Abstract
This retrospective cohort study investigated the association between the use of clazosentan and the incidence of symptomatic vasospasm, as well as rehabilitation-related outcomes, particularly, the timing of ambulation, in patients with aneurysmal subarachnoid hemorrhage. A total of 153 patients who underwent surgical clipping or endovascular coiling at our institution between January 2020 and March 2025 were included; among them, 76 received clazosentan, and 77 received conventional treatment.
The primary outcomes were the incidence of symptomatic vasospasm and the number of days to initial ambulation. Secondary outcomes included changes in body weight, peripheral oxygen saturation, and laboratory parameters one week after drug administration.
The incidence of symptomatic vasospasm was significantly lower in the clazosentan group (5.3%) than in the conventional treatment group (20.7%) (p = 0.007). In addition, ambulation was achieved significantly earlier in the clazosentan group (median: 8.5 days; interquartile range: 5–12) than in the control group (median: 11 days, interquartile range: 8–15) (p = 0.015).
Conversely, one week after administration, the clazosentan group showed a significant increase in body weight and significant decreases in peripheral oxygen saturation, serum albumin, hemoglobin, and hematocrit levels, suggesting potential systemic effects.
These findings suggest that clazosentan use may be associated with a lower incidence of symptomatic vasospasm and earlier ambulation in patients with aneurysmal subarachnoid hemorrhage; however, careful monitoring of systemic status is warranted during rehabilitation.
Keywords: clazosentan, subarachnoid hemorrhage, cerebral vasospasm, neurorehabilitation, early mobilization
Introduction
Prognostic factors in aneurysmal subarachnoid hemorrhage (aSAH) include aneurysm rebleeding, acute hydrocephalus, and delayed cerebral ischemia (DCI), among which cerebral vasospasm–a major cause of DCI–typically occurs between days 4 and 14 after onset and may lead to neurological deterioration.1,2)
In particular, symptomatic vasospasm (SVS) has been associated with cerebral infarction and poor functional outcomes,3) highlighting the need for more effective strategies for its prevention and management.
Traditional treatments such as calcium channel blockers, vasodilators, and fluid management have been used for decades; however, these approaches have not substantially reduced the risk of infarction, and more effective pharmacological interventions are warranted.4)
Clazosentan is a selective endothelin A (ETA) receptor antagonist that inhibits the potent vasoconstrictor endothelin-1 (ET-1) and may be effective in preventing cerebral vasospasm.5)
Its efficacy and safety have been demonstrated in the CONSCIOUS clinical trial series (CONSCIOUS-1, -2, and -3), a series of international multicenter clinical trials,6,7) and it was approved in Japan in 2022 for use after surgical clipping or endovascular coiling in patients with aSAH.
However, adverse effects such as pleural effusion, peripheral edema, hypotension, and hypoxemia have been reported,8) necessitating close monitoring of systemic status and careful consideration of the drug's impact on rehabilitation.
In particular, fluid retention-related hypoxemia and circulatory instability may hinder early mobilization during the acute phase.
Although the vasospasm-suppressing effect of clazosentan is well-established, its impact on rehabilitation outcomes–such as the timing of ambulation and recovery of activities of daily living (ADLs)–remains unclear.
Therefore, its clinical role in promoting functional recovery has not been fully elucidated.
Recent studies have suggested that early physical therapy in acute stroke patients contributes to improved functional outcomes and reduced length of hospital stay durations, and similar benefits may apply to patients with aSAH.9)
Thus, it is important to examine whether vasospasm suppression with clazosentan is associated with improved rehabilitation outcomes, which may inform future strategies for optimizing post-aSAH care.
In this study, we compared patients treated with clazosentan and those receiving conventional therapy, focusing on (1) the incidence of SVS, (2) systemic indicators related to fluid and circulatory dynamics, and (3) rehabilitation progress, including the number of days to initial ambulation.
