Symptomatic Vasospasm Refractory to Clazosentan after Subarachnoid Hemorrhage of Ruptured Vertebral Artery Dissecting Aneurysm: Clinical Implications from Two Contrasting Cases.

Clazosentan prevents vasospasms after aneurysmal subarachnoid hemorrhage (SAH). However, clinical data on patients with SAH with ruptured vertebral artery dissecting aneurysms (VADAs) are limited. We report the case of a 49-year-old male patient with mild-grade (WFNS grade 1) thick and diffuse (modified Fisher grade 3) SAH who underwent endovascular trapping of a ruptured VADA, resulting in a poor functional outcome with a modified Rankin Scale score of 4 due to severe symptomatic vasospasm refractory to clazosentan, requiring repeated rescue endovascular therapies and chronic communicating hydrocephalus. A retrospective analysis of the clot density in the basal and Sylvian cisterns, assessed by the Hounsfield unit (HU) values of serial CT scans, in this patient showed persistent higher values, distinct from another VADA case that showed a decline in HU values with a good clinical course. These results imply the limited effectiveness of clazosentan in cases of thick and diffuse SAH after a ruptured VADA, even in good-clinical-grade patients treated with less invasive modalities. The HU values may become a simple quantitative marker for predicting symptomatic vasospasms and chronic hydrocephalus.

Letter to the editor: "Beyond nimodipine: advanced neuroprotection strategies for aneurysmal subarachnoid hemorrhage vasospasm and delayed cerebral ischemia".

This letter commends the article by Luzzi et al. on alternative neuroprotection strategies for aneurysmal subarachnoid hemorrhage (SAH). It highlights the pharmacological advantages of nicardipine, cilostazol, and clazosentan over nimodipine in managing cerebral vasospasm and delayed cerebral ischemia. Emphasizing the need for personalized medicine, it advocates for integrating genetic screening and advanced monitoring techniques to tailor treatments to individual patient profiles. This approach could significantly improve clinical outcomes by optimizing drug efficacy and minimizing adverse effects.

Beyond nimodipine: advanced neuroprotection strategies for aneurysmal subarachnoid hemorrhage vasospasm and delayed cerebral ischemia.

The clinical management of aneurysmal subarachnoid hemorrhage (SAH)-associated vasospasm remains a challenge in neurosurgical practice, with its prevention and treatment having a major impact on neurological outcome. While considered a mainstay, nimodipine is burdened by some non-negligible limitations that make it still a suboptimal candidate of pharmacotherapy for SAH. This narrative review aims to provide an update on the pharmacodynamics, pharmacokinetics, overall evidence, and strength of recommendation of nimodipine alternative drugs for aneurysmal SAH-associated vasospasm and delayed cerebral ischemia. A PRISMA literature search was performed in the PubMed/Medline, Web of Science, ClinicalTrials.gov, and PubChem databases using a combination of the MeSH terms "medical therapy," "management," "cerebral vasospasm," "subarachnoid hemorrhage," and "delayed cerebral ischemia." Collected articles were reviewed for typology and relevance prior to final inclusion. A total of 346 articles were initially collected. The identification, screening, eligibility, and inclusion process resulted in the selection of 59 studies. Nicardipine and cilostazol, which have longer half-lives than nimodipine, had robust evidence of efficacy and safety. Eicosapentaenoic acid, dapsone and clazosentan showed a good balance between effectiveness and favorable pharmacokinetics. Combinations between different drug classes have been studied to a very limited extent. Nicardipine, cilostazol, Rho-kinase inhibitors, and clazosentan proved their better pharmacokinetic profiles compared with nimodipine without prejudice with effective and safe neuroprotective role. However, the number of trials conducted is significantly lower than for nimodipine. Aneurysmal SAH-associated vasospasm remains an area of ongoing preclinical and clinical research where the search for new drugs or associations is critical.

The effectiveness and safety of clazosentan in treating aneurysmal subarachnoid hemorrhage: A systematic review and meta-analysis.

