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NINDS

Tissue Plasminogen Activator for Acute Ischemic Stroke

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Year of Publication: 1995

Authors: The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group

Journal: New England Journal of Medicine

Citation: N Engl J Med 1995;333:1581–1587

Link: https://doi.org/10.1056/NEJM199512143332401

PDF: https://www.nejm.org/doi/pdf/10.1056/NEJM199512143332401

Clinical Question

Does intravenous tissue plasminogen activator (tPA) administered within 3 hours of stroke onset improve clinical outcomes in patients with acute ischemic stroke?

Bottom Line

Intravenous tPA given within 3 hours of ischemic stroke onset significantly improves functional outcomes at 3 months, despite an increased risk of symptomatic intracranial hemorrhage.

Major Points

  • Landmark two-part trial that led to FDA approval of IV tPA for acute ischemic stroke within 3 hours (June 1996).
  • Part 1 (n=291): Tested whether tPA improves NIHSS by ≥4 points or resolves the deficit at 24 hours — primary endpoint not significant (47% tPA vs 39% placebo, RR 1.2, 95% CI 0.9–1.6, P=0.21), favorable trend only.
  • Part 2 (n=333, pivotal): Tested 90-day functional outcomes using a global test statistic across 4 scales — significantly favored tPA (global OR 1.7, 95% CI 1.2–2.6, P=0.008).
  • Individual 90-day outcomes (Part 2, tPA vs placebo): mRS 0–1: 39% vs 26% (P=0.019); Barthel Index 95–100: 50% vs 38% (P=0.026); Glasgow Outcome Scale 1: 44% vs 32% (P=0.025); NIHSS ≤1: 31% vs 20% (P=0.033).
  • Symptomatic ICH within 36 hours: 6.4% (20/312, tPA) vs 0.6% (2/312, placebo), P<0.001. Six additional symptomatic ICHs occurred between 36 hours and 3 months (4 tPA, 2 placebo); 11 total deaths were attributed to intracerebral hemorrhage.
  • Mortality at 3 months: 17% (tPA) vs 21% (placebo), not significant (P=0.30). Increased sICH did not translate into excess mortality.
  • Benefit was consistent across stroke subtypes (small-vessel, large-vessel, cardioembolic, other) and across time strata — combined global OR 1.9 (95% CI 1.2–2.9) for 0–90 min and 1.9 (95% CI 1.3–2.9) for 91–180 min.
  • Any ICH within 36 hours (symptomatic + asymptomatic): 10.9% (34/312, tPA) vs 3.5% (11/312, placebo); asymptomatic ICH rates were similar between groups.

Design

Study Type: Randomized, double-blind, placebo-controlled trial (two-part)

Randomization: 1

Blinding: Patients, treating physicians, and outcome assessors were blinded

Enrollment Period: January 1991 – October 1994

Follow-up Duration: 3 months

Centers: 8

Countries: United States

Sample Size: 624

Analysis: Intention-to-treat; Mantel–Haenszel tests for proportions stratified by clinical center and time to treatment; Part 2 primary tested with a global Wald statistic from a generalized linear model with logit-link function; significance set at P<0.05

Inclusion Criteria

  • Clinical diagnosis of ischemic stroke with clearly defined time of onset
  • Able to initiate treatment within 3 hours of symptom onset
  • Deficit measurable on the NIH Stroke Scale
  • Baseline CT scan showing no evidence of intracranial hemorrhage

Exclusion Criteria

  • Another stroke or serious head trauma within the preceding 3 months
  • Major surgery within 14 days
  • History of intracranial hemorrhage
  • Rapidly improving or minor symptoms
  • Symptoms suggesting subarachnoid hemorrhage
  • Gastrointestinal or urinary tract hemorrhage within 21 days
  • Arterial puncture at a non-compressible site within 7 days
  • Seizure at onset of stroke
  • Systolic BP >185 mm Hg or diastolic BP >110 mm Hg (or requiring aggressive treatment to bring BP under these limits)
  • Current use of anticoagulants, or heparin within 48 hours with elevated aPTT
  • Prothrombin time >15 seconds
  • Platelet count <100,000/mm³
  • Blood glucose <50 mg/dL or >400 mg/dL

Baseline Characteristics

CharacteristicControlActive
Mean AgePart 1: 66 ± 11 years; Part 2: 66 ± 13 yearsPart 1: 67 ± 10 years; Part 2: 69 ± 12 years
Sex - Female~41%~43%
Sex - Male~59%~57%
Race - White (non-Hispanic)~64%~66%
Race - Black~28%~26%
Race - Hispanic~6%~6%
Race - Asian/Other~2%~2%
WeightPart 1: 80 ± 18 kg; Part 2: 80 ± 21 kgPart 1: 76 ± 15 kg; Part 2: 76 ± 16 kg
NIH Stroke Scale ScorePart 1: median 14 (range 1–32); Part 2: median 15 (range 2–33)Part 1: median 14 (range 1–37); Part 2: median 14 (range 2–37)
Hypertension~66%~67%
Diabetes Mellitus~20%~22%
Myocardial Infarction~20%~23%
Angina Pectoris~23%~21%
Congestive Heart Failure~18%~15%
Atrial Fibrillation~18%~19%
History of Stroke~13%~14%
History of TIA~17%~17%
Aspirin Therapy~28%~40%
Smoking (year before stroke)~36%~34%
No Preexisting Disability~92%~93%
Stroke Subtype - Small-Vessel Occlusive~10%~16%
Stroke Subtype - Cardioembolic~44%~44%
Stroke Subtype - Large-Vessel Occlusive~44%~37%
Stroke Subtype - Other~3%~3%
Onset-to-Treatment ≤90 min46% (145/312)50% (157/312)
Onset-to-Treatment 91–180 min54% (167/312)50% (155/312)

