clazosentan and Subarachnoid-Hemorrhage

Clazosentan has been studied to treat cerebral vasospasm after aneurysmal subarachnoid hemorrhage (aSAH).This meta-analysis of randomized controlled trials updates the current knowledge regarding the efficacy and safety of clazosentan compared with placebo after aSAH.. Databases were systematically searched for randomized controlled trials directly comparing the use of clazosentan and placebo for the treatment of cerebral vasospasm after aSAH. Additional eligibility criteria were the report of any of the outcomes of interest (vasospasm, morbidity, functional outcome, or mortality). The primary outcome was vasospasm-related delayed cerebral ischemia (DCI). The analyses were stratified by clazosentan dosage (low or high dose) and aneurysm treatment modality (clipping or coiling). The Cochrane RoB-2 tool was used for studies quality assessment.. Six studies comprising 7 clinical trials were included, involving 2778 patients. Clazosentan decreased the risk of vasospasm-related DCI (risk ratio [RR] 0.56, 95% CI 0.38-0.81) and delayed ischemic neurological deficit (RR 0.63, 95% 0.50-0.80). Angiographic vasospasm (RR 0.54, 95% CI 0.47-0.61) was also decreased. Functional outcomes (favorable Glasgow Outcome Scale, RR 0.99, 95% CI 0.79-1.24) and death (RR 1.03, 95% CI 0.71-1.49) did not change. Meanwhile, adverse events were increased by clazosentan (RR 1.54, 95% CI 1.35-1.76).. Clazosentan decreased vasospasm-related DCI and angiographic vasospasm but did not improve functional outcomes or mortality. Adverse events were increased by clazosentan.

Topics: Brain Ischemia; Cerebral Infarction; Dioxanes; Humans; Subarachnoid Hemorrhage; Treatment Outcome; Vasospasm, Intracranial

Clazosentan (PIVLAZ

Topics: Dioxanes; Endothelin A Receptor Antagonists; Humans; Pyridines; Pyrimidines; Subarachnoid Hemorrhage; Sulfonamides; Tetrazoles; Vasospasm, Intracranial

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

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.. 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 α-spending monitoring boundary effect of relative risk (RR) reduction. A stratified analysis of clazosentan dosage was performed.. 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.. 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.

Topics: Databases, Bibliographic; Dioxanes; Endothelin Receptor Antagonists; Humans; Pyridines; Pyrimidines; Subarachnoid Hemorrhage; Sulfonamides; Tetrazoles; Treatment Outcome

Clazosentan therapy after aneurysmal subarachnoid hemorrhage (SAH) has been found to be effective in reducing the incidence of vasospasm in randomized controlled trials. However, while vasospasm-related morbidity, including delayed ischemic neurological deficits (DINDs) and delayed cerebral infarctions, was consistently decreased, statistical significance was not demonstrated and outcomes were not affected by clazosentan treatment. The objective of this meta-analysis was to determine whether clazosentan treatment after aneurysmal SAH significantly reduced the incidence of DINDs and delayed cerebral infarctions and improved outcomes.. All randomized controlled trials investigating the effect of clazosentan were retrieved via searches with sensitive and specific terms. Six variables were abstracted after the assessment of the methodological quality of the trials. Analyses were performed following the method guidelines of the Cochrane Back Review Group.. Four randomized, placebo-controlled trials met eligibility criteria, enrolling a total of 2181 patients. The meta-analysis demonstrated a significant decrease in the incidence of DINDs (relative risk [RR] 0.76 [95% CI 0.62-0.92]) and delayed cerebral infarction (RR 0.79 [95% CI 0.63-1.00]) in patients treated with clazosentan after aneurysmal SAH. However, this treatment regimen was not shown to outcomes including functional outcomes measured by Glasgow Outcome Scale-Extended (RR 1.12 [95% CI 0.96-1.30]) or mortality (RR 1.02 [95%CI 0.70-1.49]). Adverse events, including pulmonary complications, anemia, and hypotension, were all significantly increased in patients who received clazosentan therapy.. The results of the present meta-analysis show that treatment with clazosentan after aneurysmal SAH significantly reduced the incidence of the vasospasm-related DINDs and delayed cerebral infarctions, but did not improve poor neurological outcomes in patients with aneurysmal SAH. Further study is required to elucidate the dissociation between vasospasm-related morbidity and outcomes.

Topics: Dioxanes; Endothelin A Receptor Antagonists; Humans; Morbidity; Pyridines; Pyrimidines; Randomized Controlled Trials as Topic; Subarachnoid Hemorrhage; Sulfonamides; Tetrazoles; Treatment Outcome; 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

Increased vascular contractility plays an important role in the development of cerebral vasospasm following subarachnoid hemorrhage (SAH). Increased vascular contractility can be attributed to either endothelial dysfunction or increased contractility of vascular smooth muscle. Endothelial damage and dysfunction cause impairment of endothelium-dependent vasodilation of the cerebral artery after SAH. In addition to endothelial damage and dysfunction, receptor upregulation in vascular smooth muscle contributes to the induction and enhancement of contractile responses to agonists. Our recent data revealed that feedback regulation of the activity of the G protein-coupled receptor and myofilament Ca(2+) sensitivity is impaired after SAH. This impaired feedback regulation is suggested to cause a sustained contractile response to various agonists, thereby contributing to increased vascular contractility. In addition, three current topics are reviewed: endothelin type A receptor antagonists, 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors for treatment, and cortical spreading depolarization for the mechanism of cerebral vasospasm.

Topics: Calcium; Cortical Spreading Depression; Dioxanes; Endothelium, Vascular; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Muscle, Smooth, Vascular; Myofibrils; Pyridines; Pyrimidines; Receptors, G-Protein-Coupled; Subarachnoid Hemorrhage; Sulfonamides; Tetrazoles; Vasospasm, Intracranial

Cerebral vasospasm (CVS) after aneurysmal subarachnoid hemorrhage remains a considerable challenge in neurocritical care medicine. This review aims to cover the recent novel aspects and results in CVS treatment.. On the basis of the recent literature, treatment focusing on CVS alone is outdated. A considerable amount of evidence suggests CVS not to be the sole cause of delayed cerebral ischemia (DCI) and poor outcome. Early brain injury, cortical spreading depolarization, inflammation and microthrombosis have recently been discussed as additional factors. The results of a well designed phase III trial, using an endothelin-1 antagonist, indicated a decrease in the occurrence of CVS but did not change the clinical outcome significantly. Induced hypertension is currently recommended for treating suspected DCI, whereas hemodilution and hypervolemia are not. Endovascular intervention is only recommended in case of refractory symptomatic CVS. A couple of newer treatment strategies are under evaluation. Phase III trials are underway for magnesium sulfate and statins. Clinical trials aiming specifically at recently discussed factors other than CVS have not been reported.. Reviewing the recent literature, there have been some updates on recommendations and newer treatment modalities are under evaluation. However, a novel treatment with convincing evidence has not been reported so far.

Topics: Antihypertensive Agents; Clinical Trials, Phase III as Topic; Critical Care; Dioxanes; Female; Humans; Hypertension; Magnesium Sulfate; Male; Pyridines; Pyrimidines; Subarachnoid Hemorrhage; Sulfonamides; Tetrazoles; Vasospasm, Intracranial

Survivors of aneurysmal subarachnoid hemorrhage (SAH) may suffer functional dependence, cognitive impairment, and mood disorders. Cerebral vasospasm and delayed cerebral ischemia are associated with poor outcome in SAH and have been the subjects of intense investigation for decades. Recently a series of clinical trials was performed in SAH patients using an endothelin receptor antagonist. The results of these trials emphasize the disconnect between attenuation of cerebral vasospasm and improvement in functional outcome. The purpose of this review article is to evaluate the utilization of animal models for the development of drugs targeting the endothelin pathway in SAH and, given the recent endothelin receptor antagonist clinical trial results and lessons from the ischemic neuroprotection field, reflect on an alternative approach to in vivo preclinical drug testing in SAH.

Topics: Animals; Clinical Trials as Topic; Dioxanes; Drug Discovery; Endothelin Receptor Antagonists; Endothelins; Humans; Pyridines; Pyrimidines; Recovery of Function; Subarachnoid Hemorrhage; Sulfonamides; Tetrazoles; Vasospasm, Intracranial

Endothelin is considered to be a key mediator of vasospasm after subarachnoid hemorrhage. A meta-analysis of randomized trials on the effectiveness of endothelin receptor antagonists in subarachnoid hemorrhage has been published previously, but since then new major trials have been published. We present the results of a systematic review and meta-analysis update.. We searched the Cochrane Library, the Cochrane Central Register of Controlled Trials, and PubMed with the following terms: subarachnoid hemorrhage AND (endothelin receptor antagonist OR clazosentan OR TAK-044 OR bosentan). All randomized, placebo-controlled trials investigating the effect of any endothelin receptor antagonists in patients with subarachnoid hemorrhage were included. Primary outcome was poor functional outcome (defined as death or dependency). Secondary outcomes were vasospasm, cerebral infarction as defined by investigators, and case fatality during follow-up. Data were pooled and effect sizes were expressed as risk ratio (RR) estimates with 95% confidence intervals (CI). We also calculated RR for several common complications.. in 5 trials with 2601 patients, endothelin receptor antagonists did not affect functional outcome (RR, 1.06: 95% CI, 0.93-1.22) despite a decreased incidence of angiographic vasospasm (RR, 0.58; 95% CI, 0.48-0.71). No effect was observed on vasospasm-related cerebral infarction (RR, 0.76; 95% CI, 0.53-1.11), any new cerebral infarction (RR, 1.04; 95% CI, 0.91-1.19), or case-fatality (RR, 1.04; 95% CI, 0.78-1.39). Endothelin receptor antagonists increased the risk of lung complications (RR, 1.79; 95% CI, 1.52-2.11), pulmonary edema (RR, 2.12; 95% CI, 1.32-3.39), hypotension (RR, 2.42: 95% CI, 1.78-3.29), and anemia (RR, 1.47; 95% CI, 1.19-1.83).. These results argue against the use of endothelin receptor antagonists in patients with subarachnoid hemorrhage.

Topics: Bosentan; Contraindications; Dioxanes; Endothelin Receptor Antagonists; Humans; Incidence; Peptides, Cyclic; Pyridines; Pyrimidines; Receptors, Endothelin; Subarachnoid Hemorrhage; Sulfonamides; Tetrazoles; Treatment Outcome; Vasospasm, Intracranial

A subarachnoid hemorrhage (SAH) is a serious and potentially life-threatening condition where blood leaks out of blood vessels over the surface of the brain. Delayed ischemic neurological deficit (DIND) and the related feature of vasospasm, where patients experience a delayed deterioration, have long been recognized as the leading potentially treatable cause of death and disability in patients with SAH. Endothelin is a potent, long-lasting endogenous vasoconstrictor that has been implicated in the pathogenesis of DIND. Therefore, endothelin receptor antagonists (ETAs) have emerged as a promising therapeutic option for SAH-induced cerebral vasospasm.. To assess the efficacy and tolerability of ETAs for SAH.. We searched the Cochrane Stroke Group Trials Register (December 2011), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2011, Issue 11), MEDLINE (1950 to December 2011), EMBASE (1946 to December 2011) and the Chinese Biomedical Database (1978 to December 2011). In an effort to identify further published, unpublished and ongoing trials we searched additional Chinese databases, ongoing trials registers, Google Scholar and Medical Matrix, handsearched journals, scanned reference lists, and contacted researchers and pharmaceutical companies.. We only included randomized controlled trials (RCTs) that compared an ETA with placebo for SAH in adult (18 years of age or older) patients who met the diagnostic criteria for SAH based on clinical symptoms, with confirmation on computerized tomography scan results or angiography. Two review authors independently selected RCTs according to the inclusion criteria. We resolved disagreements by discussion with a third review author.. Two review authors independently selected relevant articles and assessed their eligibility according to the inclusion and exclusion criteria. We resolved disagreements by discussion with a third review author. We used the random-effects model and expressed the results as risk ratio (RR) for dichotomous outcomes and mean difference (MD) for continuous outcomes with 95% confidence intervals (CI).. We included four RCTs with 2024 participants that compared ETAs with placebo for SAH. All RCTs were multicenter, double-blind studies with a low risk of bias. ETAs reduced the incidence of DIND (RR 0.80; 95% CI 0.67 to 0.95) and angiographic vasospasm (RR 0.62; 95% CI 0.52 to 0.72) but did not reduce the incidence of unfavorable outcomes (RR 0.87; 95% CI 0.74 to 1.02) or mortality (RR 1.05; 95% CI 0.77 to 1.45). ETAs increased the incidence of hypotension (RR 2.53; 95% CI 1.77 to 3.62) and pneumonia (RR 1.56; 95% CI 1.23 to 1.97).. ETAs appear to reduce DIND and angiographic vasospasm but there were adverse events and the impact on clinical outcome is unclear. Additional well-designed RCTs are needed.

