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Hacke W, et al. "Thrombolysis with Alteplase 3 to 4.5 Hours after Acute Ischemic Stroke". The New England Journal of Medicine. 2008. 359(13):1317-1329.
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Clinical Question

In patients with acute ischemic stroke, does the administration of alteplase, a tissue plasminogen activator (tPA), reduce disability at 3 months?

Bottom Line

Intravenous alteplase improved neurologic outcomes within 4.5 hours of stroke onset among patients with acute ischemic stroke. Despite an increased incidence of intracranial hemorrhage, there was no mortality benefit.

Major Points

The 2008 European Cooperative Acute Stroke Study III (ECASS III) demonstrated a benefit of intravenous alteplase beyond the conventional 3-hour time window established in the NINDS trial (1995), effectively extending the window for alteplase to 4.5 hours. The primary outcome was disability at 3 months, and ECASS III found a greater proportion of patients randomized to alteplase with complete or near complete neurologic recovery (NNT 14). Despite a 10-fold increase in symptomatic intracerebral hemorrhage, there was no difference in mortality between alteplase and placebo groups. Of note, patients with severe signs of stroke were excluded, and the placebo group had higher rates of prior stroke, which may have accounted for the worsened outcomes.

ECASS III contradicted the results of earlier negative trials, ECASS II (1998)[1]and ATLANTIS B[2] (1999). However, these earlier trials evaluated treatment windows up to 6 hours and had fewer patients between 3 and 4.5 hours. The 2008 observational study, SITS-ISTR,[3] and a 2014 meta-analysis[4] supported the benefit of alteplase up to 4.5 hours, but reiterated the fact that the sooner alteplase is initiated, the more likely it is to be beneficial.


AHA/ASA Early management of acute ischemic stroke (2013) [5]

  • Intravenous tPA for selected patients up to 3 hours after onset of ischemic stroke (class I level A)
  • Eligible patients should receive tPA as quickly as possible, ideally within 60 minutes of hospital arrival (class I level A)
  • Intravenous tPA for selected patients between 3-4.5 after onset of ischemic stroke (class I level B)

Canadian Stroke Best Practice Recommendations: Hyperacute Stroke Care Guidelines (2015, adapted) [6]

  • Intravenous tPA for selected patients within 4-5 hours of onset of stroke symptoms (Level A)
  • tPA dose is 0.9 mg/kg (max 90 mg total dose (Level A)


  • Multi-center, double-blind, parallel-group, randomized, placebo-controlled trial
  • N=821
    • Alteplase (n=418)
    • Placebo (n=418)
  • Setting: 130 centers in 19 European countries
  • Follow-up: 3 months
  • Median time for administration: 3 hours 59 minutes


Inclusion Criteria

  • Age 18-80 years
  • Clinical diagnosis of acute ischemic stroke
  • Able to receive study drug 3-4.5 hours after clear onset of symptoms
    • Original parameters were 3-4 hours, but this was increased to 4.5 hours after the trial began due to small population recruited

Exclusion Criteria

  • Intracranial hemorrhage on CT or MRI
  • Symptoms of subarachnoid hemorrhage even without signs on CT
  • Major ischemic infarct on CT or MRI
  • NIHSS score >25
  • Seizure at onset of stroke
  • Unknown onset of symptoms or greater than 4.5 hours prior to drug administration
  • Symptoms minor or rapidly improving prior to administration
  • Stroke or head trauma within 3 months
  • History of combination of previous stroke and diabetes
  • Heparin within past 48 hours and PTT greater than upper level of normal
  • Oral anticoagulant therapy
  • Platelets <100k
  • SBP >185, DBP >110; or aggressive anti-hypertensives required to reduce BP below these ranges
  • Blood glucose <50 or >400mg/dl
  • Major surgery or trauma within 3 months
  • Other disorders associated with increased risk of bleeding

Baseline Characteristics

  • Mean age: 65 years
  • Male: 63.2% vs. 57.3% (P=0.10)
  • Weight: 78 kg
  • NIHSS score: 10.7 vs. 11.6 (P=0.03)
  • SBP: 153 mmHg
  • DBP: 84 mmHg
  • Diabetes: 15.7%
  • Previous use of antiplatelet agents: 31.8%
  • Hypertension: 62.6%
  • Atrial flutter or fibrillation: 13.2%
  • History of stroke: 7.7% vs. 14.1% (P=0.003)
  • Smoking status
    • Never smoked: 47%
    • Ex-smoker: 23%
    • Current smoker: 30%
  • Time to treatment initiation: 3 hr 59 min vs. 3 hr 58 min
    • ≥3.0 to ≤3.5: 9.6% vs. 10.4%
    • ≥3.5 to ≤4.0: 45.7% vs. 47.9%
    • ≥4.0 to ≤4.5: 41.6% vs. 36.7%


