NINDS Study

OR 1.81, 95% Cl 1.46-2.24), most of which were related to symptomatic intracranial hemorrhage (OR 3.37, 95% Cl 2.68. 22). In addition, a pooled analysis of six major randomized placebo-controlled IV rt-PA stroke trials (Alteplase Thrombolysis for Acute Noninterventional Therapy in Ischemic Stroke (ATLANTIS) I and II, European Cooperative Acute Stroke Study (ECASS) I and II, and NINDS I and II), including 2775 patients who were treated with IV rt-PA or placebo within 360 minutes of stroke onset, confirmed the beneht up to 3 hours and suggested a potential beneht beyond 3 hours for some patients. The pattern of a decreasing chance of a favorable 3-month outcome as the time interval from stroke onset to start of treatment increased was consistent with the findings of the original NINDS study. ... 

The concept of critical flow thresholds provides the rational basis for attempts to salvage the ischemic penumbra. In the clinical environment, the successful application of thrombolysis in stroke patients (NINDS Study Group 1995) could be shown to be related to this issue fair clinical outcome correlated positively with early recanalization (von Kummer et al. 1995) and even small improvements of local CBF in the 10% range predicted the reversibility of ischemic tissue changes (Butcher et al. 2003). 

The NINDS study of rt-PA within three hours of stroke onset in 624 patients reported a larger treatment effect (National Institute of Neurological Disorders and Stroke rt-PA Study Group 1995) than that seen overall for all studies included in the systematic reviews 160 additional patients per 1000 patients treated were alive and independent at three months in the thrombolysis group, representing a number needed to treat of seven to prevent all death. This was despite an increase in the incidence of cerebral hemorrhage, with an excess of 58 bleeds per 1000 patients treated. The improved outcome in the thrombolysis group was maintained at one year (Kwiatkowski et at 1999). 

This section will review the phase III clinical trials of IV thrombolytic agents for acute ischemic stroke, organized by the type of agent and the time window from stroke onset to study drug delivery (Table 3.1). The 1995 National Institute of Neurological Disorders and Stroke (NINDS) rt-PA trial is presented first because it showed that IV rt-PA, given within 3 hours of stroke onset, reduced stroke-related disability. This trial was the basis for the United States Food and Drug Administration (FDA) approval for rt-PA for use in acute ischemic stroke. 

The current use of IV rt-PA for acute stroke thrombolysis is based on the NINDS rt-PA study, a two-part randomized, double blind, placebo-controlled trial. " This trial was preceded by two open-label, dose-escalation safety studies that suggested that treatment within 180 minutes of stroke onset, and rt-PA dosages no higher than 0.95 mg/kg, was safe and effective. ... 

Based primarily on the study protocol of the 1995 NINDS rt-PA study.Many centers would also exclude patients with known documented endocarditis or aortic dissection, and those with CT hypoattenuation in more than one third of the middle cerebral artery territory. There are insufficient data to support the use of rt-PA for ischemic stroke in pregnancy or in the pediatric population (age <18 years). 

ECASS-II was designed to test a lower dose of rt-PA (0.9 mg/kg) during the same 0-6-hours time period after stroke onset, using similar inclusion criteria as in ECASS-I. ° The primary endpoint was the proportion with a favorable outcome on the mRS scale (defined as a score of 0 or 1). There was no difference in this outcome between rt-PA-treated and placebo controls (40% vs. 37%, p = 0.28). A separate analysis of the 158 subjects enrolled within 3 hours of stroke onset also showed no difference in the proportion with a favorable outcome (42% vs. 38%, p = 0.63) this result, however, must be treated with caution because in ECASS-II there was a substantially lower number of patients treated within 3 hours of stroke onset, compared to the 1995 NINDS rt-PA study. Parenchymal hematoma on post-treatment CT was seen in 12% of rt-PA-treated and 3% of placebo patients (p < 0.001). The 90-day mortality rate was 11 % for the rt-PA group and 11 % for the placebo group (p = 0.54). Protocol violations were much less frequent in ECASS-II compared to ECASS-I (9% vs. 18%), probably because of standardized training in CT interpretation at the study sites. 

The combined experience with IV rt-PA treatment beyond 3 hours, therefore, suggests reduced effectiveness compared to treatment within 3 hours. A pooled analysis of the ATLANTIS, ECASS, and NINDS rt-PA studies confirmed that the odds of a favorable 3-month outcome, defined as minimal or no poststroke disability on the BI, mRS, and NIHSS, decreased with increasing stroke onset to start of treatment time (OTT) (p = 0.005). The odds ratios for favorable outcome with rt-PA treatment were 2.8 (95% Cl 1.8. 5) for OTT 0-90 minutes, 1.6 (95% Cl 1.1-2.2) for 91-180 minutes, 1.4 (95% Cl 1.1-1.9) for 181-270 minutes, and 1.2 (95% Cl 0.9-1.5) for 271-360 minutes. This finding, that earlier treatment is associated with more therapeutic efficacy, supports the adage that in the delivery of acute stroke therapy time is brain. " The rate of sICH was not associated with OTT. ... 

A combined analysis of the ATLANTIS, ECASS-11, and NINDS rt-PA study data found that females had a greater benefit from rt-PA than males (p = 0.04), despite similar initial stroke severity and rates of slCH." This finding may not be relevant to the clinical, FDA-approved use of rt-PA, because most of the analyzed subjects from ATLANTIS and ECASS-11 were randomized greater than 3 hours after stroke onset. Therefore, sex should not be a criterion for patient selection for thrombolysis. 

