Endothelin Receptor Antagonists for Aneurysmal Subarachnoid Hemorrhage

Vergouwen, Mervyn D.I.; Algra, Ale; Rinkel, Gabriël J. E.

doi:10.1161/strokeaha.112.666693

Cited by 72 publications

(40 citation statements)

References 18 publications

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“…A greater proportion of subjects treated with macitentan versus placebo exhibited peripheral oedema and anaemia. Fluid retention and anaemia are known to be associated with ERAs as a class of agents in general, with increased risks of these events having been reported previously in subjects with pulmonary arterial hypertension as well as chronic heart failure [16][17][18][19][20][21]. There was no difference between the two treatment arms with regards to the incidence of death; rather, the observed difference in risk between the groups up to month 12 was mainly driven by acute exacerbation.…”

Section: Discussionmentioning

confidence: 55%

Macitentan for the treatment of idiopathic pulmonary fibrosis: the randomised controlled MUSIC trial

Raghu¹,

Million-Rousseau²,

Morganti³

et al. 2013

Eur Respir J

244

149

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Idiopathic pulmonary fibrosis is a progressive, fatal disease. This prospective, randomised, double-blind, multicentre, parallel-group, placebo-controlled phase II trial (NCT00903331) investigated the efficacy and safety of the endothelin receptor antagonist macitentan in idiopathic pulmonary fibrosis.Eligible subjects were adults with idiopathic pulmonary fibrosis of ,3 years duration and a histological pattern of usual interstitial pneumonia on surgical lung biopsy. The primary objective was to demonstrate that macitentan (10 mg once daily) positively affected forced vital capacity versus placebo.Using a centralised system, 178 subjects were randomised (2:1) to macitentan (n5119) or placebo (n559). The median change from baseline up to month 12 in forced vital capacity was -0.20 L in the macitentan arm and -0.20 L in the placebo arm. Overall, no differences between treatments were observed in pulmonary function tests or time to disease worsening or death. Median exposures to macitentan and placebo were 14.5 months and 15.0 months, respectively. Alanine and/or aspartate aminotransferase elevations over three times upper limit of normal arose in 3.4% of macitentan-treated subjects and 5.1% of placebo recipients.In conclusion, the primary objective was not met. Long-term exposure to macitentan was well tolerated with a similar, low incidence of elevated hepatic aminotransferases in each treatment group. @ERSpublications Long-term exposure to macitentan was well tolerated in IPF in a trial that did not meet its primary end-point

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Section: Discussionmentioning

confidence: 55%

Macitentan for the treatment of idiopathic pulmonary fibrosis: the randomised controlled MUSIC trial

Raghu¹,

Million-Rousseau²,

Morganti³

et al. 2013

Eur Respir J

244

149

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“…Angiographic vasospasm occur in up to 70% of patients after SAH, yet less than half develop ischemic neurologic symptoms [2] . RCTs within the last decades investigating vasospasm treatment have failed to prevent DCI or to improve outcome [26,27] questioning the causal relationship of vasospasm as sole contributor to DCI development [2][3][4] . The present data show that DCI occurred predominantly in the vascular territory of peak spastic vessels supporting the role of vasospasm.…”

Section: Discussionmentioning

confidence: 99%

Is Hypothermia Helpful in Severe Subarachnoid Hemorrhage? An Exploratory Study on Macro Vascular Spasm, Delayed Cerebral Infarction and Functional Outcome after Prolonged Hypothermia

Kuramatsu

Kollmar²,

Gerner³

et al. 2015

Cerebrovasc Dis

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Background: Therapeutic hypothermia (TH) is an established treatment after cardiac arrest and growing evidence supports its use as neuroprotective treatment in stroke. Only few and heterogeneous studies exist on the effect of hypothermia in subarachnoid hemorrhage (SAH). A novel approach of early and prolonged TH and its influence on key complications in poor-grade SAH, vasospasm and delayed cerebral ischemia (DCI) was evaluated. Methods: This observational matched controlled study included 36 poor-grade (Hunt and Hess Scale >3 and World Federation of Neurosurgical Societies Scale >3) SAH patients. Twelve patients received early TH (<48 h after ictus), mild (35°C), prolonged (7 ± 1 days) and were matched to 24 patients from the prospective SAH database. Vasospasm was diagnosed by angiography, macrovascular spasm serially evaluated by Doppler sonography and DCI was defined as new infarction on follow-up CT. Functional outcome was assessed at 6 months by modified Rankin Scale (mRS) and categorized as favorable (mRS score 0-2) versus unfavorable (mRS score 3-6) outcome. Results: Angiographic vasospasm was present in 71.0% of patients. TH neither influenced occurrence nor duration, but the degree of macrovascular spasm as well as peak spastic velocities were significantly reduced (p < 0.05). Frequency of DCI was 87.5% in non-TH vs. 50% in TH-treated patients, translating into a relative risk reduction of 43% and preventive risk ratio of 0.33 (95% CI 0.14-0.77, p = 0.036). Favorable functional outcome was twice as frequent in TH-treated patients 66.7 vs. 33.3% of non-TH (p = 0.06). Conclusion: Early and prolonged TH was associated with a reduced degree of macrovascular spasm and significantly decreased occurrence of DCI, possibly ameliorating functional outcome. TH may represent a promising neuroprotective therapy possibly targeting multiple pathways of DCI development, notably macrovascular spasm, which strongly warrants further evaluation of its clinical impact.

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“…30,99,100 Metaanalysis of trial results con firmed that clazosentan reduced angiographic vasospasm without a significant effect on outcome. 101 Drug adverse effects included hypotension and pulmonary compli cations, which could have counteracted the beneficial effects of the drug.…”

Section: Clinical Trialsmentioning

confidence: 99%

Delayed neurological deterioration after subarachnoid haemorrhage

2013

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Subarachnoid haemorrhage (SAH) causes early brain injury (EBI) that is mediated by effects of transient cerebral ischaemia during bleeding plus effects of the subarachnoid blood. Secondary effects of SAH include increased intracranial pressure, destruction of brain tissue by intracerebral haemorrhage, brain shift, and herniation, all of which contribute to pathology. Many patients survive these phenomena, but deteriorate days later from delayed cerebral ischaemia (DCI), which causes poor outcome or death in up to 30% of patients with SAH. DCI is thought to be caused by the combined effects of angiographic vasospasm, arteriolar constriction and thrombosis, cortical spreading ischaemia, and processes triggered by EBI. Treatment for DCI includes prophylactic administration of nimodipine, and current neurointensive care. Prompt recognition of DCI and immediate treatment by means of induced hypertension and balloon or pharmacological angioplasty are considered important by many physicians, although the evidence to support such approaches is limited. This Review summarizes the pathophysiology of DCI after SAH and discusses established treatments for this condition. Novel strategies--including drugs such as statins, sodium nitrite, albumin, dantrolene, cilostazol, and intracranial delivery of nimodipine or magnesium--are also discussed.

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Endothelin Receptor Antagonists for Aneurysmal Subarachnoid Hemorrhage

Cited by 72 publications

References 18 publications

Macitentan for the treatment of idiopathic pulmonary fibrosis: the randomised controlled MUSIC trial

Macitentan for the treatment of idiopathic pulmonary fibrosis: the randomised controlled MUSIC trial

Is Hypothermia Helpful in Severe Subarachnoid Hemorrhage? An Exploratory Study on Macro Vascular Spasm, Delayed Cerebral Infarction and Functional Outcome after Prolonged Hypothermia

Delayed neurological deterioration after subarachnoid haemorrhage

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