  • CT or MRI performed before randomization and 22-36 hours after treatment
  • Randomized to alteplase or placebo
    • Intravenous alteplase 0.9 mg/kg total dose. 10% as bolus, remainder administered by continuous infusion over 60 minutes
  • Assessments at enrollment, at 1, 2, and 24 hours after administration, and on days 7, 30, and 90.
    • National Institutes of Health Stroke Scale (NIHSS)
    • Modified Ranking Scale (mRS),[7] scores of 0 or 1 are favorable
    • Barthel Index
    • Glasgow Outcome Scale (GOS)


Comparisons are alteplase vs. placebo.

Primary Outcomes

90-day disability (mRS score of 0 or 1)
52.4% vs. 45.2% (OR 1.34; 95% CI 1.02-1.76; P=0.04)
Favoring alteplase, after adjustment for confounders (OR 1.42; 95% CI 1.02-1.98; P=0.04; NNT=14)

Secondary Outcomes

Global outcome (mRS, NIHSS, Barthel Index, Glasgow Outcome Scale)
Favoring alteplase (OR 1.28; 95% CI 1.00-1.65; P<0.05)
Bartel Index score ≥95: 63.4% vs. 58.6% (OR 1.23; 95% CI 0.93-1.62; P=0.16)
NIHSS score of 0 or 1: 50.2% vs. 43.2% (OR 1.33; 95% CI 1.01-1.75; P=0.04)
GOS score of 1: 51.0% vs. 45.4% (OR 1.25; 95% CI 0.95-1.64; P=0.11)

Adverse events

Any intracranial hemorrhage
27.0% vs. 17.6% (OR 1.73; 95% CI 1.24-2.42; P=0.001; NNH=11)
Symptomatic intracranial hemorrhage
2.4% vs. 0.2% (OR 9.85; 95% CI 1.26-77.32; P=0.008; NNH=45) according to ECASS III definition
7.9% vs. 3.5% (OR 2.38; 95% CI 1.25-4.52; P=0.006; NNH=23) according to NINDS definition
7.7% vs. 8.4% (OR 0.80; 95% CI 0.54-1.49; P=0.68)


  • Placebo group had higher rates of previous stroke (7.7% vs. 14.1%; P=0.003), which could account for the worsened outcome of the placebo group.
  • Study excluded patients with severe stroke signs.
  • The study protocol was changed during the trial.


Funding from Boehringer Ingelheim, maker of Actilyse (alteplase). Multiple disclosures.

  1. Hacke W, et al. "Randomised double-blind placebo-controlled trial of thrombolytic therapy with intravenous alteplase in acute ischaemic stroke (ECASS II)." The Lancet. 1998;352(9136):1245-1251.
  2. Clark WM, et al. "Recombinant tissue-type plasminogen activator (Alteplase) for ischemic stroke 3 to 5 hours after symptom onset." JAMA. 1999;282(21):2019-2026.
  3. Wahlgren N, et al. "Thrombolysis with alteplase 3-4.5 h after acute ischaemic stroke (SITS-ISTR): an observational study." The Lancet. 2008;372(9646):1303-9.
  4. Emberson J, et al. "Effect of treatment delay, age, and stroke severity on the effects of intravenous thrombolysis with alteplase for acute ischaemic stroke: a meta-analysis of individual patient data from randomised trials." The Lancet. 2014;384:1929-1935.
  5. PDF file - Jauch EC, et al. "Guidelines for the early management of patients with acute ischemic stroke: A guideline for healthcare professionals from the American Heart Association/American Stroke Association." Stroke. 2013;44:870-947.
  6. Casaubon LK, et al. Heart and Stroke Foundation of Canada Canadian Stroke Best Practices Advisory Committee (2015), Canadian Stroke Best Practice Recommendations: Hyperacute Stroke Care Guidelines, Update 2015. International Journal of Stroke
  7. First Publication of the mRS - Farrell B, et al. "The United Kingdom transient ischaemic attack (UK-TIA) aspirin trial: final results." Journal of Neurology, Neurosurgery & Psychiatry 1991;54(12):1044-1054.