Topics: Brain Ischemia; Conflict of Interest; Dioxanes; Endothelin Receptor Antagonists; Humans; Hypotension; Pneumonia; Pyridines; Pyrimidines; Randomized Controlled Trials as Topic; Research Support as Topic; Subarachnoid Hemorrhage; Sulfonamides; Tetrazoles; Vasospasm, Intracranial

Cerebral vasospasm is the most important potentially treatable cause of mortality and morbidity following aneurysmal subarachnoid hemorrhage (aSAH). Clazosentan, a selective endothelinreceptor antagonist, has been suggested to help reduce the incidence of vasospasm in patients with aSAH. However, the results were controversial in previous trials. This meta-analysis attempts to assess the effect of clazosentan in patients with aSAH.. We systematically searched Pubmed, Embase, and the Cochrane Library from their inception until June, 2012. All randomized controlled trials (RCTs) related to the effect of clazosentan in aSAH were included. The primary outcomes included the incidence of angiographic vasospasm, new cerebral infarction (NCI), delayed ischemic neurological deficits (DIND), and vasospasm-related morbidity/mortality (M/M); the second outcomes included the occurrence of rescue therapy, all-cause-mortality, and poor outcome. 4 RCTs were included with a total of 2156 patients. The risk of angiographic vasospasm (relative risk [RR] =0.58; 95% CI, 0.48 to 0.71), DIND (RR=0.76; 95% CI, 0.62 to 0.92), and vasospasm-related M/M (RR=0.80; 95% CI, 0.67 to 0.96) were statistically significantly reduced in the clazosentan group. Patients treated with clazosentan had a reduced occurrence of rescue therapy (RR=0.62; 95% CI, 0.49 to 0.79). However, no statistically significant effects were observed in NCI (RR=0.74; 95% CI, 0.52 to 1.04), mortality (RR=1.03; 95% CI, 0.71 to 1.49), and poor outcome (RR=1.12; 95% CI, 0.96 to 1.30).. Our pooling data supports that clazosentan is probably effective in preventing the occurrence of angiographic vasospasm, vasospasm-related DIND, vasospasm related M/M, and rescue therapy. However, no evidence lends significant supports to the benefits of clazosentan in decreasing the occurrence of NCI, mortality or improving the functional outcome.

Topics: Brain Ischemia; Cause of Death; Confidence Intervals; Dioxanes; Humans; Incidence; Placebos; Pyridines; Pyrimidines; Randomized Controlled Trials as Topic; Subarachnoid Hemorrhage; Sulfonamides; Tetrazoles; Treatment Outcome; 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

Cerebral vasospasm is the classic cause of delayed neurological deterioration leading to cerebral ischemia and infarction, and thus, poor outcome and occasionally death, after aneurysmal subarachnoid hemorrhage (SAH). Advances in diagnosis and treatment, principally nimodipine, intensive care management, hemodynamic manipulations, and endovascular neuroradiology procedures, have improved the prospects for these patients, but outcomes remain disappointing. A phase 2b clinical trial (CONSCIOUS-1) demonstrated marked prevention of vasospasm with the endothelin antagonist, clazosentan, yet patient outcome was not improved. The most likely explanation is that the study was underpowered to detect the relatively small improvements in outcome that would be seen with prevention of vasospasm, especially when assessed using relatively insensitive measures such as the modified Rankin and Glasgow outcome scales. Other possible explanations for this result are that adverse effects of treatment affected the beneficial effects of the drug. It also is possible that alternative causes of neurological deterioration and poor outcome after SAH, including delayed effects of acute global cerebral ischemia, thromboembolism, microcirculatory dysfunction, and cortical spreading depression, play a role. Clazosentan reduced angiographic vasospasm in a dose-dependent manner in patients with aneurysmal SAH following coiling or clipping of the aneurysm. Reducing the incidence of vasospasm should have an important effect on clinical outcome. A phase 3 clinical trial (CONSCIOUS-2) will focus on quantifying this outcome in patients undergoing aneurysm clipping receiving placebo or 5 mg/h of clazosentan.

Topics: Clinical Trials, Phase II as Topic; Dioxanes; Endothelins; Humans; Pyridines; Pyrimidines; Subarachnoid Hemorrhage; Sulfonamides; Tetrazoles; Vasospasm, Intracranial

Clazosentan has been investigated globally for the prevention of cerebral vasospasm after aneurysmal subarachnoid hemorrhage (aSAH). The authors evaluated its effects on vasospasm-related morbidity and all-cause mortality following aSAH in Japanese patients.. Two similar double-blind, placebo-controlled phase 3 studies were conducted in 57 Japanese centers in patients with aSAH, after aneurysms were secured by endovascular coiling in one study and surgical clipping in the other. In each study, patients were randomly administered intravenous clazosentan (10 mg/hr) or placebo (1:1) starting within 48 hours of aSAH and for up to 15 days after aSAH. Stratified randomization based on World Federation of Neurosurgical Societies grade was performed using a centralized interactive web response system. Vasospasm-related morbidity and all-cause mortality within 6 weeks post-aSAH, including new cerebral infarcts and delayed ischemic neurological deficits as well as all-cause mortality, were the first primary endpoint in each study. The second primary endpoint was all-cause morbidity (new cerebral infarct or delayed ischemic neurological deficit from any causes) and all-cause mortality (all-cause morbidity/mortality) within 6 weeks post-aSAH. The incidence of individual components of the primary morbidity/mortality endpoints within 6 weeks and patient outcome at 12 weeks post-aSAH (including the modified Rankin Scale scores) were also evaluated. The above analyses were also performed in the population pooled from both studies.. In each study, 221 patients were randomized and 220 were included in the full analysis set of the primary analysis (109 in each clazosentan group, 111 in each placebo group). Clazosentan significantly reduced the incidence of vasospasm-related morbidity and all-cause mortality after aneurysm coiling (from 28.8% to 13.6%; relative risk reduction 53%; 95% CI 17%-73%) and after clipping (from 39.6% to 16.2%; relative risk reduction 59%; 95% CI 33%-75%). All-cause morbidity/mortality and poor outcome (dichotomized modified Rankin Scale scores) were significantly reduced by clazosentan after preplanned study pooling. Treatment-emergent adverse events were similar to those reported previously.. Clazosentan significantly reduced the combined incidence of vasospasm-related morbidity and all-cause mortality post-aSAH with no unexpected safety findings. Clinical trial registration nos.: JapicCTI-163368 and JapicCTI-163369 (https://www.clinicaltrials.jp).

Topics: Cerebral Infarction; Humans; Japan; Morbidity; Subarachnoid Hemorrhage; Treatment Outcome; Vasospasm, Intracranial

Cerebral vasospasm occurs within 4 to 14 days from the onset of aneurysmal subarachnoid hemorrhage (aSAH) in 40 to 70% of patients. Of patients with cerebral vasospasm, 17 to 40% experience delayed ischemic neurological deficits and about half of them develop cerebral infarction. Although the mechanism of the onset of cerebral vasospasm has not been fully elucidated, one of mechanisms is considered that after the onset of aSAH, the level of endothelin, a potent and sustained vasoconstriction substance, increases by production induced by oxyhemoglobin and release from erythrocytes and thus cerebral vasospasm develops via endothelin (ET)

Topics: Cerebral Infarction; Endothelin Receptor Antagonists; Humans; Quality of Life; Receptor, Endothelin A; Sodium; Subarachnoid Hemorrhage; Treatment Outcome; Vasospasm, Intracranial

For patients presenting with an aneurysmal subarachnoid hemorrhage (aSAH), delayed cerebral ischemia (DCI) is a significant cause of morbidity and mortality. The REACT study is designed to assess the safety and efficacy of clazosentan in preventing clinical deterioration due to DCI in patients with aSAH.. REACT is a prospective, multicenter, randomized phase 3 study that is planned to enroll 400 patients with documented aSAH from a ruptured cerebral aneurysm, randomized 1:1 to 15 mg/hour intravenous clazosentan vs. placebo, in approximately 100 sites and 15 countries. Eligible patients are required to present at hospital admission with CT evidence of significant subarachnoid blood, defined as a thick and diffuse clot that is more than 4 mm in thickness and involves 3 or more basal cisterns. The primary efficacy endpoint is the occurrence of clinical deterioration due to DCI up to 14 days post-study drug initiation. The main secondary endpoint is the occurrence of clinically relevant cerebral infarction at Day 16 post-study drug initiation. Other secondary endpoints include the modified Rankin Scale (mRS) and the Glasgow Outcome Scale-Extended (GOSE) score at Week 12 post-aSAH, dichotomized into poor and good outcome. Radiological results and clinical endpoints are centrally evaluated by independent committees, blinded to treatment allocation. Exploratory efficacy endpoints comprise the assessment of cognition status at 12 weeks and quality of life at 12 and 24 weeks post aSAH.. In the REACT study, clazosentan is evaluated on top of standard of care to determine if it reduces the risk of clinical deterioration due to DCI after aSAH. The selection of patients with thick and diffuse clots is intended to assess the benefit/risk profile of clazosentan in a population at high risk of vasospasm-related ischemic complications post-aSAH. TRIAL REGISTRATION (ADDITIONAL FILE 1): ClinicalTrials.gov (NCT03585270). EU Clinical Trial Register (EudraCT Number: 2018-000241-39).

Topics: Brain Ischemia; Cerebral Infarction; Clinical Deterioration; Humans; Prospective Studies; Quality of Life; Subarachnoid Hemorrhage; Vasospasm, Intracranial

Clazosentan, an endothelin-1 receptor antagonist, has been shown to prevent the development of large vessel angiographic vasospasm after aneurysmal subarachnoid hemorrhage (aSAH). It has been hypothesized that clazosentan can also reverse established angiographic vasospasm.. The REVERSE (resynchronization reverses remodeling in systolic left ventricular dysfunction) study was a prospective, multicenter, open-label, 2-stage pilot study of adult patients with aSAH who had received intravenous clazosentan (15 mg/hour) after developing moderate-to-severe angiographic vasospasm. The primary efficacy endpoint was the reversal of global cerebral vasospasm in large cerebral artery segments 3 hours after clazosentan initiation. The secondary endpoints included large artery vasospasm reversal at 24 hours and the maximum change in the angiographic cerebral circulation time. The change in vasospasm severity in the proximal and distal segments was investigated in an exploratory analysis.. The primary efficacy endpoint was met in 3 of 11 evaluable patients (27.3%; 95% confidence interval, 6.0-61.0). However, recruitment was stopped after stage 1 in accordance with the predefined interim analysis criteria. In the exploratory analysis, 50.0% and 77.8% of the patients showed a significant reversal of vasospasm or improvement to the admission state in ≥2 distal segments at 3 and 24 hours and 28.6% and 77.8% in ≥2 proximal segments, respectively.. Although the main analysis showed a reversal of large vessel vasospasm 3 hours after clazosentan initiation in a few patients, the exploratory analysis indicated a clear pharmacodynamic dilating effect on vasospastic cerebral vessels at 24 hours in most patients, in particular, in the distal arterial beds. This observation supported the inclusion of patients with established vasospasm in the ongoing REACT (prevention and treatment of vasospasm with clazosentan) trial.

