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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?

Study Overview

Objective

To evaluate the effectiveness and safety of tPA (0.9mg/kg) within a 3-hour window from stroke onset.

Study Summary

IV tPA (0.9 mg/kg) within 3 hours of stroke onset significantly improved 90-day functional outcomes (global OR 1.7, 95% CI 1.2–2.6, p=0.008).
mRS 0–1 at 90 days: 39% (tPA) vs 26% (placebo), p=0.019; NNT = 8 for one additional independent survivor.
Symptomatic ICH within 36h: 6.4% vs 0.6% (p<0.001); NNH = 18.
Mortality at 3 months: 17% vs 21% (p=0.30) — non-significant trend favoring tPA.
Benefit was greatest 0–90 minutes from onset and consistent across stroke subtypes.
Foundation of modern thrombolysis — led to FDA approval of IV tPA in 1996.

Intervention

tPA administered at 0.9 mg/kg, up to 90 mg, within 3 hours of stroke onset.

Patients per Arm

tPA: 312, Placebo: 312

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

Characteristic	Control	Active
Mean Age	Part 1: 66 ± 11 years; Part 2: 66 ± 13 years	Part 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%
Weight	Part 1: 80 ± 18 kg; Part 2: 80 ± 21 kg	Part 1: 76 ± 15 kg; Part 2: 76 ± 16 kg
NIH Stroke Scale Score	Part 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 min	46% (145/312)	50% (157/312)
Onset-to-Treatment 91–180 min	54% (167/312)	50% (155/312)

Arms

Field	tPA Group	Control
Intervention	Intravenous 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
Duration	Single infusion within 3 hours of stroke onset	Single infusion within 3 hours of stroke onset

Outcomes

Outcome	Type	Control	Intervention	HR / OR / RR	P-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.	Primary	Part 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 1.7	Part 2 global: P=0.008; Part 1 primary (24 h NIHSS): P=0.21
mRS 0–1 at 90 days (Part 2)	Secondary	26%	39%	OR 1.7 (1.1–2.6)	0.019
Barthel Index 95–100 at 90 days (Part 2)	Secondary	38%	50%	OR 1.6 (1.1–2.5)	0.026
Glasgow Outcome Scale 1 at 90 days (Part 2)	Secondary	32%	44%	OR 1.6 (1.1–2.5)	0.025
NIHSS ≤1 at 90 days (Part 2)	Secondary	20%	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)	Secondary	39% (57/147)	47% (67/144)	RR 1.2 (0.9–1.6)	0.21
Mortality at 3 months (combined)	Secondary	21% (64/312)	17% (54/312)		0.30
Symptomatic intracerebral hemorrhage within 36 hours	Adverse	0.6% (2/312)	6.4% (20/312)		<0.001
Any intracerebral hemorrhage within 36 hours (symptomatic + asymptomatic)	Adverse	3.5% (11/312)	10.9% (34/312)		Not reported for total (P<0.001 applies to symptomatic only)
Fatal intracerebral hemorrhage within 36 hours	Adverse	0.3% (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 days	Adverse	0% (0/312)	1.6% (5/312)		Not reported (transfusion status not stated)
Minor external bleeding within 10 days	Adverse	3%	23%
New ischemic stroke	Adverse	Part 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)