Third International Stroke Trial - IST-3


The goal of the trial was to evaluate treatment with intravenous thrombolytic therapy compared with control among a broad range of patients presenting within 6 hours from onset of ischemic stroke.


Intravenous thrombolytic therapy will improve survival.

Study Design

  • Randomized
  • Parallel

Patient Populations:

  • Patients with acute ischemic stroke within 6 hours from symptom onset
  • No intracranial hemorrhage or structural brain lesion that could mimic stroke (such as cerebral tumor)

    Number of enrollees: 3,035
    Duration of follow-up: 6 months
    Mean patient age: 53% of patients >80 years
    Percentage female: 52%


  • Clear contraindication to intravenous thrombolytic therapy

Primary Endpoints:

  • The proportion of patients alive and independent at 6 months; independence was assessed by the Oxford Handicap Score

Drug/Procedures Used:

Patients within 6 hours from the onset of ischemic stroke were randomized to 0.9 mg/kg (maximum 90 mg) intravenous recombinant tissue plasminogen inhibitor (rt-PA) (n = 1,515) versus control (n = 1,520).

rt-PA was given as 10% bolus and the remaining dose was given over 1 hour.

Concomitant Medications:

Patients in the control group received early aspirin.

Principal Findings:

Overall, 3,035 patients were randomized. Among the participants, 52% were women, 53% were >80 years of age, 33% received rt-PA 4.5-6 hours after symptom onset, and 35% had a systolic blood pressure ≥165 mm Hg. The median time from onset of symptoms to rt-PA was 4.2 hours.

At 6 months, the proportion of patients alive and independent were 37% in the rt-PA group versus 35% in the control group (p = 0.18). Benefit appeared to be greater in older patients (>80 years), more severe strokes, and early treatment (within 3 hours).

Deaths within 7 days: 11% vs. 7% (p = 0.001)
Deaths between 7 days and 6 months: 16% vs. 20% (p = 0.002)
Fatal plus nonfatal symptomatic edema of original infarct: 4% vs. 3% (p = 0.014)
Fatal plus nonfatal intracranial hemorrhage: 7% vs. 1% (p < 0.0001)
Recurrent ischemic stroke: 1% vs. 1% (p = 0.85)
Total myocardial infarction: 2% vs. 2% (p = 0.86)


Among an older cohort of patients with acute ischemic stroke, the use of intravenous rt-PA within 6 hours resulted in both benefit and harm. Among recipients of rt-PA, more patients died within 7 days due to an increase in total intracranial hemorrhage. However, between 7 days and 6 months, fewer patients in the rt-PA group died.

An unexpected finding was that benefit from rt-PA appeared greater in patients >80 years of age. Another unexpected finding was an excess of fatal plus nonfatal neurological deterioration due to brain edema in the rt-PA group, which is unexplained and counter to previous trials. This trial highlights that older patients need to be represented in future stroke trials.


IST-3 Collaborative Group. The benefits and harms of intravenous thrombolysis with recombinant tissue plasminogen activator within 6 h of acute ischaemic stroke (the third international stroke trial [IST-3]): a randomised controlled trial. Lancet 2012;379:2352-2363.

Clinical Topics: Dyslipidemia, Lipid Metabolism

Keywords: Thrombolytic Therapy, Myocardial Infarction, Stroke, Neoplasms, Intracranial Hemorrhages, Follow-Up Studies, Blood Pressure, Tissue Plasminogen Activator, Brain Edema

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