Clinical outcomes before and after the introduction of clazosentan in aneurysmal subarachnoid hemorrhage: a multicenter retrospective study of clipping and endovascular treatment

Abstract

OBJECTIVE: Definitive treatment for aneurysmal subarachnoid hemorrhage (aSAH) includes microsurgical clipping and endovascular treatment (EVT). In randomized trials such as ISAT and BRAT, EVT showed superiority in short-term outcomes and comparable or favorable long-term results. Delayed cerebral ischemia is one of the most important determinants of clinical outcomes after treatment for aneurysmal subarachnoid hemorrhage caused by ruptured intracranial aneurysms. Although its pathophysiology is multifactorial, cerebral vasospasm has long been considered a major contributing factor. In Japan, fasudil has traditionally been used as a perioperative pharmacological agent for the prevention of cerebral vasospasm; since 2022, clazosentan has also become available. This study aimed to compare outcomes between clipping and EVT before and after the introduction of clazosentan in patients with aSAH. METHODS: Using RECOVER registry data, we analyzed patients with aSAH who underwent definitive treatment with clipping or EVT within 48 h of onset and received either fasudil or clazosentan between 2021 and 2024. The primary endpoint was a favorable functional outcome at discharge, defined as a modified Rankin Scale (mRS) score of 0-2. Secondary endpoints included cerebral vasospasm, delayed cerebral ischemia (DCI), pulmonary complications, hypotension, cerebral edema, and new intracranial hemorrhage. In multivariable analyses, we adjusted for age, World Federation of Neurosurgical Societies (WFNS) grade, Fisher group, anterior circulation aneurysm, and the use of cerebrospinal fluid drainage. The study period was divided into the fasudil era and the clazosentan era, corresponding to the periods before and after the introduction of clazosentan, respectively. RESULTS: A total of 496 patients were analyzed, of whom 57.5% underwent microsurgical clipping. Overall, favorable outcomes at discharge, defined as an mRS score of 0-2, were significantly more frequent in the EVT group than in the clipping group (59.2% vs 48.4%, p = 0.004). In the fasudil era, the EVT group showed a higher proportion of favorable outcomes than the clipping group (59.0% vs 41.5%, p = 0.007), whereas no statistically significant between-group difference was observed in the clazosentan era (72.6% vs 62.7%, p = 0.15). Among secondary outcomes, the incidence of vasospasm-related DCI was not significantly different between the groups, although it was numerically lower in the EVT group. CONCLUSION: Functional outcomes appeared more favorable in both the clipping and EVT groups during the clazosentan era. Across all study periods, the observed proportion of patients with favorable functional outcomes was higher in the EVT group than in the clipping group. However, because formal interaction testing did not identify statistically significant effect modification, the apparent reduction in between-group differences observed in the clazosentan era should be interpreted with caution and considered hypothesis-generating. Further prospective studies are needed to clarify the clinical relevance of these era-based observations.