An Update on the Efficacy and Safety Profile of Clazosentan in Cerebral Vasospasm After Aneurysmal Subarachnoid Hemorrhage: A Meta-Analysis

Song, Jié; Xue, Yue-Qin; Yan-ju, Wang; Xu, Peng; Sun, D Z; Chen, Wei

doi:10.1016/j.wneu.2018.11.143

Cited by 11 publications

(9 citation statements)

References 19 publications

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“…SpO 2 is the percentage of oxyhemoglobin in the blood to the total hemoglobin volume, which is used to assess the patient's breathing and circulation. Peak airway pressure is the highest pressure experienced during ventilator insufflation, and it is determined by lung compliance, airway resistance, tidal volume, and other factors [ 30 ]. As a result, the findings suggest that the incidence of intraoperative respiratory depression in patients is unrelated to the use of various cis-atracurium doses and that the analysis could be induced by intravenous injections of propofol and sufentanil.…”

Section: Discussionmentioning

confidence: 99%

Clinical Usage of Different Doses of Cis-Atracurium in Intracranial Aneurysm Surgery and Its Effect on Motor-Evoked Potentials

Qiao

Fan

2022

Computational and Mathematical Methods in Medicine

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The objective of this work was to investigate the effect of different doses of cis-atracurium on patients undergoing general anesthesia induction (GAI) during intracranial aneurysm surgery (ICAS). In this work, 90 patients who underwent ICAS under the elective motor-evoked potential (MEP) monitoring in the First Affiliated Hospital of Northwest University (Xi’an No. 1 Hospital) from January 2021 to May 2022 were enrolled as the research objects. Randomly, they were rolled into a S1 group (30 cases, 2 times 95% effective dose (ED95) cis-atracurium), a S2 group (30 cases, 3 times ED95 cis-atracurium), and a S3 group (30 cases, 4 times ED95 cis-atracurium). The endotracheal intubation conditions, the train-of-four (TOF) rate (TOFR), body movement, and spontaneous breathing were compared among the three groups of patients. The results showed that the MEP inhibition time of the patients in the S3 group was much longer than that of the S1 and S2 groups, but it showed no significant difference between the S1 group and S2 group ( P > 0.05 ). The good rates of endotracheal intubation conditions in the S2 group (100%) and S3 group (100%) were obviously higher than the rate in the S1 group (43.33%). The TOFRs of patients in S2 and S3 groups at time t2 and t3 were lower obviously to that at time t0, while the TOFRs of patients in S3 group at time t2 and t3 were still lower in contrast to the S2 group ( P < 0.05 ). The mean arterial pressure (MAP) and heart rate (HR) of patients in all groups were lower at t1, t2, and t3 than at t0 ( P < 0.05 ), while the differences among different groups were not remarkable ( P > 0.05 ). Finally, using 3 times ED95 cis-atracurium for GAI could reduce the risk of intraoperative body movement and spontaneous breathing, as well as the residual degree of muscle relaxation, in patients with ICAS, without affecting MEP monitoring, improving endotracheal intubation conditions, and increasing safety during open neurosurgery operations.

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Section: Discussionmentioning

confidence: 99%

Clinical Usage of Different Doses of Cis-Atracurium in Intracranial Aneurysm Surgery and Its Effect on Motor-Evoked Potentials

Qiao

Fan

2022

Computational and Mathematical Methods in Medicine

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“…Investigators have tested multiple pharmacological interventions for preventing mortality and DCI and improving neurological and functional outcomes after aSAH that have been summarized in several systematic reviews using conventional meta-analytic methods. 12–16 These reviews have been largely restricted to comparing the effects of a single drug to placebo with no attempt to assess their comparative effectiveness. To clarify their relative merit, we conducted a comprehensive systematic review and network meta-analysis of trials addressing therapeutic benefits of pharmacological treatments in patients with aSAH.…”

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confidence: 99%

Prophylactic Therapies for Morbidity and Mortality After Aneurysmal Subarachnoid Hemorrhage: A Systematic Review and Network Meta-Analysis of Randomized Trials

