Atorvastatin in Acute Stroke Treatment

Summary

Recent clinical trials and meta-analyses of b-hydroxy-bmethylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) have demonstrated a significant reduction in ischemic stroke in patients with a history of coronary artery disease, both with and without elevations of serum cholesterol. Recent data suggest that statins have other beneficial properties in addition to the retardation of atherosclerosis. Asahi et al demonstred that Statins increased eNOS and tPA mRNA levels but did not change mRNA levels of PAI-1 and that In eNOS knockout mice, atorvastatin reduced the volume of ischemic tissue and improved neurologic outcomes after arterial occlusion by blood clot emboli. In addition to their lipid-lowering effects, it has been speculated that statins may also have beneficial effects on cerebral circulation and brain parenchyma during ischaemic stroke and reperfusion. Aslanyan et al reported that statin use was associated with reduced mortality at 1 month during the follow-up. In patients with recent stroke or TIA and without known coronary heart disease, 80 mg of atorvastatin per day reduced the overall incidence of strokes and of cardiovascular events, despite a small increase in the incidence of hemorrhagic stroke period . Recently the investigators group reported that lacunar strokes compared to nonlacunar ones exhibited significantly lower plasma levels of TNF-α and IL1-β, P-selectin and ICAM-1 24-72 h and 7-10 days after stroke onset (4). At extracranial arterial territories, inflammation plays a crucial role mediating all the stages of the atherosclerosis process . Similarly, thrombosis and defective fibrinolysis may also contribute to the progression of atherosclerotic lesions . Interestingly, both mechanisms might have a relevant role in the pathogenesis of intracranial large artery atherosclerosis and ischemic stroke Moreover our group showed that Patients with cardioembolic and atherothrombotic stroke subtypes showed significantly higher median plasma levels of TNF-α, IL-6, IL-1β whereas the lacunar subtype showed significantly lower median plasma levels of TNF-α, IL-6 and IL-1β and that immunoinflammatory marker plasma levels are significantly related to ischemic lesion volume. A meta-analysis showed that statins may possess antithrombotic property because these drugs were reported to reduce periprocedural infarction in patients undergoing percutaneous coronary intervention . This clinical benefit was detected after median, 0.5 days of treatment with statins (indicating that statins could potentially exert an antithrombotic effect even earlier than supposed from pharmacological studies. Violi et al recently showed the first evidence that atorvastatin acutely and simultaneously decreases oxidative stress and platelet activation by directly inhibiting platelet Nox2 and ultimately platelet isoprostanes and thromboxane A2 so providinf a rationale for the use of statins to prevent or modulate coronary thrombosis. Whereas recent data suggest that inflammatory reactions are involved in the pathogenesis and progression of cerebral ischaemia , no study has evaluated effects of atorvastatin 80 mg/day after a recent stroke on stroke outcome and on immunoinflammatory markers so to evaluate acute antithrombotic and anti-inflammatory effects of atorvastatin also in acute cerebrovascular event setting. On this basis the primary objective of the study was to evaluate the separate effects of atorvastatin in vivo on immunoinflammatory markers and on stroke prognosis in patients with recent acute ischemic stroke classified as atherothrombotic.