Methods
Study design and participants
This was a single-center, retrospective cohort study involving patients diagnosed with aSAH between January 2020 and March 2025 at our institution. Eligible patients met the following inclusion criteria: (1) underwent surgical clipping or endovascular treatment for ruptured cerebral aneurysms, (2) received clazosentan within 48 hrs of onset, and (3) initiated and completed rehabilitation during the acute hospitalization period.
The clazosentan group comprised consecutive patients admitted after May 2022, when the drug became available at our hospital, and those who had documented rehabilitation records. Similarly, the conventional treatment group included consecutive patients admitted between January 2020 and April 2022, with confirmed rehabilitation records. Patients managed conservatively without surgery were excluded because rehabilitation was not performed because of reasons such as terminal illness, advanced dementia, or refusal of active treatment.
Exclusion criteria were as follows: (1) one patient who died shortly after rehabilitation was initiated, (2) two patients with terminal malignancy or severe dementia who did not undergo active treatment or rehabilitation, (3) two patients who received clazosentan later than 48 hrs after onset, and (4) one patient with a mild condition (grade 1) who did not receive rehabilitation. Ultimately, 153 patients were included in the analysis, consisting of 76 in the clazosentan group and 77 in the conventional treatment group.
The required sample size was calculated based on a domestic phase III trial of clazosentan, assuming a difference in event rates of 28.8% versus 13.6%, with a two-sided α of 0.05, 80% power, and 1:1 allocation, yielding a target of 252 patients (126 per group).10) However, since clazosentan was approved for reimbursement in May 2022, only 76 eligible patients were available by the end of the observation period in March 2025. Although extending the control group was considered, treatment protocols and rehabilitation practices had undergone changes over time. Therefore, both groups were limited to periods with consistent therapeutic and rehabilitation practices within the institution. SVS in this study was defined in accordance with the 2009 consensus at the 25th Spasm Symposium as new or worsening neurological symptoms not attributable to other causes, supported by objective findings such as arterial narrowing of responsible vessels, new cerebral infarctions, decreased cerebral blood flow, or elevated flow velocity.11) The diagnosis was confirmed by two or more board-certified neurosurgeons.
Rehabilitation was initiated after approval by the attending physician and implemented when deemed safe by a physical or occupational therapist based on systemic and neurological evaluations. In both groups, range-of-motion exercises, muscle strengthening, and bedside sitting were typically initiated during ventricular or lumbar drainage when permitted by the attending physician. However, ambulation training was generally deferred until the drainage tubes were removed. These rehabilitation activities were based on an institutional mobilization protocol that had been in routine use during the study period. A unified early mobilization protocol was applied across both groups within the institution.
Each activity was defined according to standard rehabilitation medicine criteria as follows:12)
Sitting: the first day when the patient could maintain a seated position with stable trunk and pelvis control.
Standing: the first day when the patient could maintain an upright position, with or without assistive devices.
Ambulation: the first day the patient was able to perform a continuous forward movement using both legs alternately, regardless of assistance.
This study was approved by the institutional ethics committee (approval number: 24-14) and was conducted in accordance with the Declaration of Helsinki and the Ethical Guidelines for Medical and Health Research Involving Human Subjects in Japan. Informed consent was obtained via an opt-out procedure, as approved by the ethics committee.
Statistical analysis
The normality of continuous variables was assessed using the Shapiro-Wilk test. For variables that followed a normal distribution, group comparisons were performed using the independent samples t-test. For non-normally distributed variables, the Mann-Whitney U test was applied. Categorical variables were compared using Fisher's exact test.
To evaluate the association between clazosentan use and the incidence of SVS, logistic regression models were constructed with SVS as the dependent variable. Propensity scores were calculated using logistic regression, with clazosentan use as the dependent variable and relevant covariates as predictors. To examine the influence of potential confounders and confirm the robustness of the results, three propensity score-adjusted logistic regression models were constructed with stepwise inclusion of clinically relevant covariates.
Model 1: Propensity score based on age and sex.
Model 2: Propensity score based on age, sex, World Federation of Neurosurgical Societies grade, and hypertension.
