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Neurosurgical Review

, Volume 36, Issue 2, pp 279–287 | Cite as

Continued statin therapy could improve the outcome after spontaneous intracerebral hemorrhage

  • J. H. Tapia-PérezEmail author
  • R. Rupa
  • R. Zilke
  • S. Gehring
  • B. Voellger
  • T. Schneider
Original Article
First Online:

Abstract

Spontaneous intracerebral hemorrhage (ICH) often represents a devastating event despite maximal therapeutic efforts. Statins are drugs primarily used as cholesterol reducers with several pleiotropic effects that may result in neuroprotection. In this study, we assessed the continued use of statins after acute ICH. From January 2008 to October 2010, we analyzed a retrospective cohort of 178 patients with acute ICH. Patients with head injury, cerebral tumors, hemorrhage after ischemic stroke, and having a National Institute Health Stroke Scale (NIHSS) score of greater than 30 points on admission were excluded. In 29 patients, statins were continued within the first 24 h after onset of ICH and, subsequently, given daily until discharge, whereas 149 nonusers were used as controls. Inpatient mortality, NIHSS, and Glasgow Outcome Score (GOS) at discharge as well as mortality after 10 days, 3 months, and 6 months were recorded as outcomes. Additionally, changes of C-reactive protein (CRP) and white blood cell (WBC) counts, as well as aspartate transaminase and alanine transaminase levels were assessed. Except for the number of hypertensive and diabetic patients, characteristics on admission were similar between both groups. No mortality was observed in statin users, whereas 19 controls (12.7 %) died (p = 0.04) until discharge; after 10 days, 3 months, and 6 months, a similar trend was found. After 6 months, statin use was associated to lower mortality in regression models (OR = 0.32, 95 % CI = 0.11–0.95, p = 0.04). In the same way, statin use was related to NIHSS reduction (−3.53, 95 % CI = −7.59 to 0.42, p = 0.07). In mixed models, changes of WBC counts and CRP levels were associated with statin use. The hepatic enzymes were similar between groups. The continued use of statins after ICH could be associated to early neurological improvement and may reduce mortality within 6 months. Immunomodulation as a pleiotropic effect of statins may represent one of the underlying mechanisms.

Keywords

Intracerebral hemorrhage Immunomodulation Pleiotropic effect Statins 
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Notes

Acknowledgments

We thank Prof. Kropf, Institut für Biometrie und Medizinische Informatik, Otto-von-Guericke-Universität, Magdeburg, Germany for his suggestions regarding the statistical analysis.

