Neurocritical Care

, Volume 13, Issue 3, pp 416–424

Preventing Vasospasm Improves Outcome After Aneurysmal Subarachnoid Hemorrhage: Rationale and Design of CONSCIOUS-2 and CONSCIOUS-3 Trials

  • R. Loch Macdonald
  • Randall T. Higashida
  • Emanuela Keller
  • Stephan A. Mayer
  • Andy Molyneux
  • Andreas Raabe
  • Peter Vajkoczy
  • Isabel Wanke
  • Aline Frey
  • Angelina Marr
  • Sébastien Roux
  • Neal F. Kassell
Taking a Closer Look at Trials


Cerebral vasospasm after aneurysmal subarachnoid hemorrhage (aSAH) is a frequent but unpredictable complication associated with poor outcome. Current vasospasm therapies are suboptimal; new therapies are needed. Clazosentan, an endothelin receptor antagonist, has shown promise in phase 2 studies, and two randomized, double-blind, placebo-controlled phase 3 trials (CONSCIOUS-2 and CONSCIOUS-3) are underway to further investigate its impact on vasospasm-related outcome after aSAH. Here, we describe the design of these studies, which was challenging with respect to defining endpoints and standardizing endpoint interpretation and patient care. Main inclusion criteria are: age 18–75 years; SAH due to ruptured saccular aneurysm secured by surgical clipping (CONSCIOUS-2) or endovascular coiling (CONSCIOUS-3); substantial subarachnoid clot; and World Federation of Neurosurgical Societies grades I–IV prior to aneurysm-securing procedure. In CONSCIOUS-2, patients are randomized 2:1 to clazosentan (5 mg/h) or placebo. In CONSCIOUS-3, patients are randomized 1:1:1 to clazosentan 5, 15 mg/h, or placebo. Treatment is initiated within 56 h of aSAH and continued until 14 days after aSAH. Primary endpoint is a composite of mortality and vasospasm-related morbidity within 6 weeks of aSAH (all-cause mortality, vasospasm-related new cerebral infarction, vasospasm-related delayed ischemic neurological deficit, neurological signs or symptoms in the presence of angiographic vasospasm leading to rescue therapy initiation). Main secondary endpoint is extended Glasgow Outcome Scale at week 12. A critical events committee assesses all data centrally to ensure consistency in interpretation, and patient management guidelines are used to standardize care. Results are expected at the end of 2010 and 2011 for CONSCIOUS-2 and CONSCIOUS-3, respectively.


Aneurysmal subarachnoid hemorrhage Cerebral vasospasm Clazosentan CONSCIOUS studies Clinical outcome 


