Randomized Trial of Clazosentan in Patients With Aneurysmal Subarachnoid Hemorrhage Undergoing Endovascular Coiling

Macdonald, R. Loch; Higashida, Randall T.; Keller, Emanuela; Mayer, Stephan A.; Molyneux, Andy; Raabe, Andreas; Vajkoczy, Peter; Wanke, Isabel; Bach, Doris; Frey, Aline; Nowbakht, Pegah; Roux, Sébastiên; Kassell, Neal F.

doi:10.1161/strokeaha.111.648980

Cited by 258 publications

(229 citation statements)

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“…A large research effort has been invested in studying and targeting individual aspects of the complex vasculopathy after SAH, e.g., with vasoconstrictor receptor antagonists and antiinflammatory drugs, 23,24 but without clinical success. To observe clinical effect, it may be necessary to target a broad range of the pathologic processes in the cerebral vasculature.…”

Section: Discussionmentioning

confidence: 99%

Signal Transduction in Cerebral Arteries after Subarachnoid Hemorrhage—A Phosphoproteomic Approach

Parker

Larsen

Edvinsson

et al. 2013

J Cereb Blood Flow Metab

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After subarachnoid hemorrhage (SAH), pathologic changes in cerebral arteries contribute to delayed cerebral ischemia and poor outcome. We hypothesize such changes are triggered by early intracellular signals, targeting of which may prevent SAH-induced vasculopathy. We performed an unbiased quantitative analysis of early SAH-induced phosphorylations in cerebral arteries and evaluated identified signaling components as targets for prevention of delayed vasculopathy and ischemia. Labeled phosphopeptides from rat cerebral arteries were quantified by high-resolution tandem mass spectrometry. Selected SAH-induced phosphorylations were validated by immunoblotting and monitored over a 24-hour time course post SAH. Moreover, inhibition of key phosphoproteins was performed. Major SAH-induced phosphorylations were observed on focal adhesion complexes, extracellular regulated kinase 1/2 (ERK1/2), calcium calmodulin-dependent kinase II, signal transducer and activator of transcription (STAT3) and c-Jun, the latter two downstream of ERK1/2. Inhibition of ERK1/2 6-hour post SAH prevented increases in cerebrovascular constrictor receptors, matrix metalloprotease-9, wall thickness, and improved neurologic outcome. STAT3 inhibition partially mimicked these effects. The study shows that quantitative mass spectrometry is a strong approach to study in vivo vascular signaling. Moreover, it shows that targeting of ERK1/2 prevents delayed pathologic changes in cerebral arteries and improves outcome, and identifies SAH-induced signaling components downstream and upstream of ERK1/2.

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Section: Discussionmentioning

confidence: 99%

Signal Transduction in Cerebral Arteries after Subarachnoid Hemorrhage—A Phosphoproteomic Approach

Parker

Larsen

Edvinsson

et al. 2013

J Cereb Blood Flow Metab

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“…After exclusion of the duplicate studies and those that did not meet the inclusion criteria, there were 6 qualifying RCTs. 3,27,28,30,42,43 Of these, 2 possible RCTs were excluded: one did not include clazosentan treatment 44 and another had no related end points. 3 Finally, 4 randomized, placebo-controlled trials, enrolling 2181 patients in total, investigating the effect of clazosentan on vasospasm-related morbidity, poor outcomes, and drug-related adverse events in patients with aneurysmal SAH met eligibility criteria (Fig.…”

Section: Search Resultsmentioning

confidence: 99%

“…30 Moreover, the CONSCIOUS-3 trial also showed clazosentan, at a dose of 15 mg/hr, significantly reduced vasospasmrelated morbidity and mortality. 28 However, clazosentan, at the doses used in the CONSCIOUS-2 and CONSCIOUS-3 trials, did not improve outcomes measured by the GOSE.…”

mentioning

confidence: 94%

“…18,50 Specifically, clazosentan is an endothelin receptor antagonist under investigation for the prevention of vasospasm and vasospasm-related morbidity. 3,4,8,24,[27][28][29][30]37,40,42,43,[45][46][47] Recently, a series of well-designed clinical trials was performed using clazosentan in patients with SAH. In a Phase IIa trial, clazosentan reduced moderate or severe angiographic vasospasm by 55% relative to placebo (p = 0.008).…”

mentioning

confidence: 99%

“…3,27,28,30,42,43 To date, there has not been a meta-analysis to investigate the effects of clazosentan in the treatment of SAH. The goal of this meta-analysis was to determine whether clazosentan is effective in preventing cerebral vasospasm-related DIND and delayed cerebral infarction and improving outcomes in patients who have suffered an aneurysmal SAH.…”

mentioning

confidence: 99%

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Dissociation of vasospasm-related morbidity and outcomes in patients with aneurysmal subarachnoid hemorrhage treated with clazosentan: a meta-analysis of randomized controlled trials

