Preventing Vasospasm Improves Outcome After Aneurysmal Subarachnoid Hemorrhage: Rationale and Design of CONSCIOUS-2 and CONSCIOUS-3 Trials
Rent the article at a discountRent now
* Final gross prices may vary according to local VAT.Get Access
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.
- Lovelock CE, Rinkel GJ, Rothwell PM. Time trends in outcome of subarachnoid hemorrhage: population-based study and systematic review. Neurology. 2010;74:1494–501. CrossRef
- Hackett ML, Anderson CS. Health outcomes 1 year after subarachnoid hemorrhage. An international population-based study. Neurology. 2000;55:658–62.
- Mayer SA, Kreiter KT, Copeland D, et al. Global and domain-specific cognitive impairment and outcome after subarachnoid hemorrhage. Neurology. 2002;59:1750–8. CrossRef
- Kirkness CJ, Thompson JM, Ricker BA, et al. The impact of aneurysmal subarachnoid hemorrhage on functional outcome. J Neurosci Nurs. 2002;34:134–41. CrossRef
- Macdonald RL, Pluta MR, Zhang JH. Cerebral vasospasm after subarachnoid hemorrhage: the emerging revolution. Nat Clin Pract Neurol. 2007;3:256–63. CrossRef
- 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. CrossRef
- 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.
- 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.
- 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. CrossRef
- 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.
- Rabenstein AA, Lanzino G, Wijdicks EFM. Multidisciplinary management and emerging therapeutic strategies in aneurysmal subarachnoid haemorrhage. Lancet Neurol. 2010;9:504–19. CrossRef
- 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. CrossRef
- 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. CrossRef
- Macdonald RL. Clazosentan: an endothelin receptor antagonist for treatment of vasospasm after subarachnoid hemorrhage. Expert Opin Investig Drugs. 2008;17:1761–7. CrossRef
- 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.
- Vergouwen MD. Effect of endothelin-receptor antagonists on delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage remains unclear. Stroke. 2009;40:e714. CrossRef
- Millikan CH. Cerebral vasospasm and ruptured intracranial aneurysm. Arch Neurol. 1975;32:433–49.
- 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.
- 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. CrossRef
- 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. CrossRef
- 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.
- 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. CrossRef
- Brandt JSM, Folstein M. The telephone interview for cognitive status. Neuropsychiatry Neuropsychol Behav Neurol. 1988;1:111–7.
- Food and Drug Administration clinical/medical guidelines. 2010. http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm064981.htm. Accessed 5 August 2010.
- 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. CrossRef
- Rosengart AJ, Schultheiss KE, Tolentino J, Macdonald RL. Prognostic factors for outcome in patients with aneurysmal subarachnoid hemorrhage. Stroke. 2007;38:2315–21. CrossRef
- Fergusen S, Macdonald RL. Predictors of cerebral infarction in patients with aneurysmal subarachnoid hemorrhage. Neurosurgery. 2007;60:658–67, discussion 667.
- 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. CrossRef
- 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. CrossRef
- Kreiter KT, Mayer SA, Howard G, et al. Sample size estimates for clinical trials of vasospasm in subarachnoid hemorrhage. Stroke. 2009;40:2362–7. CrossRef
- 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. CrossRef
- Jongbloed L. Prediction of function after stroke: a critical review. Stroke. 1986;17:765–76.
- 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. CrossRef
- Preventing Vasospasm Improves Outcome After Aneurysmal Subarachnoid Hemorrhage: Rationale and Design of CONSCIOUS-2 and CONSCIOUS-3 Trials
Volume 13, Issue 3 , pp 416-424
- Cover Date
- Print ISSN
- Online ISSN
- Humana Press Inc
- Additional Links
- Aneurysmal subarachnoid hemorrhage
- Cerebral vasospasm
- CONSCIOUS studies
- Clinical outcome
- Industry Sectors
- Author Affiliations
- 1. Division of Neurosurgery, St. Michael’s Hospital, University of Toronto, 30 Bond Street, Toronto, Ontario, M5B 1W8, Canada
- 2. Division of Neurointerventional Radiology, University of California, San Francisco Medical Center, San Francisco, CA, USA
- 3. Universitätsspital Zürich, Neurochirurgische Klinik, Zürich, Switzerland
- 4. Department of Neurology, Columbia University, New York, NY, USA
- 5. Nuffield Department of Surgery, John Radcliffe Hospital, University of Oxford, Oxford, UK
- 6. Inselspital Bern, Universitätsklinik für Neurochirurgie, Bern, Switzerland
- 7. Department of Neurosurgery, Charite Universitätsmedizin Berlin, Berlin, Germany
- 8. Clinic Hirslanden, Zürich, Switzerland
- 9. Actelion Pharmaceuticals Ltd, Allschwil, Switzerland
- 10. Department of Neurosurgery, University of Virginia, Charlottesville, VA, USA