References

  1. 1.
    Amarenco P, Bogousslavsky J, Callahan A 3rd, Goldstein LB, Hennerici M, Rudolph AE, Sillesen H, Simunovic L, Szarek M, Welch KM, Zivin JA, The Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) investigators (2006) High-dose atorvastatin after stroke or transient ischemic attack. N Engl J Med 355:549–559PubMedCrossRefGoogle Scholar
  2. 2.
    Baigent C, Keech A, Kearney PM, Blackwell L, Buck G, Pollicino C, Kirby A, Sourjina T, Peto R, Collins R, Simes R, Cholesterol Treatment Trialists’ (CTT) Collaborators (2005) Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins. Lancet 366:1267–1278PubMedCrossRefGoogle Scholar
  3. 3.
    Biffi A, Devan WJ, Anderson CD, Ayres AM, Schwab K, Cortellini L, Viswanathan A, Rost NS, Smith EE, Goldstein JN, Greenberg SM, Rosand J (2011) Statin use and outcome after intracerebral hemorrhage: case–control study and meta-analysis. Neurology 76:1581–1588PubMedCrossRefGoogle Scholar
  4. 4.
    Blanco M, Nombela F, Castellanos M, Rodriguez-Yáñez M, García-Gil M, Leira R, Lizasoain I, Serena J, Vivancos J, Moro MA, Dávalos A, Castillo J (2007) Statin treatment withdrawal in ischemic stroke: a controlled randomized study. Neurology 69:904–910PubMedCrossRefGoogle Scholar
  5. 5.
    Broderick J, Connolly S, Feldmann E, Hanley D, Kase C, Krieger D, Mayberg M, Morgenstern L, Ogilvy CS, Vespa P, Zuccarello M, American Heart Association; American Stroke Association Stroke Council; High Blood Pressure Research Council; Quality of Care and Outcomes in Research Interdisciplinary Working Group 2007 (2007) Guidelines for the management of spontaneous intracerebral hemorrhage in adults. Stroke 38(6):2001–2023PubMedCrossRefGoogle Scholar
  6. 6.
    Bruno A, Saha C, Williams LS (2006) Using change in the National Institutes of Health Stroke Scale to measure treatment effect in acute stroke trials. Stroke 37:920–921PubMedCrossRefGoogle Scholar
  7. 7.
    Cleophas TJ, Zwinderman AH, van Ouwerkerk B (2012) Clinical research: a novel approach to the analysis of repeated measures. Am J Ther 19:e1–e7PubMedCrossRefGoogle Scholar
  8. 8.
    Eichel R, Khoury ST, Ben-Hur T, Keidar M, Paniri R, Leker RR (2010) Prior use of statins and outcome in patients with intracerebral haemorrhage. Eur J Neurol 17:78–83PubMedCrossRefGoogle Scholar
  9. 9.
    Fletcher B, Berra K, Ades P, Braun LT, Burke LE, Durstine JL, Fair JM, Fletcher GF, Goff D, Hayman LL, Hiatt WR, Miller NH, Krauss R, Kris-Etherton P, Stone N, Wilterdink J, Winston M, Council on Cardiovascular Nursing, Council on Arteriosclerosis, Thrombosis, and Vascular Biology, Council on Basic Cardiovascular Sciences, Council on Cardiovascular Disease in the Young, Council on Clinical Cardiology, Council on Epidemiology and Prevention, Council on Nutrition, Physical Activity, and Metabolism, Council on Stroke, Preventive Cardiovascular Nurses Association (2005) Managing abnormal blood lipids: a collaborative approach. Circulation 112:3184–3209PubMedCrossRefGoogle Scholar
  10. 10.
    Fildes JE, Shaw SM, Williams SG, Yonan N (2009) Potential immunologic effects of statins in cancer following transplantation. Cancer Immunol Immunother 58:461–467PubMedCrossRefGoogle Scholar
  11. 11.
    Goldstein LB, Amarenco P, Szarek M, Callahan A 3rd, Hennerici M, Sillesen H, Zivin JA, Welch KM, Investigators SPARCL (2008) Hemorrhagic stroke in the stroke prevention by aggressive reduction in cholesterol levels study. Neurology 70:2364–2370PubMedCrossRefGoogle Scholar
  12. 12.
    Gomis M, Ois A, Rodríguez-Campello A, Cuadrado-Godia E, Jiménez-Conde J, Subirana I, Dávalos A, Roquer J (2009) Outcome of intracerebral haemorrhage patients pre-treated with statins. Eur J Neurol 17:443–448PubMedCrossRefGoogle Scholar
  13. 13.
    Gonçalves I, Cherfan P, Söderberg I, Nordin Fredrikson G, Jonasson L (2009) Effects of simvastatin on circulating autoantibodies to oxidized LDL antigens: relation with immune stimulation markers. Autoimmunity 42:203–208PubMedCrossRefGoogle Scholar
  14. 14.
    Greenwood J, Steinman L, Zamvil SS (2006) Statin therapy and autoimmune disease: from protein prenylation to immunomodulation. Nature Rev Immunol 6:358–370CrossRefGoogle Scholar
  15. 15.