  1. 1.
    Lovelock CE, Rinkel GJ, Rothwell PM. Time trends in outcome of subarachnoid hemorrhage: population-based study and systematic review. Neurology. 2010;74:1494–501.CrossRefPubMedGoogle Scholar
  2. 2.
    Hackett ML, Anderson CS. Health outcomes 1 year after subarachnoid hemorrhage. An international population-based study. Neurology. 2000;55:658–62.PubMedGoogle Scholar
  3. 3.
    Mayer SA, Kreiter KT, Copeland D, et al. Global and domain-specific cognitive impairment and outcome after subarachnoid hemorrhage. Neurology. 2002;59:1750–8.CrossRefPubMedGoogle Scholar
  4. 4.
    Kirkness CJ, Thompson JM, Ricker BA, et al. The impact of aneurysmal subarachnoid hemorrhage on functional outcome. J Neurosci Nurs. 2002;34:134–41.CrossRefPubMedGoogle Scholar
  5. 5.
    Macdonald RL, Pluta MR, Zhang JH. Cerebral vasospasm after subarachnoid hemorrhage: the emerging revolution. Nat Clin Pract Neurol. 2007;3:256–63.CrossRefPubMedGoogle Scholar
  6. 6.
    Crowley RW, Medel R, Kassell NF, Dumont AS. New insights into the causes and therapy of cerebral vasospasm following subarachnoid hemorrhage. Drug Discov Today. 2008;13:254–60.CrossRefPubMedGoogle Scholar
  7. 7.
    Bederson JB, Connolly ES Jr, Batjer HH, et al. 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. 2009;40:994–1025. Erratum in Stroke 2009;4(7):e518.Google Scholar
  8. 8.
    Dorhout Mees S, Rinkel GJE, Feigin VL, et al.; on behalf of the Cochrane Collaboration. Calcium antagonists for aneurysmal subarachnoid haemorrhage (review). Cochrane Database Syst Rev. 2007;3:CD000277.Google Scholar
  9. 9.
    Egge A, Waterloo K, Sjøholm H, Solberg T, Ingebrigsten T, Romner B. Prophylactic hyperdynamic postoperative fluid therapy after aneurysmal subarachnoid hemorrhage: a clinical, prospective, randomized, controlled study. Neurosurgery. 2001;49:593–606.CrossRefPubMedGoogle Scholar
  10. 10.
    Lennihan L, Mayer SA, Fink ME, et al. Effect of hypervolemic therapy on cerebral blood flow after subarachnoid hemorrhage: a randomized controlled trial. Stroke. 2000;31:383–91.PubMedGoogle Scholar
  11. 11.
    Rabenstein AA, Lanzino G, Wijdicks EFM. Multidisciplinary management and emerging therapeutic strategies in aneurysmal subarachnoid haemorrhage. Lancet Neurol. 2010;9:504–19.CrossRefGoogle Scholar
  12. 12.
    Zhao J, Zhou D, Guo J, et al. Effect of fasudil hydrochloride, a protein kinase inhibitor on cerebral vasospasm and delayed cerebral ischemic symptoms after aneurysmal subarachnoid hemorrhage. Neurol Med Chir (Tokyo). 2006;46:421–8.CrossRefGoogle Scholar
  13. 13.
    Vajkoczy P, Meyer B, Weidauer S, et al. 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 2a study. J Neurosurg. 2005;103:9–17.CrossRefPubMedGoogle Scholar
  14. 14.
    Macdonald RL. Clazosentan: an endothelin receptor antagonist for treatment of vasospasm after subarachnoid hemorrhage. Expert Opin Investig Drugs. 2008;17:1761–7.CrossRefPubMedGoogle Scholar
  15. 15.
    Macdonald RL, Kassell NF, Mayer S, et al.; on behalf of the CONSCIOUS-1 Investigators. Clazosentan to overcome neurological ischemia and infarction occurring after subarachnoid hemorrhage (CONSCIOUS-1): randomized, double-blind, placebo-controlled phase 2 dose-finding trial. Stroke. 2008;39:3015–21.Google Scholar
  16. 16.
    Vergouwen MD. Effect of endothelin-receptor antagonists on delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage remains unclear. Stroke. 2009;40:e714.CrossRefPubMedGoogle Scholar
  17. 17.
    Millikan CH. Cerebral vasospasm and ruptured intracranial aneurysm. Arch Neurol. 1975;32:433–49.PubMedGoogle Scholar
  18. 18.
    Dumont AS, Crowley W, Monteith SJ, Ilodigwe D, Kassell NF, Macdonald RL. Endovascular treatment or neurosurgical clipping of ruptured intracranial aneurysms: effect on angiographic vasospasm, delayed ischemic neurological deficit, cerebral infarction and clinical outcome. Stroke. 2010; in press.Google Scholar
  19. 19.
    Wilson JT, Pettigrew LE, Teasdale GM. Structured interviews for the Glasgow Outcome Scale and the extended Glasgow Outcome Scale: guidelines for their use. J Neurotrauma. 1998;15:573–85.CrossRefPubMedGoogle Scholar
