The NINDS stroke study group response.

The National Institute of Neurological Disorders and Stroke (NINDS) investigators would like to respond to the recent articles in the British Medical Journal and Western Journal of Medicine. Please excuse the necessary length of our combined reply. First Dr. Mann’s comments: we also encourage physicians to think independently and would like to provide further information in response to Dr. Mann’s four main points. This is done in the spirit of discussion and not debate. We hope the readers of the BMJ and WJM will take time to consider our response. We thought our previous peer-reviewed reports had addressed Dr. Mann’s questions. Dr. Mann writes that in order to obtain valid results, critical prognostic variables have to be prespecified, and corrected for, in the design of any randomized controlled trial. This is true, but Dr. Mann’s choice of prognostic variables is different than ours. What we think is important is predicting who will respond to tissue plasminogen activator (TPA). Dr. Mann is most concerned with who will do well despite therapy. There is good evidence from the NINDS study that over a broad range of the baseline NIH stroke scale, patients treated with TPA do better than those who are not treated with TPA. Contrary to Dr. Mann’s assertion, the National Institutes of Health Stroke Scale (NIHSS) was a prespecified variable that was known to predict outcome and it was corrected for in the usual way in the original publication. The data in the two trials composing the study confirm that NIHSS does not reliably predict response to therapy. The only group in which the benefit is not apparent without correcting for other variables is the group with very mild strokes; that is, having 0 to 5 on their baseline NIHSS (9% of the patients in the study, 7% 90 minutes, 11% 90 minutes). In this case, there are few patients to evaluate and the outcome variables may not have been sensitive to different degrees of minimal disability. As Dr. Mann points out, almost all of these patients had minimal or no disability at three months whether or not they were treated with TPA. Even though it makes the argument more complicated, we would also like to point out that there are other baseline variables that predict outcome. Age of the patient is just one example. Dr. Mann also writes that randomization into the TPA and placebo groups was flawed in the NINDS trial. There is no evidence that the randomization process was flawed. The result of the randomization, however, was not an equal assignment of baseline stroke scale in every small subgroup. This happens in all trials. Fortunately, as you will see below, the effect of the drug is so large that it overpowers these imbalances. In the 91 to 180 minute group, the average baseline NIHSS score was lower for the patients assigned randomly (in a process that was not flawed) to the placebo group. We feel that our published analyses did account for this imbalance in our assertion that the drug reduced disability at three months. We hope that the data provided here will make the validity of the statistics more clear. We understand how Dr. Mann could at first glance suspect that this imbalance in randomization could alone account for the apparent effectiveness of TPA shown in the NINDS trial. We had recommended as a group that there be a goal of one hour door to needle time because it was so apparent and logical to us that early treatment was critical. Several years after the results of the trial were published, though, it was clear that the door to needle time varied widely and that physicians were delaying treatment of patients even within the three hour window. Therefore we looked more thoroughly to see if time to treatment predicted a better response to treatment. In our post-hoc analysis, it did appear that door to needle time was important even within three hours from stroke onset. What we failed to make clear was that the baseline difference in stroke scale in the 91 to 180 minute group did NOT account for the effectiveness of TPA in the entire trial. In other words, there were not so many more patients in the TPA treated group with baseline NIHSS scores of 0 to 5 that were treated 91 to 180 minutes that their predictably good outcome could have explained the entire effect of the drug. To make this as clear as possible, we provide the following data tables with the qualification that they do not account for other significant variables that predict outcome such as age. It is also very important to remember that these post-hoc analyses involving subgroups without sufficient statistical power to answer the meaningful question should be considered as “hypothesis generating” and providing a rationale for From the Department of Neurology, University of Texas-Houston Medical School, Houston, TX, for the National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. 1052-3057/02/1103/4-0003$35.00/0 doi:10.1053/jscd.2002.130044