tPA for acute stroke: balancing baseline imbalances =================================================== * David Gladstone * Michael Hill * Sandra Black Mann draws attention to 2 important points: (1) stroke outcome depends heavily on initial stroke severity as measured by the National Institutes of Health Stroke Scale (NIHSS), and (2) baseline imbalances in stroke severity could potentially affect the results of a stroke trial. However, the assertion that the NINDS tPA trial results are invalid is incorrect. The original NINDS trial publication (1995)1 reported the treatment and placebo groups to be well balanced in terms of initial stroke severity (median NIHSS 14 v. 15). According to further data published 5 years later in a post-hoc analysis,2 it does appear that there were more patients in the tPA group with mild stroke (NIHSS 0–5) and fewer patients with very severe stroke (NIHSS >> 20) compared to placebo. This imbalance was evident primarily in the 91–180 minute onset-to-treatment cohort and less prominent in the 0–90 minute cohort or in the entire study cohort. No baseline imbalances were in favour of the tPA group for patients with moderate or severe stroke (NIHSS 6–10, 11–15, 16–20). Mann speculates that the positive results of the NINDS trial were driven by this baseline imbalance in stroke severity. However, the actual data do not bear this out. We obtained data directly from the NINDS investigators to clarify this issue (see Table 1). These data show that even if one excludes the subgroups with baseline imbalances (NIHSS 0–5 or >> 20), the efficacy of tPA in the NINDS trial still holds true — a 16.6% absolute benefit for patients with moderate severity stroke (NIHSS 6–10) and a 10.4% absolute benefit for patients with severe stroke (NIHSS 11–20). This is reassuring since in clinical practice the major target of tPA therapy is patients with moderate to severe deficits. The overall benefit of tPA, therefore, does not appear to be driven by baseline imbalances in the very mild or very severe subgroups. View this table: [Table1](http://www.cmaj.ca/content/166/13/1652/T1) Table 1. Contrary to Mann's speculation that there might be an excessive benefit in the NIHSS 0–5 or >> 20 subgroups driving the overall benefit attributable to tPA in the trial, actually much less benefit is derived for patients in these subgroups. Caution is advised in interpreting subgroup analysis, however, because this trial was not powered to determine efficacy in these subgroups. These raw data are explored further in the multivariable analysis published by the NINDS investigators in which adjustment is made for baseline NIHSS score and other potential confounding variables.3 tPA was the most important predictor of outcome and no interaction effects were seen, suggesting the effect of tPA was robust across all patient groups. Other important predictors were the interaction of age with baseline NIHSS score, diabetes, interaction of age with mean blood pressure and early CT ischemic changes. The interaction term NIHSS score by age implies that both age and baseline NIHSS were independent predictors of outcome; statistically, however, age modifies the effect of baseline NIHSS score such that at older ages the baseline NIHSS becomes increasingly important in magnitude as a predictor of outcome. Because of this, it is not possible to clinically interpret an odds ratio for baseline NIHSS score or age in isolation — only their interaction has clinical meaning, and it is correct to report only the interaction term as the NINDS investigators had done. Therefore, it is not true that adjustment for baseline NIHSS was not considered. The effect of tPA was robust even after accounting for baseline NIHSS score. Mann's reference to a Food and Drug Administration submission is not relevant here because it refers to a nonrandomized, open-label, dose-escalation study of angiographic recanalization, not the NINDS tPA stroke trial. **David Gladstone** Fellow Division of Neurology Sunnybrook and Women's College Health Sciences Centre Toronto, Ont. **Michael Hill** Assistant Professor Calgary Stroke Program Dept. of Clinical Neurosciences University of Calgary Foothills Medical Centre Calgary, Alta. **Sandra Black** Head, Division of Neurology and Medical Director Regional Stroke Program Sunnybrook and Women's College Health Sciences Centre Toronto, Ont. ## References 1. 1. National Institute of Neurological Disorders and Stroke rtPA Stroke Study Group. Tissue plasminogen activator for acute ischemic stroke. N Engl J Med 1995;333:1581-7. [CrossRef](http://www.cmaj.ca/lookup/external-ref?access_num=10.1056/NEJM199512143332401&link_type=DOI) [PubMed](http://www.cmaj.ca/lookup/external-ref?access_num=7477192&link_type=MED&atom=%2Fcmaj%2F166%2F13%2F1652.atom) [Web of Science](http://www.cmaj.ca/lookup/external-ref?access_num=A1995TK06500001&link_type=ISI) 2. 2. Marler JR, Tilley BC, Lu M, Brott TG, Lyden PC, Grotta JC, et al. Early stroke treatment associated with better outcome: the NINDS rt-PA stroke study. Neurology 2000;55:1649-55. [Abstract/FREE Full Text](http://www.cmaj.ca/lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6OToibmV1cm9sb2d5IjtzOjU6InJlc2lkIjtzOjEwOiI1NS8xMS8xNjQ5IjtzOjQ6ImF0b20iO3M6MjI6Ii9jbWFqLzE2Ni8xMy8xNjUyLmF0b20iO31zOjg6ImZyYWdtZW50IjtzOjA6IiI7fQ==) 3. 3. The NINDS tPA Stroke Study Group. Generalized efficacy of tPA for Acute Stroke: subgroup analysis of the NINDS tPA Stroke Trial. Stroke 1997; 28:2119-25. [Abstract/FREE Full Text](http://www.cmaj.ca/lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6OToic3Ryb2tlYWhhIjtzOjU6InJlc2lkIjtzOjEwOiIyOC8xMS8yMTE5IjtzOjQ6ImF0b20iO3M6MjI6Ii9jbWFqLzE2Ni8xMy8xNjUyLmF0b20iO31zOjg6ImZyYWdtZW50IjtzOjA6IiI7fQ==)