NINDS Trial: IV tPA for Acute Ischemic Stroke (0-3 Hours)
In patients with acute ischemic stroke within 3 hours of symptom onset, does IV alteplase 0.9 mg/kg improve neurologic outcome at 90 days compared with placebo?
The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group (NEJM 1995) · doi:10.1056/NEJM199512143332401 · 624 patients
Population
Included
- Ischemic stroke with clearly defined onset time
- Treatment initiation within 180 minutes of onset
- Measurable NIHSS deficit
- Non-contrast CT without intracranial hemorrhage
- Ischemic stroke with a clearly defined time of onset
- Treatment able to be initiated within 180 minutes (3 hours) of symptom onset
- A measurable neurological deficit on the NIHSS
- Baseline non-contrast CT of the brain showing no evidence of intracranial hemorrhage
Excluded
- SBP >185 or DBP >110 mmHg
- Rapidly improving or minor symptoms
- Recent surgery, stroke, or trauma
- Anticoagulants with elevated PTT
- Platelets <100,000; glucose <50 or >400 mg/dL
- Seizure at stroke onset
- Stroke or serious head trauma within the preceding 3 months
- Major surgery within 14 days
- History of intracranial hemorrhage
- Systolic blood pressure >185 mmHg or diastolic blood pressure >110 mmHg at the time of treatment (or requiring aggressive treatment to reduce BP to these limits)
- Rapidly improving or minor symptoms
- Symptoms suggestive of subarachnoid hemorrhage
- Gastrointestinal or urinary tract hemorrhage within the preceding 21 days
- Arterial puncture at a non-compressible site within the preceding 7 days
- Seizure at the onset of stroke
- Taking anticoagulants or had received heparin within the 48 hours preceding onset with an elevated aPTT
- Prothrombin time >15 seconds
- Platelet count <100,000/mm³
- Blood glucose <50 mg/dL or >400 mg/dL
Source: NINDS rt-PA Stroke Study Group, NEJM 1995;333:1581–1587; PMID 7477192· Retrieved 2026-06-08
Primary Outcome
mRS 0–1 at 90 Days
Study Arms
- Agent
- Alteplase (Activase, Genentech), recombinant tissue plasminogen activator (t-PA)
- Dose
- 0.9 mg/kg (maximum 90 mg)
- Route
- IV
- Frequency
- 10% of the total dose as an IV bolus, then the remaining 90% as a constant IV infusion
- Duration
- 60-minute infusion (remainder after bolus)
- Co-interventions
- Best medical care; protocol prohibited anticoagulants AND antiplatelet agents for 24 hours after treatment; blood pressure maintained within prespecified limits
Dose/administration verbatim from NINDS NEJM 1995 p.1582 (Randomization and Treatment). Two-part design: Part 1 (n=291) and Part 2 (n=333); 624 total. The mandatory 24-h antithrombotic prohibition and BP control originated in this protocol. No NCT (1995 predates registry).
- Agent
- Matching placebo (supplied by Genentech)
- Dose
- Volume-matched to alteplase
- Route
- IV
- Frequency
- Identical 10% bolus then constant-infusion schedule
- Duration
- 60-minute infusion
- Co-interventions
- Best medical care; identical 24-hour prohibition of anticoagulants and antiplatelet agents; same BP control
Double-blind, placebo-controlled, 1:1, permuted-block randomization stratified by center and onset-to-treatment time (0–90 vs 91–180 min). Source: NINDS NEJM 1995 p.1582.
Safety
Symptomatic ICH within 36h
6.4%
0.6%
Combined Parts 1+2: 6.4% tPA vs 0.6% placebo (P<0.001). Of 28 sICH patients, 17 (61%) died by 3 months. ICH risk is the central safety trade-off of IV thrombolysis.
90-day mortality
17%
21%
17% tPA vs 21% placebo (P=0.30). No significant difference despite higher sICH. Fatal outcomes were balanced by improved functional outcomes overall.
Trial Design
Type
- Two-part randomized controlled trial
- Double-blind, placebo-controlled
- 1:1 allocation (Alteplase vs. Placebo)
Timeline
Enrolled 1991-1994
N
624
Enrollment
624 patients across 8 US centers, 2 parts (291 + 333). Enrolled January 1991 – October 1994. Published NEJM 1995. Foundational FDA approval data for IV alteplase in acute ischemic stroke.
Bedside Pearl
NINDS established IV alteplase for 0–3 h acute ischemic stroke (NNT ~7 for mRS 0–1). Time-stratified analysis (Marler 2000) confirmed earlier treatment is better. Door-to-needle <60 min, target <30 min.