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Evevident
Original paper
1995NEJMNeurology

NINDS tPA

Tissue plasminogen activator for acute ischemic stroke

RCTAcute ischemic stroke

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Overview

IV alteplase within 3 hours improved functional outcomes after acute ischemic stroke despite increased symptomatic intracranial hemorrhage.

Clinical takeaway

The NINDS tPA trial established time-sensitive IV thrombolysis as foundational acute ischemic stroke therapy.

Key result

Alteplase increased the odds of a favorable outcome at 3 months (global OR 1.7; 95% CI 1.2-2.6).

Practice impact

Urgent stroke recognition and eligibility screening for thrombolysis became standard.

Evidence

Study design

Randomized, double-blind, placebo-controlled trial (two parts).

Enrollment

624

Follow-up

3 months (primary); outcomes also assessed at 12 months.

Geography

United States

Clinical question

Does IV alteplase improve outcomes in acute ischemic stroke treated within 3 hours?

Population

  • Patients with acute ischemic stroke who could be treated with study drug within 3 hours of symptom onset.

Intervention

Intravenous alteplase 0.9 mg/kg (maximum 90 mg).

Comparator

Placebo.

Primary outcome

Favorable outcome at 3 months (global statistic across mRS, Barthel Index, Glasgow Outcome Scale, and NIHSS).

Despite a higher rate of symptomatic intracranial hemorrhage, IV alteplase within 3 hours increased the likelihood of minimal or no disability at 3 months.

Global odds ratio / 1.7 / CI 95% CI 1.2-2.6 / p=0.008

Key results

  • Global odds ratio for a favorable outcome at 3 months was 1.7 (95% CI 1.2-2.6) favoring alteplase.
  • Absolute increase of roughly 11-13 percentage points in patients with minimal or no disability.
  • Symptomatic intracranial hemorrhage within 36 hours occurred in 6.4% with alteplase vs 0.6% with placebo.
  • Mortality at 12 months did not differ significantly (24% vs 21%).

Harms

  • Symptomatic intracranial hemorrhage within 36 hours was markedly increased (6.4% vs 0.6%).
  • Overall mortality was not significantly higher despite the bleeding risk.

Clinical Use

When to cite

  • When discussing alteplase for acute ischemic stroke as time-sensitive functional-outcome therapy with meaningful bleeding risk.

Practice impact

  • Urgent stroke recognition and eligibility screening for thrombolysis became standard.

Applicability

  • Most applicable to patients with acute ischemic stroke who can be treated within 3 hours of symptom onset.

Limitations

  • Narrow 3-hour time window and strict eligibility criteria (the window was later extended to 4.5 hours by ECASS III).
  • Bleeding risk requires careful exclusion of stroke mimics and contraindications.
  • Predates modern imaging and endovascular therapy.

Common misinterpretations

  • The benefit is improved function, not reduced mortality; alteplase does not lower death rates.
  • A favorable risk-benefit balance depends on treating early and screening out patients at high hemorrhage risk.

Related evidence

MR CLEAN - Later Trial

Citation

National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. Tissue plasminogen activator for acute ischemic stroke. N Engl J Med. 1995;333(24):1581-1587. doi:10.1056/NEJM199512143332401

Despite an increased incidence of symptomatic intracerebral hemorrhage, treatment with intravenous t-PA within three hours of the onset of ischemic stroke improved clinical outcome at three months.