Third International Stroke Trial - IST-3

May 23, 2012
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Author/Summarized by Author:
Anthony A. Bavry, MD, MPH, FACC
Summary Reviewer:
Deepak L. Bhatt, MD, MPH, MBA, FACC
Trial Sponsor:
UK Medical Research Council, Health Foundation UK, Stroke Association UK, Research Council of Norway, Arbetsmarknadens Partners Forsakringsbolag Insurances Sweden, Swedish Heart and Lung Fund, The Foundation of Marianne and Marcus Wallenberg, Polish Ministry of Science and Foundation, Australian Heart Foundation, Australian National Health and Medical Research Council, Swiss National Research Foundation, Swiss Heart Foundation, Assessorato alla Sanita, Regione dell’Umbria, Italy, Danube University
Date Published:
01/01/2012
Date Updated:
05/23/2012
Original Posted Date:
05/23/2012
References

Description:

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.

Hypothesis:

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%

Exclusions:

  • 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)

Interpretation:

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.

References:

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.

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


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