Neurocritical Care

, Volume 12, Issue 2, pp 285–296 | Cite as

Statins in the Management of Patients with Aneurysmal Subarachnoid Hemorrhage: A Systematic Review and Meta-analysis

  • Andreas H. KramerEmail author
  • Jeffrey J. Fletcher
Review Article


Background: Delayed ischemic neurological deficits (DINDs) contribute to morbidity and mortality following aneurysmal subarachnoid hemorrhage (SAH). Based on promising preliminary reports, some clinicians routinely administer statins to prevent DINDs. Methods: Without language restriction, we searched MEDLINE, EMBASE, the Cochrane Central Register, references of review articles, proceedings of the International Stroke Conference, and gray literature sources. Studies were selected if they compared outcomes between statin-treated and untreated patients during the 2 weeks following SAH. Data were extracted and appraised independently and in duplicate, using standardized forms. Fixed or random effects models, as appropriate based on the degree of study heterogeneity, were applied to calculate summary measures. Results: Four RCTs, two “pseudo” RCTs, five cohort studies, and one case–control study met eligibility criteria. In the RCTs, which enrolled a total of 309 patients, statins were found to significantly reduce the occurrence of DINDs [OR 0.38 (0.23–0.65); P < 0.001], but not mortality [OR 0.51 (0.25–1.02); P = 0.06] or poor neurological recovery [OR 0.81 (0.49–1.32); P = 0.39]. Observational studies assessed 1,542 patients, of whom 385 received statins. Statin-use was not associated with any reduction in DINDs [OR 0.96 (0.71–1.31); P = 0.80], mortality [OR 1.16 (0.78–1.73); P = 0.47] or poor neurological recovery [OR 1.20 (0.84–1.72); P = 0.31]. When the results of all studies were combined, statins had no statistically significant effect. Conclusions: Existing RCTs suggest that statins reduce DINDs, with a possible trend toward lower mortality. These findings are not supported by observational research. Although not assessed in all studies, current data do not indicate that statins improve neurological outcomes.


Subarachnoid hemorrhage Vasospasm Delayed ischemic neurological deficits Statins Meta-analysis 



We thank Drs. Mancedo, Jaschinski and Lynch for providing additional information about their studies.