Dayyani

Sadeghirad

Grotta

et al. 2022

Stroke

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Background: Aneurysmal subarachnoid hemorrhage (aSAH) is associated with high mortality and morbidity. We aimed to determine the relative benefits of pharmacological prophylactic treatments in patients with aneurysmal subarachnoid hemorrhage by performing a network meta-analysis of randomized trials. Methods: We searched Medline, Web of Science, Embase, Scopus, ProQuest, and Cochrane Central to February 2020. Pairs of reviewers independently identified eligible trials, extracted data, and assessed the risk of bias. Eligible trials compared the prophylactic effects of any oral or intravenous medications or intracranial drug-eluting implants to one another or placebo or standard of care in adult hospitalized patients with confirmed aneurysmal subarachnoid hemorrhage. We used the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach to assess the certainty of the evidence. Results: We included 53 trials enrolling 10 415 patients. Nimodipine likely reduces all-cause mortality compared to placebo (odds ratio [OR],0.73 [95% CI, 0.53–1.00]; moderate certainty; absolute risk reduction (ARR), −3.35%). Nimodipine (OR, 1.46 [95% CI, 1.07–1.99]; high certainty; absolute risk increase, 8.25%) and cilostazol (OR, 3.73 [95% CI, 1.14–12.18]; moderate certainty; absolute risk increase, 23.15%) were the most effective treatments in improving disability at the longest follow-up. Compared to placebo, clazosentan (10 mg/kg; OR, 0.39 [95% CI, 0.22–0.68]; high certainty; ARR, −16.65%), nicardipine (OR, 0.48 [95% CI, 0.24–0.94]; moderate certainty; ARR, −13.70%), fasudil (OR, 0.55 [95% CI, 0.31–0.98]; moderate certainty; ARR, −11.54%), and magnesium (OR, 0.66 [95% CI, 0.46–0.94]; high certainty; ARR, −8.37%) proved most effective in reducing the likelihood of delayed cerebral ischemia. Conclusions: Nimodipine and cilostazol are likely the most effective treatments in preventing morbidity and mortality in patients with aneurysmal subarachnoid hemorrhage. Clazosentan, nicardipine, fasudil, and magnesium showed beneficial effects on delayed cerebral ischemia and vasospasm but they were not found to reduce mortality or disability. Future trials are warranted to elaborately investigate the prophylactic effects of medications that may improve mortality and long-term functional outcomes, such as cilostazol and clazosentan. REGISTRATION: URL: https://www.crd.york.ac.uk/PROSPERO/ ; Unique identifier: CRD42019122183.

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“…Clazosentan is an intravenously (i.v.) administered selective ET-1 receptor type A antagonist (ERA) inhibiting ET-1mediated vasoconstriction and has demonstrated efficacy by reducing the frequency and severity of cerebral vasospasm following severe aSAH in two phase 2 studies and one phase 3 study (5)(6)(7). It is in development for the prevention and treatment of vasospasm associated with aSAH at a dose of 15 mg/h i.v.…”

Section: Introductionmentioning

confidence: 99%

Association Between Vomiting and QT Hysteresis: Data from a TQT Study with the Endothelin A Receptor Antagonist Clazosentan

Juif

Dingemanse

Voors-Pette

et al. 2020

AAPS J

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This study investigated the potential QT liability of the selective endothelin-1 A receptor antagonist clazosentan at a therapeutic (20 mg/h) and supratherapeutic (60 mg/h) intravenous (i.v.) dose. A randomized, placebo-and moxifloxacin-controlled, double-blind, 3period, crossover study was conducted in 36 healthy subjects receiving clazosentan (20 mg/h followed by 60 mg/h i.v. for 3 h each), placebo (i.v. for 6 h), and moxifloxacin (single oral dose of 400 mg concomitantly with placebo i.v. for 6 h). At least three replicate ECGs were extracted from Holter recordings at predefined time points from 1 h pre-dose to 24 h after end of infusion. Pharmacokinetic blood sampling was performed for concentration/QT analysis (primary endpoint). For moxifloxacin, the lower bound of the 90% confidence interval (CI) of baseline-and placebo-corrected QTcF (ΔΔQTcF) was > 5 ms at its maximum plasma concentration together with a positive slope of the concentration/QT regression line demonstrating assay sensitivity. For clazosentan, time of peak exposure preceded maximum ΔΔQTcF by 4 h indicating delayed QT-prolonging effects leading to invalidity of the concentration/QT analysis. The secondary by-time-point analysis revealed QT liability of clazosentan (i.e., upper bound of 90% CI ΔΔQTcF > 10 ms). Delayed QT prolongation (i.e., hysteresis) was predominantly observed in subjects with nausea and vomiting, potentially caused by vagal reaction and/or decreases in potassium concentration. By contrast, there was no association with other adverse events, food intake, or concomitant medication. In conclusion, clazosentan at therapeutic and supratherapeutic doses has QT liability with hysteresis effects being associated with nausea and vomiting.

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An Update on the Efficacy and Safety Profile of Clazosentan in Cerebral Vasospasm After Aneurysmal Subarachnoid Hemorrhage: A Meta-Analysis

Cited by 11 publications

References 19 publications

Clinical Usage of Different Doses of Cis-Atracurium in Intracranial Aneurysm Surgery and Its Effect on Motor-Evoked Potentials

Clinical Usage of Different Doses of Cis-Atracurium in Intracranial Aneurysm Surgery and Its Effect on Motor-Evoked Potentials

Prophylactic Therapies for Morbidity and Mortality After Aneurysmal Subarachnoid Hemorrhage: A Systematic Review and Network Meta-Analysis of Randomized Trials

Association Between Vomiting and QT Hysteresis: Data from a TQT Study with the Endothelin A Receptor Antagonist Clazosentan

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