Atorvastatin reduces cerebral vasospasm and infarction after aneurysmal subarachnoid hemorrhage in elderly Chinese adults

Junhui Chen, Mingchang Li, Xun Zhu, Lei Chen, Shuo Yang, Chunlei Zhang, Ting Wu, Xiaoyan Feng, Yuhai Wang, Qianxue Chen, Junhui Chen, Mingchang Li, Xun Zhu, Lei Chen, Shuo Yang, Chunlei Zhang, Ting Wu, Xiaoyan Feng, Yuhai Wang, Qianxue Chen

Abstract

We explored whether acute atorvastatin treatment would improve clinical outcomes and reduce the incidence of cerebral vasospasm after aneurysmal subarachnoid hemorrhage in elderly Chinese adults. Patients (60 to 90 years old) were admitted to intensive care units after surgery to clip or embolize their aneurysms. We assessed 592 patients and assigned 159 to receive atorvastatin (20 mg/day) and 158 to receive placebo once daily for up to 14 days. The primary outcome was the Glasgow outcome scale at 6 months, and secondary outcomes were cerebral vasospasm, 30-days all-cause mortality, cerebral infarction, and delayed ischemic neurological deficit. The incidence of postoperative cerebral vasospasm (39.3% vs 56%, P =0.004) and cerebral infarction (18.7% vs 27.3%, P=0.027) were significantly lower in the atorvastatin group. The study did not detect benefits in the use of atorvastatin for 6 months clinical outcome or 30-day all-cause mortality, but it suggests that atorvastatin together with nimodipine can reduce cerebral vasospasm and cerebral infarction after subarachnoid hemorrhage.

Keywords: CVS; RCT; atorvastatin; subarachnoid hemorrhage.

Conflict of interest statement

CONFLICTS OF INTEREST: All authors declare that they have no conflicts of interests.

Figures

Figure 1
Figure 1
Trial profile. VS: cerebral vasospasm. DIND: delayed ischemic neurological deficit.
Figure 2
Figure 2
Study design. aSAH=aneurysmal subarachnoid hemorrhage. GOS= Glasgow outcome scale. TCD: Transcranial Doppler
Figure 3
Figure 3
Distributions of GOS score in the atorvastatin and placebo groups. Data are number of patients with each GOS score. Tested with Mann-Whitney U test; P=0.393.
Figure 4
Figure 4
Subgroup analyses for primary outcome Subgroup analyses for good outcome (GOS 5), RR=risk ratio. (A) Subgroup analyses for good outcome (GOS 5) in age, Hunt-Hess, clot size and surgical procedure, gender and aneurysm size showed no difference between groups. (B) Heterogeneity test showed no heterogeneity in age, Hunt-Hess, clot size and surgical procedure subgroups (I2=0); gender (I2=9%) and aneurysm size (I2=28%) subgroups had no significant heterogeneity.
Figure 5
Figure 5
30-day all-cause mortality. Relative risk reduction percentages are rounded. Event rate (%) for 30-day all-cause mortality. RR 0.87, P=0.149, 95% CI 0.33–2.35.
Figure 6
Figure 6
Key secondary primary endpoints Event rate (%) for each of the individual components of the key secondary primary endpoint (all-treated, endpoint substituted; planned analysis). DIND=delayed ischemic neurological deficit.