Arms

FieldtPA GroupControl
InterventionIntravenous alteplase (rt-PA) 0.9 mg/kg (max 90 mg): 10% given as IV bolus over 1 minute, remaining 90% infused over 60 minutes. No anticoagulants or antiplatelet agents allowed for 24 hours after treatment. BP management per protocol: if SBP >185 or DBP >110, treat with IV labetalol before and during infusion; hold tPA if BP not controlled. 24-hour follow-up CT required before starting antithrombotics.Intravenous saline placebo, same administration protocol
DurationSingle infusion within 3 hours of stroke onsetSingle infusion within 3 hours of stroke onset

Outcomes

OutcomeTypeControlInterventionHR / OR / RRP-value
Part 2 (pivotal) primary: global test statistic combining favorable outcomes on 4 scales at 90 days (mRS 0–1, Barthel Index ≥95, Glasgow Outcome Scale 1, NIHSS ≤1). Part 1 primary: improvement of ≥4 points on NIHSS or complete resolution of neurologic deficit at 24 hours.PrimaryPart 2 global test: favorable outcome rates 26–38% across the 4 scales. Part 1 primary (24 h NIHSS improvement): 39% (57/147).Part 2 global test: favorable outcome rates 31–50% across the 4 scales. Part 1 primary (24 h NIHSS improvement): 47% (67/144).Part 2 global OR 1.7Part 2 global: P=0.008; Part 1 primary (24 h NIHSS): P=0.21
mRS 0–1 at 90 days (Part 2)Secondary26%39%OR 1.7 (1.1–2.6)0.019
Barthel Index 95–100 at 90 days (Part 2)Secondary38%50%OR 1.6 (1.1–2.5)0.026
Glasgow Outcome Scale 1 at 90 days (Part 2)Secondary32%44%OR 1.6 (1.1–2.5)0.025
NIHSS ≤1 at 90 days (Part 2)Secondary20%31%OR 1.7 (1.0–2.8)0.033
NIHSS improvement ≥4 points or resolution at 24 hours (Part 1 primary, 0–180 min)Secondary39% (57/147)47% (67/144)RR 1.2 (0.9–1.6)0.21
Mortality at 3 months (combined)Secondary21% (64/312)17% (54/312)0.30
Symptomatic intracerebral hemorrhage within 36 hoursAdverse0.6% (2/312)6.4% (20/312)<0.001
Any intracerebral hemorrhage within 36 hours (symptomatic + asymptomatic)Adverse3.5% (11/312)10.9% (34/312)Not reported for total (P<0.001 applies to symptomatic only)
Fatal intracerebral hemorrhage within 36 hoursAdverse0.3% (1/312)2.9% (9/312)Not reported by group (11 total ICH-attributed deaths by 3 months, group-specific breakdown not given)
Serious systemic bleeding within 10 daysAdverse0% (0/312)1.6% (5/312)Not reported (transfusion status not stated)
Minor external bleeding within 10 daysAdverse3%23%
New ischemic strokeAdversePart 1: 7%; Part 2: 4%Part 1: 8%; Part 2: 4%

Subgroup Analysis

Benefit of tPA was consistent across prespecified subgroups: age, baseline stroke severity, stroke subtype (small-vessel, large-vessel, cardioembolic, other), and use of aspirin before stroke. In the combined analysis, the global OR for a favorable 3-month outcome was 1.9 (95% CI 1.2–2.9) for patients treated 0–90 min from onset and 1.9 (95% CI 1.3–2.9) for those treated 91–180 min — benefit was significant in both time strata. Adjustment for baseline imbalances (aspirin use, weight, age) increased the Part 2 global OR to 2.0 (95% CI 1.3–3.1).

Criticisms

  • 6.4% symptomatic ICH rate — acceptable risk/benefit, but led to initial reluctance in adoption.
  • Strict 3-hour window limited generalizability; later trials (ECASS III, IST-3) extended to 4.5 hours.
  • Part 1 primary endpoint (24-hour NIHSS improvement) was not significant — only Part 2 (90-day outcomes) was positive.
  • Excluded rapidly improving or minor stroke symptoms — debated whether these patients may also benefit (later addressed by PRISMS and TEMPO-2).
  • No advanced imaging selection (CTA, CTP, MRI) — all decisions based on non-contrast CT only.
  • Small sample size (624) by modern standards, though sufficient for the effect size observed.
  • Limited racial diversity — ~65% White, ~27% Black — limited data in Hispanic and Asian populations.
  • No vascular imaging required — stroke subtypes classified retrospectively, vessel occlusion status unknown.
  • Protocol mandated BP control <185/110 but no standardized antihypertensive protocol across sites.

Funding

National Institute of Neurological Disorders and Stroke (NINDS), National Institutes of Health (NIH)

Based on: NINDS (New England Journal of Medicine, 1995)

Authors: The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group

Citation: N Engl J Med 1995;333:1581–1587

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