Статины у пациента с ишемическим инсультом: как рано начинать терапию?

Несмотря на важность гиполипидемической терапии для вторичной профилактики острого нарушения мозгового кровообращения по ишемическому типу, сроки начала терапии статинами у пациентов с ишемическим инсультом или рестарта ранее принимавшейся терапии строго не определены. В то же время продолжают накапливаться данные о наличии иных (помимо гиполипидемического механизма клинической эффективности) «плейотропных» механизмов действия статинов, в том числе при ишемии, определяя необходимость внедрения их в реальную клиническую практику. В настоящем обзоре обсуждаются данные об эффективности тактики раннего назначения статинов при ишемическом инсульте у различных групп пациентов и определяется непосредственно время назначения статинов после появления острой неврологической симптоматики, формируется оригинальная позиция авторов по данному вопросу.

1. Amarenco P, Bogousslavsky J, Callahan A, Goldstein LB, Hennerici M, Rudolph AE et al. High-dose atorvastatin after stroke or transient ischemic attack. N Engl J Med. 2006;355(6):549–559. doi:10.1056/NEJMoa061894

2. Amarenco P, Kim JS, Labreuche J, Charles H, Abtan J, Béjot Y et al. A comparison of two LDL cholesterol targets after ischemic stroke. N Engl J Med. 2020;382(1):9. doi:10.1056/NEJMoa1910355

3. Catapano AL, Graham I, De Backer G, Wiklund O, Chapman MJ, Drexel H et al. 2016 ESC/EAS Guidelines for the management of dyslipidaemias. Eur Heart J. 2016;37(39):2999– 3058. doi:10.1093/eurheartj/ehw272

4. Mach F, Baigent C, Catapano AL, Koskinas KC, Casula M, Badimon L et al. 2019 ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk. Eur Heart J. 2020;41(1):111–188. doi:10.1093/eurheartj/ehz455

5. Kernan WN, Ovbiagele B, Black HR, Bravata DM, Chimowitz MI, Ezekowitz MD et al. Guidelines for the prevention of stroke in patients with stroke and transient ischemic attack: a guideline for healthcare professionals from the American Heart Association/ American Stroke Association. Stroke. 2014;45(7):2160–2236. doi:10.1161/STR.0000000000000024

6. Goldberg RB, Stone NJ, Grundy SM. The 2018 AHA/ ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/ NLA/PCNA Guidelines on the management of blood cholesterol in diabetes. Diabetes Care. 2020;43(8):1673–1678. doi:10.2337/dci19-0036

7. Powers WJ, Rabinstein AA, Ackerson T, Adeoye OM, Bambakidis NC, Becker K et al. 2018 Guidelines for the early management of patients with acute ischemic stroke: a Guideline for Healthcare Professionals from the American Heart Association/ American Stroke Association. Stroke. 2018;49(3):e46–e110. doi:10.1161/STR.0000000000000158

8. Merwick Á, Albers GW, Arsava EM, Ay H, Calvet D, Coutts SB et al. Reduction in early stroke risk in carotid stenosis with transient ischemic attack associated with statin treatment. Stroke. 2013;44(10):2814–2820. doi:10.1161/STROKEAHA.113.001576

9. Flint AC, Conell C, Ren X, Kamel H, Chan SL, Rao VA et al. Statin adherence is associated with reduced recurrent stroke risk in patients with or without atrial fibrillation. Stroke. 2017;48(7):1788– 1794. doi:10.1161/STROKEAHA.117.017343

10. Amarenco P, Labreuche J. Lipid management in the prevention of stroke: review and updated meta-analysis of statins for stroke prevention. Lancet Neurol. 2009;8(5):453–463. doi:10.1016/S1474-4422(09)70058-4

11. Sanossian N, Saver JL, Liebeskind DS, Kim D, Razinia T, Ovbiagele B. Achieving target cholesterol goals after stroke: is inhospital statin initiation the key? Arch Neurol. 2006;63(8):1081– 1083. doi:10.1001/archneur.63.8.1081