Topics: Adult; Angiography, Digital Subtraction; Cerebral Angiography; Dioxanes; Embolization, Therapeutic; Endothelin A Receptor Antagonists; Endovascular Procedures; Female; Humans; Infusions, Intravenous; Male; Middle Aged; Neurosurgical Procedures; Pilot Projects; Pyridines; Pyrimidines; Subarachnoid Hemorrhage; Sulfonamides; Surgical Instruments; Tetrazoles; Vasospasm, Intracranial; Young Adult

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

Clazosentan has been explored worldwide for the prophylaxis of cerebral vasospasm after aneurysmal subarachnoid hemorrhage (aSAH). In a dose-finding trial (CONSCIOUS-1) conducted in Israel, Europe, and North America, clazosentan (1, 5, and 15 mg/h) significantly reduced the incidence of cerebral vasospasm, but its efficacy in Japanese and Korean patients was unknown. We conducted a double-blind comparative study to evaluate the occurrence of cerebral vasospasm in Japanese and Korean patients with aSAH.. The aim of this multicenter, double-blind, randomized, placebo-controlled, dose-finding phase 2 clinical trial, was to evaluate the efficacy, pharmacokinetics, and safety of clazosentan (5 and 10 mg/h) against cerebral vasospasm after clipping surgery in Japanese and Korean patients with aSAH. Patients aged between 20 and 75 years were administered the study drug within 56 h after the aneurysm rupture and up to day 14 post-aSAH. The incidence of vasospasm, defined as an inner artery diameter reduction of major intracranial arteries ≥34% based on catheter angiography, was compared between each treatment group. Cerebral infarction due to vasospasm at 6 weeks and patients' outcome at 3 months was also compared.. Among 181 enrolled patients, 158 completed the study and were analyzed. The incidence of vasospasm up to day 14 after aSAH onset was 80.0% in the placebo group (95% CI 67.0-89.6), 38.5% in the 5 mg/h clazosentan group (95% CI 25.3-53.0), and 35.3% in the 10 mg/h clazosentan group (95% CI 22.4-49.9), indicating that the incidence of vasospasm was significantly reduced by clazosentan treatment (placebo vs. 5 mg/h clazosentan, p < 0.0001; placebo vs. 10 mg/h clazosentan, p < 0.0001). The occurrence of cerebral infarction due to vasospasm was 20.8% in the placebo group (95% CI 10.8-34.1), 3.8% in the 5 mg/h clazosentan group (95% CI 0.5-13.2), and 4.2% in the 10 mg/h clazosentan group (95% CI 0.5-14.3), indicating that clazosentan significantly reduced the occurrence of cerebral infarctions caused by vasospasm (placebo vs. 5 mg/h clazosentan, p = 0.0151; placebo vs. 10 mg/h clazosentan, p = 0.0165). The overall incidence of all-cause death and/or vasospasm-related morbidity/mortality was significantly reduced in the 10 mg/h clazosentan group compared with the placebo group (p = 0.0003).. These results suggest that clazosentan prevents cerebral vasospasm and subsequent cerebral infarction, and could thereby improve outcomes after performing a clipping surgery for aSAH in Japanese and Korean patients.

Topics: Adult; Aged; Angiography, Digital Subtraction; Cerebral Angiography; Cerebral Infarction; Dioxanes; Double-Blind Method; Endothelin A Receptor Antagonists; Female; Humans; Japan; Male; Middle Aged; Neurosurgical Procedures; Pyridines; Pyrimidines; Republic of Korea; Subarachnoid Hemorrhage; Sulfonamides; Tetrazoles; Time Factors; Treatment Outcome; Vasodilator Agents; Vasospasm, Intracranial; Young Adult

Shunt-dependent hydrocephalus is a common complication of aneurysmal subarachnoid hemorrhage (aSAH). There is a need to identify patients who require ventriculoperitoneal shunt (VPS) insertion so that any modifiable risk factors can be addressed early after aSAH.. Exploratory analysis was performed on 413 patients enrolled in CONSCIOUS-1, a prospective randomized controlled trial of patients with aSAH treated with clazosentan. The association between clinical and neuroimaging covariates and VPS placement was first determined by univariate analysis. Covariates with P < 0.15 on univariate analysis were then analyzed in a multivariate logistic regression model. Receiver operating characteristic curve analysis was used to define optimal predictive thresholds. The published literature was reviewed to determine the overall rate of VPS insertion after aSAH.. Overall, 17.2% (71/413) of patients required VPS insertion. Multivariate analysis demonstrated that insertion of an external ventricular drain (odds ratio, 6.21; 95% confidence interval, 2.51-16.91) and increasing volume of cerebrospinal fluid (CSF) drainage per day (odds ratio, 1.004; 95% confidence interval, 1.000-1.009) were associated with VPS insertion. Receiver operating characteristic curve analysis revealed an optimal daily CSF output threshold of 78 mL was predictive of VPS insertion. Among 41,789 patients with aSAH from 66 published studies, the overall VPS insertion rate was 12.7%.. The presence of an external ventricular drain and increased daily CSF output (above 78 mL/day) seems to be predictive of subsequent VPS insertion after aSAH. Although we could not identify modifiable risk factors for needing a VPS, nevertheless, these findings identify patients at greatest risk of VPS placement and inform treatment decisions as well as patient expectations.

Topics: Cerebrospinal Fluid Shunts; Dioxanes; Double-Blind Method; Female; Humans; Hydrocephalus; Male; Middle Aged; Predictive Value of Tests; Prospective Studies; Pyridines; Pyrimidines; Risk Factors; ROC Curve; Subarachnoid Hemorrhage; Sulfonamides; Tetrazoles; Tomography, X-Ray Computed; Treatment Outcome; Ventriculoperitoneal Shunt

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

Predictors of outcome after aneurysmal subarachnoid hemorrhage have been determined previously through hypothesis-driven methods that often exclude putative covariates and require a priori knowledge of potential confounders. Here, we apply a data-driven approach, principal component analysis, to identify baseline patient phenotypes that may predict neurological outcomes.. Principal component analysis was performed on 120 subjects enrolled in a prospective randomized trial of clazosentan for the prevention of angiographic vasospasm. Correlation matrices were created using a combination of Pearson, polyserial, and polychoric regressions among 46 variables. Scores of significant components (with eigenvalues>1) were included in multivariate logistic regression models with incidence of severe angiographic vasospasm, delayed ischemic neurological deficit, and long-term outcome as outcomes of interest.. Sixteen significant principal components accounting for 74.6% of the variance were identified. A single component dominated by the patients' initial hemodynamic status, World Federation of Neurosurgical Societies score, neurological injury, and initial neutrophil/leukocyte counts was significantly associated with poor outcome. Two additional components were associated with angiographic vasospasm, of which one was also associated with delayed ischemic neurological deficit. The first was dominated by the aneurysm-securing procedure, subarachnoid clot clearance, and intracerebral hemorrhage, whereas the second had high contributions from markers of anemia and albumin levels.. Principal component analysis, a data-driven approach, identified patient phenotypes that are associated with worse neurological outcomes. Such data reduction methods may provide a better approximation of unique patient phenotypes and may inform clinical care as well as patient recruitment into clinical trials.. http://www.clinicaltrials.gov. Unique identifier: NCT00111085.

Topics: Brain Ischemia; Cerebral Angiography; Dioxanes; Double-Blind Method; Female; Humans; Intracranial Hemorrhages; Male; Middle Aged; Nervous System Diseases; Phenotype; Principal Component Analysis; Prospective Studies; Pyridines; Pyrimidines; Subarachnoid Hemorrhage; Sulfonamides; Tetrazoles; Tomography, X-Ray Computed; Treatment Outcome; Vasospasm, Intracranial

This paper describes the pharmacokinetic/pharmacodynamic modelling of clazosentan in patients with aneurysmal subarachnoid haemorrhage (aSAH), and the impact of collecting data in an intensive care unit (ICU) setting. Factors influencing data quality, analysis, and interpretation are provided with recommendations for future clinical studies in ICU settings.. CONSCIOUS-2 was a phase III study involving 1,157 patients with aSAH. Secured by surgical clipping, patients were infused with clazosentan or placebo for up to 14 days post-aSAH. Clazosentan exposure relationships with vital signs, QT intervals, and AST/ALT values as well as efficacy and safety endpoints were characterised using population PK/PD and logistic regression models.. Clazosentan clearance was influenced by age, sex, Asian origin, and disease status at baseline, and increased with time. Volume of distribution showed a sex difference. Exposure had no relationship with any efficacy endpoint or ALT/AST values, but was related to the increasing probability of lung complications. Blood pressure decreased proportionally to clazosentan concentrations, and the presence of clazosentan was associated with QT interval increases. Implausible values in the concentration data reflect the specific ICU challenges, possibly arising from PK sampling from the infusion arm or haemodilution.. Population PK/PD modelling of CONCIOUS-2 data provided clinically relevant knowledge about various effects of clazosentan in the aSAH patient population in a real clinical setting. The quality of data and analyses could be improved by the collection of additional data and stricter training of study personnel. Differences in clinical practice between sites and geographical regions are more challenging to overcome.

Topics: Adolescent; Critical Care; Dioxanes; Double-Blind Method; Female; Humans; Intensive Care Units; Male; Middle Aged; Pyridines; Pyrimidines; Subarachnoid Hemorrhage; Sulfonamides; Tetrazoles

Atrophy in specific brain areas correlates with poor neuropsychological outcome after subarachnoid hemorrhage (SAH). Few studies have compared global atrophy in SAH with outcome. The authors examined the relationship between global brain atrophy, clinical factors, and outcome after SAH.. This study was a post hoc exploratory analysis of the Clazosentan to Overcome Neurological Ischemia and Infarction Occurring After Subarachnoid Hemorrhage (CONSCIOUS-1) trial, a randomized, double-blind, placebo-controlled trial of 413 patients with aneurysmal SAH. Patients with infarctions or areas of encephalomalacia on CT, and those with large clip/coil artifacts, were excluded. The 97 remaining patients underwent CT at baseline and 6 weeks, which was analyzed using voxel-based volumetric measurements. The percentage difference in volume between time points was compared against clinical variables. The relationship with clinical outcome was modeled using univariate and multivariate analysis.. Older age, male sex, and systemic inflammatory response syndrome (SIRS) during intensive care stay were significantly associated with brain atrophy. Greater brain atrophy was significantly associated with poor outcome on the modified Rankin scale (mRS), severity of deficits on the National Institutes of Health Stroke Scale (NIHSS), worse executive functioning, and lower EuroQol Group-5D (EQ-5D) score. Adjusted for confounders, brain atrophy was not significantly associated with Mini-Mental State Examination and Functional Status Examination scores. Brain atrophy was not associated with angiographic vasospasm or delayed ischemic neurological deficit.. Worse mRS score, NIHSS score, executive functioning, and EQ-5D scores were associated with greater brain atrophy and older age, male sex, and SIRS burden. These data suggest outcome is associated with factors that cause global brain injury independent of focal brain injury.

Topics: Adult; Age Distribution; Aged; Atrophy; Brain; Cerebral Infarction; Dioxanes; Double-Blind Method; Embolization, Therapeutic; Encephalitis; Endothelin A Receptor Antagonists; Female; Humans; Male; Middle Aged; Multivariate Analysis; Neuropsychological Tests; Postoperative Complications; Pyridines; Pyrimidines; Recovery of Function; Risk Factors; Sex Distribution; Subarachnoid Hemorrhage; Sulfonamides; Tetrazoles; Treatment Outcome

Delayed ischemic neurological deficit (DIND) following aneurysmal subarachnoid hemorrhage (SAH) remains a significant cause of mortality and disability. The administration of colloids and the induction of a positive fluid balance during the vasospasm risk period remain controversial. Here, we compared DIND and outcomes among propensity score-matched cohorts who did and did not receive colloids and also tested the effect of a positive fluid balance on these endpoints.. Exploratory analysis was performed on 413 patients enrolled in CONSCIOUS-1, a prospective randomized trial of clazosentan for the prevention of angiographic vasospasm. Propensity score matching was performed on the basis of age, gender, pre-existing heart conditions, hypertension, nicotine use, World Federation of Neurosurgical Societies scores, aneurysm location, clazosentan treatment, subarachnoid clot burden, and severity of angiographic vasospasm. Inferential statistics were used for group-wise comparisons.. One hundred twenty-three subjects were matched (41 received colloids, whereas 82 did not). The covariate balance and propensity score distributions were acceptable. There was no difference between the groups with respect to DIND (17 vs. 22%; p = 0.64) or the presence (48 vs. 51%; p = 0.71) or volume of delayed infarcts (volume >7.5 cm3; 62 vs. 48%; p = 0.41). Similarly, no differences were found on multivariate analysis between patients who did and did not have a positive fluid balance, although patients with severe angiographic vasospasm had more delayed infarcts with a negative fluid balance (p = 0.01). Among all subjects, the administration of colloids and a positive fluid balance were associated with worse outcomes on the NIHSS (p = 0.04) and modified Rankin (p = 0.02) scales, respectively.. Colloid administration and induction of a positive fluid balance during the vasospasm risk period may be associated with poor outcomes in specific patient groups. Patient selection is of utmost importance when managing the fluid status of patients with aneurysmal SAH.