Shen¹,

Pan²,

Fan³

et al. 2013

JNS

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Object Clazosentan therapy after aneurysmal subarachnoid hemorrhage (SAH) has been found to be effective in reducing the incidence of vasospasm in randomized controlled trials. However, while vasospasm-related morbidity, including delayed ischemic neurological deficits (DINDs) and delayed cerebral infarctions, was consistently decreased, statistical significance was not demonstrated and outcomes were not affected by clazosentan treatment. The objective of this meta-analysis was to determine whether clazosentan treatment after aneurysmal SAH significantly reduced the incidence of DINDs and delayed cerebral infarctions and improved outcomes. Methods All randomized controlled trials investigating the effect of clazosentan were retrieved via searches with sensitive and specific terms. Six variables were abstracted after the assessment of the methodological quality of the trials. Analyses were performed following the method guidelines of the Cochrane Back Review Group. Results Four randomized, placebo-controlled trials met eligibility criteria, enrolling a total of 2181 patients. The meta-analysis demonstrated a significant decrease in the incidence of DINDs (relative risk [RR] 0.76 [95% CI 0.62–0.92]) and delayed cerebral infarction (RR 0.79 [95% CI 0.63–1.00]) in patients treated with clazosentan after aneurysmal SAH. However, this treatment regimen was not shown to outcomes including functional outcomes measured by Glasgow Outcome Scale-Extended (RR 1.12 [95% CI 0.96–1.30]) or mortality (RR 1.02 [95%CI 0.70–1.49]). Adverse events, including pulmonary complications, anemia, and hypotension, were all significantly increased in patients who received clazosentan therapy. Conclusions The results of the present meta-analysis show that treatment with clazosentan after aneurysmal SAH significantly reduced the incidence of the vasospasm-related DINDs and delayed cerebral infarctions, but did not improve poor neurological outcomes in patients with aneurysmal SAH. Further study is required to elucidate the dissociation between vasospasm-related morbidity and outcomes.

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Sex Disparities in Enrollment in Recent Randomized Clinical Trials of Acute Stroke

et al. 2021

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IMPORTANCEThe underenrollment of women in randomized clinical trials represents a threat to the validity of the evidence supporting clinical guidelines and potential disparities in access to novel treatments. OBJECTIVE To determine whether women were underenrolled in contemporary randomized clinical trials of acute stroke therapies published in 9 major journals after accounting for their representation in underlying stroke populations.DATA SOURCES MEDLINE was searched for acute stroke therapeutic trials published between January 1, 2010, and June 11, 2020.STUDY SELECTION Eligible articles reported the results of a phase 2 or 3 randomized clinical trial that enrolled patients with stroke and/or transient ischemic attack and examined a therapeutic intervention initiated within 1 month of onset.DATA EXTRACTION Data extraction was performed by 2 independent authors in duplicate. Individual trials were matched to estimates of the proportion of women in underlying stroke populations using the Global Burden of Disease database. MAIN OUTCOMES AND MEASURESThe primary outcome was the enrollment disparity difference (EDD), the absolute difference between the proportion of trial participants who were women and the proportion of strokes in the underlying disease populations that occurred in women. Random-effects meta-analyses of the EDD were performed, and multivariable metaregression was used to explore the associations of trial eligibility criteria with disparity estimates. RESULTSThe search returned 1529 results, and 115 trials (7.5%) met inclusion criteria. Of 121 105 randomized patients for whom sex was reported, 52 522 (43.4%) were women. The random-effects summary EDD was −0.053 (95% CI, −0.065 to −0.040), indicating that women were underenrolled by 5.3 percentage points. This disparity persisted across virtually all geographic regions, intervention types, and stroke types, apart from subarachnoid hemorrhage (0.117 [95% CI, 0.084 to 0.150]). When subarachnoid hemorrhage trials were excluded, the summary EDD was −0.067 (95% CI, −0.078 to −0.057). In the multivariable metaregression analysis, an upper age limit of 80 years as an eligibility criterion was associated with a 6-percentage point decrease in the enrollment of women.CONCLUSIONS AND RELEVANCE Further research is needed to understand the causes of the underenrollment of women in acute stroke trials. However, to maximize representation, investigators should avoid imposing age limits on enrollment.

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Randomized Trial of Clazosentan in Patients With Aneurysmal Subarachnoid Hemorrhage Undergoing Endovascular Coiling

Cited by 258 publications

References 21 publications

Signal Transduction in Cerebral Arteries after Subarachnoid Hemorrhage—A Phosphoproteomic Approach

Signal Transduction in Cerebral Arteries after Subarachnoid Hemorrhage—A Phosphoproteomic Approach

Dissociation of vasospasm-related morbidity and outcomes in patients with aneurysmal subarachnoid hemorrhage treated with clazosentan: a meta-analysis of randomized controlled trials

Sex Disparities in Enrollment in Recent Randomized Clinical Trials of Acute Stroke

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