Sex differences in perihematomal edema volume and outcome after intracerebral hemorrhage
Authors: Witsch Jens , Cao Quy , Song Jae W. , Luo Yunshi , Sloane Kelly L. , Rothstein Aaron , Favilla Christopher G. , Cucchiara Brett L. , Kasner Scott E. , Messé Steve R. , Choi Huimahn A. , McCullough Louise D. , Mayer Stephan A. , Gusdon Aaron M. 
Published: September 2023

ObjectiveTo determine whether in patients with intracerebral hemorrhage (ICH) perihematomal edema (PHE) volume trajectories differ by sex.MethodsWe conducted a post-hoc analysis of the Factor-VII-for-Acute-Hemorrhagic-Stroke-Treatment (FAST) trial that randomized patients with ICH to receive recombinant activated Factor VIIa or placebo. Computerized planimetry calculated PHE and ICH volumes on serial CT scans (at baseline [within 3 hours of onset], at 24, and at 72 hours). Generalized estimating equations examined interactions between sex, CT-timepoints, and FAST treatment-arm on PHE and ICH volumes. Mixed and multivariate logistic models examined associations between sex, PHE, and outcomes.Results781 with supratentorial ICH (mean age 65 years) were included. Compared to women (n=296), men (n=485) had similar median ICH (14.9 versus 13.6 ml, p=0.053), and PHE volumes (11.1 versus 10.5 ml, p=0.56) at baseline but larger ICH and PHE at 24 hours (19.0 versus 14.0, p<0.001; 22.2 versus 15.7, p<0.001) and 72 hours (16.0 versus 11.8, p<0.001; 28.7 versus 19.9, p<0.001). Men had higher absolute PHE expansion (p<0.001), and more hematoma expansion (growth ≥33% or 6 mL at 24 hours, 33% versus 22%, p<0.001). An interaction between sex and CT-timepoints on PHE (p<0.001) but not on ICH volumes confirmed a steeper PHE trajectory in men. PHE expansion (per 5mL, odds radio, 1.19, 95%-confidence interval 1.10-1.28), but not sex, was associated with poor outcome.ConclusionsPHE expansion and trajectory in men were significantly higher. PHE expansion was associated with poor outcomes independent of sex. Mechanisms leading to sex differences in PHE trajectories merit further investigation.What is already known on this topicPrior research has reported sex differences in intracerebral hemorrhage (ICH) characteristics and some studies suggest worse outcome after ICH in women. However, we do not have a good understanding whether there are sex differences in perihematomal edema (PHE) volume trajectories, or whether sex, independent of confounders, is associated with poor after ICH.What this study adds:In this post-hoc analysis of 781 patients with supratentorial ICH from the Factor-VII-for-Acute-Hemorrhagic-Stroke-Treatment (FAST) trial in which patients underwent brain CT imaging time-locked to symptom onset (within 3 hours of symptom onset, at 24 hours, and at 72 hours), men compared to women had similar ICH and PHE volumes at baseline, but larger ICH expansion and PHE expansion on follow up imaging. The PHE but not the ICH volume trajectory across scans was significantly higher in men than in women. While PHE expansion was associated with poor outcome at 90 days, outcome between the sexes was similar at 90 days, and sex was not associated with outcome.How this study might affect research, practice or policy:The finding of heightened early PHE and ICH expansion in men may inform study design, patient recruitment strategies, and pre-specification of subgroup analyses in future interventional trials. The findings of this study also suggest that focusing on sex-specific factors may allow novel mechanistic insight into PHE, a major cause of secondary injury and poor outcome after ICH.