BACKGROUND: Aneurysmal subarachnoid hemorrhage (aSAH) is a severe event often complicated by cerebral vasospasm (CV). This study aimed to assess the efficacy and safety of clazosentan, an endothelin receptor antagonist, in reducing CV, delayed cerebral ischemia (DCI), and the need for rescue therapy in aSAH patients, while evaluating its impact on functional outcomes and mortality. METHODS: We conducted a literature search across multiple databases to identify relevant studies evaluating the effects of clazosentan in aSAH patients. Both cohort studies and randomized controlled trials (RCTs) were included. The primary outcomes were vasospasm incidence, moderate to severe vasospasm, DCI, and the need for rescue therapy. Secondary outcomes included functional outcomes, mortality, and adverse events. The data were pooled as Risk ratios (R/R) with 95 % confidence intervals (CI) using RevMan 5.4 software. RESULTS: A total of 11 studies, including 10 published and one unpublished, comprising 8,469 patients were included in the meta-analysis. Clazosentan significantly reduced the incidence of vasospasm (R/R = 0.49: 0.34-0.70), moderate to severe vasospasm (R/R = 0.53: 0.46-0.61), DCI (R/R = 0.70: 0.59-0.82), and the need for rescue therapy (R/R = 0.65: 0.52-0.83) compared to placebo. However, no significant improvement in functional outcomes or mortality rates was observed. Clazosentan was associated with increased rates of pulmonary adverse events (R/R = 1.89: 1.64-2.18), hypotension (R/R = 2.47: 1.79-3.42), and anemia (R/R = 1.49: 1.23-1.79) but no increased risk of hepatobiliary adverse events or cerebral hemorrhage. CONCLUSIONS: Clazosentan demonstrates efficacy in reducing vasospasm, moderate to severe vasospasm, DCI, and the need for rescue therapy in aSAH patients, but does not significantly improve functional outcomes or mortality rates. While associated with specific adverse events, clazosentan may be a valuable adjunctive therapy in the management of aSAH, particularly in a high-risk population for vasospasm.

The BCL-2 inhibitor APG-2575 resets tumor-associated macrophages toward the M1 phenotype, promoting a favorable response to anti-PD-1 therapy via NLRP3 activation.

The main challenges in the use of immune checkpoint inhibitors (ICIs) are ascribed to the immunosuppressive tumor microenvironment and the lack of sufficient infiltration of activated CD8+ T cells. Transforming the tumor microenvironment (TME) from "cold" to "hot" and thus more likely to potentiate the effects of ICIs is a promising strategy for cancer treatment. We found that the selective BCL-2 inhibitor APG-2575 can enhance the antitumor efficacy of anti-PD-1 therapy in syngeneic and humanized CD34+ mouse models. Using single-cell RNA sequencing, we found that APG-2575 polarized M2-like immunosuppressive macrophages toward the M1-like immunostimulatory phenotype with increased CCL5 and CXCL10 secretion, restoring T-cell function and promoting a favorable immunotherapy response. Mechanistically, we demonstrated that APG-2575 directly binds to NF-κB p65 to activate NLRP3 signaling, thereby mediating macrophage repolarization and the activation of proinflammatory caspases and subsequently increasing CCL5 and CXCL10 chemokine production. As a result, APG-2575-induced macrophage repolarization could remodel the tumor immune microenvironment, thus improving tumor immunosuppression and further enhancing antitumor T-cell immunity. Multiplex immunohistochemistry confirmed that patients with better immunotherapeutic efficacy had higher CD86, p-NF-κB p65 and NLRP3 levels, accompanied by lower CD206 expression on macrophages. Collectively, these data provide evidence that further study on APG-2575 in combination with immunotherapy for tumor treatment is required.

Unfavorable Outcome After Good Grade Aneurysmal Subarachnoid Hemorrhage: Exploratory Analysis.

OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Effects of clazosentan, cilostazol, and statins on aneurysmal subarachnoid hemorrhage: A protocol for systematic review and meta-analysis.

BACKGROUND: 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. METHODS: 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. RESULTS: The results of this NMA will be submitted to a peer-reviewed journal for publication. CONCLUSION: 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.

α2-Adrenergic Receptor in Liver Fibrosis: Implications for the Adrenoblocker Mesedin.