    Gruenbacher G, Gander H, Nussbaumer O, Nussbaumer W, Rahm A, Thurnher M (2010) IL-2 costimulation enables statin-mediated activation of human NK cells, preferentially through a mechanism involving CD56+ dendritic cells. Cancer Res 70:9611–9620PubMedCrossRefGoogle Scholar
  16. 16.
    Heart Protection Study Collaborative Group (2002) MRC/BHF heart protection study of cholesterol lowering with simvastatin in 20, 536 high-risk individuals: a randomised placebo-controlled trial. Lancet 360:7–22CrossRefGoogle Scholar
  17. 17.
    Italian Acute Stroke Study Group (1988) Haemodilution in acute stroke: results of the Italian haemodilution trial. Lancet 1:318–321Google Scholar
  18. 18.
    Jacobson TA (2006) Statin safety: lessons from new drug applications for marketed statins. Am J Cardiol 97:44C–51CPubMedCrossRefGoogle Scholar
  19. 19.
    Jung KH, Chu K, Jeong SW, Han SY, Lee ST, Kim JY, Kim M, Roh JK (2004) HMG-CoA reductase inhibitor, atorvastatin, promotes sensorimotor recovery, suppressing acute inflammatory reaction after experimental intracerebral hemorrhage. Stroke 35:1744–1749PubMedCrossRefGoogle Scholar
  20. 20.
    Karki K, Knight RA, Han Y, Yang D, Zhang J, Ledbetter KA, Chopp M, Seyfried DM (2009) Simvastatin and atorvastatin improve neurological outcome after experimental intracerebral hemorrhage. Stroke 40:3384–3389PubMedCrossRefGoogle Scholar
  21. 21.
    Kasner SE (2006) Clinical interpretation and use of stroke scales. Lancet Neurol 5:603–612PubMedCrossRefGoogle Scholar
  22. 22.
    Kilic U, Bassetti CL, Kilic E, Xing H, Wang Z, Hermann DM (2005) Post-ischemic delivery of the 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor rosuvastatin protects against focal cerebral ischemia in mice via inhibition of extracellular-regulated kinase-1/-2. Neuroscience 134(3):901–906PubMedCrossRefGoogle Scholar
  23. 23.
    Kothari RU, Brott TG, Broderick JP, Barsan WG, Sauerbeck LR, Zuccarello M, Khoury J (1996) The ABCs measuring intracranial hemorrhage volumes. Stroke 27:1304–1305PubMedCrossRefGoogle Scholar
  24. 24.
    Lakhan SE, Bagchi S, Hofer M (2010) Statins and clinical outcome of acute ischemic stroke: a systematic review. Int Arch Med 3:22PubMedCrossRefGoogle Scholar
  25. 25.
    Leker RR, Khoury ST, Rafaeli G, Shwartz R, Eichel R, Tanne D, Investigators NASIS (2009) Prior use of statins improves outcome in patients with intracerebral hemorrhage. Prospective data from the National Acute Stroke Israeli Surveys (NASIS). Stroke 40:2581–2584PubMedCrossRefGoogle Scholar
  26. 26.
    Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group (1998) Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. N Engl J Med 339:1349–1357CrossRefGoogle Scholar
  27. 27.
    Lynch JR, Wang H, McGirt MJ, Floyd J, Friedman AH, Coon AL (2005) Simvastatin reduces vasospasm after aneurysmal subarachnoid hemorrhage results of a pilot randomized clinical trial. Stroke 36:2024–2026PubMedCrossRefGoogle Scholar
  28. 28.
    Mayer SA, Brun NC, Broderick J, Davis SM, Diringer MN, Skolnick BE, Steiner T, United States NovoSeven ICH Trial Investigators (2006) Recombinant activated factor VII for acute intracerebral hemorrhage: US phase IIA trial. Neurocrit Care 4:206–214PubMedCrossRefGoogle Scholar
  29. 29.
    Mendelow AD, Gregson BA, Fernandes HM, Murray GD, Teasdale GM, Hope DT, Karimi A, Shaw MD, Barer DH, STICH investigators (2005) Early surgery versus initial conservative treatment in patients with spontaneous supratentorial intracerebral haematomas in the International Surgical Trial in Intracerebral Haemorrhage (STICH): a randomised trial. Lancet 365:387–397PubMedGoogle Scholar
  30. 30.
    Naval NS, Abdelhak TA, Zeballos P, Urrunaga N, Mirski MA, Carhuapoma JR (2008) Prior statin use reduces mortality in intracerebral hemorrhage. Neurocrit Care 8:6–12PubMedCrossRefGoogle Scholar
  31. 31.
    Poungvarin N, Bhoopat W, Viriyavejakul A, Rodprasert P, Buranasiri P, Sukondhabhant S, Hensley MJ, Strom BL (1987) Effects of dexamethasone in primary supratentorial intracerebral hemorrhage. N Engl J Med 316:1229–1233PubMedCrossRefGoogle Scholar
  32. 32.
    Sacks FM, Pfeffer MA, Moye LA, Rouleau JL, Rutherford JD, Cole TG, Brown L, Warnica JW, Arnold JM, Wun CC, Davis BR, Braunwald E (1996) Cholesterol and recurrent events trial investigators. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. N Engl J Med 335:1001–1009PubMedCrossRefGoogle Scholar
