Pivlaz (clazosentan) / Idorsia, Nxera Pharma - LARVOL DELTA

Clazosentan Administration Was Not Associated with Intracranial Pressure Elevation in Aneurysmal Subarachnoid Hemorrhage: A Retrospective Study with Direct ICP Monitoring. (PubMed, J Clin Med) - " This single-center retrospective study included 59 patients with aSAH who underwent continuous direct ICP monitoring, of whom 23 received clazosentan and 24 received fasudil. In this retrospective single-center cohort, no statistically significant ICP elevation was observed during clazosentan administration under standard neurosurgical management. Although the small sample size limits statistical power and a false-negative result cannot be excluded, these findings may help inform clinical decision-making regarding clazosentan use in patients with poor-grade aSAH."

Journal • Retrospective data • Cardiovascular • Cerebral Hemorrhage • Hematological Disorders • Subarachnoid Hemorrhage

The Clinical Factors Associated with Clazosentan Discontinuation and Exploratory Associations with Discharge and Six-Month Outcomes in Aneurysmal Subarachnoid Hemorrhage: A Multicenter DCI Japan Registry Study. (PubMed, J Clin Med) - "Clazosentan discontinuation was associated with age ≥ 76 years (OR for discontinuation: 2.33, 95% CI 1.03-5.28), World Federation of Neurosurgical Societies Grade V (OR 6.52 [2.70-15.78]), larger aneurysm size (OR 1.15 [1.03-1.29]), Fisher computed tomography group 4 (OR 2.61 [1.08-6.30]), and Fasudil hydrochloride hydrate use (OR 3.96 [1.77-8.87]). Clazosentan discontinuation was associated with poor outcome at discharge and at 6 months, although the latter was attenuated in sensitivity analysis. Some factors were associated with clazosentan discontinuation, highlighting the clinical relevance of careful systemic monitoring during clazosentan therapy, particularly in patient populations underrepresented in prior trials."

Journal • Cardiovascular • Hematological Disorders • Subarachnoid Hemorrhage

Clazosentan, Endothelin-A Receptor Antagonist, Suppresses Interleukin-6 Expression in Cerebrospinal Fluid after Subarachnoid Hemorrhage. (PubMed, Neurol Med Chir (Tokyo)) - "Ten patients received fasudil hydrochloride (FH), a Rho kinase inhibitor, and 12 received CLA. CLA suppressed IL-6 expression during the acute phase, which may contribute to delayed upregulation of IP-10 and MIG. Suppression of IL-6 may represent a key mechanism underlying the anti-inflammatory effects of CLA following SAH."

Journal • Hematological Disorders • Subarachnoid Hemorrhage • CCL2 • IFNG • IL6

Addition of Clazosentan to Fasudil Is Associated with Increased Cerebral Blood Volume without Changes in Cerebral Blood Flow after Aneurysmal Subarachnoid Hemorrhage: A CT Perfusion Study. (PubMed, World Neurosurg) - "The addition of clazosentan to fasudil was associated with increased cerebral blood volume, without significant changes in cerebral blood flow or mean transit time. These findings may be consistent with altered microvascular capacitance but should not be interpreted as evidence of improved tissue perfusion or clinical outcomes."

Journal • Cardiovascular • Cerebral Hemorrhage • Hematological Disorders • Subarachnoid Hemorrhage

Clinical outcomes before and after the introduction of clazosentan in aneurysmal subarachnoid hemorrhage: a multicenter retrospective study of clipping and endovascular treatment. (PubMed, Neurosurg Rev) - "Functional outcomes appeared more favorable in both the clipping and EVT groups during the clazosentan era. Across all study periods, the observed proportion of patients with favorable functional outcomes was higher in the EVT group than in the clipping group. However, because formal interaction testing did not identify statistically significant effect modification, the apparent reduction in between-group differences observed in the clazosentan era should be interpreted with caution and considered hypothesis-generating. Further prospective studies are needed to clarify the clinical relevance of these era-based observations."

Clinical data • Journal • Retrospective data • Cardiovascular • Cerebral Hemorrhage • CNS Disorders • Hematological Disorders • Hypotension • Subarachnoid Hemorrhage • Vascular Neurology

Association of Pretreatment Hepatic Function Markers with Clazosentan-Associated Fluid Retention in Patients with Subarachnoid Hemorrhage. (PubMed, Biol Pharm Bull) - "These findings suggest that an elevated pretreatment ALBI score may be linked to an increased risk of clazosentan-associated fluid retention. Further validation in patients with varying degrees of hepatic function is warranted to establish its clinical utility."

