Combination Therapy with Clazosentan and Fasudil Hydrochloride Under Strict Fluid Management Is Associated with Reduced Cerebral Vasospasm After Aneurysmal Subarachnoid Hemorrhage

Abstract Objective Cerebral vasospasm following aneurysmal subarachnoid hemorrhage (aSAH) is a major cause of delayed cerebral ischemia (DCI) and poor functional outcomes. Although clazosentan, a selective endothelin A receptor antagonist, suppresses cerebral vasospasm, concerns remain regarding fluid retention–related complications. The efficacy and safety of combination therapy with clazosentan and fasudil hydrochloride under strict fluid management have not been fully established. We retrospectively evaluated the efficacy and safety of this combination therapy. Methods We analyzed patients with aSAH due to ruptured cerebral aneurysms treated at our institution between January 2020 and December 2025. Patients were divided into two groups: a 30-month pre-introduction period (pre-clazosentan group) and a 30-month post-introduction period (fasudil + clazosentan group). The pre-clazosentan group received multidrug therapy centered on fasudil hydrochloride, whereas the fasudil + clazosentan group received additional clazosentan (10 mg/h) on top of fasudil hydrochloride. Outcome measures included symptomatic and radiographic cerebral vasospasm, vasospasm-related cerebral infarction, hyponatremia, pleural effusion/pulmonary edema, and modified Rankin Scale (mRS) scores at discharge and at 3 months. Results Compared with the pre-clazosentan group, the fasudil + clazosentan group had significantly lower incidences of symptomatic cerebral vasospasm (3% vs. 19%, p = 0.012), definitive DCI (7% vs. 21%, p = 0.002), angiographic vasospasm, and hyponatremia (9% vs. 26%, p = 0.028). Pulmonary edema occurred more frequently in the fasudil + clazosentan group (35% vs. 13%, p = 0.02); however, clazosentan was discontinued because of severe pulmonary edema in only five patients (7%). Favorable functional outcomes (mRS < 3) were significantly more frequent at discharge (48% vs. 28%, p = 0.041) and at 3 months (55% vs. 39%, p = 0.048). Multivariable logistic regression identified combination therapy as an independent predictor of favorable functional outcomes (odds ratio, 2.597; 95% confidence interval, 1.087–6.211; p = 0.032). Conclusions Our findings suggest that combination therapy with clazosentan and fasudil hydrochloride, when implemented under strict fluid management, may contribute to the suppression of cerebral vasospasm and improved functional outcomes after aSAH.