  33. 33.
    Schwartz GG, Olsson AG, Ezekowitz MD, Ganz P, Oliver MF, Waters D, Zeiher A, Chaitman BR, Leslie S, Stern T, Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) Study Investigators (2001) Effects of atorvastatin on early recurrent ischemic events in acute coronary syndromes: the MIRACL study: a randomized controlled trial. JAMA 285:1711–1718PubMedCrossRefGoogle Scholar
  34. 34.
    Sever PS, Dahlof B, Poulter NR, Wedel H, Beevers G, Caulfield M, Collins R, Kjeldsen SE, Kristinsson A, McInnes GT, Mehlsen J, Nieminen M, O’Brien E, Ostergren J, ASCOT investigators (2003) Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than average cholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial–Lipid Lowering Arm (ASCOT-LLA): a multicentre randomised controlled trial. Lancet 361:1149–1158PubMedCrossRefGoogle Scholar
  35. 35.
    Seyfried D, Han Y, Lu D, Chen J, Bydon A, Chopp M (2004) Improvement in neurological outcome after administration of atorvastatin following experimental intracerebral hemorrhage in rats. J Neurosurg 101:104–107PubMedCrossRefGoogle Scholar
  36. 36.
    Sillberg VA, Wells GA, Perry JJ (2008) Do statins improve outcomes and reduce the incidence of vasospasm after aneurysmal subarachnoid hemorrhage: a meta-analysis. Stroke 39:2622–2626PubMedCrossRefGoogle Scholar
  37. 37.
    Sironi L, Gianazza E, Gelosa P, Guerrini U, Nobili E, Gianella A, Cremonesi B, Paoletti R, Tremoli E (2005) Rosuvastatin, but not simvastatin, provides end-organ protection in stroke-prone rats by antiinflammatory effects. Arterioscler Thromb Vasc Biol 25:598–603PubMedCrossRefGoogle Scholar
  38. 38.
    Staffa JA, Chang J, Green L (2002) Cerivastatin and reports of fatal rhabdomyolysis [letter]. N Engl J Med 346:539–540PubMedCrossRefGoogle Scholar
  39. 39.
    Tapia-Pérez JH, Sanchez-Aguilar M, Schneider T (2010) The role of statins in neurosurgery. Neurosurg Rev 33:259–270PubMedCrossRefGoogle Scholar
  40. 40.
    Tapia-Pérez JH, Sánchez-Aguilar M, Torres-Corzo JG, González-Aguirre D, Gordillo-Moscoso A, Rodríguez-Leyva I, Chalita-Williams JC (2009) Use of statins for the treatment of spontaneous intracerebral hemorrhage: results of a pilot study. Cen Eur Neurosurg 70:15–20CrossRefGoogle Scholar
  41. 41.
    Tseng MY, Hutchinson PJ, Czosnyka M, Richards H, Pickard JD, Kirkpatrick PJ (2007) Effects of acute pravastatin treatment on intensity of rescue therapy, length of inpatient stay, and 6- month outcome in patients after aneurysmal subarachnoid hemorrhage. Stroke 38:1545–1550PubMedCrossRefGoogle Scholar
  42. 42.
    Wang J (2010) Preclinical and clinical research on inflammation after intracerebral hemorrhage. Prog Neurobiol 92:463–477PubMedCrossRefGoogle Scholar
  43. 43.
    Waters DD (2005) Safety of high-dose atorvastatin therapy. Am J Cardiol 96(suppl):69F–75FPubMedCrossRefGoogle Scholar
  44. 44.
    Westover MB, Bianchi MT, Eckman MH, Greenberg SM (2011) Statin use following intracerebral hemorrhage: a decision analysis. Arch Neurol 68:573–579PubMedCrossRefGoogle Scholar
  45. 45.
    Woo D, Broderick JP (2002) Spontaneous intracerebral hemorrhage: epidemiology and clinical presentation. Neurosurg Clin N Am 13:265–279PubMedCrossRefGoogle Scholar
  46. 46.
    Wood WG, Eckert GP, Igbavboa U, Müller WE (2010) Statins and neuroprotection: a prescription to move the field forward. Ann N Y Acad Sci 1199:69–76PubMedCrossRefGoogle Scholar
  47. 47.
    Yu YL, Kumana CR, Lauder IJ, Cheung YK, Chan FL, Kou M, Chang CM, Cheung RT, Fong KY (1992) Treatment of acute cerebral hemorrhage with intravenous glycerol: a double-blind, placebo-controlled, randomized trial. Stroke 23:967–971PubMedCrossRefGoogle Scholar
  48. 48.
    Zacco A, Togo J, Spence K, Ellis A, Lloyd D, Furlong S, Piser T (2003) 3-Hydroxy-3-Methyilglutaryl coenzyme A reductase inhibitors protect cortical Neurons from excitotoxicity. J Neurosci 23:1104–1111Google Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2012

Authors and Affiliations

  • J. H. Tapia-Pérez
    • 1
    Email author
  • R. Rupa
    • 1
  • R. Zilke
    • 1
  • S. Gehring
    • 1
  • B. Voellger
    • 1
  • T. Schneider
    • 1
  1. 1.Klinik für NeurochirurgieOtto-von-Guericke UniversitätMagdeburgGermany

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