Model 3: Propensity score additionally adjusted for hydrocephalus and treatment modality (clipping or coiling).
Odds ratios and 95% confidence intervals were calculated to estimate the strength of the association between clazosentan use and SVS. These multi-model analyses were regarded as sensitivity analyses to assess the consistency of results across model specifications.
The cumulative incidence of SVS was compared between groups using Kaplan-Meier analysis, and statistical significance was evaluated with the log-rank test. The between-group comparison of the number of days to initial ambulation was illustrated using a box plot.
All analyses were performed using R software (version 4.3.0; R Foundation for Statistical Computing, Vienna, Austria). A two-sided p < 0.05 was considered statistically significant. Missing data were minimal (<5%) and balanced between groups; therefore, complete case analysis was applied.
Results
Baseline patient characteristics
A total of 153 patients were included in the analysis, consisting of 76 in the clazosentan group and 77 in the control group. No significant differences were observed between the two groups with respect to age, sex, body weight, peripheral oxygen saturation (SpO2), comorbidities, World Federation of Neurosurgical Societies grade, treatment modality (surgical clipping or endovascular coiling), use of mechanical ventilation, cerebrospinal fluid drainage, presence of hydrocephalus, laboratory findings, echocardiographic findings, or cardiothoracic ratio (Table 1). Additional baseline characteristics are provided in Supplementary Table 1.
Table 1.
Baseline Characteristics of the Study Population
| Variables | Control group (n = 77) | Clazosentan group (n = 76) | p-Value |
|---|---|---|---|
| Age, y | 64.3 ± 15.4 | 62.4 ± 12.0 | 0.389 |
| Female, % | 59 (76.6) | 55 (72.4) | 0.582 |
| Body weight, kg | 60.3 ± 12.0 | 60.0 ± 13.3 | 0.882 |
| SpO2, % | 97.0 [96.0-98.0] | 97.0 [96.0-98.0] | 0.801 |
| Hypertension, % | 43 (55.8) | 37 (48.7) | 0.420 |
| Dyslipidemia, % | 21 (27.3) | 17 (22.7) | 0.576 |
| Diabetes, % | 9 (11.7) | 7 (9.3) | 0.793 |
| WFNS grade, % | 0.805 | ||
| Grade 1 | 39 (50.6) | 38 (50.0) | |
| Grade 2 | 18 (23.4) | 16 (21.0) | |
| Grade 3 | 7 (9.1) | 5 (6.6) | |
| Grade 4 | 11 (14.3) | 12 (15.8) | |
| Grade 5 | 2 (2.6) | 5 (6.6) | |
| Treatment modality, % | 0.598 | ||
| Clipping | 52 (67.5) | 54 (71.1) | |
| Coiling | 25 (32.5) | 22 (28.9) | |
| Hydrocephalus, % | 16 (20.8) | 14 (18.4) | 0.839 |
| Ventilator use, % | 49 (63.6) | 41 (53.9) | 0.252 |
| Ventilation, days | 1.0 [0.0-1.0] | 1.0 [0.0-1.0] | 0.084 |
| CSF drainage, % | 54 (70.1) | 61 (80.3) | 0.131 |
| Drainage duration, days | 5.0 [0.0-7.0] | 4.0 [3.0-6.25] | 0.965 |
| Albumin, g/dL | 4.2 [4.0-4.4] | 4.2 [3.9-4.4] | 0.921 |
| Hemoglobin, g/dL | 13.3 [12.4-14.6] | 13.1 [12.0-13.9] | 0.323 |
| Hematocrit, % | 38.6 [36.3-40.4] | 39.2 [35.3-41.8] | 0.500 |
| BNP, pg/mL | 48.5 [23.3-121.7] | 60.3 [34.4-98.0] | 0.402 |
| LVEF, % | 72.4 [68.1-76.2] | 73.0 [69.2-75.2] | 0.811 |
| Cardiothoracic ratio, % | 56.6 [53.1-60.4] | 55.1 [51.0-59.5] | 0.081 |
Data are presented as mean ± standard deviation, median [interquartile range], or percentage, as appropriate.
