NINDS rt-PA Stroke Trial

Before 1995, a physician managing acute ischemic stroke could offer supportive care, aspirin, and little else. Thrombolysis had been approached cautiously because early trials had high rates of intracerebral hemorrhage, but pilot studies suggested that t-PA helped when started within three hours of onset. 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 randomized, double-blind trial in two parts. Part 1, with 291 patients, asked whether rt-PA improved neurological status at 24 hours; part 2, with 333, tested outcomes at three months on four 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.

Part 1 found no significant difference in neurological improvement at 24 hours, but the three-month data were clear, and part 2 confirmed them (global odds ratio for a favorable outcome 1.7). 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. Mortality at three months was 17 percent with t-PA and 21 percent with placebo, a difference that was not significant.

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. Hospitals set up stroke teams and began tracking door-to-needle times.

Subsequent work refined patient selection. 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, used brain scans to find patients with salvageable tissue who benefited from clot removal by thrombectomy well beyond that window.