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The NINDS Trial - rtPA in Acute Stroke


The NINDS rt-PA Acute Stroke Trial
  • This was a landmark trial with a good study design and funding from the National Institutes of Health and serves as the basis for the current use of tPA for acute ischemic stroke within 3 hours of onset of symptoms, have no evidence of hemorrhage on a head CT scan, and measurable deficit using the NIH Stroke Scale.
    • This trial is considered landmark because it was the basis for alteplase's approval back in 1996 by the FDA and in 2002 by EMEA.
  • While this trial did not show neurologic improvement at 24 hours or improvements in mortality, it did demonstrated improvement in neurologic outcomes at 90 days with a NNT of a favorable outcome to be 7. 
    • A follow up analysis of the NINDS Trial showed this improved neurologic at 1 year.
  • The lack of mortality benefit was most likely due to the higher incidence of intracerebral hemorrhage, many of which were unfortunately fatal.

NINDS rt-PA in Acute Stroke Trial Summary

  • NINDS Study Group. Tissue Plasminogen Activator for Acute Ischemic Stroke. N Engl J Med 1995;333(24):1581-1587. PubMed
    Level of Evidence 1
    Study Design Prospective, Multicenter, Randomized, Double-Blind Trial in the United States (1991-1994)
    Sample Size

    N = 624 (total)

    • Part 1: n = 291; To determine if there was an early (< 24 hrs)
    • Part 2: n = 333; To determine if there was a late effect (3 months)
    Inclusion Criteria
    • Presenting within 3 hrs of onset of stroke symptoms
    • A deficit measurable on the NIH Stroke Scale (NIHSS)
    • Baseline CT brain showing no hemorrhage
    Exclusion Criteria
    • Stroke or serious head trauma within 3 months
    • Major surgery
    • History of intracerebral hemorrhage
    • SBP > 185 mm Hg or DBP > 100
    • Rapidly improving symptoms
    • GI or urinary hemorrhage in the past 21 days
    • Seizure at the onset of stroke
    • Taking anticoagulants
    • Platelets < 100,000
    • Glucose < 50 or > 400 mg/dL
    • Placebo
    • rt-PA
    Follow Up 24 hours and 3 months
    Primary Endpoint

    To determine if IV tPA has improved clinical outcome if administered within 3 hours of onset of stroke symptoms.

    Secondary Endpoint

    The trial was broken into 2 parts (using the Barthel Index, modified Rankin scale, Glasgow outcome, and NIHSS).

    • To determine if there was an early (< 24 hrs)
    • To determine if there was a late effect (3 months)
    • There was no significant difference in improvement in neurologic outcome at 90 days with tPA compared to placebo
    • tPA demonstrated an improvement in neurologic outcome at 90 days compared to placebo; Odds ratio of 1.7
    • Symptomatic hemorrhage within 36 hrs occurred in 6.4% of patients getting tPA vs. 0.6% of patients getting placebo
    • No significant difference in mortality at 3 months (17% for tPA vs 21% for placebo; p = 0.3)
    NNT = 7 (at 3 months)
    Conclusions Patients presenting within 3 hrs of onset of stroke symptoms only had an improvement in neurologic outcomes at 3 months despite a higher risk of intracranial bleeding.
    Location 8 medical centers around the United States between 1991-1994
    Funding National Institutes of Health (NIH)
    Comments Does an intracranial bleed always mean negative outcome? In this trial, they seemed to be fatal which is likely why there was no improvement in mortality.  Furthermore, the benefit only found at 90 days, raised concerns about the findings and caution to the strength of its recommendation.

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MESH Terms & Keywords

  • tPA Alteplase, Acute Ischemic Stroke, NINDS rt-PA trial