BNP: B-type natriuretic peptide; CSF: cerebrospinal fluid; LVEF: left ventricular ejection fraction; SpO2: peripheral oxygen saturation; WFNS: World Federation of Neurosurgical Societies
Incidence of symptomatic vasospasm
The incidence of SVS was significantly lower in the clazosentan group (5.3%, 4/76) than in the control group (20.7%, 16/77) (p = 0.007) (Table 2).
Table 2.
Changes One Week After Clazosentan Administration
| Parameters | Control group (n = 77) | Clazosentan group (n = 76) | p-Value |
|---|---|---|---|
| Body weight change, kg | −1.50 ± 2.90 | 1.65 ± 2.59 | <0.001 |
| SpO2, % | 97.0 [96.0-98.0] | 92.5 [90.0-95.0] | <0.001 |
| SpO2 change, % | 0.0 [−1.00 to 1.00] | −4.0 [−7.00 to −2.00] | <0.001 |
| SVS, n (%)a | 16 (20.7) | 4 (5.3) | 0.007 |
| Albumin, g/dL | 3.1 [2.9-3.3] | 2.9 [2.6-3.1] | 0.002 |
| Hemoglobin, g/dL | 10.9 [9.5-12.0] | 9.7 [9.0-10.8] | 0.001 |
| Hematocrit, % | 30.5 [27.3-33.9] | 28.2 [26.1-30.6] | 0.012 |
| BNP, pg/mL | 168.7 [66.0-243.6] | 84.1 [47.9-121.9] | 0.223 |
| Cardiothoracic ratio, % | 55.9 [52.4-59.7] | 53.9 [51.10-58.3] | 0.188 |
| Pleural effusion, % | 15 (19.5) | 22 (28.9) | 0.187 |
Data are presented as mean ± standard deviation, median [interquartile range], or percentage, as appropriate. Body weight change represents the difference from admission.
SVS: symptomatic vasospasm
aSVS was defined as occurring within 14 days of onset.
The Kaplan-Meier analysis showed a significantly lower cumulative incidence of SVS in the clazosentan group (log-rank test, p = 0.007) (Fig. 1).
Fig. 1.
Kaplan–Meier curves comparing the cumulative incidence of symptomatic vasospasm (SVS) between the clazosentan and control groups. The incidence of SVS was significantly lower in the clazosentan group (p = 0.007, log-rank test). The median number of days to initial ambulation is also indicated.
To assess the robustness of these findings, sensitivity analyses were conducted using three logistic regression models, each incorporating different levels of covariate adjustment via propensity scores. In all models, clazosentan use remained significantly associated with a reduced incidence of SVS (Fig. 2).
Fig. 2.
Forest plot showing adjusted odds ratios (ORs), 95% confidence intervals (CIs), and p-values for the incidence of symptomatic vasospasm (SVS) in the clazosentan group versus the control group, based on three logistic regression models with different propensity score adjustments.
Model 1 adjusted for age and sex; model 2 adjusted for age, sex, World Federation of Neurosurgical Societies (WFNS) grade, and hypertension; and model 3 adjusted for age, sex, WFNS grade, hypertension, hydrocephalus, and treatment modality (clipping or coiling).
Changes in systemic parameters one week after administration
One week after drug administration, the clazosentan group showed a significant increase in body weight compared with the control group (+1.65 kg vs −1.5 kg; p < 0.001).
In contrast, SpO2 (92.5% vs 97%; p < 0.001), serum albumin (2.85 g/dL vs 3.1 g/dL; p = 0.002), hemoglobin (9.7 g/dL vs 10.9 g/dL; p = 0.001), and hematocrit (28.2% vs 30.5%; p = 0.012) were significantly lower in the clazosentan group (Table 2).
Rehabilitation and discharge-related outcomes
There were no significant differences between groups in the number of days from admission to sitting, or standing.
