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

A review

Restricted access

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.

Abbreviations used in this paper:CONSCIOUS = Clazosentan in Aneurysmal Subarachnoid Hemorrhage; DIND = delayed ischemic neurological deficit; GOSE = Glasgow Coma Scale–Extended; RCT = randomized controlled trial; RR = relative risk; SAH = subarachnoid hemorrhage; WFNS = World Federation of Neurosurgical Societies.
Article Information

Contributor Notes

Address correspondence to: Ren-Ya Zhan, M.D., Department of Neurosurgery, First Affiliated Hospital, College of Medicine, Zhejiang University, No. 79 Qingchun Road, Hangzhou City, 310003 Zhejiang Province, People's Republic of China. email: sjzju@163.com.Please include this information when citing this paper: published online May 3, 2013; DOI: 10.3171/2013.3.JNS121436.

© AANS, except where prohibited by US copyright law.

Headings
References
  • 1

    Al-Khindi TMacdonald RLSchweizer TA: Cognitive and functional outcome after aneurysmal subarachnoid hemorrhage. Stroke 41:e519e5362010

    • Search Google Scholar
    • Export Citation
  • 2

    Asano TIkegaki ISuzuki YSatoh SShibuya M: Endothelin and the production of cerebral vasospasm in dogs. Biochem Biophys Res Commun 159:134513511989

    • Search Google Scholar
    • Export Citation
  • 3

    Barth MCapelle HHMünch EThomé CFiedler FSchmiedek P: Effects of the selective endothelin A (ET(A)) receptor antagonist Clazosentan on cerebral perfusion and cerebral oxygenation following severe subarachnoid hemorrhage—preliminary results from a randomized clinical series. Acta Neurochir (Wien) 149:9119182007

    • Search Google Scholar
    • Export Citation
  • 4

    Beck JRaabe A: Clazosentan: prevention of cerebral vasospasm and the potential to overcome infarction. Acta Neurochir Suppl 110:1471502011

    • Search Google Scholar
    • Export Citation
  • 5

    Bederson JBConnolly ES JrBatjer HHDacey RGDion JEDiringer MN: Guidelines for the management of aneurysmal subarachnoid hemorrhage: a statement for healthcare professionals from a special writing group of the Stroke Council, American Heart Association. Stroke 40:99410252009

    • Search Google Scholar
    • Export Citation
  • 6

    Cahill JZhang JH: Subarachnoid hemorrhage: is it time for a new direction?. Stroke 40:3 SupplS86S872009

  • 7

    Castanares-Zapatero DHantson P: Pharmacological treatment of delayed cerebral ischemia and vasospasm in subarachnoid hemorrhage. Ann Intensive Care 1:122011

    • Search Google Scholar
    • Export Citation
  • 8

    Chen GTariq AAi JSabri MJeon HJTang EJ: Different effects of clazosentan on consequences of subarachnoid hemorrhage in rats. Brain Res 1392:1321392011

    • Search Google Scholar
    • Export Citation
  • 9

    Crowley RWMedel RKassell NFDumont AS: New insights into the causes and therapy of cerebral vasospasm following subarachnoid hemorrhage. Drug Discov Today 13:2542602008

    • Search Google Scholar
    • Export Citation
  • 10

    de Oliveira JGBeck JUlrich CRathert JRaabe ASeifert V: Comparison between clipping and coiling on the incidence of cerebral vasospasm after aneurysmal subarachnoid hemorrhage: a systematic review and meta-analysis. Neurosurg Rev 30:22312007

    • Search Google Scholar
    • Export Citation
  • 11

    DerSimonian RLaird N: Meta-analysis in clinical trials. Control Clin Trials 7:1771881986

  • 12

    Dorhout Mees SMRinkel GJFeigin VLAlgra Avan den Bergh WMVermeulen M: Calcium antagonists for aneurysmal subarachnoid haemorrhage. Cochrane Database Syst Rev 3:CD0002772007

    • Search Google Scholar
    • Export Citation
  • 13

    Dreier JPWoitzik JFabricius MBhatia RMajor SDrenckhahn C: Delayed ischaemic neurological deficits after subarachnoid haemorrhage are associated with clusters of spreading depolarizations. Brain 129:322432372006

    • Search Google Scholar
    • Export Citation
  • 14

    Egge AWaterloo KSjøholm HSolberg TIngebrigsten TRomner B: Prophylactic hyperdynamic postoperative fluid therapy after aneurysmal subarachnoid hemorrhage: a clinical, prospective, randomized, controlled study. Neurosurgery 49:5936062001

    • Search Google Scholar
    • Export Citation
  • 15

    Fergusen SMacdonald RL: Predictors of cerebral infarction in patients with aneurysmal subarachnoid hemorrhage. Neurosurgery 60:6586672007

    • Search Google Scholar
    • Export Citation
  • 16

    Furlan ADPennick VBombardier Cvan Tulder M: 2009 updated method guidelines for systematic reviews in the Cochrane Back Review Group. Spine (Phila Pa 1976) 34:192919412009

