Clazosentan for Aneurysmal Subarachnoid Hemorrhage: An Updated Meta-Analysis with Trial Sequential Analysis

OBJECTIVE: Clazosentan, an endothelin receptor antagonist, reduced vasospasm and delayed ischemic neurologic deficit (DIND) but did not improve outcome after subarachnoid hemorrhage (SAH) in clinical trials. However, a lack of dose-dependent analysis and potential overestimation of clazosentan's effect are concerning. We used stratified analysis and trial sequential analysis (TSA) of existing data to investigate the effects of clazosentan on SAH outcome. METHODS: Studies from PubMed, Embase, and Cochrane were reviewed for eligibility. Primary outcomes were DIND requiring rescue therapy, all-cause mortality, and vasospasm-related morbidity at 6 weeks. Secondary outcomes were moderate-to-severe angiographic vasospasm, new cerebral infarction, and poor clinical outcome at 3 months. TSA was performed to assess the required information size and the alpha-spending monitoring boundary effect of relative risk (RR) reduction. A stratified analysis of clazosentan dosage was performed. RESULTS: Five studies (N = 2317) were included. Clazosentan significantly reduced the risk of DIND requiring rescue therapy (RR, 0.625; 95% confidence interval [CI], 0.462-0.846) and vasospasm (RR, 0.543; 95% CI, 0.464-0.635), but did not significantly affect mortality or vasospasm-related morbidity (RR, 0.775; 95% CI, 0.578-1.039), new cerebral infarction (RR, 0.604; 95% CI, 0.383-0.952), or outcome (RR, 1.131; 95% CI, 0.959-1.334). TSA revealed that the studies were underpowered to evaluate the effects of clazosentan on mortality and vasospasm-associated morbidity. We found 10-15 mg/h of clazosentan administration was associated with lower rates of vasospasm and new cerebral infarctions compared with 5 mg/h. CONCLUSIONS: Clazosentan reduced the risk of DIND requiring rescue therapy and moderate-to-severe vasospasm. Further meta-analyses based on individual patient data with different clazosentan doses and more refined outcome measures are necessary to clarify clazosentan's efficacy in improving post-SAH outcome.