References

    1. Steiner T, Juvela S, Unterberg A, Jung C, Forsting M, Rinkel G, and European Stroke Organization. European Stroke Organization guidelines for the management of intracranial aneurysms and subarachnoid haemorrhage. Cerebrovasc Dis. 2013; 35:93–112. 10.1159/000346087
    1. Rosengart AJ, Schultheiss KE, Tolentino J, Macdonald RL. Prognostic factors for outcome in patients with aneurysmal subarachnoid hemorrhage. Stroke. 2007; 38:2315–21. 10.1161/STROKEAHA.107.484360
    1. Komotar RJ, Schmidt JM, Starke RM, Claassen J, Wartenberg KE, Lee K, Badjatia N, Connolly ES Jr, Mayer SA. Resuscitation and critical care of poor-grade subarachnoid hemorrhage. Neurosurgery. 2009; 64:397–410; discussion 410-1. 10.1227/01.NEU.0000338946.42939.C7
    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. 10.1212/WNL.0b013e3181dd42b3
    1. Macdonald RL, Higashida RT, Keller E, Mayer SA, Molyneux A, Raabe A, Vajkoczy P, Wanke I, Bach D, Frey A, Marr A, Roux S, Kassell N. 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. 2011; 10:618–25. 10.1016/S1474-4422(11)70108-9
    1. Matsuda N, Naraoka M, Ohkuma H, Shimamura N, Ito K, Asano K, Hasegawa S, Takemura A. Effect of Cilostazol on Cerebral Vasospasm and Outcome in Patients with Aneurysmal Subarachnoid Hemorrhage: A Randomized, Double-Blind, Placebo-Controlled Trial. Cerebrovasc Dis. 2016; 42:97–105. 10.1159/000445509
    1. 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. 10.1016/j.drudis.2007.11.010
    1. Abla AA, Wilson DA, Williamson RW, Nakaji P, McDougall CG, Zabramski JM, Albuquerque FC, Spetzler RF. The relationship between ruptured aneurysm location, subarachnoid hemorrhage clot thickness, and incidence of radiographic or symptomatic vasospasm in patients enrolled in a prospective randomized controlled trial. J Neurosurg. 2014; 120:391–97. 10.3171/2013.10.JNS13419
    1. Connolly ES Jr, Rabinstein AA, Carhuapoma JR, Derdeyn CP, Dion J, Higashida RT, Hoh BL, Kirkness CJ, Naidech AM, Ogilvy CS, Patel AB, Thompson BG, Vespa P, and American Heart Association Stroke Council, and Council on Cardiovascular Radiology and Intervention, and Council on Cardiovascular Nursing, and Council on Cardiovascular Surgery and Anesthesia, and Council on Clinical Cardiology. Guidelines for the management of aneurysmal subarachnoid hemorrhage: a guideline for healthcare professionals from the American Heart Association/american Stroke Association. Stroke. 2012; 43:1711–37. 10.1161/STR.0b013e3182587839
    1. Lee YM, Chen WF, Chou DS, Jayakumar T, Hou SY, Lee JJ, Hsiao G, Sheu JR. Cyclic nucleotides and mitogen-activated protein kinases: regulation of simvastatin in platelet activation. J Biomed Sci. 2010; 17:45. 10.1186/1423-0127-17-45
    1. Chen JH, Yang LK, Chen L, Wang YH, Wu Y, Jiang BJ, Zhu J, Li PP. Atorvastatin ameliorates early brain injury after subarachnoid hemorrhage via inhibition of AQP4 expression in rabbits. Int J Mol Med. 2016; 37:1059–66. 10.3892/ijmm.2016.2506
    1. Chen JH, Wu T, Yang LK, Chen L, Zhu J, Li PP, Hu X, Wang YH. Protective effects of atorvastatin on cerebral vessel autoregulation in an experimental rabbit model of subarachnoid hemorrhage. Mol Med Rep. 2018; 17:1651–59. 10.3892/mmr.2017.8074
    1. Budohoski KP, Czosnyka M, Kirkpatrick PJ, Smielewski P, Steiner LA, Pickard JD. Clinical relevance of cerebral autoregulation following subarachnoid haemorrhage. Nat Rev Neurol. 2013; 9:152–63. 10.1038/nrneurol.2013.11
    1. Kirkpatrick PJ, Turner CL, Smith C, Hutchinson PJ, Murray GD, and STASH Collaborators. Simvastatin in aneurysmal subarachnoid haemorrhage (STASH): a multicentre randomised phase 3 trial. Lancet Neurol. 2014; 13:666–75. 10.1016/S1474-4422(14)70084-5
