Effects of Blood Pressure Lowering Across Hematoma Volume in Acute Intracerebral Hemorrhage: Pooled Analysis of the Four <scp>INTERACT</scp> and <scp>ATACH</scp> ‐2 Trials

OBJECTIVE: The objective of this study was to assess the heterogeneity in treatment effect of intensive blood pressure (BP)-lowering across hematoma volume after acute intracerebral hemorrhage (ICH). METHODS: We undertook a pooled analysis of individual patient data from the pivotal trials of early intensive BP-lowering in ICH (the Intensive Blood Pressure Reduction in Acute Cerebral Hemorrhage Trial 4 [INTERACT4] and Antihypertensive Treatment of Acute Cerebral Hemorrhage 2 [ATACH-2] studies). The primary outcome was functional recovery, defined by the distribution of scores on modified Rankin scale (mRS). Secondary outcomes were hematoma expansion (HE) over 24 hours, defined by absolute (<0, 0-6, 6-12.5, and >12.5 ml) and relative HE (<0, 0-33, 33-66, and >66%). Generalized linear mixed models with trial as a random effect were conducted. We further assessed effect modification by hematoma volume and plotted the treatment effect curve. RESULTS: Among 6,125 individuals with available hematoma volume, intensive BP-lowering improved functional recovery (odds ratio [OR] for unfavorable shift in mRS score = 0.90, 95% confidence interval [CI] = 0.82 to 0.99, p = 0.027). In 3,897 participants with available HE, intensive BP-lowering reduced the risk of absolute (OR = 0.88, 95% CI = 0.78 to 0.99, p = 0.043) and relative (OR = 0.88, 95% CI = 0.78 to 0.99, p = 0.034) HE. We found effect modification of treatment on functional outcome and absolute HE by hematoma volume (p for interaction = 0.043 and 0.025, respectively). U-shaped curves were observed, with benefits seen in cases with hematoma volume of 7.5 to 27.5 and 7.0 to 32.5 ml, respectively, both peaking at 20 ml. INTERPRETATION: Early intensive BP-lowering improves functional outcome and reduces HE in ICH. Heterogeneity by hematoma volume indicates the importance of patient selection in future trials and clinical practice. ANN NEUROL 2026.