Topics: Aged; Cerebral Infarction; Colloids; Critical Care; Dioxanes; Double-Blind Method; Endothelin A Receptor Antagonists; Female; Fluid Therapy; Humans; Male; Middle Aged; Propensity Score; Prospective Studies; Pyridines; Pyrimidines; Radiography; Severity of Illness Index; Subarachnoid Hemorrhage; Sulfonamides; Tetrazoles; Vasodilator Agents; Vasospasm, Intracranial; Water-Electrolyte Balance

There is a correlation between poor neuropsychological outcome and focal regions of atrophy in patients with subarachnoid hemorrhage (SAH). No study has investigated the impact of global brain atrophy on outcome after SAH. In other neurological disorders, such as multiple sclerosis, a correlation has been found between global atrophy and outcome. This analysis of patients entered into a randomized clinical trial of clazosentan in patients with SAH (CONSCIOUS-1) investigated the relationship between global cerebral atrophy, clinical factors, and outcome.The 413 patients in the CONSCIOUS-1 study underwent cranial computed tomography (CT) on admission and 6 weeks after SAH. After patients with large clip/coil artefacts and those with infarctions on CT were excluded, 97 patients remained and had voxel-based volumetric measurements of the baseline and 6-week CT scans. The percentage difference in volume between times was taken and analysed against clinical variables. Relationships were modeled using univariate and multivariate analysis.Age, female gender, and higher body temperature during the patient's stay in the intensive care unit were significantly correlated with brain atrophy. Greater brain atrophy significantly correlated with poor outcome (modified Rankin scale), more severe neurological deficits on the National Institute of Health Stroke Scale (NIHSS), and poorer health status (EQ-5D).

Topics: Adult; Analysis of Variance; Atrophy; Body Weight; Brain Injuries; Cerebral Cortex; Dioxanes; Double-Blind Method; Female; Follow-Up Studies; Humans; Male; Middle Aged; Pyridines; Pyrimidines; Statistics, Nonparametric; Subarachnoid Hemorrhage; Sulfonamides; Tetrazoles; Time Factors; Tomography, X-Ray Computed; Trauma Severity Indices; Treatment Outcome

We report here results of a randomized, double-blind, placebo-controlled study ( http://www.ClinicalTrials.gov , NCT00558311) that investigated the effect of clazosentan (5 mg/h, n = 768) or placebo (n = 389) administered for up to 14 days in patients with aneurysmal subarachnoid hemorrhage (SAH) repaired by surgical clipping. The primary endpoint was a composite of all-cause mortality, new cerebral infarction or delayed ischemic neurological deficit due to vasospasm, and rescue therapy for vasospasm. The main secondary endpoint was the Glasgow Outcome Scale Extended (GOSE), which was dichotomized. Twenty-one percent of clazosentan- compared to 25% of placebo-treated patients met the primary endpoint (relative risk reduction [RRR] [95% CI]: 17% [-4% to 33%]; p = 0.10). Poor outcome (GOSE score ≤ 4) occurred in 29% of clazosentan- and 25% of placebo-treated patients (RRR: -18% [-45% to 4%]; p = 0.10). In prespecified subgroups, mortality/vasospasm-related morbidity was reduced in clazosentan-treated patients by 33% (8-51%) in poor WFNS (World Federation of Neurological Surgeons) grade (≥III) and 25% (5-41%) in patients with diffuse, thick SAH. Lung complications, anemia and hypotension occurred more frequently with clazosentan. Mortality (week 12) was 6% in both groups. The results showed that clazosentan nonsignificantly decreased mortality/vasospasm-related morbidity and nonsignificantly increased poor functional outcome in patients with aneurysmal SAH undergoing surgical clipping.

Topics: Adolescent; Adult; Aged; Dioxanes; Double-Blind Method; Female; Follow-Up Studies; Glasgow Coma Scale; Glasgow Outcome Scale; Humans; International Cooperation; Logistic Models; Male; Middle Aged; Neurosurgical Procedures; Pyridines; Pyrimidines; Subarachnoid Hemorrhage; Sulfonamides; Surgical Instruments; Tetrazoles; Vasodilator Agents; Vasospasm, Intracranial; Young Adult

Patients undergoing neurosurgical clipping or endovascular coiling of a ruptured aneurysm may differ in their risk of vasospasm.. Because clot clearance affects vasospasm, we tested the hypothesis that clot clearance differs in patients depending on method of aneurysm treatment.. Exploratory analysis was performed on 413 patients from CONSCIOUS-1, a prospective randomized trial of clazosentan for the prevention of angiographic vasospasm in patients with aneurysmal subarachnoid hemorrhage (SAH). Clot clearance was measured by change in Hijdra score between baseline computed tomography and one performed 24 to 48 hours after aneurysm treatment. Angiographic vasospasm was assessed by the use of catheter angiography 7 to 11 days after SAH, and delayed ischemic neurological deficit (DIND) was determined clinically. Extended Glasgow Outcome Score (GOSE) was assessed 3 months after SAH, and poor outcome was defined as death, vegetative state, or severe disability. Multivariable ordinal and binary logistic regression were used.. There was no significant difference in the rate of clot clearance between patients undergoing clipping or coiling (P = .56). Coiling was independently associated with decreased severity of angiographic vasospasm (odds ratio [OR] 0.53, 95% confidence interval [CI] 0.33-0.86), but not with DIND or GOSE. Greater clot clearance decreased the risk of severe angiographic vasospasm (OR 0.86, 95% CI 0.81-0.91), whereas higher baseline Hijdra score predicted increased angiographic vasospasm (OR 1.17, 95% CI 1.11-1.23) and poor GOSE (OR 1.09, 95% CI 1.04-1.14).. Aneurysm coiling and increased clot clearance were independently associated with decreased severity of angiographic vasospasm in multivariate analysis, although no differences in clot clearance were seen between coiled and clipped patients.

Topics: Adult; Angiography; Dioxanes; Endovascular Procedures; Female; Humans; Male; Middle Aged; Neurologic Examination; Prospective Studies; Pyridines; Pyrimidines; Receptor, Endothelin A; Retrospective Studies; Subarachnoid Hemorrhage; Sulfonamides; Surgical Instruments; Tetrazoles; Thrombosis; Time Factors; Tomography, X-Ray Computed; Ultrasonography, Doppler, Transcranial; Vasospasm, Intracranial

The presence of low-density areas on CT is used in clinical decision-making regarding treatment of angiographic vasospasm as well as in research as a surrogate marker for severity of angiographic vasospasm. We assess the interobserver variability in attributing hypodensities on CT to angiographic vasospasm-related delayed ischemic neurological deficit.. Three experienced reviewers, 2 neurosurgeons, and a neuroradiologist independently reviewed CT scans of 413 patients enrolled in the Clazosentan to Overcome Neurological iSChemia and Infarction OccUrring after Subarachnoid hemorrhage (CONSCIOUS-1) trial, who universally underwent catheter angiography to determine severity of angiographic vasospasm. Interobserver variability was calculated using the κ statistic and the χ(2) test was used to determine associations between dichotomized outcomes.. There was considerable interobserver variability in attributing CT hypodensities to vasospasm-related delayed ischemic neurological deficit (κ=0.51-0.78; 95% CI, 0.35-0.90). Patients with hypodensities attributed to delayed ischemic neurological deficit were significantly more likely to have severe angiographic vasospasm (P=0.001), but a substantial proportion of these patients (19%) also had mild or no spasm. CT hypodensities had a sensitivity and specificity of 41% and 93%, respectively, in identifying patients with severe angiographic vasospasm, even with expert consensus that these represent angiographic vasospasm-related delayed ischemic neurological deficit.. We find considerable interobserver variability in attributing CT hypodensities to angiographic vasospasm and propose that they may not be a robust marker of severity of angiographic vasospasm, even with unanimous expert agreement that they are a result of vasospasm-related delayed ischemic neurological deficit.. URL: www.clinicaltrials.gov. Unique identifier: NCT00111085.

Topics: Adult; Decision Making; Dioxanes; Humans; Pyridines; Pyrimidines; Radiography; Sensitivity and Specificity; Subarachnoid Hemorrhage; Sulfonamides; Tetrazoles; Vasospasm, Intracranial

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

Early identification of patients at risk of angiographic vasospasm after aneurysmal subarachnoid hemorrhage (SAH) may mitigate its sequelae. One mechanism that may contribute to angiographic vasospasm is increased central sympathetic activity, which is also thought to cause electrocardiographic (ECG) changes after SAH. Here, we perform the first study to determine the association between ECG changes and angiographic vasospasm after SAH.. Exploratory analysis was performed on 413 patients from CONSCIOUS-1, a prospective randomized trial of clazosentan for the prevention of angiographic vasospasm. ECGs were obtained within 24 hours of aneurysm rupture and during the vasospasm risk period. Angiographic vasospasm was assessed using catheter angiography at baseline and 7 to 11 days after SAH. Multivariate logistic regression was used to identify significant associations.. The most prevalent finding on ECG both immediately following SAH and during the vasospasm risk period was QT prolongation (42% and 25%, respectively). A prolonged QT interval and tachycardia on the baseline ECG were associated with angiographic vasospasm (OR, 1.86; 95% CI, 1.00-3.45; and OR, 10.83; 95% CI, 1.17-100.50, respectively). QT prolongation on ECG during the vasospasm risk period was also associated with angiographic vasospasm (OR, 3.53; 95% CI, 1.67-7.39). No ECG findings were associated with delayed ischemic neurological deficit, but tachycardia and ST changes were associated with worse clinical outcome.. QT prolongation and tachycardia on ECG were independently associated with angiographic vasospasm after aneurysmal SAH on multivariate analysis.. URL: http://clinicaltrials.gov. Unique Identifier: NCT00111085.

Topics: Adult; Aged; Aneurysm, Ruptured; Brain Ischemia; Cerebral Angiography; Databases, Factual; Dioxanes; Electrocardiography; Female; Humans; Logistic Models; Male; Middle Aged; Multivariate Analysis; Myocardial Stunning; Nervous System Diseases; Potassium; Predictive Value of Tests; Prognosis; Prospective Studies; Pyridines; Pyrimidines; Risk Factors; Subarachnoid Hemorrhage; Sulfonamides; Tetrazoles; Treatment Outcome; Vasospasm, Intracranial

The purpose of this open-label, parallel-group study was to investigate the effect of severe renal impairment on the pharmacokinetics (PK), tolerability, and safety of clazosentan, an intravenous endothelin receptor antagonist. Clazosentan was administered as a continuous intravenous infusion of 1 mg/h for a period of 6 hours in 9 subjects with severe renal impairment (group A) and 8 healthy subjects (group B) (creatinine clearance <30 mL/min and >80 mL/min, respectively). The subjects in both groups were well matched for sex, body mass index, and age (±10 years). The PK parameters of clazosentan were calculated by both model-independent and model-dependent methods. The differences in the PK parameters between the subjects with severe renal impairment and healthy subjects were minor. The geometric means for area under the curve (AUC) during the infusion, AUC(0-t), (AUC from zero to time t of the last measured concentration above the limit of quantification) AUC(0-∞) (AUC from zero to infinity), and concentration at steady state were 7%, 8%, 8%, and 8%, respectively, higher in group A than in group B. The results obtained after 2-compartmental modeling were in agreement with those obtained after noncompartmental analysis. Administration of clazosentan was well tolerated in both groups. The data suggest that there is no need for dose adjustment of clazosentan in patients with renal impairment.

