tPA for acute stroke: balancing baseline imbalances
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* Jeffrey Mann

In a recent *CMAJ* article,1 David Gladstone and Sandra Black stated that the National Institute of Neurological Disorders and Stroke (NINDS) study2 provided valid evidence that patients treated with tissue plasminogen activator (tPA) within 3 hours of symptom onset achieved greater neurologic recovery and experienced less disability than patients who received placebo. Additional data published by the NINDS investigators3 and the US Food and Drug Administration medical officer's review of data submitted in support of a new drug application,4 show a significant in baseline stroke severity between the tPA-treated and placebo groups in the NINDS trial. Statistical correction for this baseline imbalance has not been provided in published reports and commentaries concerning this trial. Because baseline stroke severity has a significant effect on stroke outcome, I believe that accurate interpretation the results of the NINDS trial, or any similar trial, is not possible without using a statistically appropriate analytic equation to account for the differences in stroke severity between the trial groups. 

The TOAST stroke trial5 demonstrated that very small differences in baseline stroke severity have large effects on stroke outcome. I applied stroke outcome information derived from this trial to the NINDS data.6 My analysis indicates that the difference in stroke outcome between the treatment and placebo groups in the NINDS trial may be accounted for solely by the baseline imbalance in stroke severity between the groups. 

**Jeffrey Mann** Emergency Physician Salt Lake City, Utah

## References

1.  1. Gladstone DJ, Black SE. Update on intravenous tissue plasminogen activator for acute stroke: from clinical trials to clinical practice. CMAJ 2001; 165 (3):311-7.
    
    [Abstract/FREE Full Text](http://www.cmaj.ca/lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6NDoiY21haiI7czo1OiJyZXNpZCI7czo5OiIxNjUvMy8zMTEiO3M6NDoiYXRvbSI7czoyNDoiL2NtYWovMTY2LzEzLzE2NTEuMy5hdG9tIjt9czo4OiJmcmFnbWVudCI7czowOiIiO30=) 

2.  2. 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%2F1651.3.atom) 
    
    [Web of Science](http://www.cmaj.ca/lookup/external-ref?access_num=A1995TK06500001&link_type=ISI) 

3.  3. Marler JR, Tilley BC, Lu M, Brott TG, Lyden PC, Grotta JC, et al, for the NINDS rt-PA Stroke Study Group. Early stroke treatment associated with better stroke outcome: the NINDS rt-PA stroke study. Neurology 2000;55 (11): 1649-55. 
    
    [Abstract/FREE Full Text](http://www.cmaj.ca/lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6OToibmV1cm9sb2d5IjtzOjU6InJlc2lkIjtzOjEwOiI1NS8xMS8xNjQ5IjtzOjQ6ImF0b20iO3M6MjQ6Ii9jbWFqLzE2Ni8xMy8xNjUxLjMuYXRvbSI7fXM6ODoiZnJhZ21lbnQiO3M6MDoiIjt9) 

4.  4. US Food and Drug Administration. *Clinical review of TTATTS for pre-licence application 96-0350.* Available: [www.fda.gov/cber/review/altegen061896r1.pdf](http://www.fda.gov/cber/review/altegen061896r1.pdf) (accessed 2001 Sep 20). 
    
    

5.  5. Adams HP, Davis PH, Leira EC, Chang KC, Bendixen BH, Clarke W, et al. Baseline NIH stroke scale score strongly predicts outcome after stroke: a report of the Trial of Org 10172 in Acute Stroke Treatment (TOAST). Stroke 1999; 30 (11): 2496. 
    
    

6.  6. Mann J. *Truths regarding the NINDS tPA * *for acute ischemic stroke trial: setting the record straight.* Available: [www.homestead.com/emguidemaps/files/tpaforstroke.html](http://www.homestead.com/emguidemaps/files/tpaforstroke.html) (accessed 2001 Sep 20).