    • Search Google Scholar
    • Export Citation
  • 17

    Guyatt GOxman ADAkl EAKunz RVist GBrozek J: GRADE guidelines: 1. Introduction-GRADE evidence profiles and summary of findings tables. J Clin Epidemiol 64:3833942011

    • Search Google Scholar
    • Export Citation
  • 18

    Hansen-Schwartz JHoel NLZhou MXu CBSvendgaard NAEdvinsson L: Subarachnoid hemorrhage enhances endothelin receptor expression and function in rat cerebral arteries. Neurosurgery 52:118811952003

    • Search Google Scholar
    • Export Citation
  • 19

    Higgins JPThompson SGDeeks JJAltman DG: Measuring inconsistency in meta-analyses. BMJ 327:5575602003

  • 20

    Ibrahim GMVachhrajani SIlodigwe DKassell NFMayer SARuefenacht D: Method of aneurysm treatment does not affect clot clearance after aneurysmal subarachnoid hemorrhage. Neurosurgery 70:1021092012

    • Search Google Scholar
    • Export Citation
  • 21

    Kassell NFSasaki TColohan ARNazar G: Cerebral vasospasm following aneurysmal subarachnoid hemorrhage. Stroke 16:5625721985

  • 22

    Kassell NFTorner JCHaley EC JrJane JAAdams HPKongable GL: The International Cooperative Study on the Timing of Aneurysm Surgery. Part 1: Overall management results. J Neurosurg 73:18361990

    • Search Google Scholar
    • Export Citation
  • 23

    Kessler IMPacheco YGLozzi SPde Araújo AS JrOnishi FJde Mello PA: Endothelin-1 levels in plasma and cerebrospinal fluid of patients with cerebral vasospasm after aneurysmal subarachnoid hemorrhage. Surg Neurol 64:Suppl 1S1:2S1:52005

    • Search Google Scholar
    • Export Citation
  • 24

    Kramer AFletcher J: Do endothelin-receptor antagonists prevent delayed neurological deficits and poor outcomes after aneurysmal subarachnoid hemorrhage? A meta-analysis. Stroke 40:340334062009

    • Search Google Scholar
    • Export Citation
  • 25

    Lau JIoannidis JPSchmid CH: Quantitative synthesis in systematic reviews. Ann Intern Med 127:8208261997

  • 26

    Lennihan LMayer SAFink MEBeckford APaik MCZhang H: Effect of hypervolemic therapy on cerebral blood flow after subarachnoid hemorrhage: a randomized controlled trial. Stroke 31:3833912000

    • Search Google Scholar
    • Export Citation
  • 27

    Macdonald RLHigashida RTKeller EMayer SAMolyneux ARaabe A: Clazosentan, an endothelin receptor antagonist, in patients with aneurysmal subarachnoid haemorrhage undergoing surgical clipping: a randomised, double-blind, placebo-controlled phase 3 trial (CONSCIOUS-2). Lancet Neurol 10:6186252011

    • Search Google Scholar
    • Export Citation
  • 28

    Macdonald RLHigashida RTKeller EMayer SAMolyneux ARaabe A: Randomized trial of clazosentan in patients with aneurysmal subarachnoid hemorrhage undergoing endovascular coiling. Stroke 43:146314692012

    • Search Google Scholar
    • Export Citation
  • 29

    Macdonald RLHunsche ESchüler RWlodarczyk JMayer SA: Quality of life and healthcare resource use associated with angiographic vasospasm after aneurysmal subarachnoid hemorrhage. Stroke 43:108210882012

    • Search Google Scholar
    • Export Citation
  • 30

    Macdonald RLKassell NFMayer SRuefenacht DSchmiedek PWeidauer S: Clazosentan to overcome neurological ischemia and infarction occurring after subarachnoid hemorrhage (CONSCIOUS-1): randomized, double-blind, placebo-controlled phase 2 dose-finding trial. Stroke 39:301530212008

    • Search Google Scholar
    • Export Citation
  • 31

    Macdonald RLPluta RMZhang JH: Cerebral vasospasm after subarachnoid hemorrhage: the emerging revolution. Nat Clin Pract Neurol 3:2562632007

    • Search Google Scholar
    • Export Citation
  • 32

    Mantel NHaenszel W: Statistical aspects of the analysis of data from retrospective studies of disease. J Natl Cancer Inst 22:7197481959

    • Search Google Scholar
    • Export Citation
  • 33

    Mascia LFedorko LStewart DJMohamed FterBrugge KRanieri VM: Temporal relationship between endothelin-1 concentrations and cerebral vasospasm in patients with aneurysmal subarachnoid hemorrhage. Stroke 32:118511902001

    • Search Google Scholar
    • Export Citation
  • 34

    Moher DLiberati ATetzlaff JAltman DG: Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. J Clin Epidemiol 62:100610122009

    • Search Google Scholar
    • Export Citation
  • 35

    Rabinstein AALanzino GWijdicks EF: Multidisciplinary management and emerging therapeutic strategies in aneurysmal subarachnoid haemorrhage. Lancet Neurol 9:5045192010