Topics: Adult; Dioxanes; Endothelin A Receptor Antagonists; Female; Half-Life; Humans; Infusions, Intravenous; Kidney Failure, Chronic; Male; Metabolic Clearance Rate; Middle Aged; Models, Biological; Pyridines; Pyrimidines; Renal Insufficiency; Severity of Illness Index; Subarachnoid Hemorrhage; Sulfonamides; Tetrazoles; Vasospasm, Intracranial

Cerebral vasospasm is a common complication occurring after aneurysmal subarachnoid hemorrhage (SAH). It is recognized as a leading preventable cause of morbidity and mortality in this patient group, but its management is challenging, and new treatments are needed. Clazosentan is an endothelin receptor antagonist designed to prevent endothelin-mediated cerebral vasospasm. Vajkoczy et al. (Neurosurg 103:9-17, 2005) initially demonstrated that clazosentan reduced moderate/severe angiographically proven vasospasm by 55% relative to placebo. These findings led to the initiation of the CONSCIOUS trial program to further examine the efficacy and safety of clazosentan in reducing angiographic vasospasm and improving clinical outcome after aneurysmal SAH. In the first of these studies, CONSCIOUS-1, 413 patients were randomized to placebo or clazosentan 1, 5 or 15 mg/h. Clazosentan reduced angiographic vasospasm dose-dependently relative to placebo with a maximum risk reduction of 65% with the highest dose. Despite this, there was no benefit of clazosentan on the secondary protocol-defined morbidity/mortality endpoint; however, additional post-hoc and modified endpoint analyses provided some evidence for a potential clinical benefit. Two additional large-scale studies (CONSCIOUS-2 and CONSCIOUS-3) are now underway to further investigate the potential of clazosentan to improve long-term clinical outcome.

Topics: Adult; Aged; Cerebral Angiography; Cerebral Infarction; Cohort Studies; Dioxanes; Dose-Response Relationship, Drug; Double-Blind Method; Female; Humans; International Cooperation; Male; Middle Aged; Pyridines; Pyrimidines; Subarachnoid Hemorrhage; Sulfonamides; Tetrazoles; Tomography Scanners, X-Ray Computed; Vasospasm, Intracranial; Young Adult

Clazosentan, an endothelin receptor antagonist, significantly and dose-dependently reduced angiographic vasospasm after aneurysmal subarachnoid haemorrhage (aSAH). We investigated whether clazosentan reduced vasospasm-related morbidity and all-cause mortality.. In this randomised, double-blind, placebo-controlled, phase 3 study, we randomly assigned patients with aSAH secured by surgical clipping to clazosentan (5 mg/h, n=768) or placebo (n=389) for up to 14 days (27 countries, 102 sites, inpatient and outpatient settings) using an interactive web response system. The primary composite endpoint (week 6) included all-cause mortality, vasospasm-related new cerebral infarcts, delayed ischaemic neurological deficit due to vasospasm, and rescue therapy for vasospasm. The main secondary endpoint was dichotomised extended Glasgow outcome scale (GOSE; week 12). This trial is registered with ClinicalTrials.gov, number NCT00558311.. In the all-treated dataset, the primary endpoint was met in 161 (21%) of 764 clazosentan-treated patients and 97 (25%) of 383 placebo-treated patients (relative risk reduction 17%, 95% CI -4 to 33; p=0·10). Poor functional outcome (GOSE score ≤4) occurred in 224 (29%) clazosentan-treated patients and 95 (25%) placebo-treated patients (-18%, -45 to 4; p=0·10). Lung complications, anaemia, and hypotension were more common with clazosentan. Mortality (week 12) was 6% in both groups.. Clazosentan at 5 mg/h had no significant effect on mortality and vasospasm-related morbidity or functional outcome. Further investigation of patients undergoing endovascular coiling of ruptured aneurysms is needed to fully understand the potential usefulness of clazosentan in patients with aSAH.. Actelion Pharmaceuticals.

Topics: Dioxanes; Dose-Response Relationship, Drug; Double-Blind Method; Endothelin A Receptor Antagonists; Female; Glasgow Outcome Scale; Humans; Male; Pyridines; Pyrimidines; Subarachnoid Hemorrhage; Sulfonamides; Surgical Instruments; Tetrazoles; Treatment Outcome; Vasospasm, Intracranial

Numerous abnormal findings may be evident on CT scans after aneurysmal subarachnoid hemorrhage (SAH). Here, the authors assess the interobserver variability in the radiological interpretation of the initial CT scan following SAH.. Two experienced reviewers, a neurosurgeon and a neuroradiologist, independently prospectively reviewed the initial CT scans of 413 patients enrolled in the CONSCIOUS-1 trial. Measured variables included SAH, intraventricular hemorrhage, intracerebral hemorrhage, subdural hematoma, chronic infarction, midline shift, and hydrocephalus. To assess interobserver variability, weighted kappa values and intraclass correlation coefficients (ICCs) were calculated and Bland-Altman analysis was performed.. Moderate to substantial agreement was found for most of the CT scanning findings. There was fair to moderate interobserver agreement between reviewers when determining the extent of SAH based on a descriptive categorical classification (kappa 0.41; 95% CI 0.33-0.49), and better agreement when a semiquantitative scale was used (ICC 0.56; 95% CI 0.49-0.62). There was poor agreement between reviewers for the presence of hydrocephalus (kappa 0.34; 95% CI 0.20-0.48), but substantial to near perfect agreement on ventriculocranial ratio measurements (ICC 0.77; 95% CI 0.72-0.81).. The authors' findings suggest that there is considerable interobserver variability in the interpretation of CT scans after SAH. Quantitative measures may reduce interobserver variability in comparison with qualitative or categorical scales. Variability in interpretation of CT scans has implications for patient care and conduct of clinical trials. It may be beneficial to develop standardized assessments to ensure consistent evaluation of measured variables.

Topics: Cerebral Infarction; Cerebral Ventricles; Dioxanes; Humans; Hydrocephalus; Neuroradiography; Neurosurgery; Observer Variation; Prospective Studies; Pyridines; Pyrimidines; Reproducibility of Results; Subarachnoid Hemorrhage; Sulfonamides; Tetrazoles; Tomography, X-Ray Computed; Vasospasm, Intracranial

Systemic inflammatory response syndrome (SIRS) may develop after aneurysmal subarachnoid hemorrhage (SAH). We investigated factors associated with SIRS after SAH, whether SIRS was associated with complications of SAH such as vasospasm, cerebral infarction, and clinical outcome, and whether SIRS could contribute to a difference in outcome between patients treated by endovascular coiling or neurosurgical clipping of the ruptured aneurysm.. This was exploratory analysis of 413 patients in the CONSCIOUS-1 study. SIRS was diagnosed if the patient had at least 2 of 4 variables (hypothermia/fever, tachycardia, tachypnea, and leukocytosis/leukopenia) within 4 days of admission. Clinical outcome was measured on the Glasgow outcome scale 3 months after SAH. The relationship between clinical and radiologic variables and SIRS, angiographic vasospasm, delayed ischemic neurologic deficit (DIND), cerebral infarction, vasospasm-related infarction, and clinical outcome were modeled with uni- and multivariable analyses.. 63% of patients developed SIRS. Many factors were associated with SIRS in univariate analysis, but only poor WFNS grade and pneumonia were independently associated with SIRS in multivariable analysis. SIRS burden (number of SIRS variables per day over the first 4 days) was associated with poor outcome, but not with angiographic vasospasm, DIND, or cerebral infarction. The method of aneurysm treatment was not associated with SIRS.. SIRS was associated with poor outcome but not angiographic vasospasm, DIND, or cerebral infarction after SAH in the CONSCIOUS-1 data. There was no support for the notion that neurosurgical clipping is associated with a greater risk of SIRS than endovascular coiling.

Topics: Adult; Cerebral Infarction; Databases as Topic; Dioxanes; Double-Blind Method; Female; Fever; Humans; Hypothermia; Leukocytosis; Male; Middle Aged; Placebos; Pyridines; Pyrimidines; Receptor, Endothelin A; Subarachnoid Hemorrhage; Sulfonamides; Systemic Inflammatory Response Syndrome; Tachycardia; Tetrazoles; Treatment Failure; Treatment Outcome; Vasospasm, Intracranial

This randomized, double-blind, placebo-controlled, dose-finding study assessed efficacy and safety of 1, 5, and 15 mg/h intravenous clazosentan, an endothelin receptor antagonist, in preventing vasospasm after aneurysmal subarachnoid hemorrhage.. Patients (n=413) were randomized to placebo or clazosentan beginning within 56 hours and continued up to 14 days after initiation of treatment. The primary end point was moderate or severe angiographic vasospasm based on centrally read, blinded evaluation of digital subtraction angiography at baseline and 7 to 11 days postsubarachnoid hemorrhage. A morbidity/mortality end point, including all-cause mortality, new cerebral infarct from any cause, delayed ischemic neurological deficit due to vasospasm, or use of rescue therapy, was evaluated by local assessment. Clinical outcome was assessed by the extended Glasgow Outcome Scale at 12 weeks.. Moderate or severe vasospasm was reduced in a dose-dependent fashion from 66% in the placebo group to 23% in the 15 mg/h clazosentan group (risk reduction, 65%; 95% CI, 47% to 78%; P<0.0001). No significant effects were seen on secondary end points. Post hoc analysis using a centrally assessed morbidity/mortality end point that included death and rescue therapy but only cerebral infarcts and delayed ischemic neurological deficit due to vasospasm on central review showed a trend toward improvement with clazosentan (37%, 28%, and 29% in the 1, 5, and 15 mg/h groups versus 39% in the placebo group, nonsignificant). Clazosentan was associated with increased rates of pulmonary complications, hypotension, and anemia.. Clazosentan significantly decreased moderate and severe vasospasm in a dose-dependent manner and showed a trend for reduction in vasospasm-related morbidity/mortality in patients with aneurysmal subarachnoid hemorrhage when centrally assessed. Overall, the adverse effects were manageable and not considered serious.

Topics: Adolescent; Adult; Aged; Dioxanes; Dose-Response Relationship, Drug; Double-Blind Method; Female; Glasgow Outcome Scale; Humans; Infarction; Ischemia; Middle Aged; Placebos; Pyridines; Pyrimidines; Subarachnoid Hemorrhage; Sulfonamides; Tetrazoles; Treatment Outcome; Vasospasm, Intracranial

To study the effects of clazosentan, a new selective endothelin receptor subtype A antagonist, on cerebral perfusion and cerebral oxygenation following severe aneurysmal subarachnoid haemorrhage (aSAH).. All 12 patients treated at our institution in the context of a phase IIa, multicenter, randomized trial on clazosentan's safety and efficacy in reducing the incidence of angiographic cerebral vasospasm were included in this substudy. The phase IIa study (n = 34) consisted of two parts: a double-blind, randomized Part A (clazosentan 0.2 mg/kg/h versus placebo) and an open-label Part B (clazosentan 0.4 mg/kg/h for 12 h followed by 0.2 mg/kg/h) for patients with established vasospasm. In parallel to the phase IIa study protocol, which included assessment of vasospasm by angiography and transcranial Doppler sonography, we determined regional cerebral blood flow (rCBF), cerebrovascular resistance, and regional tissue oxygenation.. Cerebral perfusion was comparable between treatment groups during the early post-bleeding period (rCBF placebo, 22.6 +/- 3.5 ml/100 g/min versus rCBF clazosentan, 23.9 +/- 1.1 ml/100 g/min). By the time of control angiography (day 8 after aSAH), rCBF decreased by 50% in the placebo group (11.3 +/- 6.7 ml/ 100 g/min) while it remained stable in the clazosentan group (23.5 +/- 12.9 ml/100 g/min). During Part B of the study, all 3 patients who developed haemodynamically relevant vasospasm during placebo treatment, showed a sustained improvement in rCBF upon conversion to clazosentan.. These preliminary data suggest that clazosentan reduces the extent of vasospasm-associated impairment of cerebral perfusion following aSAH. Furthermore, clazosentan may exert beneficial actions on overt vasospasm-associated hypoperfusion.