    1. Macdonald RL, Kassell NF, Mayer S, Ruefenacht D, Schmiedek P, Weidauer S, Frey A, Roux S, Pasqualin A, Investigators C, and 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. 10.1161/STROKEAHA.108.519942
    1. Chou SH, Smith EE, Badjatia N, Nogueira RG, Sims JR 2nd, Ogilvy CS, Rordorf GA, Ayata C. A randomized, double-blind, placebo-controlled pilot study of simvastatin in aneurysmal subarachnoid hemorrhage. Stroke. 2008; 39:2891–93. 10.1161/STROKEAHA.107.505875
    1. Wong GK, Chan DY, Siu DY, Zee BC, Poon WS, Chan MT, Gin T, Leung M, Zhu XL, Liang M, Tan HB, Lee MW, Wong CK, et al., and HDS-SAH Investigators. High-dose simvastatin for aneurysmal subarachnoid hemorrhage: multicenter randomized controlled double-blinded clinical trial. Stroke. 2015; 46:382–88. 10.1161/STROKEAHA.114.007006
    1. Uekawa K, Hasegawa Y, Ma M, Nakagawa T, Katayama T, Sueta D, Toyama K, Kataoka K, Koibuchi N, Kawano T, Kuratsu J, Kim-Mitsuyama S. Rosuvastatin ameliorates early brain injury after subarachnoid hemorrhage via suppression of superoxide formation and nuclear factor-kappa B activation in rats. J Stroke Cerebrovasc Dis. 2014; 23:1429–39. 10.1016/j.jstrokecerebrovasdis.2013.12.004
    1. Cheng G, Wei L, Zhi-Dan S, Shi-Guang Z, Xiang-Zhen L. Atorvastatin ameliorates cerebral vasospasm and early brain injury after subarachnoid hemorrhage and inhibits caspase-dependent apoptosis pathway. BMC Neurosci. 2009; 10:7. 10.1186/1471-2202-10-7
    1. Chen J, Chen G, Li J, Qian C, Mo H, Gu C, Yan F, Yan W, Wang L. Melatonin attenuates inflammatory response-induced brain edema in early brain injury following a subarachnoid hemorrhage: a possible role for the regulation of pro-inflammatory cytokines. J Pineal Res. 2014; 57:340–47. 10.1111/jpi.12173
    1. McGirt MJ, Garces Ambrossi GL, Huang J, Tamargo RJ. Simvastatin for the prevention of symptomatic cerebral vasospasm following aneurysmal subarachnoid hemorrhage: a single-institution prospective cohort study. J Neurosurg. 2009; 110:968–74. 10.3171/2008.10.JNS08901
    1. Garg K, Sinha S, Kale SS, Chandra PS, Suri A, Singh MM, Kumar R, Sharma MS, Pandey RM, Sharma BS, Mahapatra AK. Role of simvastatin in prevention of vasospasm and improving functional outcome after aneurysmal sub-arachnoid hemorrhage: a prospective, randomized, double-blind, placebo-controlled pilot trial. Br J Neurosurg. 2013; 27:181–86. 10.3109/02688697.2012.757293
    1. Diringer MN, Dhar R, Scalfani M, Zazulia AR, Chicoine M, Powers WJ, Derdeyn CP. Effect of High-Dose Simvastatin on Cerebral Blood Flow and Static Autoregulation in Subarachnoid Hemorrhage. Neurocrit Care. 2016; 25:56–63. 10.1007/s12028-015-0233-7
    1. Vergouwen MD, Meijers JC, Geskus RB, Coert BA, Horn J, Stroes ES, van der Poll T, Vermeulen M, Roos YB. 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. 10.1038/jcbfm.2009.59
    1. Choi KS, Kim JM, Yi HJ, Lee SH, Lim T, Kim W, Cho Y, Cheong JH. Dose-related effect of statins in patients with endovascular coiling or microsurgical clipping for aneurysmal subarachnoid hemorrhage: updated study-level meta-analysis. Eur J Clin Pharmacol. 2017; 73:1071–81. 10.1007/s00228-017-2221-7
    1. Shen J, Huang KY, Zhu Y, Pan JW, Jiang H, Weng YX, Zhan RY. Effect of statin treatment on vasospasm-related morbidity and functional outcome in patients with aneurysmal subarachnoid hemorrhage: a systematic review and meta-analysis. J Neurosurg. 2017; 127:291–301. 10.3171/2016.5.JNS152900
    1. Chang CZ, Wu SC, Kwan AL, Lin CL. Preconditioning with pitavastatin, an HMG-CoA reductase inhibitor, attenuates C-Jun N-terminal kinase activation in experimental subarachnoid hemorrhage-induced apoptosis. Acta Neurochir (Wien). 2015; 157:1031–41. 10.1007/s00701-015-2399-3

Source: PubMed

Szponzorok és közreműködők

Egészségi állapot

Kábítószer-beavatkozások

3
Iratkozz fel