Neurology & Psychiatry · 1995
NINDS rt-PA Stroke Trial
National Institute of Neurological Disorders and Stroke recombinant tissue plasminogen activator Stroke Study
Before 1995, a physician managing acute ischemic stroke could offer supportive care, aspirin, and little else. Two large European thrombolysis trials in the early 1990s had enrolled patients up to six hours after symptom onset and found no benefit; the question was whether the time window, the dose, or the drug itself was at fault. The NINDS investigators bet on time: if the penumbra was the target, treatment had to arrive before it became infarct.
The National Institute of Neurological Disorders and Stroke funded a two-part trial at eight academic centers across the United States. Part 1 asked whether rt-PA improved neurological status at 24 hours; Part 2 used three-month outcomes on four validated disability scales. All 624 patients received treatment within three hours of documented symptom onset, and the dose was fixed at 0.9 mg/kg intravenously. Concurrent anticoagulation was prohibited to limit hemorrhage risk.
Neither part showed a statistically significant difference at 24 hours on the primary neurological endpoint, but the three-month data were clear. Patients who received rt-PA were at least 30 percent more likely to have minimal or no disability at 90 days across all four outcome measures: the National Institutes of Health Stroke Scale, the Barthel Index, the modified Rankin Scale, and the Glasgow Outcome Scale. The price was a symptomatic intracranial hemorrhage rate of 6.4 percent on rt-PA versus 0.6 percent on placebo. Crucially, 30-day mortality was similar in both groups, indicating that the hemorrhage risk did not eliminate the functional benefit.
The FDA approved intravenous rt-PA for ischemic stroke in June 1996, making it the first pharmacologic treatment for the condition. The approval created pressure on hospitals to reorganize; treating patients within three hours from symptom onset required rapid triage, immediate brain imaging, and stroke-team activation at all hours. This drove the creation of designated stroke units and door-to-needle time tracking programs modeled on the systems already used for STEMI.
Subsequent work refined patient selection rather than abandoning the drug. The ECASS III trial in 2008 extended the treatment window to 4.5 hours in selected patients. Later imaging-based trials, including DAWN and DEFUSE 3 published in 2018, identified patients with salvageable penumbra who benefited from thrombectomy or thrombolysis well beyond that window. All of that work built on the NINDS finding that time from onset was the defining variable.
Key People
- NINDS rt-PA Stroke Study Group — NIH-funded multicenter group that designed and conducted the trial
- John Marler — NINDS program officer and principal organizer of the study
- Thomas Brott — Cincinnati stroke neurologist, lead clinical investigator
- Joseph Broderick — Co-investigator who contributed to trial design and hemorrhage analysis
N Engl J Med. 1995
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