  1. 1.
    Kassell NF, Torner JC, Haley EC Jr, Jane JA, Adams HP, Kongable GL. The International Cooperative Study on the Timing of Aneurysm Surgery. Part 1: Overall management results. J Neurosurg. 1990;73:18–36.CrossRefPubMedGoogle Scholar
  2. 2.
    Bederson JB, Connolly ES, 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.CrossRefPubMedGoogle Scholar
  3. 3.
    Dorhout Mees SM, Rinkel GJ, Feigin VL, et al. Calcium antagonists for aneurysmal subarachnoid haemorrhage. for aneurysmal subarachnoid hemorrhage. Cochrane Database Syst Rev 2007;3:CD000277.Google Scholar
  4. 4.
    van den Bergh WM, Mees SM, Rinkel GJ. Intravenous magnesium versus nimoidpine in the treatment of patients with aneurysmal subarachnoid hemorrhage: a randomized study. Neurosurgery. 2006;59:1152.CrossRefGoogle Scholar
  5. 5.
    Macdonald RL, Kassell NF, Mayer S, et al. 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.CrossRefPubMedGoogle Scholar
  6. 6.
    Sugawara T, Ayer R, Zhang JH. Role of statins in cerebral vasospasm. Acta Neurochir Suppl. 2008;104:287–90.CrossRefPubMedGoogle Scholar
  7. 7.
    Tseng M, Czosnyka M, Richards H, Pickard JD, Kirkpatrick PJ. Effects of acute treatment with pravastatin on cerebral vasospasm, autoregulation, and delayed ischemic deficits after aneurysmal subarachnoid hemorrhage: a phase II randomized placebo-controlled trial. Stroke. 2005;36:1627–32.CrossRefPubMedGoogle Scholar
  8. 8.
    Lynch JR, Wang H, McGirt MJ, et al. Simvastatin reduces vasospasm after aneurysmal subarachnoid hemorrhage: results of a pilot randomized clinical trial. Stroke. 2005;36:2024–6.CrossRefPubMedGoogle Scholar
  9. 9.
    Sillberg VA, Wells GA, Perry JJ. Do statins improve outcomes and reduce the incidence of vasospasm after aneurysmal subarachnoid hemorrhage: a meta-analysis. Stroke. 2008;39:2622–6.CrossRefPubMedGoogle Scholar
  10. 10.
    Liberati A, Altman DG, Tetzlaff J, et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. Ann Intern Med. 2009;151:W65–94.PubMedGoogle Scholar
  11. 11.
    Stroup DF, Berlin JA, Morton SC, et al. Meta-analysis of observational studies in epidemiology: a proposal for reporting. Meta-analysis of observational studies in epidemiology (MOOSE) group. JAMA. 2000;283:2008–12.CrossRefPubMedGoogle Scholar
  12. 12.
    Jadad AR, Moore RA, Carroll D, Jenkinson C, Reynolds DJ, Gavaghan DJ, et al. Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trial. 1996;17:1–12.CrossRefGoogle Scholar
  13. 13.
    Shulz KF, Chalmers I, Hayes RJ, Altman DG. Empirical evidence of bias dimensions of methodological quality associated with estimates of treatment effects in controlled trials. JAMA. 1995;273:408–12.CrossRefGoogle Scholar
  14. 14.
    Deeks JJ, Dinnes J, D’Amico R, Sowden AJ, Sakarovitch C, Song F, et al. Health Technol Assess. 2003;7:1–173.Google Scholar
  15. 15.
    von Elm E, Altman DG, Egger M, Pocock SJ, Gotzsche PC, Vandenbroucke JP. STROBE Initiative. The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies. Lancet. 2007;370:1453–7.CrossRefGoogle Scholar
  16. 16.
    Hijdra A, van Gijn J, Nagelkerke NJ, Vermeulen M, van Crevel H. Prediction of delayed cerebral ischemia, rebleeding, and outcome after aneurysmal subarachnoid hemorrhage. Stroke. 1988;19:1250–6.PubMedGoogle Scholar
  17. 17.
    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
  18. 18.
    Higgins JP, Thompson SG. Quantifying heterogeneity in a meta-analysis. Stat Med. 2002;21:1539–58.CrossRefPubMedGoogle Scholar
  19. 19.
    Egger M, Smith GD, Phillips AN. Meta-analysis: principles and procedures. BMJ. 1997;315:1533–7.PubMedGoogle Scholar
  20. 20.
    Chou SH, Smith EE, Badjatia N, Nogueira RG, Sims JR, Ogilvy CS, et al. A randomized, double-blind, placebo-controlled pilot study of simvastatin in aneurysmal subarachnoid hemorrhage. Stroke. 2008;39:2891–3.CrossRefPubMedGoogle Scholar
  21. 21.
    Vergouwen MD, Meijers JC, Geskus RB, Coert BA, Horn J, Stroes ES, et al. Biologic effects of simvastatin in patients with aneurysmal subarachnoid hemorrhage: a double-blind placebo-controlled randomized trial. J Cereb Blood Flow Metab. 2009;29:1444–53.CrossRefPubMedGoogle Scholar
  22. 22.
    Jaschinski U, Scherer K, Lichtwarck M, Forst H. Impact of treatment with pravastatin on delayed ischemic disease and mortality after aneurysmal subarachnoid hemorrhage. Crit Care. 2008;12(Suppl 2):P112.CrossRefGoogle Scholar
  23. 23.
    Macedo S, Bello Y, Silva A, Siqueira C, Siqueira S, Brito L. Effects of simvastatin in prevention of vasospasm in nontraumatic subarachnoid hemorrhage: preliminary data. Crit Care. 2009;13(Suppl 1):P103.CrossRefGoogle Scholar
  24. 24.
    Kramer AH, Gurka MJ, Nathan B, Dumont AS, Kassell NF, Bleck TP. Statin use was not associated with less vasospasm or improved outcome after subarachnoid hemorrhage. Neurosurgery. 2008;62:422–7.CrossRefPubMedGoogle Scholar
  25. 25.
    Kerz T, Victor A, Beyer C, Trapp I, Heid F, Reisch R. A case control study of statin and magnesium administration in patients after aneurysmal subarachnoid hemorrhage: incidence of delayed cerebral ischemia and mortality. Neurol Res. 2008;30:893–7.CrossRefPubMedGoogle Scholar
  26. 26.
    Kern M, Lam MM, Knuckey NW, Lind CR. Statins may not protect against vasospasm in subarachnoid hemorrhage. J Clin Neurosci. 2009;16:527–30.CrossRefPubMedGoogle Scholar
  27. 27.
    McGirt MJ, Garces Ambrossi GL, Huang J, Tamargo RJ. Simvastatin for the prevention of symptomatic cerebral vasospasm following aneurysmal subarachnoid hemorrhage; a ginle-institution prospective cohort study. J Neurosurg. 2009;110:968–74.CrossRefPubMedGoogle Scholar
  28. 28.
    Singhal AB, Topcuoglu MA, Dorer DJ, Ogilvy CS, Carter BS, Koroshetz WJ. SSRI and statin use increases the risk for vasospasm after subarachnoid hemorrhage. Neurology. 2005;64:1008–13.PubMedGoogle Scholar
  29. 29.
    Mokowitz SI, Ahrens C, Provencio JJ, Chow M, Rasmussen PA. Prehemorrhage statin use and the risk of vasospasm after aneurysmal subarachnoid hemorrhage. Surg Neurol. 2009;71:311–8.CrossRefGoogle Scholar
  30. 30.
    Nolan CP, Macdonald RL. Can angiographic vasospasm be used as a surrogate marker in evaluating therapeutic interventions for cerebral vasospasm? Neurosurg Focus 2006;15(21):1–8.CrossRefGoogle Scholar
  31. 31.
    Haley EC Jr, Kassell NF, Torner JC. A randomized trial of nicardipine in subarachnoid hemorrhage: angiographic and transcranial Doppler ultrasound results. A report of the Cooperative Aneurysm Study. J Neurosurg. 1993;78:548–53.CrossRefPubMedGoogle Scholar
  32. 32.
    Jang YG, Ilodigwe D, Macdonald RL. Metaanalysis of tirilazad mesylate in patients with aneurysmal subarachnoid hemorrhage. Neurocrit Care. 2009;10:141–7.CrossRefPubMedGoogle Scholar
  33. 33.
  34. 34.
  35. 35.

Copyright information

© Humana Press Inc. 2009

Authors and Affiliations

  1. 1.Departments of Critical Care Medicine and Clinical Neurosciences, Hotchkiss Brain InstituteUniversity of CalgaryCalgaryCanada
  2. 2.Department of NeurosurgeryUniversity of MichiganAnn ArborUSA

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