The NINDS rtPA Stroke Study was conducted at the same time as ECASS I. The NINDS trial was the first large, randomized, double-blinded trial to show benefit of a thrombolytic in acute stroke (15). Patients were enrolled if they presented within 3 hr of an acute ischemic stroke and had a deficit [as measured by the National Institute of Health (NIH) Stroke Scale, (NIHSS)], and a CT scan that showed no evidence of hemorrhage. Noteworthily, no patients were excluded due to signs of early ischemic change, as in the ECASS trials. Table 1 contains a complete list of inclusion and exclusion criteria. Once patients were randomized, they were either administered IV rtPA at a total dose of 0.9 mg/kg (10% as bolus, remainder over 1 hr) or placebo. No patients were administered anticoagulants or antiplatelets for 24 hr after infusion of study drug, and blood pressure was strictly maintained at <185/110. The trial was split into two parts. Part 1 was designed to test if rtPA had early clinical effect. Part 2 was designed to test if rtPA improved clinical outcome at three months. Excellent protocol adherence was reported for both parts of the trial, with at least 90% of patients receiving the full dose of study drug.
Part 1 enrolled 291 patients, and by a predetermined randomization scheme, patients were stratified into two blocks according to length of time from onset of stroke to start of treatment, i.e., either 0 to 90 min or 91 to 180 min. The primary hypothesis of early clinical improvement was defined as a complete resolution of symptoms or an improvement from baseline NIHSS score of 4 or more points at 24 hr after the onset of stroke. Of the 144 patients who received rtPA, 67 (47%) showed an early clinical improvement, whereas of the 147 patients who received placebo, 57 (39%) showed an early clinical improvement (p = 0.21). Symptomatic ICH occurred in eight (6%) of patients treated with rtPA, and none occurred in the placebo group.
In the interim analysis of the results from Part 1, the Data and Safety Monitoring Board determined that the prospectively determined secondary outcome favored the rtPA group. A new trial was recommended, which exactly replicated the first trial, but with a primary hypothesis that a consistent and persuasive difference would be observed between the two groups in terms of improvement to little or no deficit three months after the treatment.
Part 2 enrolled 333 patients. Primary outcome was measured by the Barthel Index (score 95 or 100), the mRS (grade 0 -1), the Glasgow Coma Scale (grade 1), and the NIHSS (score 0 or 1). The proportion of patients with improved clinical outcome was significantly higher in the rtPA group than in the placebo group. Symptomatic ICH occurred in 12 (7%) patients treated with rtPA and 2 (1%) patients in the placebo group.
Combining the two parts of the NINDS trial, a significant benefit was revealed for rtPA at 3 months, measured by all four functional outcome scales. The aggregate rate of symptomatic ICH was 6.4% in the rtPA-treated group and 0.6% in the placebo group (p < 0.001). However, no significant difference in mortality was reported between the rtPA group (17%) and the placebo
Table 1 Intravenous Tissue Plasminogen Activator Administration Inclusion/Exclusion Criteria for Ischemic Stroke
group (21%; p=0.30). Although certain rtPA-treated subgroups had worse clinical outcomes than the overall treatment group, all subgroups responded favorably to rtPA therapy when compared to their matched placebo groups (16). This trial was also the first large randomized trial that did not exclude any subtype of ischemic stroke (i.e., large vessel vs. small vessel or thrombotic vs. embolic).
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