Gender Differences in tPA-Related Arterial Recanalization
To the Editor:
We were very interested in the results of the study by Savitz et al,1 which showed dramatic differences in the rates of recanalization between men and women in a small sample of tPA-treated patients from their institution. However, in this article, they mischaracterize our prior study2 as demonstrating “that women, treated with intravenous tPA within 6 hours of stroke onset had better functional outcome after 90 days compared with men.” Although our study did find that women had a greater treatment-effect with tPA than men, this was because placebo-treated women had worse outcomes than placebo-treated men, whereas tPA-treated women had similar outcomes to tPA-treated men. This is consistent with large registries of tPA-treated patients showing similar outcomes between men and women,3 and also with large general stroke registries (ie, primarily untreated patients) showing worse outcomes for women.4,5
Thus, greater benefit with tPA for 1 group does not necessarily imply better outcomes for that group. Making this distinction clear emphasizes the need for using placebo-controlled data to look at factors that influence treatment-effect because the differential impact of tPA on functional outcome between the genders would not be found if only tPA-treated patients are analyzed. The distinction is also important when considering mechanisms because the treatment-interaction we described requires (at least) two gender-specific effects to be at play. An explanation is needed not only for the enhanced treatment-effect of tPA among women, but also for the worse outcome in untreated women compared with men. Although higher tPA-related recanalization rates might be a potential explanation for the former observation, it cannot explain the latter observation.
Savitz SI, Schlaug G, Caplan L, Selim M. Arterial occlusive lesions recanalize more frequently in women than in men after intravenous tissue plasminogen activator administration for acute stroke. Stroke. 2005; 36: 1447–1451.
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.
Hill MD, Buchan AM. For the Canadian Altepase for Stroke Effectiveness Study (CASES) Investigators. Canadian Medical Association Journal. 2005; 172: 1307–1312.
Kapral MK, Fang J, Hill MD, Silver F, Richards J, Jaigobin C, Cheung AM. Investigators of the Registry of the Canadian Stroke Network. Sex differences in stroke care and outcomes: Results from the registry of the Canadian Stroke Network. Stroke. 2005; 36: 809–814.
Holroyd-Leduc JM, Kapral MK, Austin PC, Tu JV. Sex differences and similarities in the management and outcome of stroke patients. Stroke. 2000; 31: 1833–1837.
We appreciate the comments of Drs Kent and Hill. In their article, Kent et al1 found that women receiving recombinant tissue plasminogen activator (rtPA) were significantly more likely than those receiving placebo to have a near-normal functional outcome, defined as mRS ≤1 at 90 days, as opposed to men where there was no overall difference between placebo- and rtPA-treated patients. They report “women were significantly more likely to benefit from rtPA compared with men.” Our statement that “women treated with IV rtPA within 6 hours of stroke onset had better functional outcome after 90 days compared with men” is therefore not inconsistent with their own reporting. Perhaps, it would have been more accurate to state that rtPA-treated women achieved better functional outcomes at 90 days compared with placebo controls, in contrast to men who did not benefit from rtPA compared with their placebo counterparts. Because women achieve a better treatment effect from thrombolysis compared with men, and regardless of the semantics used to describe this finding, we sought to determine what factors might account for this difference and therefore chose to study differences in recanalization rates. The authors themselves speculate on possible factors that could account for this gender-based difference, allude to possible differences in reperfusion, and, connected with this idea, mention changes in coagulation parameters. For these reasons, we appropriately referenced their report as part of the backdrop to our study.
We agree that improved recanalization does not necessarily translate into better functional outcomes and tempered our discussion with this reservation. In fact, we question the use of functional outcome at 90 days as the sole and direct measure of possible benefit from thrombolysis given multitudinous confounding variables over a 3-month period.
Finally, we agree that the mechanisms underlying worse outcomes from stroke in untreated women need to be explored in further studies. However, such an important subject was not the focus of our study. An equally alarming issue from Kent et al’s study1 is that men apparently do not derive benefit from intravenous thrombolysis. This, too, needs to be explained in further studies.