Topics: Adult; Brain; Cerebral Angiography; Cerebrovascular Circulation; Dioxanes; Double-Blind Method; Drug-Related Side Effects and Adverse Reactions; Endothelin A Receptor Antagonists; Female; Humans; Male; Middle Aged; Oxygen; Pyridines; Pyrimidines; Severity of Illness Index; Subarachnoid Hemorrhage; Sulfonamides; Tetrazoles; Ultrasonography, Doppler, Transcranial; Vascular Resistance; Vasospasm, Intracranial

The goal of this study was to investigate the safety and tolerability of the novel endothelin A (ETA) receptor antagonist clazosentan in patients with subarachnoid hemorrhage (SAH) and its potential to reduce the incidence and severity of cerebral vasospasm following surgical clipping of the aneurysm.. This Phase IIa multicenter study had two parts: a double-blind, randomized Part A (some patients given clazosentan [0.2 mg/kg/hr] and others given placebo), in which statistical inference was performed, and an open-label Part B (patients with established vasospasm given clazosentan [0.4 mg/kg/hr for 12 hours followed by 0.2 mg/kg/hr]) for exploratory purposes only. Primary end points were the incidence and severity of angiographic vasospasm on Day 8 after SAH and the safety and tolerability of the drug. Thirty-four patients (Hunt and Hess Grades III and IV and Fisher Grade > or = 3) were recruited and 32 (15 in the clazosentan group and 17 in the placebo group) were retained in the intent-to-treat population; 19 patients entered Part B. In Part A, treatment with clazosentan resulted in a reduced incidence of angiographically evident cerebral vasospasm (40% compared with 88% of patients, p = 0.008). In addition, the severity of vasospasm was reduced in the clazosentan group (p = 0.012). In Part B of the study, in 50% of assessable patients who were initially treated with placebo reversal of vasospasm was observed following the initiation of clazosentan therapy. The incidence of new infarctions was 15% in the clazosentan group and 44% in the placebo group (p = 0.130). There was no adverse event pattern indicating a specific organ toxicity of clazosentan.. This study indicates that clazosentan reduces the frequency and severity of cerebral vasospasm following severe aneurysmal SAH with the incidence and severity of adverse events comparable to that of placebo.

Topics: Adult; Blood Flow Velocity; Cerebrovascular Circulation; Dioxanes; Double-Blind Method; Endothelin A Receptor Antagonists; Female; Follow-Up Studies; Humans; Male; Middle Aged; Pyridines; Pyrimidines; Radiography; Receptor, Endothelin A; Severity of Illness Index; Subarachnoid Hemorrhage; Sulfonamides; Tetrazoles; Treatment Outcome; Vasospasm, Intracranial

Topics: Dioxanes; Humans; Pyridines; Pyrimidines; Subarachnoid Hemorrhage; Tetrazoles; Vasospasm, Intracranial

Aneurysmal subarachnoid hemorrhage (aSAH) may lead to cerebral vasospasm, significantly associated with morbidity and mortality. In double-blind, placebo-controlled phase 3 studies, clazosentan reduces cerebral vasospasm-related morbidity and all-cause mortality in patients with aSAH. There are no reports about the clinical efficacy of clazosentan combination therapy with some other drugs. Initially, we explored the efficacy of clazosentan combination therapy with cilostazol, statin, and antiepileptic drugs. Subsequently, we assessed the add-on effect of fasudil to clazosentan combination therapy for aSAH patients. This multicenter, retrospective, observational cohort study included Japanese patients with aSAH between June 2022 and March 2023. The primary outcome was the ordinal score on the modified Rankin Scale (mRS; range, 0-6, with elevated scores indicating greater disability) at discharge. Among the 47 cases (women 74.5%; age 64.4 ± 15.0 years) undergoing clazosentan combination therapy, 29 (61.7%) resulted in favorable outcomes. Overall, vasospasm occurred in 16 cases (34.0%), with four cases (8.5%) developing vasospasm-related delayed cerebral ischemia (DCI). Both hypotension and vasospasm-related DCI were related to unfavorable outcome at discharge. Fasudil were added in 18 (38.3%) cases. Despite adding fasudil to clazosentan combination therapy, the incidence of aSAH-related vasospasm did not decrease. Added-on fasudil to combination therapy related to pulmonary edema, vasospasm, and vasospasm-related DCI, and unfavorable outcomes. Clazosentan combination therapy could potentially result in favorable outcomes for aSAH patients to prevent post-aSAH vasospasm-related DCI. The add-on effect of fasudil to combination therapy did not demonstrate a significant impact in reducing aSAH-related vasospasm or improving outcomes at discharge.

Topics: Aged; Brain Ischemia; Cerebral Infarction; Female; Humans; Middle Aged; Retrospective Studies; Subarachnoid Hemorrhage; Vasospasm, Intracranial

Clazosentan, an endothelin-1 receptor antagonist, has been shown to prevent the development of large vessel angiographic vasospasm after aneurysmal subarachnoid hemorrhage. We hypothesized that clazosentan can improve cerebral perfusion for territories affected by angiographically confirmed vasospasm.. The REVERSE study (REversal of Vasospasm with clazosEntan post-aneuRysmal Subarachnoid hEmorrhage) was a prospective multicenter open-label pilot study of adult patients with aneurysmal subarachnoid hemorrhage who received intravenous clazosentan after developing moderate to severe angiographic vasospasm. Using the radiographic data from the REVERSE study and additional retrospective radiographic data from our tertiary medical center, we compared the impact of intravenous clazosentan with intraarterial vasodilator therapy (medical standard of care) on vasospasm reversal using time to peak perfusion (TTPP; the time interval between the peak opacification of contrast dye in the main artery supplying an anatomically defined territory and the parenchymal phase when the dye is diffusely present in the brain parenchyma).. Both intravenous clazosentan (n = 7 vessels) and intraarterial vasodilator therapy (n = 11 vessels) resulted in a statistically significant improvement in TTPP at 24 h post intervention, when compared with the TTPP just prior to intervention for territories with angiographically confirmed severe vasospasm in the proximal arteries at baseline (linear mixed-effect model, p = 0.02). The clazosentan and intraarterial vasodilator therapy groups exhibited no statistically significant interaction term [time x treatment group (medical standard of care vs. clazosentan)] in our model (p = 0.71), suggesting similar temporal course of two therapies.. In our small pilot study, intravenous clazosentan administered for at least 24 h had an effect comparable with that of intraarterial vasodilator therapy in reversing angiographically confirmed severe vasospasm. Our results may indicate that clazosentan, in an appropriately selected patient cohort, could offer a noninvasive approach for alleviating vasospasm.

Topics: Adult; Dioxanes; Humans; Perfusion; Pilot Projects; Prospective Studies; Pyridines; Pyrimidines; Retrospective Studies; Subarachnoid Hemorrhage; Sulfonamides; Tetrazoles; Treatment Outcome; Vasospasm, Intracranial

Aneurysmal subarachnoid hemorrhage (aSAH) is a disease caused by the infiltration of blood into the subarachnoid space due to the rupture of an intracranial aneurysm. It is a serious cerebrovascular disease, with a mortality rate of about 40% worldwide, which seriously threatens human life and health. Many drugs are used to treat aSAH and its complications, and some have been tested in systematic reviews and have shown good effects. But which drug has the best effect remains unclear. This network meta-analysis (NMA) aims to assess the effectiveness and feasibility of clazosentan, cilostazol, and statins in patients with aSAH.. We will search for EMBASE.com, PubMed, the Cochrane Library, and Web of Science from inception to December 2019. Randomized controlled trials (RCTs) reporting efficacy and safety of clazosentan, cilostazol, and statins compared with the control, or compared with each other for the treatment of aSAH will be included. Two independent reviewers will assess the risk of bias of the included RCTs with the Cochrane "Risk of bias" tool. The pairwise meta-analysis will be performed with the random-effects model. The NMA will be performed in a Bayesian hierarchical framework using Markov Chain Monte Carlo method in WinBUGS 1.4.3. Egger test and funnel plot will be used to assess the publication bias. We will evaluate the quality of evidence for each outcome according to the GRADE approach.. The results of this NMA will be submitted to a peer-reviewed journal for publication.. This study will summarize up-to-date evidence to compare the efficacy and safety of clazosentan, cilostazol, and statins on aSAH.PROSPERO registration number: CRD42019147523.

Topics: Cilostazol; Clinical Protocols; Dioxanes; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Meta-Analysis as Topic; Pyridines; Pyrimidines; Review Literature as Topic; Subarachnoid Hemorrhage; Sulfonamides; Tetrazoles

Patients with good-grade aneurysmal subarachnoid hemorrhage (aSAH) are thought to recover well, yet some do not. This work sought to identify predictors of unfavorable functional outcome after good-grade aSAH.. We performed a post-hoc analysis of the CONSCIOUS-1 trial. Patients with World Federation of Neurosurgical Societies grades I or II aSAH were included. The primary outcome was unfavorable functional outcome (defined as a modified Rankin Scale score >2) at 12 weeks. Parametric and nonparametric testing were used as appropriate. Variables were classified as modifiable or nonmodifiable, depending on whether they were present at patient admission. Stepwise logistic regression models were created for modifiable and nonmodifiable predictors of outcome. Independent predictors in the respective multivariate analyses were combined into a final multivariate regression model.. We included 301 patients, 67 of whom (22%) had an unfavorable outcome. Of the nonmodifiable predictors, higher admission systolic blood pressure (P = 0.002) and female sex (P = 0.011) were independently associated with unfavorable outcome. Potentially modifiable independent predictors of outcome were delayed cerebral ischemia (P = 0.039), higher maximum temperature (0.036), suffering a respiratory system complication (P = 0.004), and suffering an intracranial hemorrhagic complication (P = 0.022). All variables found to be independently predictive of poor outcome in their respective models retained statistical significance in the combined multivariate analysis.. About 1 in 5 good-grade aSAH patients enrolled in CONSCIOUS-1 suffered an unfavorable functional outcome. Admission systolic blood pressure, female sex, hyperthermia, delayed cerebral ischemia, respiratory complications, and intracranial hemorrhagic complications may be predictive of outcome.

Topics: Adult; Dioxanes; Female; Humans; Male; Middle Aged; Neuroprotective Agents; Pyridines; Pyrimidines; Risk Factors; Subarachnoid Hemorrhage; Sulfonamides; Tetrazoles; Treatment Outcome

Background and Purpose- Clazosentan, an endothelin receptor antagonist, has been shown to reduce angiographic vasospasm and vasospasm-related morbidity after aneurysmal subarachnoid hemorrhage (SAH), although no effect on long-term functional outcome has been demonstrated. Thick clot on initial computed tomography is associated with an increased risk of vasospasm and delayed cerebral ischemia. In this post hoc analysis, we hypothesized that use of clazosentan in this subpopulation would provide stronger benefit. Methods- We analyzed SAH patients enrolled in the CONSCIOUS-2 and CONSCIOUS-3 studies (Clazosentan to Overcome Neurological Ischemia and Infarction Occurring After Subarachnoid Hemorrhage) and compared the effects of clazosentan 5 mg/h, 15 mg/h, and placebo starting the day after aneurysm repair. The analysis was performed separately based on the presence or absence of thick (≥4 mm) and diffuse (≥3 cisterns) SAH on admission computed tomography. The primary composite end point was all-cause mortality and vasospasm-related morbidity at 6 weeks, and the main secondary end point was the extended Glasgow Outcome Scale at 3 months, adjusted for admission clinical grade. Results- Of 1718 randomized patients, 919 (53%) had thick and diffuse SAH. The primary composite end point in this group occurred in 36% of placebo-treated patients (n=294), 30% patients treated with clazosentan 5 mg/h (n=514; relative risk, 0.82; 95% CI, 0.67-0.99), and 19% patients treated with clazosentan 15 mg/h (n=111; relative risk, 0.54; 95% CI, 0.36-0.80). Despite this, death or poor functional outcome (Glasgow Outcome Scale ≤4) occurred in 33% of placebo-treated patients, 34% of patients treated with clazosentan 5 mg/h (relative risk 1.02; 95% CI, 0.84-1.23), and 35% of patients treated with clazosentan 15 mg/h (relative risk 1.14; 95% CI, 0.88-1.48). Conclusions- In an enriched population with thick and diffuse SAH, clazosentan at a dose of 5 and 15 mg/h was able to significantly reduce vasospasm-related morbidity in a dose-dependent manner. The absence of an effect on long-term functional status likely reflects the complexity and multiplicity of factors that contribute to poor outcome after SAH. Clinical Trial Registration- URL: https://www.clinicaltrials.gov. Unique identifier: NCT00558311; NCT00940095.

