Response by Dula et al to Letter Regarding Article, “Neuroimaging in Ischemic Stroke is Different between Men and Women in the DEFUSE 3 Cohort”

We thank Ramos et al. for their interest in our recent study on sex differences in admission perfusion imaging and ischemic core growth in the DEFUSE 3 cohort. We agree that differences in neuroimaging characteristics between men and women are complex and to accurately characterize the role of sex, many confounding factors can be incorporated to inform on implications for treatment and imaging selection for clinical trials. It is with this understanding that we chose the highly-selected DEFUSE 3 cohort which is a uniform sample of patients with large vessel occlusion (LVO). Of patients screened for DEFUSE 3 but not randomized due to large core or no mismatch, the proportion of women was 21/45 (47%) with large core; and women 5/8 (63%) with mismatch ratio <1.8 and/or mismatch volume <15 mL. The results of our study showed that sex differences exist in baseline imaging characteristics, process measures, clinical outcomes, and imaging outcomes within the DEFUSE 3 group of patients with an LVO, favorable imaging profile, functional independence prior to stroke, and presentation between 6–16 hours from last known well.

We agree that including stroke etiology in the adjusted analysis could alter the effect size of the difference of collateral status between women and men, possibly improving robustness, interpretability and generalizability. Evaluation of the TOAST etiology by sex of the DEFUSE 3 cohort did not result in significant sex differences (p = 0.303 for overall comparison and p = 0.112 for specific to sex difference between large artery atherosclerosis and cardioembolic source). Despite higher incidence of LAA in men and subsequent higher collateral grade found in this group, there is no report of collateral grade by sex in Guglielmi’s analysis of the MR-CLEAN registry.¹ However, Berkhemer did indicate that women demonstrated a higher collateral grade within the MR CLEAN patient cohort², p = 0.031. We acknowledge that the literature is inconsistent in regards to sex differences in collateral status. In the noted analysis of a large unselected patient group presented by Nannoni,³ as with many sub-analyses of sex differences, results are difficult to interpret without knowledge of cohort demographics by sex, i.e. age distribution (females tend to be older), NIHSS (females tend to present with more severe strokes), onset to CT time (females tend to present later) as in supplementary data, these variables seem to correlate with collateral grade.³

Future challenges include studies designed and powered to assess the influence of sex. Large observational studies considering sex-specific confounders would lead to greater generalizability of clinical trials. Incorporation of female-specific risk factors as well as incorporation of larger proportions of patients >75 years old is imperative. By presenting sex differences in a highly selected group of slow-progressing LVOs, this article is a necessary step towards understanding of the role of sex on ischemic stroke evolution.