    • Search Google Scholar
    • Export Citation
  • 36

    Rosengart AJHuo JDTolentino JNovakovic RLFrank JIGoldenberg FD: Outcome in patients with subarachnoid hemorrhage treated with antiepileptic drugs. J Neurosurg 107:2532602007

    • Search Google Scholar
    • Export Citation
  • 37

    Ruane-O'Hora TRae MGMarkos F: Effect of clazosentan, a selective endothelin A receptor antagonist, and tezosentan, a dual endothelin A/B antagonist, on pulsatile shear stress induced constriction of the iliac in the anaesthetized pig. Clin Exp Pharmacol Physiol 38:5155202011

    • Search Google Scholar
    • Export Citation
  • 38

    Sabri MAi JMacdonald RL: Dissociation of vasospasm and secondary effects of experimental subarachnoid hemorrhage by clazosentan. Stroke 42:145414602011

    • Search Google Scholar
    • Export Citation
  • 39

    Sampson MBarrowman NJMoher DKlassen TPPham BPlatt R: Should meta-analysts search Embase in addition to Medline?. J Clin Epidemiol 56:9439552003

    • Search Google Scholar
    • Export Citation
  • 40

    Schubert GASchilling LThomé C: Clazosentan, an endothelin receptor antagonist, prevents early hypoperfusion during the acute phase of massive experimental subarachnoid hemorrhage: a laser Doppler flowmetry study in rats. Laboratory investigation. J Neurosurg 109:113411402008

    • Search Google Scholar
    • Export Citation
  • 41

    Scott RBEccles FMolyneux AJKerr RSRothwell PMCarpenter K: Improved cognitive outcomes with endovascular coiling of ruptured intracranial aneurysms: neuropsychological outcomes from the International Subarachnoid Aneurysm Trial (ISAT). Stroke 41:174317472010

    • Search Google Scholar
    • Export Citation
  • 42

    Shaw MMVermeulen MMurray GDPickard JDBell BATeasdale GM: Efficacy and safety of the ETA/B receptor antagonist TAK-044 in treating subarachnoid hemorrhage. J Neurosurg 93:9929972000

    • Search Google Scholar
    • Export Citation
  • 43

    Vajkoczy PMeyer BWeidauer SRaabe AThome CRingel F: Clazosentan (AXV-034343), a selective endothelin A receptor antagonist, in the prevention of cerebral vasospasm following severe aneurysmal subarachnoid hemorrhage: results of a randomized, double-blind, placebo-controlled, multicenter phase IIa study. J Neurosurg 103:9172005

    • Search Google Scholar
    • Export Citation
  • 44

    van Tulder MFurlan ABombardier CBouter L: Updated method guidelines for systematic reviews in the Cochrane Collaboration Back Review Group. Spine (Phila Pa 1976) 28:129012992003

    • Search Google Scholar
    • Export Citation
  • 45

    Vatter HZimmermann MTesanovic VRaabe ASchilling LSeifert V: Cerebrovascular characterization of clazosentan, the first nonpeptide endothelin receptor antagonist clinically effective for the treatment of cerebral vasospasm. Part I: inhibitory effect on endothelin(A) receptor-mediated contraction. J Neurosurg 102:110111072005

    • Search Google Scholar
    • Export Citation
  • 46

    Vatter HZimmermann MTesanovic VRaabe ASeifert VSchilling L: Cerebrovascular characterization of clazosentan, the first nonpeptide endothelin receptor antagonist shown to be clinically effective for the treatment of cerebral vasospasm. Part II: effect on endothelin(B) receptor-mediated relaxation. J Neurosurg 102:110811142005

    • Search Google Scholar
    • Export Citation
  • 47

    Vergouwen MDIlodigwe DMacdonald RL: Cerebral infarction after subarachnoid hemorrhage contributes to poor outcome by vasospasm-dependent and -independent effects. Stroke 42:9249292011

    • Search Google Scholar
    • Export Citation
  • 48

    Vergouwen MDVermeulen MCoert BAStroes ESRoos YB: Microthrombosis after aneurysmal subarachnoid hemorrhage: an additional explanation for delayed cerebral ischemia. J Cereb Blood Flow Metab 28:176117702008

    • Search Google Scholar
    • Export Citation
  • 49

    Weyer GWNolan CPMacdonald RL: Evidence-based cerebral vasospasm management. Neurosurg Focus 21:3E82006

  • 50

    Xie AAihara YBouryi VANikitina EJahromi BSZhang ZD: Novel mechanism of endothelin-1-induced vasospasm after subarachnoid hemorrhage. J Cereb Blood Flow Metab 27:169217012007

    • Search Google Scholar
    • Export Citation
  • 51

    Zimmermann MSeifert V: Endothelin receptor antagonists and cerebral vasospasm. Clin Auton Res 14:1431452004

TrendMD
Metrics

Metrics

All Time Past Year Past 30 Days
Abstract Views 375 371 74
Full Text Views 150 95 4
PDF Downloads 115 64 2
EPUB Downloads 0 0 0
PubMed
Google Scholar