Clazosentan in aneurysmal subarachnoid hemorrhage: an updated systematic review and meta-analysis of efficacy and safety

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INTRODUCTION: Aneurysmal subarachnoid hemorrhage (aSAH) is a life-threatening neurological condition associated with high morbidity and mortality. Delayed cerebral ischemia (DCI), largely driven by cerebral vasospasm, remains a major determinant of poor outcomes. Clazosentan, a selective endothelin A receptor antagonist, reduces vasospasm, but its impact on clinical outcomes remains uncertain. This study aimed to evaluate its association with vasospasm-related and clinical outcomes, and its safety profile. METHODS: This systematic review and meta-analysis followed PRISMA guidelines. PubMed, Cochrane Library, and Google Scholar were searched through March 2026. Outcomes included vasospasm, cerebral infarction, DINDs, functional outcomes, mortality, and adverse events. Random-effects models (DerSimonian-Laird estimator) were applied, and predefined subgroup analyses were performed by clazosentan dose, comparator type (placebo vs. fasudil hydrochloride), aneurysm treatment modality, and study design (randomized controlled trials (RCTs) vs. observational cohort studies). Certainty of evidence for each outcome was rated using the GRADE framework, with RCT and cohort evidence rated as separate bodies of evidence. RESULTS: Sixteen studies (17 reports; 7 RCTs comparing clazosentan with placebo and 9 cohort studies comparing clazosentan with fasudil hydrochloride) were included. In RCTs clazosentan was associated with statistically significant reductions in angiographic vasospasm and rescue-therapy use (high GRADE certainty), and in vasospasm-related cerebral infarction and DINDs (moderate certainty, downgraded for publication bias). In pooled observational data versus fasudil hydrochloride, directionally concordant reductions were observed for angiographic vasospasm (low certainty) and vasospasm-related infarction (very low certainty), but no statistically significant differences were observed for DINDs or rescue therapy. However, no statistically significant differences were observed in functional outcomes or mortality in either body of evidence (moderate certainty for poor functional outcome and mortality in RCTs; very low certainty for favourable functional outcome and mortality in cohort studies). Larger effect estimates were observed with 10-15 mg doses in aggregate study-level analyses; because dose was assigned at the study level rather than randomized within patients, these gradients are descriptive rather than confirmatory of a within-patient dose-response relationship. Study design-stratified analysis showed concordant reductions in vasospasm and cerebral infarction across RCTs and cohorts, while effects on DINDs, rescue therapy, and hypotension reached significance only in RCTs. Clazosentan was associated with increased risks of anemia, hypotension, pleural effusion, pulmonary edema, and pneumonia, with no statistically significant difference in cerebral hemorrhage. CONCLUSION: Across both bodies of evidence, clazosentan was associated with statistically significant reductions in angiographic vasospasm and vasospasm-related ischemic complications in aSAH, but these surrogate gains did not translate into statistically significant improvements in survival or functional recovery in either randomized or observational evidence, and were accompanied by clinically relevant increases in anemia, hypotension, and pulmonary complications. Observational comparisons with fasudil are at serious-to-critical risk of confounding by indication, treatment selection, and temporal changes in care, and should be considered hypothesis-generating. Because demonstrable improvement in patient-centered endpoints (survival, functional recovery) has not been shown, Routine use is not supported by current evidence; any role for clazosentan is likely limited to selected high-risk patients in whom the anticipated reduction in ischemic complications is explicitly judged to outweigh the systemic harm.