The noradrenergic system is proposed to play a prominent role in the pathogenesis of liver fibrosis. While α1- and ß-adrenergic receptors (ARs) are suggested to be involved in a multitude of profibrogenic actions, little is known about α2-AR-mediated effects and their expression pattern during liver fibrosis and cirrhosis. We explored the expression of α2-AR in two models of experimental liver fibrosis. We further evaluated the capacity of the α2-AR blocker mesedin to deactivate hepatic stellate cells (HSCs) and to increase the permeability of human liver sinusoidal endothelial cells (hLSECs). The mRNA of α2a-, α2b-, and α2c-AR subtypes was uniformly upregulated in carbon tetrachloride-treated mice vs the controls, while in bile duct-ligated mice, only α2b-AR increased in response to liver injury. In murine HSCs, mesedin led to a decrease in α-smooth muscle actin, transforming growth factor-ß and α2a-AR expression, which was indicated by RT-qPCR, immunocytochemistry, and Western blot analyses. In a hLSEC line, an increased expression of endothelial nitric oxide synthase was detected along with downregulated transforming growth factor-ß. In conclusion, we suggest that the α2-AR blockade alleviates the activation of HSCs and may increase the permeability of liver sinusoids during liver injury.

Enhancing the efficacy of 5-HT uptake inhibitors in the treatment of attention deficit hyperactivity disorder.

Attention Deficit Hyperactivity Disorder (ADHD) is one of the most common childhood behavioural disorders, the frontline treatments for which are drugs with abuse potential. As a consequence, there is an urgent need to develop non addictive drug treatments with equivalent efficacy. Preclinical evidence suggests that selective serotonin uptake inhibitors (SSRIs) are likely to be effective in ADHD, however clinical reports suggest that SSRIs are of limited therapeutic value for the treatment of ADHD. We propose that this disconnect can be explained by the pattern of drug administration in existing clinical trials (administration for short periods of time, or intermittently) leading to inadequate control of the autoregulatory processes which control 5-HT release, most notably at the level of inhibitory 5-HT1A somatodendritic autoreceptors. These autoreceptors reduce the firing rate of 5-HT neurons (limiting release) unless they are desensitised by a long term, frequent pattern of drug administration. As such, we argue that the participants in earlier trials were not administered SSRIs in a manner which realises any potential benefits of targeting 5-HT in the pharmacotherapy of ADHD. In light of this, we hypothesise that there may be under-researched potential to exploit 5-HT transmission therapeutically in ADHD, either through changing the administration regime, or by pharmacological means. Recent pharmacological research has successfully potentiated the effects of SSRIs in acute animal preparations by antagonising inhibitory 5-HT1A autoreceptors prior to the administration of the SSRI fluoxetine. We suggest that combination therapies linking SSRIs and 5-HT1A antagonists are a potential way forward in the development of efficacious non-addictive pharmacotherapies for ADHD.

Thick and Diffuse Subarachnoid Blood as a Treatment Effect Modifier of Clazosentan After Subarachnoid Hemorrhage.

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.

1,3-Dioxane as a scaffold for potent and selective 5-HT1AR agonist with in-vivo anxiolytic, anti-depressant and anti-nociceptive activity.

A series of compounds generated by ring expansion/opening and molecular elongation/simplification of the 1,3-dioxolane scaffold were prepared and tested for binding affinity at 5-HT1AR and α1 adrenoceptors. The compounds with greater affinity were selected for further functional studies. N-((2,2-diphenyl-1,3-dioxan-5-yl)methyl)-2-(2-methoxyphenoxy)ethan-1-ammonium hydrogen oxalate (12) emerged as highly potent full agonist at the 5-HT1AR (pKi 5-HT1A = 8.8; pD2 = 9.22, %Emax = 92). The pharmacokinetic data in rats showed that the orally administered 12 has a high biodistribution in the brain compartment. Thus, 12 was further investigated in-vivo, showing an anxiolytic and antidepressant effect. Moreover, in the formalin test, 12 was able to decrease the late response to the noxious stimulus, indicating a potential use in the treatment of chronic pain.

Renal globotriaosylceramide facilitates tubular albumin absorption and its inhibition protects against acute kidney injury.

