Heterogeneity of Clazosentan Benefit after Aneurysmal Subarachnoid Hemorrhage Demonstrated in an Externally Validated...

Clazosentan reduces angiographic vasospasm after aneurysmal subarachnoid hemorrhage (aSAH), but functional benefit may vary across patients. We used causal machine learning to explore heterogeneity and derive an interpretable rule.

In a secondary analysis of the RECOVER dataset [multicenter retrospective cohort of aSAH treated by clipping or coiling within 48 h (N = 506)], we compared clazosentan-containing management (with or without fasudil) with fasudil-only prophylaxis. After applying inverse probability of treatment weighting for prespecified confounders [age, World Federation of Neurosurgical Societies (WFNS) grade, Fisher grade, and body mass index (BMI)], we used a causal forest to estimate conditional average treatment effects (CATEs) on favorable discharge outcome (modified Rankin Scale 0-2 at discharge). A policy tree summarized CATEs, and external validation was performed in an independent cohort (N = 181).

CATEs were heterogeneous (mean 0.18 ± 0.14). The policy tree split first on BMI (≤ 20.03 kg/m²): patients with BMI ≤ 20.03 and WFNS ≤ 2 showed no clear estimated benefit (mean CATE - 0.058), whereas those with BMI > 20.03 or WFNS > 2 showed higher estimated benefit (CATE 0.24-0.25). In external validation, the same rule identified a subgroup with higher odds of favorable recovery with clazosentan; estimates in the low-benefit subgroup were imprecise (n = 27).

In observational cohorts with limited overlap in treatment assignment, causal machine learning suggested heterogeneity in the estimated association of a clazosentan-containing strategy with discharge outcomes and produced a simple BMI/WFNS policy tree. These findings are hypothesis-generating and require prospective validation including safety endpoints and longer-term functional outcomes.