Objective: Hematoma expansion (HE) is commonly analyzed as a dichotomous outcome in intracerebral hemorrhage (ICH) trials.  In this proof-of-concept study, we propose a “HE shift” analysis model as a method to improve the evaluation of candidate ICH therapies.

Methods: Using data from the Antihypertensive Treatment of Acute Cerebral Hemorrhage II (ATACH-2) trial, we performed HE shift analysis in response to intensive blood pressure lowering by generating polychotomous strata based on a) previously established HE definitions, b) percentile/absolute quartiles of hematoma volume change, and c) quartiles of 24-hour follow-up hematoma volumes. The relationship between blood pressure treatment and HE shift was explored using proportional odds models.

Results: The primary analysis population included 863 patients. In both treatment groups, approximately one-third of patients exhibited no HE. Using a trichotomous HE stratification, the highest strata of ≥33% revealed a 5.8% reduction in hematoma growth for those randomized to intensive therapy (aOR: 0.77 [95% CI: 0.60-0.99]). Using percentile quartiles of hematoma volume change, we observed a favorable shift to reduce growth in patients treated with intensive therapy: aOR: 0.73 (0.57-0.93). Similarly, in a tetrachotomous analysis of 24-hour follow-up hematoma volumes, shifts in the highest stratum (> 21.9 mL) was most notable.

Conclusions: Our findings suggest that intensive blood pressure reduction may preferentially mitigate growth in patients at risk of high volume HE. A shift analysis model of HE provides additional insights into the biological effects of a given therapy and may be an additional way to assess hemostatic agents in future studies.

Registration: ClinicalTrials.gov Identifier: NCT01176565