clazosentan and Intracranial-Aneurysm

The present meta-analysis was conducted to provide an update on the efficacy and safety profile of clazosentan with different doses in aneurysmal subarachnoid hemorrhage (aSAH).. We performed a comprehensive and electronic search updated to September 2018 of The Cochrane Library, Embase, and PubMed to identify relevant clinical trials. Trials of the effectiveness of clazosentan in treating cerebral vasospasm after aSAH were studied. The main outcomes included new cerebral infarction (NCI), delayed ischemic neurologic deficit (DIND), vasospasm associated with morbidity/mortality, angiographic vasospasm, rescue therapy, and adverse events. We applied RevMan 5.3 software for this meta-analysis to analyze the combined pooled odds ratios (ORs) with 95% confidence intervals (CIs) using a fixed- or random-effects model on the basis of heterogeneity.. A total of 5 randomized placebo-controlled trials were included in this meta-analysis. Beneficial outcome was found in patients who received higher doses of clazosentan (>5 mg/h) after aSAH based on decreased incidence of DINDs (OR, 1.76; 95% CI, 1.16-2.69; P = 0.008), NCIs (OR, 2.31; 95% CI, 1.34-3.95; P = 0.002), and angiographic vasospasms (OR, 1.85; 95% CI, 1.19-2.89; P = 0.007). Meanwhile, other parameters, such as vasospasm-related morbidity/mortality, rescue therapy, and adverse events, showed no statistical significance (P > 0.05) between high and low doses of clazosentan.. The significant beneficial outcomes of high-dose clazosentan have been proven in preventing cerebral vasospasm and subsequent cerebral infarction compared with low-dose clazosentan, with a manageable safety profile. However, high doses of clazosentan had no significant effect on rescue therapy and vasospasm-related morbidity/mortality.

Topics: Central Nervous System Agents; Dioxanes; Humans; Intracranial Aneurysm; Pyridines; Pyrimidines; Randomized Controlled Trials as Topic; Subarachnoid Hemorrhage; Sulfonamides; Tetrazoles; Vasospasm, Intracranial

Outcome of patients with aneurysmal subarachnoid hemorrhage (SAH) has improved over the last decades. Yet, case fatality remains nearly 40% and survivors often have permanent neurological, cognitive and/or behavioural sequelae. Other than nimodipine drug or clinical trials have not consistently improved outcome. We formed a collaboration of SAH investigators to create a resource for prognostic analysis and for studies aimed at optimizing the design and analysis of phase 3 trials in aneurysmal SAH. We identified investigators with data from randomized, clinical trials of patients with aneurysmal SAH or prospectively collected single- or multicentre databases of aneurysmal SAH patients. Data are being collected and proposals to use the data and to design future phase 3 clinical trials are being discussed. This paper reviews some issues discussed at the first meeting of the SAH international trialists (SAHIT) repository meeting. Investigators contributed or have agreed to contribute data from several phase 3 trials including the tirilazad trials, intraoperative hypothermia for aneurysmal SAH trial, nicardipine clinical trials, international subarachnoid aneurysm trial, intravenous magnesium sulphate for aneurysmal SAH, magnesium for aneurysmal SAH and from prospectively-collected data from four institutions. The number of patients should reach 15,000. Some industry investigators refused to provide data and others reported that their institutional research ethics boards would not permit even deidentified or anonymized data to be included. Others reported conflict of interest that prevented them from submitting data. The problems with merging data were related to lack of common definitions and coding of variables, differences in outcome scales used, and times of assessment. Some questions for investigation that arose are discussed. SAHIT demonstrates the possibility of SAH investigators to contribute data for collaborative research. The problems are similar to those already documented in other similar collaborative efforts such as in head injury research. We encourage clinical trial and registry investigators to contact us and participate in SAHIT. Key issues moving forward will be to use common definitions (common data elements), outcomes analysis, and to prioritize research questions, among others.

Topics: Antioxidants; Brain Infarction; Calcium Channel Blockers; Critical Care; Dioxanes; Drug Therapy, Combination; Humans; Hypotension; Intracranial Aneurysm; Magnesium Compounds; Neuroprotective Agents; Nicardipine; Nimodipine; Practice Patterns, Physicians'; Pregnatrienes; Pyridines; Pyrimidines; Randomized Controlled Trials as Topic; Salvage Therapy; Sample Size; Subarachnoid Hemorrhage; Sulfonamides; Tetrazoles; Treatment Outcome; Vasodilator Agents; Vasospasm, Intracranial

Topics: Adult; Brain Ischemia; Cerebral Angiography; Clinical Trials as Topic; Combined Modality Therapy; Dioxanes; Endothelin A Receptor Antagonists; Female; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Intracranial Aneurysm; Magnesium; Male; Meta-Analysis as Topic; Middle Aged; Multicenter Studies as Topic; Neuroprotective Agents; Pyridines; Pyrimidines; Randomized Controlled Trials as Topic; Subarachnoid Hemorrhage; Sulfonamides; Tetrazoles; Vasospasm, Intracranial