  20. 20.
    Wilson JT, Pettigrew LE, Teasdale GM. Emotional and cognitive consequences of head injury in relation to the Glasgow Outcome Scale. J Neurol Neurosurg Psychiatry. 2000;69:204–9.CrossRefPubMedGoogle Scholar
  21. 21.
    van Swieten JC, Koudstaal PJ, Visser MC, Schouten HJ, van Gijn J. Interobserver agreement for the assessment of handicap in stroke patients. Stroke. 1988;19:604–7.PubMedGoogle Scholar
  22. 22.
    Farrell B, Godwin J, Richards S, Warlow C. The United Kingdom transient ischaemic attack (UK-TIA) aspirin trial: final results. J Neurol Neurosurg Psychiatry. 1991;54:1044–54.CrossRefPubMedGoogle Scholar
  23. 23.
    Brandt JSM, Folstein M. The telephone interview for cognitive status. Neuropsychiatry Neuropsychol Behav Neurol. 1988;1:111–7.Google Scholar
  24. 24.
    Food and Drug Administration clinical/medical guidelines. 2010. Accessed 5 August 2010.
  25. 25.
    Pickard JD, Murray GD, Illingworth R, et al. Effect of oral nimodipine on cerebral infarction and outcome after subarachnoid haemorrhage: British aneurysm nimodipine trial. BMJ. 1989;298:636–42.CrossRefPubMedGoogle Scholar
  26. 26.
    Rosengart AJ, Schultheiss KE, Tolentino J, Macdonald RL. Prognostic factors for outcome in patients with aneurysmal subarachnoid hemorrhage. Stroke. 2007;38:2315–21.CrossRefPubMedGoogle Scholar
  27. 27.
    Fergusen S, Macdonald RL. Predictors of cerebral infarction in patients with aneurysmal subarachnoid hemorrhage. Neurosurgery. 2007;60:658–67, discussion 667.Google Scholar
  28. 28.
    Weidauer S, Lanfermann H, Raabe A, Zanella F, Seifert V, Beck J. Impairment of cerebral perfusion and infarct patterns attributable to vasospasm after aneurysmal subarachnoid hemorrhage. Stroke. 2007;38:1831–6.CrossRefPubMedGoogle Scholar
  29. 29.
    Dankbaar JW, Rijsdijk M, van der Schaaf IC, Velthuis BK, Wermer MJ, Rinkel GJ. Relationship between vasospasm, cerebral perfusion, and delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage. Neuroradiology. 2009;51:813–9.CrossRefPubMedGoogle Scholar
  30. 30.
    Kreiter KT, Mayer SA, Howard G, et al. Sample size estimates for clinical trials of vasospasm in subarachnoid hemorrhage. Stroke. 2009;40:2362–7.CrossRefPubMedGoogle Scholar
  31. 31.
    Quinn TJ, Dawson J, Walters MR, Lees KR. Variability in modified Rankin scoring across a large cohort of international observers. Stroke. 2008;39:2975–9.CrossRefPubMedGoogle Scholar
  32. 32.
    Jongbloed L. Prediction of function after stroke: a critical review. Stroke. 1986;17:765–76.PubMedGoogle Scholar
  33. 33.
    Kramer A, Fletcher J. Do endothelin-receptor antagonists prevent delayed neurological deficits and poor outcomes after aneurysmal subarachnoid hemorrhage?: a meta-analysis. Stroke. 2009;40:3403–6.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  • R. Loch Macdonald
    • 1
  • Randall T. Higashida
    • 2
  • Emanuela Keller
    • 3
  • Stephan A. Mayer
    • 4
  • Andy Molyneux
    • 5
  • Andreas Raabe
    • 6
  • Peter Vajkoczy
    • 7
  • Isabel Wanke
    • 8
  • Aline Frey
    • 9
  • Angelina Marr
    • 9
  • Sébastien Roux
    • 9
  • Neal F. Kassell
    • 10
  1. 1.Division of NeurosurgerySt. Michael’s Hospital, University of TorontoTorontoCanada
  2. 2.Division of Neurointerventional RadiologyUniversity of California, San Francisco Medical CenterSan FranciscoUSA
  3. 3.Universitätsspital Zürich, Neurochirurgische KlinikZürichSwitzerland
  4. 4.Department of NeurologyColumbia UniversityNew YorkUSA
  5. 5.Nuffield Department of SurgeryJohn Radcliffe Hospital, University of OxfordOxfordUK
  6. 6.Inselspital Bern, Universitätsklinik für NeurochirurgieBernSwitzerland
  7. 7.Department of NeurosurgeryCharite Universitätsmedizin BerlinBerlinGermany
  8. 8.Clinic HirslandenZürichSwitzerland
  9. 9.Actelion Pharmaceuticals LtdAllschwilSwitzerland
  10. 10.Department of NeurosurgeryUniversity of VirginiaCharlottesvilleUSA

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