Stroke: Alteplase had no clear effect on combined favourable outcomes, but may improve independence.

Clinical bottom line (level 1b)

  1. Patients with acute ischaemic stroke who were given thrombolytic therapy plus alteplase were more likely to be independent at 90 days, than those given thrombolytic therapy plus placebo (NNT = 12 at 90 days) .
  2. Patients who were given alteplase had no clear difference in combined favourable outcomes, than those given placebo.
  3. There was no clear difference in mortality.
Hacke et al: Lancet 1998; 352: 1245-1251
Expires December 2002

The study

Double-blinded ?concealed randomised trial with intention-to-treat
Setting: 108 centres in 14 European countries and Australia and New Zealand

800 patients (aged median 68 years, 59% male) Clinical diagnosis of moderate to severe ischaemic hemispheric stroke, who could be treated within 6 hours of symptom onset and who showed no or only minor early signs of infarction on the initial computed tomography scan

Excluded if
  • <18 and >80 years old
  • unable to be followed for 90 days
  • current or recent (within 3 months) participation in another trial of an investigational drug
  • known hereditary or acquired haemorrhagic diathesis
  • lactation, pregnancy or parturition (within the previous 30 days)
  • inappropriate contraception in women of childbearing age
  • baseline blood glucose concentrations below 2.75 mmol/L (50 mg?dL) or above 22.0 mmol/L (400 mg/dL)
  • baseline platelet counts below 100X10^9/L
  • packed-cell volume below 25%
  • hypertension at the time of randomisation (systolic blood pressure >185 mmHg or diastolic >110 mmHg)
  • 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
  • current therapy with heparin to raise clotting time
  • signs of intracerebral haemorrhage or parenchymal hypoattenuation exceeding a third of the middle-cerebral-artery territory
  • subarachnoid haemorrhage
  • time of stroke onset not exactly known
  • coma or stupor
  • hemiplegia plus fixed eye deviation
  • minor stroke symptoms (>50% of the maximum 58 points on the Scandinavian stroke scale before randomisation, or rapid improvement of symptoms
  • seizure during the previous six months


    • Note:
  • In most patients, the precise location of the causative cardiovascular thrombus or embolus was unknown.
  • Randomisation was performed in blocks of four, with each centre allocated at least one block of the treatment group at 0-3 and 3-6 hours.
  • Pretreatment with aspirin was permitted. Intravenous heparin, oral anticoagulants, antiplatelets, haemorrheological agents, potential neuroprotectives and volume expanders were prohibited during the first 24 hours of the study. Subcutaneous heparin (not >10,000 IU) was allowed during the first 24 hours for prophylaxis of deep-vein thrombosis. Osmotic agents could be given if the intracranial pressure was raised.


    • Control Group: (n = 391, 391 analysed): Thrombolytic therapy plus placebo
    Experimental Group: (n = 409, 409 analysed): Thrombolytic therapy plus alteplase 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 minutes, followed by 60 minutes of intravenous infusion of the remaining dose

    100% followed for 90 days
    Outcome notes:
    • independence : post-hoc analysis of modified Rankin scale scores according to another standard dichotomised procedure (score of 0, 1 or 2)
    • favourable outcome on modified Rankin scale : score of 0 or 1 (on a 7-point scale that assesses overall function, where death is 6)

    The evidence

    Outcome Time to outcome CEREERRRR
    (95% CI)    		ARR
    (95% CI)    		NNT
    (95% CI)
    independence 90 days 180
    (46.0%)    		 222
    (54.3%)    		 15%
    (3% to 26%)    		 8.24%
    (1,34% to 15,15%)    		 12
    (7 to 75)
    favourable outcome on modified Rankin scale 90 days 143
    (36.6%)    		 165
    (40.3%)    		 6%
    (-5% to 16%)    		 3.77%
    (-2,97% to 10,5%)    		 27
    (NNT = 34 to infinity;
    NNH = 10 to infinity)
    mortality 104 days 42
    (10.7%)    		 43
    (10.5%)    		 2.00%
    (-46.0% to 35.0%)    		 0.23%
    (-4.04% to 4.50%)    		 438
    (NNT = 22 to infinity;
    NNH = 25 to infinity)

  • During the first 7days of the study, there were more deaths in the alteplase group from intracranial haemorrhage alone or from the combination of cerebral oedema and intracranial haemorrhage than in the placebo group. Cerebral oedema was the most common cause of death in the placebo group. After the first 7days, cause of death was similar between the groups.
  • Up to day 30, 1804 adverse effects were reported in the alteplase group and 1591 in the placebo group. However, about 66% of these were mild. After day 30, only severe effects were noted. More than 20% of adverse effects were non-specific disorders, gastrointestinal disorders, central and peripheral nervous system disorders, cardiovascular disorders and urinary system disorders.

    • Comments

    1. The analysis of independence was not a predefined endpoint, but this was pointed out in the text.
    2. The study was too small to show a clear difference in favourable outcome or mortality between the two groups.

    Citation

    1. Hacke W, Kaste M, Fieschi C, et al: Randomised double-blind placebo-controlled trial of thrombolytic therapy with intravenous alteplase in acute ischaemic stroke (ECASS II). Lancet 1998; 352: 1245-1251
    Contributor: Clare Wotton and Musab Hayatli, December 1999
    Reviewer:

    Clinical Question.
    Patient acute ischaemic stroke
    Intervention or Exposure thrombolytic therapy with alteplase
    Comparison thrombolytic therapy plus placebo
    Outcome favourable outcome on modified Rankin scale scores