Topics: Adult; Clinical Trials, Phase III as Topic; Dioxanes; Female; Humans; Male; Middle Aged; Multicenter Studies as Topic; Pyridines; Pyrimidines; Randomized Controlled Trials as Topic; Retrospective Studies; Subarachnoid Hemorrhage; Sulfonamides; Tetrazoles; Treatment Outcome; Vasospasm, Intracranial

Perturbations in cerebral microcirculation (eg, microvasospasms) and reduced neurovascular communication determine outcome after subarachnoid hemorrhage (SAH). ET-1 (endothelin-1) and its receptors have been implicated in the pathophysiology of large artery spasms after SAH; however, their role in the development of microvascular dysfunction is currently unknown. Here, we investigated whether inhibiting ET. SAH was induced in male C57BL/6 mice by filament perforation of the middle cerebral artery. Three hours after SAH, a cranial window was prepared and the pial and parenchymal cerebral microcirculation was measured in vivo using two-photon microscopy before, during, and after administration of the ET. Clazosentan treatment had no effect on the number or severity of SAH-induced cerebral microvasospasms nor did it affect neurological outcome.. Our results indicate that ET

Topics: Animals; Dioxanes; Endothelin A Receptor Antagonists; Endothelin-1; Male; Mice; Microscopy, Fluorescence, Multiphoton; Pyridines; Pyrimidines; Receptor, Endothelin A; Subarachnoid Hemorrhage; Sulfonamides; Tetrazoles; Vasospasm, Intracranial

Cerebral vasospasm and late cerebral ischemia (LCI) remain leading causes of mortality in patients experiencing a subarachnoid hemorrhage (SAH). This occurs typically 3 to 4 days after the initial bleeding and peaks at 5 to 7 days. The underlying pathophysiology is still poorly understood. Because SAH is associated with elevated levels of endothelin-1 (ET-1), focus has been on counteracting endothelin receptor activation with receptor antagonists like clazosentan, however, with poor outcome in clinical trials. We hypothesize that inhibition of intracellular transcription signaling will be an effective approach to prevent LCI. Here, we compare the effects of clazosentan versus the MEK1/2 blocker U0126 in a rat model of SAH. Although clazosentan directly inhibits the contractile responses in vivo to ET-1, it did not prevent SAH-induced upregulation of ET receptors in cerebral arteries and did not show a beneficial effect on neurologic outcome. U0126 had no vasomotor effect by itself but counteracts SAH-induced receptor upregulation in cerebral arteries and improved outcome after SAH. We suggest that because SAH induces elevated expression of several contractile receptor subtypes, it is not sufficient to block only one of these (ET receptors) but inhibition of transcriptional MEK1/2-mediated upregulation of several contractile receptors may be a viable way towards alleviating LCI.

Topics: Animals; Brain Ischemia; Butadienes; Cerebral Arteries; Dioxanes; Disease Models, Animal; Endothelin-1; Enzyme Inhibitors; Male; MAP Kinase Kinase 1; MAP Kinase Kinase 2; Nitriles; Pyridines; Pyrimidines; Rats; Rats, Sprague-Dawley; Receptors, Endothelin; Subarachnoid Hemorrhage; Sulfonamides; Tetrazoles; Up-Regulation

Subarachnoid hemorrhage (SAH) remains a condition with suboptimal functional outcomes, especially in the young population. Pharmacotherapy has an accepted role in several aspects of the disease and an emerging role in several others. No preventive pharmacologic interventions for SAH currently exist. Antiplatelet medications as well as anticoagulation have been used to prevent thromboembolic events after endovascular coiling. However, the main focus of pharmacologic treatment of SAH is the prevention of delayed cerebral ischemia (DCI). Currently the only evidence-based medical intervention is nimodipine. Other calcium channel blockers have been evaluated without convincing efficacy. Anti-inflammatory drugs such as statins have demonstrated early potential; however, they failed to provide significant evidence for the use in preventing DCI. Similar findings have been reported for magnesium, which showed potential in experimental studies and a phase 2 trial. Clazosentane, a potent endothelin receptor antagonist, did not translate to improve functional outcomes. Various other neuroprotective agents have been used to prevent DCI; however, the results have been, at best inconclusive. The prevention of DCI and improvement in functional outcome remain the goals of pharmacotherapy after the culprit lesion has been treated in aneurysmal SAH. Therefore, further research to elucidate the exact mechanisms by which DCI is propagated is clearly needed. In this article, we review the current pharmacologic approaches that have been evaluated in SAH and highlight the areas in which further research is needed.

Topics: Adrenal Cortex Hormones; Animals; Anticoagulants; Apoptosis; Brain Ischemia; Calcium Channel Blockers; Clinical Trials as Topic; Dexamethasone; Dioxanes; Disease Models, Animal; Drugs, Chinese Herbal; Estrogens; Evidence-Based Medicine; Free Radical Scavengers; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Magnesium Sulfate; Neuroprotective Agents; Nimodipine; Platelet Aggregation Inhibitors; Pregnatrienes; Progesterone; Pyridines; Pyrimidines; Receptor, Endothelin A; Subarachnoid Hemorrhage; Sulfonamides; Tetrazoles

Topics: Colloids; Dioxanes; Female; Humans; Male; Pyridines; Pyrimidines; Subarachnoid Hemorrhage; Sulfonamides; Tetrazoles; Vasodilator Agents; Vasospasm, Intracranial; Water-Electrolyte Balance

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

Delayed cerebral ischemia (DCI) is a significant cause of morbidity and mortality for patients surviving the rupture of an intracranial aneurysm. Despite an association between vasospasm and DCI, thrombosis and thromboembolism may also contribute to DCI. In this study we investigate the time course of intravascular microclot formation after experimental subarachnoid hemorrhage (SAH) and assess the effects of the following two drugs on microclot burden: mutant thrombin-activated urokinase-type plasminogen activator (scFv/uPA-T), which is bound to red blood cells for use as a thromboprophylactic agent, and clazosentan, an endothelin antagonist. In the first study, adult male C57BL/6 mice were sacrificed at 24 (n=5), 48 (n=6), 72 (n=8), and 96 (n=3) hours after SAH induced by filament perforation of the anterior cerebral artery. Sham animals (n=5) underwent filament insertion without puncture. In the second study, animals received scFv/uPA-T (n=5) 3 hours after hemorrhage, clazosentan (n=5) by bolus and subcutaneous pump after SAH just prior to skin closure, or a combination of scFv/uPA-T and clazosentan (n=4). Control (n=6) and sham (n=5) animals received saline alone. All animals were sacrificed at 48 hours and underwent intra-cardiac perfusion with 4% paraformaldehyde. The brains were then extracted and sliced coronally on a cryostat and processed for immunohistochemistry. An antibody recognizing thrombin-anti-thrombin complexes was used to detect microclots on coronal slices. Microclot burden was calculated for each animal and compared among groups. Following SAH, positive anti-thrombin staining was detected bilaterally in the following brain regions, in order of decreasing frequency: cortex; hippocampus; hypothalamus; basal ganglia. Few microclots were found in the shams. Microclot burden peaked at 48 hours and then decreased gradually. Animals receiving scFv/uPA-T and scFv/uPA-T+clazosentan had a lower microclot burden than controls, whereas animals receiving clazosentan alone had a higher microclot burden (p<0.005). The overall mortality rate in the time course study was 40%; mortality was highest among control animals in the second study. Intravascular microclots form in a delayed fashion after experimental SAH. Microclots may be safely reduced using a novel form of thromboprophylaxis provided by RBC-targeted scFv/uPA-T and represent a potential target for therapeutic intervention in the treatment of DCI.

Topics: Analysis of Variance; Animals; Cerebral Arteries; Dioxanes; Disease Models, Animal; Disease Progression; Drug Delivery Systems; Erythrocytes; Fibrinolytic Agents; Glycophorins; Male; Mice; Mice, Inbred C57BL; Pyridines; Pyrimidines; Subarachnoid Hemorrhage; Sulfonamides; Tetrazoles; Thrombosis; Time Factors; Urokinase-Type Plasminogen Activator

Endothelin receptor antagonists such as clazosentan decrease large-artery vasospasm after experimental and clinical subarachnoid hemorrhage. We used clazosentan to gain insight into the pathophysiology of subarachnoid hemorrhage by determining if decreasing vasospasm is associated with alleviation of other secondary complications of subarachnoid hemorrhage such as oxidative stress, endothelial nitric oxide synthase dysfunction, microthromboembolism, and neuronal injury.. Mice were subjected to subarachnoid hemorrhage by injection of blood into the chiasmatic cistern. They were treated with clazosentan or vehicle by continuous intraperitoneal infusion for 48 hours. Middle cerebral artery vasospasm, superoxide anion radical, peroxynitrite, microthromboemboli, endothelial nitric oxide synthase uncoupling, cerebral blood flow, neuronal injury, and mortality were assessed.. Clazosentan preserved cerebral blood flow, alleviated vasospasm, and decreased mortality but did not affect superoxide anion radical, peroxynitrite, or microthromboemboli in the brain. Endothelial nitric oxide synthase uncoupling and neuronal injury also were not reduced by clazosentan.. This study shows large-artery vasospasm is pathophysiologically independent of some other effects of subarachnoid hemorrhage. The findings have implications for development of treatments for this disease.

Topics: Animals; Apoptosis; Dioxanes; Disease Models, Animal; Endothelin A Receptor Antagonists; Mice; Mice, Transgenic; Nitric Oxide Synthase Type III; Oxidative Stress; Pyridines; Pyrimidines; Regional Blood Flow; Subarachnoid Hemorrhage; Sulfonamides; Tetrazoles; Thromboembolism; Vasospasm, Intracranial

One of the major complications after subarachnoid hemorrhage (SAH) is angiographic vasospasm in the large arteries at the base of the brain. However, a clinical trial of clazosentan demonstrated a 65% relative risk reduction in angiographic vasospasm but no effect on mortality or clinical outcome, raising questions about the role of angiographic vasospasm played in outcome after SAH. The purpose of this study was to determine if reducing or reversing angiographic vasospasm with clazosentan reduced other secondary complications such as microthromboembolism, loss of long-term potentiation (LTP) and neuronal cell death in a rat model of SAH. SAH in rats was created by injection of 300 μl non-heparinized autologous blood into the pre-chiasmatic cistern. Clazosentan, 10mg/kg bolus, or vehicle control was administered 1h after SAH intravenously, followed by a continuous infusion (1mg/kg/h) into the jugular vein using an osmotic pump. Rats treated with clazosentan had less large-artery vasospsam compared to vehicle-treated controls. However, clazosentan did not prevent the formation of microthromboemboli, neuronal cell death and degeneration and loss of LTP, suggesting there is a dissociation between large-artery angiographic vasospasm and other secondary complications of SAH. This result suggests that alleviation of angiographic vasospasm alone may not be sufficient to prevent other secondary complications or that off-target drug effects after systemic administration of clazosentan counteract the beneficial effects on angiographic vasospasm.

Topics: Analysis of Variance; Animals; Caspase 3; Chi-Square Distribution; Dioxanes; Disease Models, Animal; Electric Stimulation; Fibrinogen; Fluoresceins; Hippocampus; In Situ Nick-End Labeling; In Vitro Techniques; Long-Term Potentiation; Male; Organic Chemicals; Phosphopyruvate Hydratase; Pyridines; Pyrimidines; Rats; Rats, Sprague-Dawley; Subarachnoid Hemorrhage; Sulfonamides; Tetrazoles; Vasospasm, Intracranial

Topics: Dioxanes; Dose-Response Relationship, Drug; Endothelin Receptor Antagonists; Female; Humans; Male; Pyridines; Pyrimidines; Randomized Controlled Trials as Topic; Subarachnoid Hemorrhage; Sulfonamides; Tetrazoles; Vasospasm, Intracranial

Cerebral vasospasm after aneurysmal subarachnoid hemorrhage (aSAH) is a frequent but unpredictable complication associated with poor outcome. Current vasospasm therapies are suboptimal; new therapies are needed. Clazosentan, an endothelin receptor antagonist, has shown promise in phase 2 studies, and two randomized, double-blind, placebo-controlled phase 3 trials (CONSCIOUS-2 and CONSCIOUS-3) are underway to further investigate its impact on vasospasm-related outcome after aSAH. Here, we describe the design of these studies, which was challenging with respect to defining endpoints and standardizing endpoint interpretation and patient care. Main inclusion criteria are: age 18-75 years; SAH due to ruptured saccular aneurysm secured by surgical clipping (CONSCIOUS-2) or endovascular coiling (CONSCIOUS-3); substantial subarachnoid clot; and World Federation of Neurosurgical Societies grades I-IV prior to aneurysm-securing procedure. In CONSCIOUS-2, patients are randomized 2:1 to clazosentan (5 mg/h) or placebo. In CONSCIOUS-3, patients are randomized 1:1:1 to clazosentan 5, 15 mg/h, or placebo. Treatment is initiated within 56 h of aSAH and continued until 14 days after aSAH. Primary endpoint is a composite of mortality and vasospasm-related morbidity within 6 weeks of aSAH (all-cause mortality, vasospasm-related new cerebral infarction, vasospasm-related delayed ischemic neurological deficit, neurological signs or symptoms in the presence of angiographic vasospasm leading to rescue therapy initiation). Main secondary endpoint is extended Glasgow Outcome Scale at week 12. A critical events committee assesses all data centrally to ensure consistency in interpretation, and patient management guidelines are used to standardize care. Results are expected at the end of 2010 and 2011 for CONSCIOUS-2 and CONSCIOUS-3, respectively.

