Comparison of Clazosentan and Nimodipine on Vasospasm and Vasospasm-Related Outcomes after Aneurysmal Subarachnoid Hemorrhage : A Post-hoc Propensity Score-Matched Analysis of Six Randomized Clinical Trials

Abstract

Objective : Clazosentan is a recently approved endothelin receptor antagonist indicated for the prevention of vasospasm and related complications following aneurysmal subarachnoid hemorrhage (aSAH). To date, no direct, head-to-head comparison between clazosentan and nimodipine has been conducted. In this study, we indirectly assessed the efficacy and safety of these two drugs in preventing vasospasm and its associated outcomes after aSAH. Methods : Participants from six randomized clinical trials of clazosentan were reclassified into three subgroups based on their concomitant use of oral nimodipine: 1) a clazosentan subgroup (without nimodipine), 2) a nimodipine subgroup (without clazosentan), and 3) a placebo subgroup (receiving neither clazosentan nor nimodipine). Data from participants who received the approved dose of clazosentan 10 mg/h was analyzed. To account for heterogeneities among the analyzed studies, we performed within-study comparisons of subgroups and pooled data from the same subgroup. To further balance the three groups, we conducted a propensity score-matching and compared the outcomes among subgroups. The outcomes measured were angiographic vasospasm within 14 days after aSAH and vasospasm-related morbidity and all-cause mortality (MM) within 6 weeks, defined as death, vasospasm-related new cerebral infarcts, delayed ischemic neurological deficits, or initiation of rescue therapy. Incidence and relative risk reduction (RRR) were analyzed across subgroups, and overall safety was reviewed. Results : The pooled data from within-study comparisons demonstrated that clazosentan significantly reduced the risk of vasospasm (RRR, 0.48; 95% confidence interval [CI], 0.35 to 0.58) and MM (RRR, 0.47; 95% CI, 0.30 to 0.60) compared to placebo, whereas nimodipine did not. In the propensity score-matched analysis, clazosentan demonstrated a significant risk reduction in outcomes when compared to nimodipine (RRR, 0.63; 95% CI, 0.46 to 0.75 for vasospasm; RRR, 0.29; 95% CI, 0.04 to 0.48 for MM) and placebo (RRR, 0.59; 95% CI, 0.40 to 0.72 for vasospasm; RRR, 0.41; 95% CI, 0.21 to 0.56 for MM).The overall safety results were comparable across the three subgroups and consistent with the expected range for endothelin receptor antagonists. Conclusion : Clazosentan at 10 mg/h significantly reduced the incidence of cerebral vasospasm and MM following aSAH, compared to both placebo and nimodipine. Further clinical studies are warranted to compare the efficacy of clazosentan and nimodipine to optimize treatment strategies for aSAH.