Timeline

Start

2011-11

Primary completion

2014-01

Completion

2014-03

Publications

• Background Asahi M, Huang Z, Thomas S, Yoshimura S, Sumii T, Mori T, Qiu J, Amin-Hanjani S, Huang PL, Liao JK, Lo EH, Moskowitz MA. Protective effects of statins involving both eNOS and tPA in focal cerebral ischemia. J Cereb Blood Flow Metab. 2005 Jun;25(6):722-9. doi: 10.1038/sj.jcbfm.9600070.
• Background Aslanyan S, Weir CJ, McInnes GT, Reid JL, Walters MR, Lees KR. Statin administration prior to ischaemic stroke onset and survival: exploratory evidence from matched treatment-control study. Eur J Neurol. 2005 Jul;12(7):493-8. doi: 10.1111/j.1468-1331.2005.01049.x.
• Background Amarenco P, Bogousslavsky J, Callahan A 3rd, Goldstein LB, Hennerici M, Rudolph AE, Sillesen H, Simunovic L, Szarek M, Welch KM, Zivin JA; Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) Investigators. High-dose atorvastatin after stroke or transient ischemic attack. N Engl J Med. 2006 Aug 10;355(6):549-59. doi: 10.1056/NEJMoa061894.
• Background Licata G, Tuttolomondo A, Corrao S, Di Raimondo D, Fernandez P, Caruso C, Avellone G, Pinto A. Immunoinflammatory activation during the acute phase of lacunar and non-lacunar ischemic stroke: association with time of onset and diabetic state. Int J Immunopathol Pharmacol. 2006 Jul-Sep;19(3):639-46. doi: 10.1177/039463200601900320.
• Background Tuttolomondo A, Di Sciacca R, Di Raimondo D, Serio A, D'Aguanno G, La Placa S, Pecoraro R, Arnao V, Marino L, Monaco S, Natale E, Licata G, Pinto A. Plasma levels of inflammatory and thrombotic/fibrinolytic markers in acute ischemic strokes: relationship with TOAST subtype, outcome and infarct site. J Neuroimmunol. 2009 Oct 30;215(1-2):84-9. doi: 10.1016/j.jneuroim.2009.06.019. Epub 2009 Aug 19.
• Background Licata G, Tuttolomondo A, Di Raimondo D, Corrao S, Di Sciacca R, Pinto A. Immuno-inflammatory activation in acute cardio-embolic strokes in comparison with other subtypes of ischaemic stroke. Thromb Haemost. 2009 May;101(5):929-37.
• Background Pignatelli P, Carnevale R, Pastori D, Cangemi R, Napoleone L, Bartimoccia S, Nocella C, Basili S, Violi F. Immediate antioxidant and antiplatelet effect of atorvastatin via inhibition of Nox2. Circulation. 2012 Jul 3;126(1):92-103. doi: 10.1161/CIRCULATIONAHA.112.095554. Epub 2012 May 21.
• Background Iadecola C, Anrather J. The immunology of stroke: from mechanisms to translation. Nat Med. 2011 Jul 7;17(7):796-808. doi: 10.1038/nm.2399.
• Background Yilmaz G, Granger DN. Leukocyte recruitment and ischemic brain injury. Neuromolecular Med. 2010 Jun;12(2):193-204. doi: 10.1007/s12017-009-8074-1. Epub 2009 Jul 5.
• Background Konsman JP, Drukarch B, Van Dam AM. (Peri)vascular production and action of pro-inflammatory cytokines in brain pathology. Clin Sci (Lond). 2007 Jan;112(1):1-25. doi: 10.1042/CS20060043.
• Background Sairanen TR, Lindsberg PJ, Brenner M, Siren AL. Global forebrain ischemia results in differential cellular expression of interleukin-1beta (IL-1beta) and its receptor at mRNA and protein level. J Cereb Blood Flow Metab. 1997 Oct;17(10):1107-20. doi: 10.1097/00004647-199710000-00013.
• Background Blum A, Shamburek R. The pleiotropic effects of statins on endothelial function, vascular inflammation, immunomodulation and thrombogenesis. Atherosclerosis. 2009 Apr;203(2):325-30. doi: 10.1016/j.atherosclerosis.2008.08.022. Epub 2008 Sep 2.
• Background Antoniades C, Bakogiannis C, Leeson P, Guzik TJ, Zhang MH, Tousoulis D, Antonopoulos AS, Demosthenous M, Marinou K, Hale A, Paschalis A, Psarros C, Triantafyllou C, Bendall J, Casadei B, Stefanadis C, Channon KM. Rapid, direct effects of statin treatment on arterial redox state and nitric oxide bioavailability in human atherosclerosis via tetrahydrobiopterin-mediated endothelial nitric oxide synthase coupling. Circulation. 2011 Jul 19;124(3):335-45. doi: 10.1161/CIRCULATIONAHA.110.985150. Epub 2011 Jul 5.
• Background Santos MT, Fuset MP, Ruano M, Moscardo A, Valles J. Effect of atorvastatin on platelet thromboxane A(2) synthesis in aspirin-treated patients with acute myocardial infarction. Am J Cardiol. 2009 Dec 15;104(12):1618-23. doi: 10.1016/j.amjcard.2009.07.039.
• Background Pignatelli P, Sanguigni V, Lenti L, Loffredo L, Carnevale R, Sorge R, Violi F. Oxidative stress-mediated platelet CD40 ligand upregulation in patients with hypercholesterolemia: effect of atorvastatin. J Thromb Haemost. 2007 Jun;5(6):1170-8. doi: 10.1111/j.1538-7836.2007.02533.x.
• Background Nakamura K, Masuda H, Kariyazono H, Arima J, Iguro Y, Yamada K, Sakata R. Effects of atorvastatin and aspirin combined therapy on inflammatory responses in patients undergoing coronary artery bypass grafting. Cytokine. 2006 Dec;36(5-6):201-10. doi: 10.1016/j.cyto.2006.11.001. Epub 2007 Feb 14.
• Background Moonis M, Kane K, Schwiderski U, Sandage BW, Fisher M. HMG-CoA reductase inhibitors improve acute ischemic stroke outcome. Stroke. 2005 Jun;36(6):1298-300. doi: 10.1161/01.STR.0000165920.67784.58. Epub 2005 May 5.
• Background Reis PA, Estato V, da Silva TI, d'Avila JC, Siqueira LD, Assis EF, Bozza PT, Bozza FA, Tibirica EV, Zimmerman GA, Castro-Faria-Neto HC. Statins decrease neuroinflammation and prevent cognitive impairment after cerebral malaria. PLoS Pathog. 2012 Dec;8(12):e1003099. doi: 10.1371/journal.ppat.1003099. Epub 2012 Dec 27.
• Background Piermartiri TC, Figueiredo CP, Rial D, Duarte FS, Bezerra SC, Mancini G, de Bem AF, Prediger RD, Tasca CI. Atorvastatin prevents hippocampal cell death, neuroinflammation and oxidative stress following amyloid-beta(1-40) administration in mice: evidence for dissociation between cognitive deficits and neuronal damage. Exp Neurol. 2010 Dec;226(2):274-84. doi: 10.1016/j.expneurol.2010.08.030. Epub 2010 Sep 15.
• Tuttolomondo A, Di Raimondo D, Pecoraro R, Maida C, Arnao V, Della Corte V, Simonetta I, Corpora F, Di Bona D, Maugeri R, Iacopino DG, Pinto A. 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 Mar;95(13):e3186. doi: 10.1097/MD.0000000000003186.

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