Current approaches for the secondary prevention of ischemic stroke include the aggressive use of antithrombotic therapy, particularly antiplatelet agents, and carotid endarterectomy for eligible patients. Blood pressure lowering with angiotensin converting enzyme inhibitors and diuretics in hypertensives, glucose control to a hemoglobin A1C of less than 7% in diabetics, and statin therapy in patients with hyperlipidemia and/or cardiovascular disease are also important measures forsecondary prevention of stroke. Support for the routine use of statin therapy in all patients with ischemic stroke, regardless of lipid profile or a history of cardiovascular disease, has been, until recently, of debate. Clinical evidence found in studies such as the SPARCL trial and the Heart Protection Study now support the routine use of statin therapy in all ischemic stroke patients. This article focuses on the potential and proven benefits of statins in ischemic stroke.
Sacco RL, Adams R., Albers G., et al. Guidelines for prevention of stroke in patients with ischemic stroke or transient ischemic attack: a statement for healthcare professionals from the American Heart Association/American Stroke Association Council on Stroke: co-sponsored by the Council on Cardiovascular Radiology and Intervention: the American Academy of Neurology affirms the value of this guideline. Stroke. 2006;37(2):577-617.
2.
Scandinavian Simvastatin Survival Study Group.Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S) . Lancet.1994;344(8934):1383-1389.
3.
Plehn JF, Davis BR, Sacks FM, et al; The Care Investigators. Reduction of stroke incidence after myocardial infarction with pravastatin: the Cholesterol and Recurrent Events (CARE) study. Circulation. 1999;99(2):216-223.
4.
Amarenco P., Bogousslavsky J., Callahan A. 3rd, et al. High-dose atorvastatin after stroke or transient ischemic attack . N Engl J Med.2006;355(6):549-559.
5.
Gordon T., Castelli W., Dawber T.Lipoproteins, cardiovascular disease, and death: the Framingham Study. Arch Intern Med.1981(141):1128-1131.
6.
Dawber TR, McNamara PM, Cohen MEAn epidemioligical study of apoplexy (`strokes'). Observations in 5,209 adults in the Framingham Study on association of various factors in the development of apolplexy. Trans Am Neurol Assoc.1965(90): 237-240.
7.
Giroud M., Creisson E., Fayolle H., et al. Risk factors for primary cerebral hemorrhage: a population-based study: the Stroke Registry of Dijon. Neuroepidemiology. 1995;14(1):20-26.
8.
Okumura K., Iseki K., Wakugami K., et al. Low serum cholesterol as a risk factor for hemorrhagic stroke in men: a community-based mass screening in Okinawa, Japan. Jpn Circ J. 1999; 63(1):53-58.
9.
Woo D., Kissela BM, Khoury JC, et al. Hypercholesterolemia, HMG-CoA reductase inhibitors, and risk of intracerebral hemorrhage: a case-control study. Stroke . 2004;35(6):1360-1364.
10.
Amarenco P. , Lavallee P., Touboul PJStroke prevention, blood cholesterol, and statins. Lancet Neurol.2004;3(5):271-278.
11.
Endres M.Statins and stroke. J Cereb Blood Flow Metab.2005; 25(9):1093-1110.
12.
Prospective Studies Collaboration.Cholesterol, diastolic blood pressure, and stroke: 13,000 strokes in 450,000 people in 45 prospective cohorts. Lancet.1995;346(8991-8992): 1647-1653.
13.
Iso H., Jacobs DR Jr, Wentworth D., Neaton JD, Cohen JDSerum cholesterol levels and six-year mortality from stroke in 350,977 men screened for the multiple risk factor intervention trial. N Engl J Med.1989;320(14):904-910.
14.
The Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group.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.1998;339(19):1349-1357.
15.
Colhoun HM, Betteridge DJ, Durrington PN, et al. Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): multicentre randomised placebo-controlled trial. Lancet. 2004;364(9435):685-696.
16.
Collins R., Armitage J., Parish S., Sleigh P., Peto R.MRC/BHF Heart Protection Study of cholesterol-lowering with simvastatin in 5963 people with diabetes: a randomised placebo-controlled trial. Lancet. 2003;361(9374):2005-2016.
17.
Sever PS, Dahlof B., Poulter NR, et al. 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.2003;361(9364):1149-1158.
18.
Woscops.Influence of pravastatin and plasma lipids on clinical events in the West of Scotland Coronary Prevention Study (WOSCOPS). Circulation . 1998;97(15):1440-1445.
19.
Endres M., Laufs U., Huang Z., et al. Stroke protection by 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase inhibitors mediated by endothelial nitric oxide synthase. Proc Natl Acad Sci USA. 1998;95(15):8880-8885.
20.
Hayashi A., Suzuki M., Ogawa Y., Sonoda R., Sasamata M.Post-stroke atorvastatin treatment reduces neurological deficits and mortality rate in the stroke-prone spontaneously hypertensive rat. J Pharm Pharmacol.2004;56(7):893-898.