Background and Purpose- Anemia after aneurysmal subarachnoid hemorrhage is common and potentially modifiable. Here, we first evaluate the effect of anemia on neurological outcome and death and second, study the effects of packed red blood cell transfusion on outcome. Methods- A secondary analysis on 413 subjects in the CONSCIOUS-1 study (Clazosentan to Overcome Neurological Ischemia and Infarction Occurring After Subarachnoid Hemorrhage). Multivariable logistic regression identified independent risk factors for anemia and determined the effect of anemia on neurological outcome and death, while adjusting for selected covariates. Optimal predictive thresholds for hemoglobin levels were determined using receiver operating characteristic curve analysis. Finally, patients were pseudorandomized to transfusion using propensity score matching to study the effect of transfusions on outcome. Results- Anemia, defined as hemoglobin <10 g/dL, was present in 5% of patients at presentation, in 29% of patients after aneurysm securing (days 1-3), and in 32% of patients during the peak delayed cerebral ischemia risk period (days 5-9). Anemia after aneurysm securing (odds ratio, 1.96; 95% confidence interval, 1.07-3.59; P=0.03) and during the delayed cerebral ischemia window (odds ratio, 2.63; 95% confidence interval, 1.46-4.76; P=0.0014) was independently associated with poor neurological outcome. Anemia postaneurysm securing (odds ratio, 3.50; 95% confidence interval, 1.15-10.62; P=0.027) but not during the delayed cerebral ischemia window was associated with death. Using propensity score-matched cohorts, we found that transfusion of anemic patients did not improve long-term outcome (P=0.8) or mortality rates (P=0.9). Transfusion of patients with a hemoglobin concentration >10 g/dL was associated with improved neurological outcomes (odds ratio, 0.09; 95% confidence interval, 0.002-0.72; P=0.015), with no differences in mortality. Conclusions- Anemia after aneurysmal subarachnoid hemorrhage is associated with poor long-term neurological outcome and death. Transfusion of packed red blood cells is beneficial for patients who are not considerably anemic beforehand, suggesting further work needs to define the threshold but also the time period of anemia that is sufficient and necessary to contribute to poor outcomes. Clinical Trial Registration- URL: https://www.clinicaltrials.gov . Unique identifier: NCT00111085.

Topics: Adult; Anemia; Blood Transfusion; Brain Ischemia; Cerebral Infarction; Dioxanes; Female; Humans; Intracranial Aneurysm; Male; Middle Aged; Mortality; Pyridines; Pyrimidines; Subarachnoid Hemorrhage; Sulfonamides; Tetrazoles; Treatment Outcome

Individuals who have aneurysmal subarachnoid hemorrhages (SAHs) experience decreased health-related qualities of life (HRQoLs) that persist after the primary insult.. To identify clinical variables that concurrently associate with HRQoL outcomes by using a partial least-squares approach, which has the distinct advantage of explaining multidimensional variance where predictor variables may be highly collinear.. Data collected from the CONSCIOUS-1 trial was used to extract 29 clinical variables including SAH presentation, hospital procedures, and demographic information in addition to 5 HRQoL outcome variables for 256 individuals. A partial least-squares analysis was performed by calculating a heterogeneous correlation matrix and applying singular value decomposition to determine components that best represent the correlations between the 2 sets of variables. Bootstrapping was used to estimate statistical significance.. The first 2 components accounting for 81.6% and 7.8% of the total variance revealed significant associations between clinical predictors and HRQoL outcomes. The first component identified associations between disability in self-care with longer durations of critical care stay, invasive intracranial monitoring, ventricular drain time, poorer clinical grade on presentation, greater amounts of cerebral spinal fluid drainage, and a history of hypertension. The second component identified associations between disability due to pain and discomfort as well as anxiety and depression with greater body mass index, abnormal heart rate, longer durations of deep sedation and critical care, and higher World Federation of Neurosurgical Societies and Hijdra scores.. By applying a data-driven, multivariate approach, we identified robust associations between SAH clinical presentations and HRQoL outcomes.. EQ-VAS, EuroQoL visual analog scaleHRQoL, health-related quality of lifeICU, intensive care unitIVH, intraventricular hemorrhagePLS, partial least squaresSAH, subarachnoid hemorrhageSVD, singular value decompositionWFNS, World Federation of Neurosurgical Societies.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anxiety; Depression; Dioxanes; Female; Health Status; Humans; Intracranial Aneurysm; Least-Squares Analysis; Male; Middle Aged; Outcome Assessment, Health Care; Pain; Pyridines; Pyrimidines; Quality of Life; Self Care; Subarachnoid Hemorrhage; Sulfonamides; Tetrazoles; Young Adult

