Potential for multidrug combination therapy in patients with World Federation of Neurological Surgeons grade V...

Patients with World Federation of Neurological Surgeons (WFNS) grade V aneurysmal subarachnoid hemorrhage (SAH) have poor outcomes, and no effective pharmacological treatment has been established. This study aimed to investigate whether any of the drugs currently used in Japan, where nimodipine is not approved, are effective for WFNS grade V SAH patients. From a database of SAH patients prospectively enrolled at nine hospitals in Japan between 2013 and 2024, 297 patients (mean age, 67.3 years) who underwent microsurgical or endovascular treatment for ruptured aneurysms and had WFNS grade V SAH at admission were retrospectively analyzed. Cerebral vasospasm and delayed cerebral infarction occurred in 68 (22.9%) and 43 (14.5%) patients, respectively. Rescue therapy was performed in 34 patients (11.4%), and 3-month good outcomes (modified Rankin scale [mRS] 0-3) were achieved in 91 patients (30.6%). Multivariate analyses revealed that pre-onset mRS 1-2, admission modified Fisher grade 4, ruptured middle cerebral artery aneurysm, acute hydrocephalus, and older age were independently associated with poor outcomes, while combination drug therapy with fasudil hydrochloride (Rho-kinase inhibitor) + cilostazol (phosphodiesterase type III inhibitor) + eicosapentaenoic acid (omega-3 polyunsaturated fatty acid) or clazosentan (endothelin receptor subtype A antagonist) + cilostazol was the only independent determinant of good outcomes. The combination drug therapies were also independent inhibitors of delayed cerebral infarction (non-iatrogenic cerebral infarction on computed tomography after SAH), but not of cerebral vasospasm (≥ 50% angiographic vasospasm of a major cerebral artery) and rescue therapy (endovascular treatment and hyperdynamic therapy for delayed ischemic symptoms with and without vasospasm). This study suggested that the triple or dual drug therapy may contribute to improved outcomes in patients with WFNS grade V by suppressing vasospasm-unrelated pathologies rather than cerebral vasospasm itself, warranting further study.