NINDS

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. ... 

The NINDS rt-PA smdy was divided into two parts. NINDS part I included 291 patients and NINDS part II included 333 patients. In both parts, acute ischemic stroke patients presenting within 3 hours of symptom onset were randomized to placebo versus treatment with the human rt-PA Alteplase (Activase). The dose was 0.9 mg/kg (maximum dose 90 mg), with 10% of the total dose given as a bolus and the remaining 90% infused over 60 minutes. Inclusion and exclusion criteria for both parts are listed in Table 3.2. These criteria are now the standard clinical criteria used to determine IV rt-PA eligibility in acute stroke patients. 

The primary outcome of NINDS part I was early clinical improvement by 24 hours, dehned as complete resolution of the stroke symptoms or an improvement in the National Instimte of Health Stroke Scale (NIHSS) score by 4 or more points. There was no difference in early clinical improvement in the rt-PA group compared to the placebo group (relative risk 1.2, 95% Cl 0.9-1.6, p = 0.21). 

The primary outcome of NINDS part II was a favorable outcome at 3 months, as assessed by four commonly used assessment scales the Barthel Index (BI), modihed Rankin Scale (mRS), Glasgow Outcome Scale (GOS), and NIHSS. A... 

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). 

FIGURE 3.2 Differences between IV rt-PA and placebo-treated patients on four assessment scales using data taken from part II of the 1995 NINDS trial. Values do not total 100% because of rounding. The odds ratio for a global favorable outcome with intravenous rt-PA was 1.7 (95% Cl 1.2-2.6, p = 0.008). The global favorable outcome was defined as NIHSS, 0-1 Barthel Index, 95-100 modified Rankin Scale, 0-1 and Glasgow Outcome Scale, 5. 

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. 

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

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

Generalized efficacy of t-pa for acute stroke. Subgroup analysis of the NINDS t-pa stroke trial. Stroke. 1997 28 2119-2125. 

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. 

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 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... 

Haley Jr EC, Lewandowski C, Tilley BC. Myths regarding the NINDS rt-PA Stroke Trial setting the record straight. Ann Emerg Med 1997 30 676-682. 

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... 

Small vessel/lacunar strokes have better short- and long-term (1-year) survival as compared to other stroke subtypes. In the NINDS trial of rt-PA within 3 hours of onset, patients classified as small vessel stroke on the basis of their clinical syndrome had a 50% chance of a normal NIHSS score at 3 months if they received placebo, increasing to 70% in the treatment group. In the Lausanne cohort, 95% were independent after their first event, as opposed to only 65% of the cardioembolic strokes and 49% with large vessel atherothrombotic infarctions. Eighty-two percent of patients with small vessel stroke were independent at 1 year. Even at the time of maximal deficit, between 38% and 64% of small vessel/lacunar patients were independent, with motor impairment and extent of white matter disease adversely affecting outcomes. " In TOAST, small vessel/lacunar stroke was the only subtype associated with a favorable outcome, independent of the NIHSS score. ... 

Erankel MR, Morgenstem LB, Kwiatkowski T, Lu M, Tilley BC, Broderick JP, Libman R, Levine SR, Brott T. Predicting poor prognosis after acute ischemic stroke an analysis of the placebo group from the NINDS rt-PA stroke trial. Neurology 2000 54 A89. 

More recently, thrombolytic therapy was reported in 106 patients as part of the TEMPiS system in Bavaria, Germany. The network consists of two comprehensive and 12 regional centers connected by around-the-clock telemedicine support for stroke care. In the first year following intervention, the number of patients treated with rt-PA increased to 86 patients (2% of all patients admitted with stroke), compared to 10 patients treated in the year preceding intervention. The rate of symptomatic hemorrhage was 8.5%, similar to the NINDS trial. " ... 

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. 

Lattimore SU, Chalela J, DavisL, DeGrabaT, Ezzeddine M, Haymore J, Nyquist P, Baird AE, Hallenbeck J, Warach S. Impact of establishing a primary stroke center at a community hospital on the use of thrombol)4ic therapy the NINDS suburban hospital stroke center experience. Stroke 2003 34 e55-e57. 

---