12. Kennedy J, Hill MD, Ryckborst KJ, Eliasziw M, Demchuk AM, Buchan AM et al. Fast assessment of stroke and transient ischaemic attack to prevent early recurrence (FASTER): a randomised controlled pilot trial. Lancet Neurol. 2007;6(11):961– 969. doi:10.1016/S1474-4422(07)70250-8

13. Hong KS, Lee JS. Statins in acute ischemic stroke: a systematic review. J Stroke. 2015;17(3):282–301. doi:10.5853/jos.2015.17.3.282

14. Yoshimura S, Uchida K, Daimon T, Takashima R, Kimura K, Morimoto T.. Randomized controlled trial of early versus delayed statin therapy in patients with acute ischemic stroke: ASSORT Trial (Administration of Statin on Acute Ischemic Stroke Patient). Stroke. 2017;48(11):3057–3063. doi:10.1161/STROKEAHA.117.017623

15. Ray KK, Cannon CP, McCabe CH, McCabe CH, Cairns R, Tonkin AM et al. Early and late benefits of high-dose atorvastatin in patients with acute coronary syndromes: results from the PROVE IT-TIMI 22 trial. J Am Coll Cardiol. 2005;46(8):1405–1410. doi:10.1016/j.jacc.2005.03.077

16. Schwartz GG, Olsson AG, Ezekowitz MD, Ganz P, Oliver MF, Waters D et al. Effects of atorvastatin on early recurrent ischemic events in acute coronary syndromes: the MIRACL study: a randomized controlled trial. J Am Med Assoc. 2001;285(13):1711– 1718. doi:10.1001/jama.285.13.1711

17. Berwanger O, Santucci EV, de Barros E Silva PGM, de Andrade JesuínoI, Damiani LP et al. Effect of Loading dose of atorvastatin prior to planned percutaneous coronary intervention on major adverse cardiovascular events in acute coronary syndrome: the SECURE-PCI Randomized Clinical Trial. J Am Med Assoc. 2018;319(13):1331–1340. doi:10.1001/jama.2018.2444

18. Patti G, Cannon CP, Murphy SA, Mega S, Pasceri V, Briguor C et al. Clinical benefit of statin pretreatment in patients undergoing percutaneous coronary intervention: a collaborative patient-level meta-analysis of 13 randomized studies. Circulation. 2011;123(15):1622–1632. doi:10.1161/CIRCULATIONAHA.110.002451

19. [Electronic resource]. URL: https://www.eassociety.org/news/news.asp?id=454492&hhSearchTerms=%22Ridker%22

20. Tardif JC, Kouz S, Waters DD, Bertrand OF, Diaz R, Maggioni AP et al. Efficacy and safety of low-dose colchicine after myocardial infarction. N Engl J Med. 2019;381(26):2497–2505. doi:10.1056/NEJMoa1912388

21. Ridker PM, Everett BM, Thuren T, MacFadyen JG, Chang WH, Ballantyne C et al. Antiinflammatory therapy with canakinumab for atherosclerotic disease. N Engl J Med. 2017;377(12):1119–1131. doi:10.1056/NEJMoa1707914

22. Ridker PM, Everett BM, Pradhan A, MacFadyen JG, Solomon DH, Zaharris E et al. Low-dose methotrexate for the prevention of atherosclerotic events. N Engl J Med. 2019;380(8): 752–762. doi:10.1056/NEJMoa1809798

23. Ridker PM, Danielson E, Fonseca FA, Genest J, Gotto AM, Kastelein JJ et al. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med. 2008;359(21):2195–2207. doi:10.1056/NEJMoa0807646

24. Taguchi I, Iimuro S, Iwata H, Takashima H, Abe M, Amiya E et al. High-dose versus low-dose pitavastatin in Japanese patients with stable coronary artery disease (REAL–CAD): a Randomized Superiority Trial. Circulation. 2018;137(19):1997– 2009. doi:10.1161/CIRCULATIONAHA.117.032615

25. Mihos CG, Santana O. Pleiotropic effects of the HMG-CoA reductase inhibitors. Int J GenMed. 2011;4:261–271. doi:10.2147/IJGM.S16779

26. Фесенко Э. В., Прощаев К. И., Поляков В. И. Плейотропные эффекты статинотерапии и их роль в преодолении проблемы полиморбидности. Современные проблемы науки и образования. 2012;2. URL: http://www.science-education.ru/ru/article/view?id=5773 (дата обращения: 17.08.2020).