However, ambulation was achieved significantly earlier in the clazosentan group, with a median of 8.5 days (interquartile range [IQR]: 5–12), compared with 11 days (IQR: 8–15) in the control group (p = 0.015) (Fig. 3).
Fig. 3.
Boxplot comparing the number of days to initial ambulation between the clazosentan and control groups. Ambulation was achieved significantly earlier in the clazosentan group (median, 8.5 vs. 11 days; p = 0.015).
In addition, the incidence of aphasia was significantly lower in the clazosentan group (p = 0.034) (Table 3).
Table 3.
Physical Therapy Evaluation and Discharge Outcomes
| Outcomes | Control group (n = 77) | Clazosentan group (n = 76) | p-Value |
|---|---|---|---|
| PT initiation, days | 2.0 [1.0-3.0] | 2.0 [1.0-2.0] | 0.049 |
| Sitting initiation, days | 5.0 [3.0-7.0] | 5.0 [3.0-7.0] | 0.455 |
| Standing initiation, days | 6.0 [3.0-9.0] | 6.0 [4.0-8.0] | 0.599 |
| Walking initiation, days | 11.0 [8.0-15.0] | 8.5 [5.0-12.0] | 0.015 |
| Aphasia, % | 8 (10.8) | 1 (1.4) | 0.034 |
| Acute phase PT duration, days | 27.0 [21.0-40.0] | 26.0 [20.5-39.0] | 0.417 |
| Barthel index at discharge, points | 100.0 [70.0-100.0] | 100.0 [80.0-100.0] | 0.463 |
| Hospital stay duration, days | 39.0 [26.0-72.0] | 33.0 [23.0-62.0] | 0.259 |
| Discharge destination, % | 0.322 | ||
| home | 47 (61.0) | 49 (64.5) | |
| nursing home | 3 (3.9) | 1 (1.3) | |
| discharge to another hospital | 27 (35.1) | 26 (34.2) | |
| Discharge mRS | 0.094 | ||
| mRS 0 | 39 (50.6) | 33 (45.2) | |
| mRS 1 | 9 (11.7) | 12 (16.4) | |
| mRS 2 | 5 (6.5) | 11 (15.1) | |
| mRS 3 | 17 (22.1) | 6 (8.2) | |
| mRS 4 | 5 (6.5) | 8 (11.0) | |
| mRS 5 | 2 (2.6) | 3 (4.1) |
Initiation = number of days from admission to first achievement of each activity (with or without assistance).
mRS: modified Rankin scale; PT: physical therapy
Although the clazosentan group tended to show a higher proportion of patients with favorable modified Rankin scale (mRS) scores at discharge and shorter hospital stays, these differences were not statistically significant (Table 3).
Discussion
This retrospective cohort study showed that clazosentan use in patients with aSAH was significantly associated with a lower incidence of SVS and earlier initiation of ambulation. Clazosentan is an ETA receptor antagonist that inhibits ET-1-induced vasoconstriction, which may contribute to reduced cerebral vasospasm and subsequent DCI.13) ET-1 levels increase in the serum and cerebrospinal fluid after aSAH and are considered a major contributor to vasospasm, making ETA receptor blockade a promising therapeutic approach.14,15)
The CONSCIOUS-1 international trial showed that clazosentan significantly suppressed the development of vasospasm, and this effect was confirmed in the subsequent CONSCIOUS-2 and -3 trials.6,16) A recent meta-analysis also suggested that clazosentan may reduce the incidence of vasospasm and DCI,17) which aligns with the present findings.
However, within one week of clazosentan administration, increases in body weight and decreases in serum albumin, hemoglobin, hematocrit, and SpO2 were observed. These changes may be attributed to fluid retention resulting from the inhibition of ET-1-dependent sodium reabsorption in the renal tubules, which suppresses diuresis.18,19) Furthermore, hypoalbuminemia lowers oncotic pressure and may promote extravascular fluid leakage, potentially leading to edema and pleural effusion.20) Clazosentan has been reported to cause side effects such as edema, pleural effusion, and pulmonary congestion,6,8) which is consistent with the findings in this study.
