Findings From the Reanalysis of the NINDS Tissue Plasminogen Activator for Acute Ischemic Stroke Treatment Trial

Abstract

Background and Purpose-Following publication of concerns about the results of the National Institute of NeurologicalDisorders and Stroke (NINDS) intravenous tissue plasminogen activator (t-PA) in acute stroke treatment trial, NINDS commissioned an independent committee "to address whether there is concern that eligible stroke patients may not benefit from t-PA given according to the protocol used in the trials and, whether the subgroup imbalance (in baseline stroke severity) invalidates the entire trial." Methods-The original NINDS trial data were reanalyzed to assess the t-PA treatment effect, the effect of the baseline imbalance in stroke severity between the treatment groups on the t-PA treatment effect, and whether subgroups of patients did not benefit from receiving t-PA. Results-A clinically important and statistically significant benefit of t-PA therapy was identified despite subgroup imbalances in baseline stroke severity and an increased incidence of symptomatic intracerebral hemorrhage in t-PA treated patients. The adjusted t-PA to placebo odds ratio (OR) of a favorable outcome was 2.1 (95% CI, 1.5 to 2.9). Although these exploratory analyses found no statistical evidence that the t-PA treatment effect differed among patient subgroups, the study was not powered to detect subgroup treatment differences. Conclusions-These findings support the use of t-PA to treat patients with acute ischemic stroke within 3 hours of onset under the NINDS t-PA trial protocol. Health professionals should work collaboratively to develop guidelines to ensure appropriate use of t-PA in acute ischemic stroke patients.

4.5 Hours

“…3 Similar to the National Institute of Neurological Diseases and Stroke analysis, this made no difference and the results remain clearly and undeniably positive. 4 Intriguingly, although the link between time and treatment effect is further confirmed by these results, there was no increase in the rate of symptomatic intracerebral hemorrhage beyond 3 hours using a variety of different definitions. The rate was essentially the same as the National Institute of Neurological Diseases and Stroke trial at 7% using the conservative National Institute of Neurological Diseases and Stroke definition.…”

Thrombolysis for acute ischemic stroke: does it work?—the con position

“…6 Two groups re-analysed the NINDS data adjusting for baseline differences, with different conclusions. 7,8 Furthermore, care in a multidisciplinary stroke unit is the only proven therapy to date, with a reduction in death and disability equivalent to that claimed by thrombolysis. 9 IST-3 was the only trial to control for this variable, and it is plausible that some of the benefits seen in NINDS and ECASS-III were due to variability in level of care.…”

Intravenous Thrombolytics for Ischemic Stroke

“…At the same time, a smaller study, the Alteplase Thrombolysis for Acute Noninterventional Therapy in Ischemic Stroke (ATLANTIS) study tested delayed (3-to 5-h) administration of alteplase, but it was negative. Independent re-analysis of the NINDS data [52], and a pooled analysis of all patients in all of these 4 trials confirmed the positive effect of t-PA and demonstrated the importance of treating patients as early in the course of their infarction as possible [53]. The odds ratio of a favorable 3-month outcome increased as the onset to treatment time decreased (p=0.005).…”