, dichotomised for favourable (score 0-1)
  and unfavourable (score 2-6) outcome.

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Study setting

• Subarachnoid haemorrhage
• Time of stroke onset not exactly known
• Coma or stuporMinor stroke symptoms
• (gt50 of the maximum 58 points on the Scandinavian
  stroke scale (SSS before randomisation)
• Rapid improvement of symptoms
• Brain swelling exceeded 33 of the
  middle-cerebral-artery territory
• Seizure during the previous 6 months
• Hypertension at the time of randomisation
  (systolic blood pressure gt185 mmHg or diastolic
  blood pressure gt110 mm Hg)
• Any traumatic brain injury within the previous
  14 days
• Recent (within 3 months) surgery on the central
  nervous system haemorrhage of the
  gastrointestinal or urinary tract

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Study setting

• The randomisation schedule was known only to the
  clinical Trial Support Unit at Boehringer
  Ingelbeim and to one member of the External
  Safety Committee
• Alteplase (Boehringer Ingelheim, Ingelheim,
  Germany) and placebo were identical in appearance
  

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Study setting

• The dose of alteplase was 0.9 mg/kg bodyweight,
  with an upper dose limit of 90 mg per patient
• A bolus of 10 of the total dose was given over
  1-2 min, followed by a 60 min intravenous
  infusion of the remaining dose

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Result

• Alteplase (n409) and placebo (n391) were
  randomly assigned with stratification for time
  since symptom onset (0-3 h or 3-6 h)

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Results

• 165 (403) alteplase-group patients and 143
  (366) placebo-group patients had favourable mRS
  outcomes (absolute difference 37, p0277)
• Treatment differences were similar whether
  patients were treated within 3 h or 3-6 h

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Results

• 85 (106) patients died, with no difference
  between treatment groups at day 9014 days (43
  alteplase, 42 placebo)
• Symptomatic intracranial haemorrhage occurred in
  36 (88) alteplase-group patients and 13 (34)
  placebo-group patients.

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Interpretation

• The results do not confirm a statistical benefit
  for alteplase.
• However, we believe the trend towards efficacy
  should be interpreted in the light of evidence
  from previous trials.
• Despite the increased risk of intracranial
  haemorrhage, thrombolysis with alteplase at a
  dose of 09 mg/kg in selected patients may lead
  to a clinically relevant improvement in outcome
• The interval of thrombosis has not been well
  defined