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BACKGROUND Clazosentan is an endothelin receptor antagonist approved in Japan for preventing cerebral vasospasm and vasospasm-associated cerebral ischemia and infarction. This study included elderly patients aged ≥75 years with aneurysmal subarachnoid hemorrhage (SAH) and aimed to evaluate the factors associated with discontinuing anti-vasospasm therapy with clazosentan. MATERIAL AND METHODS In this single-center retrospective observational study, we extracted diagnostic and therapeutic work-up data of consecutive 40 patients with SAH treated with clazosentan infusion (10 mg/h) as first-line anti-vasospasm therapy between May 2022 and August 2023. Patient data were compared between the discontinued and completed groups, and related factors for the discontinuation were further analyzed. RESULTS Clazosentan was discontinued in 22% (n=9) of patients due to intolerable dyspnea accompanied by hypoxemia at 5±3 days after therapy initiation, in which 44% (n=4) were elderly (≥75 years). Patients who discontinued clazosentan therapy showed significantly lower urine volumes compared with those who completed the therapy (P<0.05). Multivariate regression analysis revealed that day-to-day urine volume variance and older age were independent risk factors for drug cessation (P<0.05). The cut-off value for predicting clazosentan discontinuation was -0.7 mL/kg/h with sensitivity of 86% and specificity of 75% (area under the curve: 0.76±0.10; 95% confidence interval: 0.56-0.96; P=0.035). CONCLUSIONS Our results suggest that approximately 20% of SAH patients suffered from intolerable respiratory symptoms attributable to hypoxemia. We found that both reduced day-to-day urine volume variation and older age are independent risk factors for drug discontinuation.

Objective: 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., Methods: 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., Results: 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., Conclusions: 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).

Objective: We sought to examine whether the effect of treatment modality and drugs for cerebral vasospasm on clinical outcomes differs between elderly and non-elderly subarachnoid hemorrhage (SAH) patients in Japan., Methods: We analyzed the J-ASPECT Study Diagnosis Procedure Combination database (n = 17,343) that underwent clipping or coiling between 2010 and 2014 in 579 hospitals. We stratified patients into two groups according to their age (elderly [≥75 years old], n = 3,885; non-elderly, n = 13,458). We analyzed the effect of treatment modality and anti-vasospasm agents (fasudil hydrochloride, ozagrel sodium, cilostazol, statin, eicosapentaenoic acid [EPA], and edaravone) on in-hospital poor outcomes (mRS 3-6 at discharge) and mortality using multivariable analysis., Results: The elderly patients were more likely to be female, have impaired levels of consciousness and comorbidity, and less likely to be treated with clipping and anti-vasospasm agents, except for ozagrel sodium and statin. In-hospital mortality and poor outcomes were higher in the elderly (15.8% vs. 8.5%, 71.7% vs. 36.5%). Coiling was associated with higher mortality (odds ratio 1.43, 95% confidence interval 1.2-1.7) despite a lower proportion of poor outcomes (0.84, 0.75-0.94) in the non-elderly, in contrast to no effect on clinical outcomes in the elderly. A comparable effect of anti-vasospasm agents on mortality was observed between non-elderly and elderly for fasudil hydrochloride (non-elderly: 0.20, 0.17-0.24), statin (0.63, 0.50-0.79), ozagrel sodium (0.72, 0.60-0.86), and cilostazol (0.63, 0.51-0.77). Poor outcomes were inversely associated with fasudil hydrochloride (0.59, 0.51-0.68), statin (0.84, 0.75-0.94), and EPA (0.83, 0.72-0.94) use in the non-elderly. No effect of these agents on poor outcomes was observed in the elderly., Conclusions: In contrast to the non-elderly, no effect of treatment modality on clinical outcomes were observed in the elderly. A comparable effect of anti-vasospasm agents was observed on mortality, but not on functional outcomes, between the non-elderly and elderly., Competing Interests: Dr. Iihara reports grants from grants from Otsuka Pharmaceutical Co., Ltd., grants from Kaneka Medix Corporation, grants from Eisai Co., Ltd., grants from Mitsubishi Tanabe Pharma Co., personal fees from Otsuka Pharmaceutical Co., Ltd., personal fees from Daiichi Sankyo Ltd, outside the submitted work; Dr. Kitazono reports grants from Otsuka Pharmaceutical Co., Ltd., Takeda Pharmaceuticals Co., Ltd, Mitsubishi Tanabe Pharma Co., Daiichi Sankyo Co., Ltd, Astellas Pharma Inc., MSD KK., and Shionogi & CO., LTD. Dr. Kamouchi reports personal fe 1 es from Daiichi Sankyo Co., Ltd, Ono pharmaceutical Co., Ltd., Bayer Yakuhin, Ltd., and Pfizer Co., Ltd.. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Background: The aim of this study was to examine the risk factor profiles and functional outcomes of subarachnoid hemorrhage (SAH) in different age groups, focusing on the effect of antiplatelet drugs when used before stroke., Methods: A total of 5344 patients with SAH were included in a multicenter, hospital-based registration study involving 95 Japanese institutes from 2000 to 2012. Patients' profiles and use of antithrombotic agents were retrospectively reviewed. A modified Rankin Scale score of 4 or more at discharge was defined as poor outcome., Results: The frequency of antithrombotic agent use increased with age; it reached its peak (10.9%) among patients in their 80s and remained constant at 7.5% for those 90 years or older. Poorer outcomes were evident as age increased. The frequency of hypertension increased with age, whereas current smoking and heavy drinking reached its peak among patients in their 40s and 50s, respectively. The use of antiplatelet agents significantly improved outcome in patients younger than 60 years (P = .04). In contrast, in the older group (≥60 years), the use of antiplatelet agents tended to worsen the outcome; patients aged 70-79 years who had used these agents had a significantly worse outcome compared with those who had not (P = .03)., Conclusions: In the present study, the influence of antiplatelet agents was different among age groups. The potential beneficial effects of antiplatelet agents must be weighed against their potential adverse effects in the context of SAH, considering the differences in age-related outcomes., (Copyright © 2015 National Stroke Association. Published by Elsevier Inc. All rights reserved.)

Introduction: It is still controversial if the selection of treatment modality (clip or coil) affects cerebral vasospasm development following aneurysmal subarachnoid hemorrhage (SAH)., Materials and Methods: We enrolled 579 SAH patients in the Prospective Registry of Subarachnoid Aneurysms Treatment project, and these patients were treated either microsurgically or endovascularly within 12 days of onset. The incidence of vasospasm was compared between patients treated with clipping and coiling., Results: Clipping (282 patients) was preferably performed for small aneurysms with a wide neck or middle cerebral artery aneurysms and was followed by cerebrospinal fluid drainage; coiling (297 patients) was preferred for older patients, larger, internal carotid artery and posterior circulation aneurysms, or treatment during a nonacute stage and more frequently followed by antithrombotic treatment. Univariate analyses showed that vasospasm-induced cerebral infarct occurred more frequently in clipped patients than in coiled patients, but this difference disappeared after multivariate analyses. Higher incidence of vasospasm-induced cerebral infarct after clipping was explained by the fact that clipping was selected more for the ruptured middle cerebral artery aneurysm with massive SAH or hematoma, in which vasospasm more frequently occurred., Conclusions: Treatment modalities (clip or coil) may not significantly affect the incidence of vasospasm.