Trial NINDS

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. 

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. ... 

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. " ... 

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. 

Cost-analysis data on the NINDS trial with tPA estimates that total health care costs (including acute and long-term costs) could be reduced by almost 5 million for every 1000 patients treated with tPA. Although tPA is expensive, when the total health care costs are factored in, savings can accrue to the health care system as a direct result of appropriate tPA therapy. ... 

On the basis of the NINDS trial and the previously reported IV rt-PA experience, rt-PA was approved in the United States, and its use was endorsed in consensus guidelines published by the American Heart Association Stroke Council [48,49] and the American Academy of Neurology [50] for treatment of acute ischemic stroke. 

Other Phase IV studies and studies based on routine clinical practice The standard treatment with Alteplase to reverse stroke stndy (STARS) [55] inclnded 389 patients treated within 3 h of stroke onset. The Canadian Activase for Stroke Effectiveness Stndy (CASES) [56] inclnded 1,132 patients from 60 centers in Canada. These two Phase IV stndies demonstrated ontcomes and safety comparable to the NINDS trials. 

Patients will be admitted to the ICU for hemodynamic monitoring for a minimum of 24 h. A noiunvasive blood pressure cuff is recommended unless sodium lutroprus-side is required. BP will be strictly controlled according to the guidelines used in the NINDS trial as listed below. Clinical deterioration associated with acute reduction in blood pressure should be evaluated immediately. 

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. ... 

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. 

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

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. 

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. 

Alteplase (rt-PA Activase) is an IV thrombolytic (fibrinolytic) that was approved for acute stroke treatment in 1996 based on the results of the National Institute of Neurological Disorders and Stroke (NINDS) rt-PA Stroke Trial.10 The current American Stroke Association guidelines include alteplase as the only Food and Drug Administration (FDA) approved acute treatment for ischemic stroke and strongly encourage early diagnosis and treatment of appropriate patients.11... 

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. 

With the development of thrombolytic therapies (NINDS Stroke-Trial 1995 Hack e et al. 1995) there is a high demand for new methods which provide detailed information on the infarcted parenchyma, especially for those methods which enable characterization of tissue that is potentially salvageable by reperfusion therapy. Since the concentration of key metabolites may play a pivotal role, MR spectroscopy may have an impact on treatment decisions. 

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