Topics: Combined Modality Therapy; Dioxanes; Dose-Response Relationship, Drug; Endothelin A Receptor Antagonists; Humans; Placebos; Postoperative Complications; Practice Guidelines as Topic; Pyridines; Pyrimidines; Randomized Controlled Trials as Topic; Subarachnoid Hemorrhage; Sulfonamides; Tetrazoles; Vasospasm, Intracranial

Subarachnoid hemorrhage (SAH) from a ruptured intracranial aneurysm is a devastating disease with high mortality and morbidity. The incidence of SAH increases with advancing age.. To determine whether age is an independent predictor of angiographic vasospasm, delayed ischemic neurological deficits (DINDs), or abnormal transcranial Doppler (TCD) measurements in patients with aneurysmal subarachnoid hemorrhage.. Data from CONSCIOUS-1 (Clazosentan to Overcome Neurological Ischemia and Infarct Occurring After Subarachnoid Hemorrhage study), a dose-finding study of clazosentan, were used. Data on angiographic vasospasm, DINDs, and TCD abnormalities were prospectively recorded as well as baseline characteristics and treatment data. Patient age was considered in 3 ways: as a continuous variable, dichotomized at age 65 years, and categorized by decade. Age was investigated as the main variable, whereas other possible confounding variables were adjusted for in the multiple logistic regression modeling with each of 3 dichotomized vasospasm outcome measures, presence or absence of angiographic vasospasm, DINDs, and TCD abnormalities as the dependent variable.. The proportions of patients with angiographic vasospasm, DINDs, and TCD abnormalities were 45%, 19%, and 81%, respectively. Age, whether considered as a continuous, dichotomous, or a categorical variable, was not significantly associated with angiographic vasospasm, DINDs, or abnormal TCD measurements.. Age does not seem to be a significant predictor for cerebral vasospasm after subarachnoid hemorrhage.

Topics: Adolescent; Adult; Aged; Aging; Angiography, Digital Subtraction; Dioxanes; Double-Blind Method; Humans; International Cooperation; Logistic Models; Middle Aged; Multicenter Studies as Topic; Predictive Value of Tests; Pyridines; Pyrimidines; Randomized Controlled Trials as Topic; Retrospective Studies; Subarachnoid Hemorrhage; Sulfonamides; Tetrazoles; Tomography, X-Ray Computed; Vasospasm, Intracranial; Young Adult

Topics: Brain Ischemia; Cerebral Angiography; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Dioxanes; Endpoint Determination; Humans; Pyridines; Pyrimidines; Randomized Controlled Trials as Topic; Subarachnoid Hemorrhage; Sulfonamides; Tetrazoles; Vasospasm, Intracranial

Topics: Brain Ischemia; Dioxanes; Endothelin Receptor Antagonists; Endpoint Determination; Humans; Meta-Analysis as Topic; Outcome Assessment, Health Care; Pyridines; Pyrimidines; Receptors, Endothelin; Reproducibility of Results; Subarachnoid Hemorrhage; Sulfonamides; Tetrazoles; Time Factors; Vasospasm, Intracranial

Acute cerebral hypoperfusion and early disturbances in cerebral autoregulation after subarachnoid hemorrhage (SAH) have been demonstrated repeatedly and have been shown to contribute significantly to acute and secondary brain injury. Acute vasoconstriction has been identified as a major contributing factor. Although increasing evidence implicates endothelin (ET)-1 in the development of cerebral vasospasm, its role in the acute phase after SAH has not yet been investigated. The purpose of this study was to further determine the role of ET in the first minutes to hours after massive experimental SAH induced by prophylactic treatment with the ET receptor antagonist clazosentan.. Subarachnoid hemorrhage was induced in 22 anesthetized rats by injection of 0.5-ml arterial, nonheparinized blood into the cisterna magna over the course of 60 seconds. In addition to monitoring intracranial pressure (ICP) and mean arterial blood pressure, laser Doppler flowmetry (LDF) probes were placed stereotactically over the cranial windows to allow online recording of cerebral blood flow (CBF) starting 30 minutes prior to SAH and continuing for 3 hours after SAH. The control group (Group A, 11 rats) received vehicle saline solution via a femoral catheter before SAH, and a second group (Group B, 11 rats) was treated prophylactically with clazosentan, an ET(A) receptor antagonist. Treatment was started 30 minutes prior to bolus injection (1 mg/kg body weight), immediately followed by a continuous infusion of 1 mg/kg body weight/hr until the end of the experiment.. Induction of SAH in the rats caused an immediate increase in ICP, which led to an acute decrease in cerebral perfusion pressure (CPP). Perfusion, as measured with LDF, was found to have decreased relative to baseline by 30 +/-20% in the control group and 20 +/-9% in the clazosentan-treated group. Intracranial pressure and CPP recovered comparably in both groups thereafter within minutes. Control animals demonstrated prolonged hypoperfusion with a loss of autoregulation independent of CPP changes, finally approaching 80% of baseline values toward the end of the experiment. The authors observed that clazosentan did not influence peracute CPP-dependent hypoperfusion, but prevented continuous CBF reduction. Laser Doppler flowmetry perfusion readings remained depressed in control animals at 73 +/-19% of baseline in comparison with 106 +/-25% of baseline in clazosentan-treated animals (p = 0.001).. The first hours after a massive experimental SAH can be characterized by a CPP-independent compromise in cerebral perfusion. Prophylactic treatment with the ET receptor antagonist clazosentan prevented hypoperfusion. It is known that in the first days after SAH, a reduction in CBF correlates clinically to high-grade SAH. Although research currently focuses on delayed vasospasm, administration of vasoactive drugs in the acute phase of SAH may reverse perfusion deficits and improve patient recovery.

Topics: Animals; Blood Pressure; Dioxanes; Endothelin Receptor Antagonists; Endothelins; Laser-Doppler Flowmetry; Male; Models, Animal; Pyridines; Pyrimidines; Rats; Rats, Sprague-Dawley; Regional Blood Flow; Subarachnoid Hemorrhage; Sulfonamides; Tetrazoles; Time Factors; Vasoconstriction; Vasospasm, Intracranial

The key role in the development of cerebral vasospasm after subarachnoid hemorrhage (SAH) is increasingly assigned to endothelin (ET)-1. Constriction of the cerebrovasculature by ET-1 is mainly mediated by the ET(A) receptor but is putatively altered during the development of cerebral vasospasm. Therefore, the aim in the present study was to characterize these alterations, with the emphasis on the ET(A) receptor.. Cerebral vasospasm was induced using the rat double-hemorrhage model and proven by perfusion weighted magnetic resonance imaging. Rats were killed on Day 5 after SAH, and immunohistochemical staining for ET(A), receptors was performed. The isometric force of basilar artery ring segments with (E+, control group) and without (E-, SAH group) endothelial function was measured. Concentration effect curves (CECs) for ET-1 were constructed by cumulative application in the absence and presence of the selective ET(A) receptor antagonist clazosentan (10(-8) or 10(-7) M).. The CEC for E+ segments was significantly shifted to the left after SAH by a factor of 3.7, whereas maximum contraction was unchanged. In E- segments, the CECs were not shifted during cerebral vasospasm but the maximum contraction was significantly enhanced. The inhibitory potency of clazosentan yielded a pA2 value of 8.6 +/- 0.2. Immunohistochemical staining of the smooth-muscle layer showed no significant increase of ET(A) receptor expression, but positive staining occurred in the endothelial space after SAH.. The present data indicate an enhanced contractile effect of the smooth-muscle ET(A) receptors in cases of cerebral vasospasm. The inhibitory potency of clazosentan on this contraction is increased. Furthermore, some evidence for an ET(A) receptor and an endothelium-dependent vasoactive effect after SAH is provided.

Topics: Animals; Basilar Artery; Dioxanes; Dose-Response Relationship, Drug; Endothelin A Receptor Antagonists; Immunohistochemistry; Isometric Contraction; Magnetic Resonance Imaging; Male; Muscle Contraction; Muscle, Smooth, Vascular; Pyridines; Pyrimidines; Rats; Rats, Sprague-Dawley; Receptor, Endothelin A; Subarachnoid Hemorrhage; Sulfonamides; Tetrazoles; Time Factors; Vasospasm, Intracranial

Clazosentan, an endothelin ETA antagonist, is under development by Actelion (formerly Axovan), under license from F Hoffman-La Roche, for the potential prevention of cerebral infarction and ischemia induced by cerebral vasospasm following subarachnoid hemorrhage. Results from the phase IIb portion of a phase IIb/III clinical study are expected in the first half of 2006.

Topics: Clinical Trials, Phase III as Topic; Dioxanes; Endothelin-1; Humans; Molecular Conformation; Pyridines; Pyrimidines; Subarachnoid Hemorrhage; Sulfonamides; Tetrazoles; Vasoconstriction; Vasoconstrictor Agents; Vasospasm, Intracranial

Topics: Dioxanes; Endothelin A Receptor Antagonists; Humans; Pyridines; Pyrimidines; Receptor, Endothelin A; Subarachnoid Hemorrhage; Sulfonamides; Tetrazoles; Vasospasm, Intracranial

Endothelin (ET) receptor antagonists are of great potential clinical interest for the treatment pathological conditions associated with vasospasm, such as subarachnoid hemorrhage (SAH). We developed for parenteral use a compound of a class of trifunctionalized heteroarylsulfonamide pyrimidines specially designed for high water solubility. Ro 61-1790 [5-methyl-pyridine-2-sulfonic acid 6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2-(2-1H-tetrazol-5-yl-+ ++pyri din-4-yl)-pyrimidin-4-ylamide] is a competitive ET antagonist with an affinity to ETA receptor in the subnanomolar range. It has a approximately 1000-fold selectivity for the ETA vs. the ETB receptor as assessed on functional assays (e.g., ET-1-induced inositol-1,4, 5-triphosphate release or ET-1-induced intracellular calcium mobilization). Ro 61-1790 also had a high functional potency for inhibiting contraction induced by ET-1 on isolated rat aorta (ETA receptors; pA2 = 9.5) or by sarafotoxin S6c on rat trachea (ETB receptors; pA2 = 6.4). In vivo, Ro 61-1790 inhibited the pressor effect of big ET-1 in pithed rats with an ID50 value of 0.05 mg/kg. Intravenous bolus of Ro 61-1790 induced a long-lasting antihypertensive effect in deoxycorticosterone acetate salt rats instrumented with telemetry. In a double-hemorrhage canine model of SAH, Ro 61-1790 both prevented and reversed cerebral vasospasm in a dose-dependent manner. In an established cerebral vasospasm, 3 mg/kg Ro 61-1790 i.v. was half as efficacious as intrabasilar papaverine. Ro 61-1790 (20 mg/kg/day) totally prevented the occurrence of vasospasm. In summary, these data demonstrate that Ro 61-1790 is a potent and selective ETA receptor antagonist suitable for parenteral use and potentially useful for preventing delayed ischemic deficit in patients with SAH.

Topics: Animals; CHO Cells; Cricetinae; Dioxanes; Dogs; Dose-Response Relationship, Drug; Endothelin Receptor Antagonists; Humans; Ischemic Attack, Transient; Male; Pyridines; Pyrimidines; Rats; Rats, Inbred WKY; Rats, Wistar; Receptor, Endothelin A; Spodoptera; Subarachnoid Hemorrhage; Sulfonamides; Tetrazoles