Original ResearchRecombinant Tissue Plasminogen Activator for Minor Strokes: The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Experience
Introduction
Intravenous recombinant tissue plasminogen activator is an effective treatment for acute ischemic stroke when given within 180 minutes of symptom onset in carefully selected patients.1 Patients treated with intravenous tissue plasminogen activator are 30% to 50% more likely to have an excellent or near-normal recovery at 3 months poststroke compared with those treated with placebo. This benefit is sustained and can also be demonstrated 1 year poststroke.2
Patients enrolled in the 2 trials within the National Institute of Neurological Disorders and Stroke (NINDS) rt-PA Stroke Study were evaluated with a variety of quantitative assessment scales, including the National Institutes of Health Stroke Scale (NIHSS), a standardized, reliable, and validated measure of the severity of the clinical neurological deficits.3, 4 Requirement for eligibility was a measurable neurologic deficit on the NIHSS (ie, a minimal NIHSS of 1). The study had several highly specific exclusion criteria about patients whose clinical deficits, as measured by the NIHSS, were relatively mild in selective spheres of neurologic deficits. Patients with these specific clinical stroke syndromes were therefore not treated. However, there was enrollment of a broad clinical spectrum of ischemic stroke patients, including some whose neurologic deficits were minor.
Given the potential risk of intracerebral hemorrhage from tissue plasminogen activator therapy, its value in patients with less severe clinical deficits has been questioned5 and is worthy of a more detailed evaluation.
It is also important to clarify the definition(s) of minor stroke and its relationship to stroke subtype and of stroke severity as defined by NIHSS,3, 4 which would allow a sharper conceptualization and standardization of the qualitative and quantitative aspects of a minor stroke.
We present further data from the NINDS rt-PA Stroke Study using post hoc exploratory analyses to further define what constitutes and could define a “minor stroke,” study the effect of tissue plasminogen activator on minor stroke (treatment effect, outcome, and intracerebral hemorrhage risk), and help address the question of whether patients with a minor stroke should be treated with tissue plasminogen activator.
Section snippets
Study Design
We undertook post hoc subgroup analyses of randomized, double-blind, clinical trials.
Setting
Academic and university-based hospitals and community hospitals screened, enrolled, and followed up eligible patients from 1991 to 1995.
Selection of Participants
Six hundred twenty-four patients with acute ischemic stroke within 180 minutes of symptom onset were included. For this investigation, subsets of the patients from the NINDS rt-PA Stroke Study who fulfilled predefined definitions of specific minor stroke syndrome definitions
Results
Patients were treated in the NINDS rt-PA Stroke Study with NIHSS scores as low as 1 and as high as 37, with a median of 14 (25th and 75th quartiles=9 and 20). Of the 624 patients randomized in the 2 trials that were performed during the study, 177 patients (99 in the tissue plasminogen activator–treated group and 78 in the placebo-treated group) had a baseline NIHSS score less than or equal to 9 (least severe quartile of patients). Of these patients, 29% had more than just motor deficits (ie,
Limitations
Because our analyses were post hoc and exploratory, our results should be considered hypothesis generating. We did not attempt to offer every possible definition of what constitutes a minor stroke; we chose only selected, quantifiable definitions based on the NIHSS because the NIHSS was used in the NINDS rt-PA Stroke Study as an inclusion criteria (measurable deficit on the NIHSS). Our analyses are based on relatively small sample sizes, and therefore we are cautious about extrapolating and
Discussion
Determining the type and severity of neurologic deficits that constitute a “minor” stroke can be problematic and is likely without current consensus. Nonetheless, determining which acute-stroke patients have a mild or slight deficit has particular relevance now that thrombolytic therapy, with its inherent hemorrhagic risks, is available. Our exploration of the boundaries of minor stroke has provided 5 definitions that take into account types of deficits, quantitative degree of neurologic
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Supervising editor: William G. Barsan, MD
Author contributions: SRL wrote the first draft and led the analyses. JPB, MRF, JCG, TK, CAL, PDL, and JRM had significant input into the content of the manuscript, substantial editing, and writing of final manuscript. TB, ECH, RL, SP, TDG, SCF, LBM, JPB, MRF, JCG, TK, CAL, PDL, JRM, and SRL had significant input into acquiring data, data analyses, and data interpretation. YL, ML, and BCT were involved with statistical design and significant input into writing of the methods section. SRL takes responsibility for the paper as a whole.
Funding and support: Supported in part by NIH/NINDS contracts NO1-NS-23373, NO1-NS-02374, NO1-NS-02377, NO1-NS-02381, NO1-NS-02379, NO1-NS-02378, NO1-NS-02376, NO1-NS-02382, and NO1-NS-02380 and by NIH/NINDS grants K24NS43992 and P01NS23393.
Reprints not available from the authors.
Address for correspondence: Steven R. Levine, MD, Stroke Program, Box 1137, Department of Neurology, The Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, NY 10029-6574; 212-241-1970, fax 212-241-6971; E-mail [email protected].
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All members are listed in Appendix 1.