Intracerebral hemorrhage after intravenous t-pa therapy for ischemic stroke. The NINDS t-pa stroke study group. Stroke. 1997 28 2109-2118. 

Fagan SC, Morgenstern LB, Petitta A, Ward RE, Tilley BC, Marler JR, Levine SR, Broderick JP, Kwiatkowski TG, Frankel M, Brott TG, Walker MD. Cost-effectiveness of tissue plasminogen activator for acute ischemic stroke. NINDS rt-PA Stroke Study Group. Neurology. 1998 50 883-890. 

The Interventional Management of Stroke (IMS I) Study was a multicenter, open-labeled, single-arm pilot study in which 80 patients (median NIHSS 18) were enrolled to receive IV rt-PA (0.6 mg/kg, 60 mg maximum, 15% of the dose as a bolus with the remainder administered over 30 minutes) within 3 hours of stroke onset (median time to initiation 140 minutes). " Additional rt-PA was subsequently administered via a microcatheter at the site of the thrombus in 62 of the 80 patients, up to a total dose of 22 mg over 2 hours of infusion or until complete recanalization. Primary comparisons were with similar subsets of the placebo and rt-PA-treated subjects from the NINDS rt-PA Stroke Trial. The 3-month mortality in IMS I subjects (16%) was numerically lower but not statistically different than the mortality of the placebo (24%) or rt-PA-treated subjects (21%) in the NINDS rt-PA Stroke Trial. The rate of symptomatic ICH (6.3%) in IMS I subjects was similar to that of the rt-PA-treated subjects (6.6%) but higher than the rate in the... 

Hacke W, Donnan G, Fieschi C, Kaste M, von Rummer R, Broderick JP, Brott T, Frankel M, Grotta JC, Haley EC Jr, Kwiatkowski T, Levine SR, Lewandowski C, Lu M, Lyden P, Marler JR, Patel S, Tilley BC, Albers G, Bluhmki E, Wilhelm M, Hamilton S ATLANTIS Trials Investigators ECASS Trials Investigators NINDS rt-PA Study Group Investigators. Association of outcome with early stroke treatment pooled analysis of ATLANTIS, ECASS, and NINDS rt-PA stroke trials. Lancet 2004 363 768-774. 

Dunn B, Davis LA, Todd JW, Chalela JA, Warach S, NINDS/NIH, Bethesda, MD for the ROSIE Investigators. Reperfusion of Stroke Safety Study Imaging Evaluation (ROSIE). Ongoing Clinical Trials Session, 29th International Stroke Conference 2004. 

The severity of the neurological deficit at the time of stroke onset is a major predictor of stroke outcome. In an analysis of the placebo-treated patients in the National Institute of Neurological Disorders and Stroke (NINDS) recombinant tissue-plasminogen activator (rt-PA) study, the best acute predictor of a poor outcome at 1 year was an National Institute of Health Stroke Scale (NIHSS) score >17 for patients over 70 years. These criteria had a high specificity (98%), but sensitivity was only 31%. The low sensitivity of the acute NIHSS score alone in predicting... 

Marler JR, Tilley BC, Lu M, Brott TG, Lyden PC, Grotta JC, Broderick JP, Levine SR, Frankel MP, Horowitz SH, Haley Jr. EC, Lewandowski CA, Kwiatkowski TP. Early stroke treatment associated with better outcome the NINDS rt-PA stroke study. Neurology 2000 55 1649-1655. 

The ATLANTIS, ECASS and NINDS rt-PA Study Group Investigators. Association of outcome with early stroke treatment pooled analysis of ATLANTIS, ECASS, and NINDS rt-PA stroke trials. Lancet 2004 363 768-74. 

Fibrinolytic agents. Intravenous fibrinolysis has been assessed in at least six major international studies. Streptokinase has been abandoned (haemorrhage) while rt-PA is given in the 3-6 hour therapeutic window (secondary analysis disclosed significant results on the RANKIN scale at 3 months (NINDS) and at 3 months (ECASS II)). 

Nicotera P (2003) Molecular switches deciding the death of injured neurons. Toxicol Sci 74 4-9 Niessen F, Hilger T, Hoehn M, Hossmann KA (2003) Differences in clot preparation determine outcome of recombinant tissue plasminogen activator treatment in experimental thromboembolic stroke. Stroke 34 2019-2024 NINDS rt-PA Stroke Study Group (1995) Tissue plasminogen activator for acute ischemic stroke. N Engl J Med 333 1581-1587... 

The less-striking benefit from thrombolysis indicated by the systematic reviews compared with that seen in the NINDS trial may result from methodological differences between trials. These include the fact that many of the earlier trials randomized patients up to six hours from stroke onset, and the likely pathophysiological variability in the patients studied. Further, in the NINDS trial, only carefully selected patients were included and these strict inclusion and exclusion criteria have made these trial results difficult to generalize to clinical practice. One study (Jorgensen et al. 1999) showed that only 5% of patients admitted to hospital in Denmark with ischemic stroke would fulfil fhe enfry criferia for this trial and that only 45% would be eligible for thrombolysis even when the time limit was ignored. 

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