21.
Laufs U., Gertz K., Dirnagl U., Bohm M., Nickenig G., Endres M.Rosuvastatin, a new HMG-CoA reductase inhibitor, upregulates endothelial nitric oxide synthase and protects from ischemic stroke in mice. Brain Res.2002;942(1-2):23-30.
22.
Liao JKBeyond lipid lowering: the role of statins in vascular protection. Int J Cardiol.2002;86(1):5-18.
23.
Kilic U., Bassetti CL, Kilic E., Xing H., Wang Z., Hermann DMPost-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 . 2005;134(3):901-906.
24.
Sironi L., Cimino M., Guerrini U., et al. Treatment with statins after induction of focal ischemia in rats reduces the extent of brain damage. Arterioscler Thromb Vasc Biol.2003;23(2): 322-327.
25.
Trinkl A., Vosko MR, Wunderlich N., Dichgans M., Hamann GFPravastatin reduces microvascular basal lamina damage following focal cerebral ischemia and reperfusion. Eur J Neurosci.2006;24(2):520-526.
26.
Laufs U., Liao JKTargeting Rho in cardiovascular disease. Circ Res.2000;87(7):526-528.
27.
Goldstein JL , Brown MSRegulation of the mevalonate pathway. Nature. 1990;343(6257):425-430.
28.
Laufs U, LaFata V, Plutzky J, Liao JK. Upregulation of endothelial nitric oxide synthase by HMG CoA reductase inhibitors. Circulation . 1998;97(12):1129-1135.
29.
Laufs U., Liao JKPost-transcriptional regulation of endothelial nitric oxide synthase mRNA stability by Rho GTPase. J Biol Chem.1998 ;273(37):24266-24271.
30.
Vaughan CJ, Delanty N.Neuroprotective properties of statins in cerebral ischemia and stroke. Stroke.1999;30(9):1969-1973.
31.
Kureishi Y. , Luo Z., Shiojima I., et al. The HMG-CoA reductase inhibitor simvastatin activates the protein kinase Akt and promotes angiogenesis in normocholesterolemic animals. Nat Med.2000;6(9):1004-1010.
32.
Delbosc S., Morena M., Djouad F., Ledoucen C., Descomps B., Cristol JPStatins, 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, are able to reduce superoxide anion production by NADPH oxidase in THP-1-derived monocytes . J Cardiovasc Pharmacol.2002;40(4):611-617.
33.
Ducrocq C., Blanchard B., Pignatelli B., Ohshima H.Peroxynitrite: an endogenous oxidizing and nitrating agent. Cell Mol Life Sci.1999;55(8-9):1068-1077.
34.
Wagner AH, Kohler T., Ruckschloss U., Just I., Hecker M.Improvement of nitric oxide-dependent vasodilatation by HMG-CoA reductase inhibitors through attenuation of endothelial superoxide anion formation. Arterioscler Thromb Vasc Biol. 2000;20(1):61-69.
35.
Wassmann S. , Laufs U., Baumer AT, et al. HMG-CoA reductase inhibitors improve endothelial dysfunction in normocholesterolemic hypertension via reduced production of reactive oxygen species. Hypertension. 2001;37(6): 1450-1457.
36.
Wassmann S. , Laufs U., Muller K., et al. Cellular antioxidant effects of atorvastatin in vitro and in vivo. Arterioscler Thromb Vasc Biol. 2002;22(2):300-305.
37.
Franzoni F. , Quinones-Galvan A., Regoli F., Ferrannini E., Galetta F.A comparative study of the in vitro antioxidant activity of statins. Int J Cardiol.2003;90(2-3):317-321.
38.
Yamamoto A. , Hoshi K., Ichihara K.Fluvastatin, an inhibitor of 3-hydroxy-3-methylglutaryl-CoA reductase, scavenges free radicals and inhibits lipid peroxidation in rat liver microsomes. Eur J Pharmacol.1998;361(1):143-149.
39.
Girona J., La Ville AE, Sola R., Plana N., Masana L.Simvastatin decreases aldehyde production derived from lipoprotein oxidation . Am J Cardiol.1999;83(6):846-851.
40.
Aviram M., Rosenblat M., Bisgaier CL, Newton RSAtorvastatin and gemfibrozil metabolites, but not the parent drugs, are potent antioxidants against lipoprotein oxidation. Atherosclerosis . 1998;138(2):271-280.
41.
Del Zoppo G , Ginis I., Hallenbeck JM, Iadecola C., Wang X., Feuerstein GZInflammation and stroke: putative role for cytokines, adhesion molecules and iNOS in brain response to ischemia. Brain Pathol.2000;10(1):95-112.
42.
Ridker PM, Rifai N., Pfeffer MA, Sacks F., Braunwald E.; The Cholesterol and Recurrent Events (CARE) Investigators. Long-term effects of pravastatin on plasma concentration of C-reactive protein. Circulation.1999;100(3):230-235.