To elucidate the physiologic function of renal globotriaosylceramide (Gb3/CD77), which up-to-date has been associated exclusively with Shiga toxin binding, we have analyzed renal function in Gb3-deficient mice. Gb3 synthase KO (Gb3S-/-) mice displayed an increased renal albumin and low molecular weight protein excretion compared to WT. Gb3 localized at the brush border and within vesicular structures in WT proximal tubules and has now been shown to be closely associated with the receptor complex megalin/cubilin and with albumin uptake. In two clinically relevant mouse models of acute kidney injury caused by myoglobin as seen in rhabdomyolysis and the aminoglycoside gentamicin, Gb3S-/- mice showed a preserved renal function and morphology, compared to WT. Pharmacologic inhibition of glucosylceramide-based glycosphingolipids, including Gb3, in WT mice corroborated the results of genetically Gb3-deficient mice. In conclusion, our data significantly advance the current knowledge on the physiologic and pathophysiologic role of Gb3 in proximal tubules, showing an involvement in the reabsorption of filtered albumin, myoglobin and the aminoglycoside gentamicin.

Reversal of Vasospasm with Clazosentan After Aneurysmal Subarachnoid Hemorrhage: A Pilot Study.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Synthesis and anti-tumor activity of [1,4] dioxino [2,3-f] quinazoline derivatives as dual inhibitors of c-Met and VEGFR-2.

Both c-Met and VEGFR-2 were important targets for cancer therapies. In order to develop reversible and non-covalent c-Met and VEGFR-2 dual inhibitors, a series of [1,4]dioxino[2,3-f]quinazoline derivatives were designed and synthesized. The enzyme assay demonstrated that most target compounds had inhibition potency on both c-Met and VEGFR-2 with IC50 values in nanomolar range especially compounds 7m and 7k. Based on further cell proliferation assay in vitro, compound 7k showed significantly anti-tumor activity in vivo on a hepatocellular carcinoma (MHCC97H cells) xenograft mouse model. We docked the compound 7m with c-Met and VEGFR-2 kinases, and interpreted the SAR of these analogues. All results indicated that the target compounds were dual inhibitors of c-Met and VEGFR-2 kinases that held promising potential in cancer therapy.

Activation of orexinergic and histaminergic pathway involved in therapeutic effect of histamine H4 receptor antagonist against cisplatin-induced anorexia in mice.

We previously reported that hypothalamic tumor necrosis factor-alpha (TNF-α) mRNA expression via histamine H4 receptors contributes to the development of cisplatin-induced anorexia; however, its precise mechanisms remain unclear. It has been reported that chemotherapeutic agents induce the suppression of orexin neuron activity, and the administration of orexin inhibits chemotherapeutic agent-induced gastric discomfort. Other studies demonstrated that the central administration of TNF-α impairs the orexinergic system, and that orexin excites the histaminergic system. We investigated the involvement of orexinergic and histaminergic systems in the therapeutic effect of an H4 receptor antagonist against cisplatin-induced anorexia. Cisplatin decreased the expression of prepro-orexin mRNA, which encodes precursors of orexin, in the hypothalamus of mice. The period of expression decreased in parallel with the onset of anorexia, and treatment with an H4 receptor antagonist (JNJ7777120, 10 mg/kg) inhibited the decrease in expression. The effect of the H4 receptor antagonist on cisplatin-induced anorexia in mice was antagonized by an orexin OX2 receptor antagonist (JNJ10397049, 5 mg/kg) rather than an orexin OX1 receptor antagonist (SB408124, 30 mg/kg). Although an OX2 receptor agonist (YNT-185, 20 mg/kg) or a histamine H3 receptor inverse agonist (ciproxifan, 1 mg/kg) inhibited the cisplatin-induced anorexia, the inhibitory effect of the OX2 receptor agonist was antagonized by an H3 receptor silent antagonist (VUF5681, 5 mg/kg). The combination of JNJ7777120 (10 mg/kg) and ciproxifan (0.5 mg/kg) completely resolved the cisplatin-induced anorexia. These results suggest that activation of the orexinergic and histaminergic pathway is involved in the therapeutic effect of an H4 receptor antagonist against cisplatin-induced anorexia.

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

OBJECTIVE: 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). METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Clazosentan for Aneurysmal Subarachnoid Hemorrhage: An Updated Meta-Analysis with Trial Sequential Analysis.

OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.