Biomarker • Journal • Retrospective data • Cardiovascular • Hematological Disorders • Subarachnoid Hemorrhage

Clazosentan Attenuates Endothelin-1-Induced ETA Protein Upregulation and Contractile Sensitization in Brain Pericytes. (PubMed, Pharmaceutics) - " These findings suggest that ET-1/ETA signaling may shift brain pericytes toward a sensitized contractile response state and that selective ETA blockade by clazosentan attenuates this process without overtly disrupting TEER-assessed barrier properties under the present in vitro conditions. These observations support further pharmacological characterization of clazosentan as a modulator of pericyte ET-1 responses."

Journal • Alzheimer's Disease • CNS Disorders • Hematological Disorders • Subarachnoid Hemorrhage • EDN1

Adjunctive Fasudil Use and Outcomes After Clazosentan Treatment for Aneurysmal Subarachnoid Hemorrhage: A Multicenter DCI Japan Registry Study. (PubMed, J Clin Med) - "Adjunctive Fasudil was independently associated with higher odds of AVS (adjusted odds ratio [aOR] 2.41, 95% confidence interval [CI] 1.21-4.81), cerebral infarction (aOR 2.10, 95% CI 1.08-4.09), and poor 6-month outcome (aOR 2.88, 95% CI 1.08-7.71), but not with poor functional outcome at discharge (aOR 1.37, 95% CI 0.62-3.03). In clazosentan-treated aneurysmal SAH, adjunctive Fasudil use was not associated with additional benefit and was associated with higher odds of AVS, cerebral infarction, and poor functional outcome at 6 months."

Journal • Cardiovascular • CNS Disorders • Hematological Disorders • Subarachnoid Hemorrhage

Neuroprotection and Enhanced Hemoglobin Excretion by Intrathecal Clazosentan in Mice With Subarachnoid Hemorrhage. (PubMed, J Am Heart Assoc) - "This study first showed that intrathecal administration of clazosentan can suppress early brain injury in terms of neuroinflammation at cerebrospinal fluid concentrations one-tenth of the clinically achievable blood concentrations, associated with enhanced lymphatic drainage of hemoglobin."

Journal • Preclinical • CNS Disorders • Hematological Disorders • Inflammation • Subarachnoid Hemorrhage • Vascular Neurology • FLT4 • VEGFC

Hypoxemia with atelectasis during clazosentan therapy after subarachnoid hemorrhage: a potential effect of suppressed hypoxic pulmonary vasoconstriction. (PubMed, Nagoya J Med Sci) - "Improvement after drug withdrawal supports this association. Clinicians should recognize that hypoxemia during clazosentan therapy may occur independently of fluid overload and warrants early respiratory evaluation."

Journal • Cardiovascular • Hematological Disorders • Respiratory Diseases • Subarachnoid Hemorrhage • EDN1

Emerging Neurovascular Interventions for the Prevention of Cerebral Vasospasm and Delayed Cerebral Ischemia After Aneurysmal Subarachnoid Hemorrhage: A Systematic Review. (PubMed, Cureus) - "Although conventional management strategies such as nimodipine administration, hemodynamic augmentation, and endovascular rescue therapy remain central to clinical practice, growing evidence suggests that delayed cerebral ischemia is a multifactorial neurovascular process extending beyond isolated large vessel vasospasm...Emerging evidence increasingly supports a broader pathophysiological model of delayed cerebral ischemia involving endothelial dysfunction, microcirculatory impairment, neuroinflammation, and autonomic dysregulation in addition to proximal arterial narrowing. Contemporary neurovascular interventions may therefore represent an important shift toward more targeted and mechanistically informed therapeutic strategies after aneurysmal subarachnoid hemorrhage, although further large-scale multicenter investigations remain necessary to establish definitive clinical benefit."

