NINDS Stroke Trial Data Reanalysis Leaves Issues Unresolved
To the Editor:
The reanalysis of the National Institute of Neurological Disorders and Stroke Stroke Trial data1 concludes there is no evidence that the imbalance in baseline stroke severity invalidated the trial results, although the issue of benefit or harm in some subgroups is undecided because of small sample size.
A plausible explanation is suggested by the graphed relationship of National Institutes of Health Stroke Scale scores and outcome. Although not concluded as such, the data indicate a nonsignificant treatment effect for the low and high stroke severity groups. The baseline imbalance in stroke severity was most pronounced in these groups, with a lesser imbalance in the intermediate groups. The overall result would not be altered if there were no benefit of treatment in the groups in which there was an imbalance, as the data show.
A previous reanalysis of the NINDS data2 showed the benefit of recombinant tissue plasminogen activator was much reduced toward the end of the 3-hour treatment window. The number needed to treat of 8 for the group overall does not apply to patients treated at that time.
There remains significant uncertainty regarding the benefit of thrombolysis for patients with mild stroke symptoms treated toward the end of the 3-hour period from symptom onset. The reanalysis of data suggests any benefit must be vanishingly small, with the substantial risks of treatment remaining. Further data, not reanalysis, would resolve this issue.
Ingall TJ, O’Fallon WM, Asplund K, Goldfrank LR, Hertzberg VS, Louis TA, Christianson TJH. Findings From the Reanalysis of the NINDS Tissue Plasminogen Activator for Acute Ischemic Stroke Treatment Trial.[Report]. Stroke. 2004; 35: 2418–2424.
Marler JR, Tilley BC, Lu M, Brott TG, Lyden PD, Grotta JC, Broderick JP, Levine SR, Frankel MP, Horowitz SH, Haley EC Jr., Lewandowski CA, Kwiatkowski TP, for the NINDS rt-PA Stroke Study Group. Early stroke treatment associated with better outcomes. The NINDS rt-PA Stroke Study. Neurology. 2000; 55: 1649–1655.
We appreciate the comments made by Dr Smith and we concur with his statement that further studies are needed to address the issues raised by the subgroup analyses performed by our committee and by the National Institute of Neurological Disorders and Stroke tPA Investigators.
Although it is biologically plausible that the time from stroke onset to treatment is related to outcome, our analysis found no evidence of such a relationship. We agree with Dr Smith that there is uncertainty regarding this issue and further studies are needed that are adequately powered to determine if there is a differential treatment effect related to time from stroke onset to treatment in patients with acute ischemic stroke who are administered tissue plasminogen activator.