43.
Ridker PM, Rifai N., Lowenthal SPRapid reduction in C-reactive protein with cerivastatin among 785 patients with primary hypercholesterolemia. Circulation. 2001;103(9): 1191-1193.
44.
Gaddam V., Li DY, Mehta JLAnti-thrombotic effects of atorvastatin—an effect unrelated to lipid lowering. J Cardiovasc Pharmacol Ther.2002 ;7(4):247-253.
Notarbartolo A., Davi G., Averna M., et al. Inhibition of thromboxane biosynthesis and platelet function by simvastatin in type IIa hypercholesterolemia. Arterioscler Thromb Vasc Biol. 1995;15(2):247-251.
47.
Vaughan CJ, Gotto AM Jr, Basson CTThe evolving role of statins in the management of atherosclerosis. J Am Coll Cardiol.2000; 35(1):1-10.
48.
Lijnen P., Echevaria-Vazquez D., Petrov V.Influence of cholesterollowering on plasma membrane lipids and function. Methods Find Exp Clin Pharmacol.1996;18(2):123-136.
49.
Osamah H., Mira R., Sorina S., Shlomo K., Michael A.Reduced platelet aggregation after fluvastatin therapy is associated with altered platelet lipid composition and drug binding to the platelets. Br J Clin Pharmacol.1997;44(1):77-83.
50.
Huhle G., Abletshauser C., Mayer N., Weidinger G., Harenberg J., Heene DLReduction of platelet activity markers in type II hypercholesterolemic patients by a HMG-CoA-reductase inhibitor. Thromb Res.1999;95(5):229-234.
51.
Undas A., Brummel-Ziedins KE, Mann KGStatins and blood coagulation. Arterioscler Thromb Vasc Biol . 2005;25(2): 287-294.
52.
Colli S., Eligini S., Lalli M., Camera M., Paoletti R., Tremoli E.Vastatins inhibit tissue factor in cultured human macrophages. A novel mechanism of protection against atherothrombosis. Arterioscler Thromb Vasc Biol. 1997;17(2): 265-272.
53.
Eto M., Kozai T., Cosentino F., Joch H., Luscher TFStatin prevents tissue factor expression in human endothelial cells: role of Rho/Rho-kinase and Akt pathways. Circulation.2002; 105(15):1756-1759.
54.
Bea F., Blessing E., Shelley MI, Shultz JM, Rosenfeld MESimvastatin inhibits expression of tissue factor in advanced atherosclerotic lesions of apolipoprotein E deficient mice independently of lipid lowering: potential role of simvastatin-mediated inhibition of Egr-1 expression and activation. Atherosclerosis. 2003;167(2):187-194.
55.
Shi J., Wang J., Zheng H., et al. Statins increase thrombomodulin expression and function in human endothelial cells by a nitric oxide-dependent mechanism and counteract tumor necrosis factor alpha-induced thrombomodulin downregulation. Blood Coagul Fibrinolysis. 2003;14(6):575-585.
56.
Kwak B., Mulhaupt F., Myit S., Mach F.Statins as a newly recognized type of immunomodulator. Nat Med.2000;6(12): 1399-1402.
57.
Wassmann S. , Laufs U., Baumer AT, et al. Inhibition of geranylgeranylation reduces angiotensin II-mediated free radical production in vascular smooth muscle cells: involvement of angiotensin AT1 receptor expression and Rac1 GTPase. Mol Pharmacol.2001;59(3):646-654.
58.
Gentlesk PJ , Wiley T., Taylor AJA prospective evaluation of the effect of simvastatin on heart rate variability in non-ischemic cardiomyopathy. Am Heart J.2005;150(3):478-483.
59.
Adams RJ, Chimowitz MI, Alpert JS, et al. Coronary risk evaluation in patients with transient ischemic attack and ischemic stroke: a scientific statement for healthcare professionals from the Stroke Council and the Council on Clinical Cardiology of the American Heart Association/American Stroke Association. Circulation.2003;108(10):1278-1290.
60.
NationalCholesterol Education Program (NCEP). Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report . Circulation. 2002;106(25):3143-3421.
61.
Carswell JL , Beard KA, Chevrette MM, Pardue CN, Hess DC, Fagan SCTracking trends in secondary stroke prevention strategies. Ann Pharmacother.2004;38(2):215-219.
62.
Stroke Council .Statins after ischemic stroke and transient ischemic attack: an advisory statement from the Stroke Council, American Heart Association and American Stroke Association. Stroke. 2004;35(4):1023.
63.
Collins R., Armitage J., Parish S., Sleight P., Peto R.Effects of cholesterol-lowering with simvastatin on stroke and other major vascular events in 20536 people with cerebrovascular disease or other high-risk conditions. Lancet. 2004;363(9411):757-767.