Journal • Review • Cardiovascular • Cerebral Hemorrhage • CNS Disorders • Hematological Disorders • Inflammation • Subarachnoid Hemorrhage • Vascular Neurology

Next-generation therapeutics and renaissance of legacy drugs targeting the endothelin system. (PubMed, Can J Physiol Pharmacol) - "Endothelin-1 (ET-1) was discovered in 1988, followed by identification of ETA and ETB receptors in 1990, enabling rapid development of the first endothelin receptor antagonists (bosentan, ambrisentan, and macitentan) for pulmonary arterial hypertension, a condition marked by elevated ET-1. Nearly a decade later, a new therapeutic wave began with the ETB agonist sovateltide (2021) for cerebral ischemic stroke, demonstrating the benefits of ETB activation...Clazosentan (ETA) for cerebral vasospasm and aprocitentan (ETA/ETB) for resistant hypertension extended endothelin-targeted therapy into more common diseases. In kidney disease, sparsentan (AT1/ETA) and atrasentan (ETA) have both been approved for IgA nephropathy, with atrasentan succeeding after earlier failed trials...This review outlines approaches for identifying legacy endothelin compounds suitable for new indications, using zibotentan, now combined with dapagliflozin to reduce fluid retention as an example. Kidney..."

Journal • Review • Cardiovascular • Glomerulonephritis • Hypertension • IgA Nephropathy • Ischemic stroke • Nephrology • Pulmonary Arterial Hypertension • Pulmonary Disease • Renal Disease • Respiratory Diseases • EDN1

Incidence of Early and In-hospital Late Seizures Following Aneurysmal Subarachnoid Hemorrhage in Patients Treated with Clazosentan: A Multicenter Retrospective Cohort Study. (PubMed, Neurol Med Chir (Tokyo)) - "Given the single-arm design and limited observation period, causal relationships could not be inferred. These findings provide descriptive data on seizure occurrence during acute hospitalization in the contemporary era of vasospasm prevention, and should be interpreted as hypothesis-generating."

Journal • Retrospective data • Cardiovascular • CNS Disorders • Epilepsy • Hematological Disorders • Subarachnoid Hemorrhage

Rescue clazosentan for symptomatic cerebral vasospasm following subarachnoid hemorrhage due to anterior cranial fossa dural arteriovenous fistula: A case report with serial angiographic evaluation. (PubMed, Surg Neurol Int) - "Following surgical occlusion, intravenous fasudil hydrochloride was administered for vasospasm prophylaxis. This case suggests that rescue administration of clazosentan may have contributed to improvement as part of multimodal vasospasm management following dAVF-related SAH, with vasodilatory effects comparable to those observed in aneurysmal SAH cases. Furthermore, short-term rescue administration of clazosentan may be tolerable in patients at high risk of fluid retention-related complications when careful fluid management and appropriate diuretic use are implemented."

Journal • Cardiovascular • CNS Disorders • Hematological Disorders • Subarachnoid Hemorrhage • Vascular Neurology

Heterogeneity of Clazosentan Benefit after Aneurysmal Subarachnoid Hemorrhage Demonstrated in an Externally Validated Causal Policy Tree. (PubMed, Neurocrit Care) - "In observational cohorts with limited overlap in treatment assignment, causal machine learning suggested heterogeneity in the estimated association of a clazosentan-containing strategy with discharge outcomes and produced a simple BMI/WFNS policy tree. These findings are hypothesis-generating and require prospective validation including safety endpoints and longer-term functional outcomes."

Heterogeneity • Journal • Cardiovascular • Hematological Disorders • Subarachnoid Hemorrhage • Vascular Neurology

Clazosentan in aneurysmal subarachnoid hemorrhage: an updated systematic review and meta-analysis of efficacy and safety. (PubMed, BMC Neurol) - "Across both bodies of evidence, clazosentan was associated with statistically significant reductions in angiographic vasospasm and vasospasm-related ischemic complications in aSAH, but these surrogate gains did not translate into statistically significant improvements in survival or functional recovery in either randomized or observational evidence, and were accompanied by clinically relevant increases in anemia, hypotension, and pulmonary complications. Observational comparisons with fasudil are at serious-to-critical risk of confounding by indication, treatment selection, and temporal changes in care, and should be considered hypothesis-generating. Because demonstrable improvement in patient-centered endpoints (survival, functional recovery) has not been shown, Routine use is not supported by current evidence; any role for clazosentan is likely limited to selected high-risk patients in whom the anticipated reduction in ischemic complications is explicitly judged to..."

Journal • Retrospective data • Review • Cardiovascular • Cerebral Hemorrhage • CNS Disorders • Hematological Disorders • Hypotension • Infectious Disease • Pneumonia • Respiratory Diseases • Subarachnoid Hemorrhage

Plasma and Cerebrospinal Fluid Pharmacokinetics of Clazosentan and its Relationship to Delayed Cerebral Ischemia in Patients with Aneurysmal Subarachnoid Hemorrhage. (PubMed, Neurocrit Care) - "During continuous intravenous infusion of clazosentan after SAH, plasma clazosentan concentrations declined while CSF concentrations were maintained, resulting in an increased CSF penetration rate. Lower CSF penetration was observed at days 10-12 in patients who developed DCI, suggesting a potential association between the relative CSF exposure of clazosentan and DCI."