27. Wahre T, Yundestat A, Smith C, Haug T, Tunheim SH, Gullestad L et al. Increased expression of interleukin-1 incoronary artery disease with down regulatory effects of HMG-CoA reductase inhibitors. Circulation. 2004;109(16):1966–1972.

28. Heo JH, Song D, Nam HS, Kim EY, Kim YD, Lee KY et al. Effect and safety of rosuvastatin in acute ischemic stroke. J Stroke. 2016;18(1):87–95. doi:10.5853/jos.2015.01578

29. Beer C, Blacker D, Bynevelt M, Hankey GJ, Puddey IB. A randomized placebo controlled trial of early treatment of acute ischemic stroke with atorvastatin and irbesartan. Int J Stroke. 2012;7(2):104–111. doi:10.1111/j.1747-4949.2011.00653.x

30. Muscari A, Puddu GM, Santoro N, Serafini C, Cenni A, Rossi V et al. The atorvastatin during ischemic stroke study: a pilot randomized controlled trial. Clin Neuropharmacol. 2011;34(4):141– 147. doi:10.1097/WNF.0b013e3182206c2f

31. Tuttolomondo A, Di Raimondo D, Pecoraro R, Maida C, Arnao V, Della Corte V et al. Early high-dosage atorvastatin treatment improved serum immune-inflammatory markers and functional outcome in acute ischemic strokes classified as large artery atherosclerotic stroke: a Randomized Trial. Medicine (Baltimore). 2016;95(13):e3186. doi:10.1097/MD.0000000000003186

32. Montaner J, Chacón P, Krupinski J, Rubio F, Millán M, Molina CA et al. Simvastatin in the acute phase of ischemic stroke: a safety and efficacy pilot trial. Eur J Neurol. 2008;15(1):82–90. doi:10.1111/j.1468-1331.2007.02015.x

33. Малыгин А. Ю., Хохлов А. Л. Применение симвастатина при ишемическом инсульте. Атеросклероз и дислипидемии. 2013;2(11):61–68.

34. Fang JX, Wang EQ, Wang W, Liu Y, Cheng G. The efficacy and safety of high-dose statins in acute phase of ischemic stroke and transient ischemic attack: a systematic review. Intern Emerg Med. 2017;12(5):679–687. doi:10.1007/s11739-017-1650-8

35. NíChróinín D, Callaly EL, Duggan J, Merwick Á, Hannon N, Sheehan Ó et al. Association between acute statin therapy, survival, and improved functional outcome after ischemic stroke: the North Dublin Population Stroke Study. Stroke. 2011;42(4):1021–1029. doi:10.1161/STROKEAHA.110.596734

36. Cappellari M, Bovi P, Moretto G, Zini A, Nencini P, Sessa M et al. The THRombolysis and STatins (THRaST) study. Neurology. 2013;80(7):655–661. doi:10.1212/WNL.0b013e318281cc83

37. Tziomalos K, Giampatzis V, Bouziana SD, Spanou M, Kostaki S, Papadopoulou M et al. Comparative effects of more versus less aggressive treatment with statins on the long-term outcome of patients with acute ischemic stroke. Atherosclerosis. 2015;243(1):65–70. doi:10.1016/j.atherosclerosis.2015.08.043

38. Cappellari M, Deluca C, Tinazzi M, Tomelleri G, Carletti M, Fiaschi A et al. Does statin in the acute phase of ischemic stroke improve outcome after intravenous thrombolysis? A retrospective study. J Neurol Sci. 2011;308(1–2):128–134. doi:10.1016/j.jns.2011.05.026