These systemic changes may pose risks during rehabilitation. Particularly, reductions in hemoglobin and hematocrit suggest impaired oxygen-carrying capacity and, when combined with decreased SpO2, may lead to insufficient oxygenation. Given the increased oxygen demand during physical activity, physiological monitoring and careful attention to cardiopulmonary stress are warranted during staged rehabilitation, including early ambulation.21) In elderly patients, these side effects may more easily lead to cardiopulmonary events, such as tachycardia or oxygenation impairment, and, therefore, require greater caution.22) During administration, it is recommended to monitor systemic symptoms, such as dyspnea, edema, and dizziness, as well as evaluate hemodynamics and the risk of pulmonary edema.8)
Interestingly, despite these adverse effects, patients in the clazosentan group began ambulation significantly earlier. SVS typically occurs 4-14 days after aSAH onset, peaking around days 5-7.23) Its suppression may prevent neurological complications, such as impaired consciousness, motor paralysis, and aphasia, thereby enabling smoother initiation of rehabilitation. In addition, SVS management often requires vasopressors and fluid resuscitation, which may necessitate bed rest. The use of clazosentan may alleviate such medical restrictions and allow uninterrupted mobilization and walking practice.
Early ambulation may have clinical implications for functional recovery. Although no significant differences were observed in mRS at discharge in this study, a previous single-center study in Japan reported significantly better mRS scores at 3 months in the clazosentan group.24) This discrepancy may reflect differences in evaluation timing, and the previous study helps to compensate for the short-term evaluation limitation of the present study. Early rehabilitation in patients with aSAH has been reported to contribute to functional recovery and ADL improvement.25) Although no significant differences were observed in mRS or the Barthel index at discharge in this study, earlier ambulation may represent an important initial step toward functional improvement.
These findings suggest that early rehabilitation should be implemented once neurological stability is achieved, considering the SVS-suppressing effects of clazosentan. Clinical stabilization associated with clazosentan may contribute to earlier resumption of walking, shorter hospital stays, and better ADL outcomes.26) However, multiple factors beyond SVS and DCI, such as headache, delirium, and cognitive dysfunction, may affect recovery. Therefore, rehabilitation professionals should collaborate with multidisciplinary teams to comprehensively assess systemic status and flexibly adjust intervention plans.27)
This study has several limitations. First, this was a single-center retrospective observational study with a sample size below the initial target. This was because of the limited availability of clazosentan during the 3-year observation period at our institution, and the period was not extended further to avoid bias from evolving treatment techniques or rehabilitation protocols. Second, although propensity score adjustment was used to control for confounders, selection bias and information bias because of missing records cannot be entirely excluded. Moreover, the diagnostic criteria for SVS and the definition of ambulation may involve a degree of subjectivity. Future multicenter prospective studies are warranted to clarify optimal dosing conditions for clazosentan, mechanisms of adverse effects, and individualized rehabilitation strategies.
Conclusions
This study indicates that the use of clazosentan in patients with aSAH may be associated with a reduced incidence of SVS and earlier initiation of ambulation. On the other hand, systemic changes, such as increased body weight and decreased SpO2, albumin, hemoglobin, and hematocrit levels, were observed, indicating the need for careful systemic management and monitoring during treatment. These findings may contribute to the development of treatment strategies and rehabilitation planning that aim to prevent SVS while promoting functional recovery. Further prospective multicenter studies are needed to evaluate optimal intervention timing and risk management in greater detail.
Conflicts of Interest Disclosure
All authors have no conflict of interest.
Declaration of Generative AI and AI-assisted Technologies in the Writing Process
During the preparation of this manuscript, the authors used ChatGPT (OpenAI) to assist with the translation of the original Japanese text into English. After using this tool, the authors carefully reviewed and revised the content and take full responsibility for the final version of the manuscript.
Supplementary Material
References
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