Journal • PK/PD data • Cardiovascular • Hematological Disorders • Subarachnoid Hemorrhage • Vascular Neurology

Management of Cerebral Vasospasm in Subarachnoid Hemorrhage (PubMed, No Shinkei Geka) - "In Japan, pharmacological management has traditionally included fasudil hydrochloride and other agents targeting the vascular tone or platelet aggregation, often combined with strategies to remove subarachnoid blood. In clinical practice, clazosentan has been associated with favorable outcomes, but requires careful management because of adverse events such as fluid retention and pulmonary complications. Future strategies should focus on optimizing treatment protocols centered on clazosentan and identifying effective combination therapies that target multiple mechanisms underlying DCI."

Journal • Review • Cardiovascular • Hematological Disorders • Subarachnoid Hemorrhage • Thrombosis

Practical Guide to Clazosentan Administration in Patients with Aneurysmal Subarachnoid Hemorrhage. (PubMed, Neurol Med Chir (Tokyo)) - No abstract available

Journal • Cardiovascular • Hematological Disorders • Subarachnoid Hemorrhage

Prevention of Vasospasm After Aneurysmal Subarachnoid Hemorrhage Using Clazosentan: Insights from Real-World Data and Combination Therapy Strategies. (PubMed, World Neurosurg) - No abstract available

Journal • Real-world evidence • Cardiovascular • Hematological Disorders • Subarachnoid Hemorrhage

Feasibility and Outcomes of Clazosentan in Ruptured Vertebrobasilar Dissecting Aneurysms: A Retrospective Cohort Study. (PubMed, Health Sci Rep) - "Clazosentan use in patients with SAH due to VBDAs appeared to be feasible and generally well tolerated without apparent excess harm. Larger prospective studies with adequate sample size are warranted to clarify the effect on clinical outcomes."

Journal • Retrospective data • Cardiovascular • Hematological Disorders • Respiratory Diseases • Subarachnoid Hemorrhage • Vascular Neurology

Subarachnoid Hemorrhage: Clazosentan vs. Fasudil for Vasospasm Prevention (SAVIOR) Study: Study Protocol for a Prospective, Multicenter, Randomized Trial. (PubMed, Neurocrit Care) - "By selecting the local standard of care as the comparator, the study is designed to generate pragmatic, high-impact evidence that can inform clinical decision-making and potentially reshape treatment guidelines for aSAH management in Japan. It will provide the first high-quality data from a direct comparison of clazosentan and fasudil, in a nimodipine-free population-a clinical question not addressed by previous international trials."

Journal • Cardiovascular • Cerebral Hemorrhage • Hematological Disorders • Subarachnoid Hemorrhage

Safety and effectiveness of clazosentan in patients after aneurysmal subarachnoid haemorrhage: a second interim report of a post-marketing surveillance in Japan. (PubMed, Neurosurg Rev) - No abstract available

Journal • P4 data • Cardiovascular • Cerebral Hemorrhage • Subarachnoid Hemorrhage

Early Positive Fluid Balance as a Clinical Marker of Systemic Capillary Leak and Clazosentan Intolerance After Aneurysmal Subarachnoid Hemorrhage. (PubMed, Neurocrit Care) - "Early positive fluid balance was a strong independent predictor of clazosentan discontinuation and was associated with poor functional outcomes. Early postoperative fluid balance may serve as a practical bedside marker of clazosentan intolerance and fluid-retentive physiological response, potentially involving increased vascular permeability. Goal-directed fluid management targeting euvolemia during the first 72 h may help optimize tolerability and enhance the therapeutic efficacy of clazosentan."

Journal • Cardiovascular • Hematological Disorders • Subarachnoid Hemorrhage

The beneficial effects of clazosentan on the perioperative management of patients with subarachnoid hemorrhage. (PubMed, Neurosurg Rev) - "Furthermore, the length of hospital stay was significantly shorter in the clazosentan group than in the fasudil group (22.3 days vs. 29.6 days, p < 0.01). Conclusion clazosentan-based management was associated with reduced angiographic vasospasm, earlier rehabilitation, and shorter hospitalization compared with fasudil-based management."

Journal • Cardiovascular • Hematological Disorders • Subarachnoid Hemorrhage