Sex-Based Differences in Response to Recombinant Tissue Plasminogen Activator in Acute Ischemic Stroke
To the Editor:
In their pooled analysis article on gender differences in response to tissue plasminogen activator therapy,1 the authors conclude that tissue plasminogen activator was not significantly effective in male stroke patients (3-month favorable stroke outcome rate of 38.5% for treated patients versus 36.7% for placebo patients; P=0.52).
However, that particular conclusion is only scientifically valid if the male placebo patients had the same baseline likelihood of a spontaneous stroke recovery as the male treated patients. Considering that the male placebo group’s favorable response rate was 36.7%, compared with 25% for the placebo patients in the 91- to 180-minute arm of the NINDS trial, it is questionable whether the treated and placebo male pooled analysis groups were balanced at baseline.
To substantiate the scientific validity of their conclusion, the authors should provide a stratified analysis in addition to a pooled (unstratified) analysis to verify that there was no significant imbalance in baseline stroke severity between the male treated and male placebo patients in their pooled analysis.2
Kent DM, Price LL, Ringleb P, Hill MD, Selker HP. Sex-based differences in response to recombinant tissue plasminogen activator in acute ischemic stroke: a pooled analysis of randomized clinical trials. Stroke. 2005; 36: 62–65.
Mann J. A Critique of the Reanalysis of the NINDS trial. Available at http://www.homestead.com/emguidemaps/JeffMannEMguidemaps.html. Accessed March 24, 2005.
We thank Dr Mann for writing to give us the opportunity to correct a misperception some might have about our study results. Dr. Mann states that we “conclude that tPA was not significantly effective in male stroke patients.” This is not correct. While we state that among men “the trend toward benefit in the overall group did not reach statistical significance,” when there is a signficant treatment-effect interaction (such as the one with symptom onset to treatment time), the absence of an overall effect is not terribly informative. The data are clear that some male patients benefit from thrombolytic therapy (eg, those treated early), but this effect is diluted by those who do not benefit (eg, those treated later in the 6-hour window). This is a very important point, as we would be quite appalled if our results were used to suggest that men should not be given thrombolytic therapy, for example, even within the currently approved 3 hour time window.
From Dr. Mann’s other comments, it appears that he is concerned that there may have been an imbalance in the baseline characteristics of the male patients in the treatment versus the placebo group that biases toward the null (and presumably that this imbalance is present only in males, thus explaining the interaction). Our results are not consistent with this hypothesis since the gender interaction was found both in the unadjusted analysis (which would not control for any imbalance in baseline characteristics) and in the logistic regression adjusted analysis (which does control for potential imbalances, including those in NIHSS score). In any event, results stratified by NIHSS (Table) are consistent with the overall result.