Clazosentan, an endothelin receptor antagonist, has been shown to reduce vasospasm after aneurysmal subarachnoid hemorrhage (aSAH). CONSCIOUS-3 assessed whether clazosentan reduced vasospasm-related morbidity and all-cause mortality postaSAH secured by endovascular coiling.. This double-blind, placebo-controlled, phase III trial randomized patients with aSAH secured by endovascular coiling to ≤ 14 days intravenous clazosentan (5 or 15 mg/h) or placebo. The primary composite end point (all-cause mortality; vasospasm-related new cerebral infarcts or delayed ischemic neurological deficits; rescue therapy for vasospasm) was evaluated 6 weeks postaSAH. The main secondary end point was dichotomized extended Glasgow Outcome Scale (week 12).. CONSCIOUS-3 was halted prematurely following completion of CONSCIOUS-2; 577/1500 of planned patients (38%) were enrolled and 571 were treated (placebo, n=189; clazosentan 5 mg/h, n=194; clazosentan 15 mg/h, n=188). The primary end point occurred in 50/189 of placebo-treated patients (27%), compared with 47/194 patients (24%) treated with clazosentan 5 mg/h (odds ratio [OR], 0.786; 95% CI, 0.479-1.289; P=0.340), and 28/188 patients (15%) treated with clazosentan 15 mg/h (OR, 0.474; 95% CI, 0.275-0.818; P=0.007). Poor outcome (extended Glasgow Outcome Scale score ≤ 4) occurred in 24% of patients with placebo, 25% of patients with clazosentan 5 mg/h (OR, 0.918; 95% CI, 0.546-1.544; P=0.748), and 28% of patients with clazosentan 15 mg/h (OR, 1.337; 95% CI, 0.802-2.227; P=0.266). Pulmonary complications, anemia, and hypotension were more common in patients who received clazosentan than in those who received placebo. At week 12, mortality was 6%, 4%, and 6% with placebo, clazosentan 5 mg/h, and clazosentan 15 mg/h, respectively.. Clazosentan 15 mg/h significantly reduced postaSAH vasospasm-related morbidity/all-cause mortality; however, neither dose improved outcome (extended Glasgow Outcome Scale).

Topics: Adolescent; Adult; Aged; Dioxanes; Disease-Free Survival; Double-Blind Method; Female; Humans; Intracranial Aneurysm; Male; Middle Aged; Pyridines; Pyrimidines; Subarachnoid Hemorrhage; Sulfonamides; Survival Rate; Tetrazoles; Vasospasm, Intracranial

Aneurysmal subarachnoid hemorrhage (aSAH) is a neurologic emergency that typically warrants initial monitoring in a critical care setting. The aim of this study is to identify clinical and radiologic features on admission that predict a protracted critical care admission following aSAH.. Exploratory posthoc analysis was performed on the 413 patients enrolled in Clazosentan to Overcome Neurological iSChemia and Infarction OccUrring after Subarachnoid hemorrhage (CONSCIOUS-1), a prospective randomized control trial of clazosentan for the prevention of vasospasm after aSAH. The association between potential clinical and radiographic covariates, and the length of stay (LOS) in a critical care unit after aSAH was determined using a Cox proportional hazards model. Covariates with a significance level of p < 0.20, on univariate analysis, were entered into a multivariate forward conditional analysis to identify independent predictors of prolonged LOS.. The mean LOS was 12.6 ± 10.6 days. On multivariate analysis, age (hazard ratio [HR] 1.01, 95 % confidence interval [CI] 1.00-1.02; p = 0.032), a history of hypertension (HR 1.30, CI 1.01-1.67; p = 0.045), and a World Federation of Neurosurgical Societies Score of IV-V on admission (HR 1.38, CI 1.05-1.81; p = 0.02) were the clinical features associated with a greater critical care LOS following aSAH. Intracerebral hemorrhage (HR 1.50, CI 1.03-2.21; p = 0.004) and increasing intraventricular clot burden (HR 1.08, CI 1.03-1.14; p = 0.037) on admission computed tomography were the radiologic features associated with prolonged LOS.. We have identified several early risk factors associated with a prolonged critical care stay following aSAH.

Topics: Adult; Age Factors; Aneurysm, Ruptured; Brain; Cerebral Ventricles; Dioxanes; Endothelin A Receptor Antagonists; Female; Humans; Hypertension; Intensive Care Units; Intracranial Aneurysm; Length of Stay; Male; Middle Aged; Multivariate Analysis; Proportional Hazards Models; Prospective Studies; Pyridines; Pyrimidines; Risk Factors; Severity of Illness Index; Subarachnoid Hemorrhage; Sulfonamides; Tetrazoles; Tomography, X-Ray Computed; Vasospasm, Intracranial