39. Kang J, Kim N, Park TH, Bang OY, Lee JS, Lee J et al. Early statin use in ischemic stroke patients treated with recanalization therapy: retrospective observational study. BMC Neurol. 2015;15:122. doi:10.1186/s12883-015-0367-4

40. Jeong HG, Kim BJ, Yang MH, Han MK, Bae HJ. Early statins after intravenous or endovascular recanalization is beneficial regardless of timing, intensity and stroke mechanism. J Stroke. 2017;19(3):370–372. doi:10.5853/jos.2017.00836

41. Zhang L, Zhang ZG, Ding GL, Jiang Q, Liu X, Meng H et al. Multitargeted effects of statin-enhanced thrombolytic therapy for stroke with recombinant human tissue-type plasminogen activator in the rat. Circulation. 2005;112(22):3486–3494. doi:10.1161/CIRCULATIONAHA.104.516757

42. Fassbender K, Dempfle CE, Mielke O, Schwartz A, Daffertshofer M, Eschenfelder C et al. Changes in coagulation and fibrinolysis markers in acute ischemic stroke treated with recombinant tissue plasminogen activator. Stroke. 1999;30(10):2101–2104.

43. Boeckh-Behrens T, Kleine JF, Zimmer C, Neff F, Scheipl F, Pelisek J et al. Thrombus histology suggests cardioembolic cause in cryptogenic stroke. Stroke. 2016;47(7):1864–1871. doi:10.1161/STROKEAHA.116.013105

44. Fracassi A, Marangoni M, Rosso P, Pallottini V, Fioramonti M, Siteni S et al. Statins and the brain: more than lipid lowering agents? CurrNeuropharmacol. 2019;17(1):59–83. doi:10.2174/1570159X15666170703101816

45. Schachter M. Chemical, pharmacokinetic and pharmacodynamic properties of statins: an update. Fundam Clin Pharmacol. 2005;19(1):117–125. doi:10.1111/j.1472-8206.2004.00299.x

46. Endres M, Laufs U, Huang Z, Nakamura T, Huang P, Moskowitz MA et al. Stroke protection by 3-hydroxy-3methylglutaryl (HMG)-CoA reductase inhibitors mediated by endothelial nitric oxide synthase. Proc Natl Acad Sci U S A. 1998;95(15):8880–8885. doi:10.1073/pnas.95.15.8880

47. Shao S, Xu M, Zhou J, Ge X, Chen G, Guo L et al. Atorvastatin attenuates ischemia/ reperfusion-induced hippocampal neurons injury via Akt-nNOS-JNK signaling pathway. Cell Mol Neurobiol. 2017;37(4):753–762. doi:10.1007/s10571-016-0412-x

48. Gasche Y, Copin JC, Sugawara T, Fujimura M, Chan PH. Matrix metalloproteinase inhibition prevents oxidative stressassociated blood-brain barrier disruption after transient focal cerebral ischemia. J Cereb Blood Flow Metab. 2001;21(12):1393– 1400. doi:10.1097/00004647-200112000-00003

49. Woo MS, Park JS, Choi IY, Kim WK, Kim HS. Inhibition of MMP-3 or –9 suppresses lipopolysaccharide-induced expression of proinflammatory cytokines and iNOS in microglia. J Neurochem. 2008;106(2):770–780. doi:10.1111/j.1471-4159.2008.05430.x

50. Sironi L, Banfi C, Brioschi M, Gelosa P, Guerrini U, Nobili E et al. Activation of NF-kB and ERK1/2 after permanent focal ischemia is abolished by simvastatin treatment. Neurobiol Dis. 2006;22(2):445–451. doi:10.1016/j.nbd.2005.12.004

51. Roy A, Jana M, Kundu M, Corbett GT, Rangaswamy SB, Mishra RK et al. HMG-CoA reductase inhibitors bind to PPARα to upregulate neurotrophin expression in the brain and improve memory in mice. Cell Metab. 2015;22(2):253–265. doi:10.1016/j.cmet.2015.05.022