Safety and effectiveness of clazosentan in patients after aneurysmal subarachnoid haemorrhage: a second interim report of a post-marketing surveillance in Japan

Japanese phase 3 trials demonstrated efficacy and safety of clazosentan for aneurysmal subarachnoid haemorrhage (aSAH) management. However, real-world data remain limited, particularly in elderly, poor-grade, outside of Fisher group 3 patients, or those on concomitant medications. Therefore, this post-marketing surveillance (PMS) programme evaluated safety and effectiveness of clazosentan in Japanese clinical practice. This second interim analysis of an ongoing PMS programme included patients with aSAH who received clazosentan postoperatively in Japan. Safety data included incidence of adverse drug reactions (ADRs) and their severity. Effectiveness endpoints were the incidence of cerebral vasospasm–related events. Exploratory endpoints were prognostic factors for fluid retention–related ADRs and vasospasm-related morbidity/mortality events identified by univariate and multivariate analyses. Of the 2967 included patients, ADRs occurred in 34.5%, serious ADRs in 8.2%, and fluid retention–related ADRs in 20.1%. Cerebral vasospasm was observed in 18.8% of patients, while 7.1% and 10.6% experienced vasospasm-related cerebral infarction and vasospasm-related morbidity/mortality events, respectively. Multivariate analysis identified age ≥ 75 years, thick and diffuse clot size, medical history, comorbidities, and vasodilatory concomitant medication use as key predictors of fluid retention–related ADRs and female sex, age ≥ 75 years, anterior circulation, thick and diffuse clot size, World Federation of Neurosurgical Societies (WFNS) grade IV/V, comorbidities, and cilostazol use (risk reduction factor) as key predictors of vasospasm-related morbidity/mortality events. Patients with fluid retention–related ADRs had a higher incidence of vasospasm-related morbidity/mortality events. This study supports clazosentan use for aSAH, emphasising careful monitoring.