Published online before print September 30, 2004, doi: 10.1161/01.STR.0000143215.61714.62
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
(Stroke. 2004;35:2706.)
© 2004 American Heart Association, Inc.
Articles |
Role of Statins in the Treatment and Prevention of Stroke
Introduction
From the University of Washington School of Medicine (K.B.), Seattle Wash, and the Henry Ford Health Sciences Center (M.C.), Detroit Mich.
Correspondence to Dr Kyra Becker, Harborview Medical Center, Box 359775, 325 9th Avenue, Seattle, Washington 98104–2499. Email kjb{at}u.washington.edu
Epidemiological studies suggest that hyperlipidemia is not a major risk factor for stroke, yet 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) decrease the risk of stroke in patients with vascular disease or at high risk of vascular disease.1–6 Moreover, the benefit of statins appears to be independent of baseline cholesterol; persons with normal cholesterol experience a similar degree of risk reduction as patients with elevated cholesterol.3 Results of dedicated stroke trials to determine the benefit of statins in secondary stroke prevention are not yet available, although the Heart Protection Study did include a large population of patients with cerebrovascular disease and stroke.3 Interestingly, among patients with a history of stroke, statins did not decrease the risk of recurrent stroke, but did decrease the risk of myocardial infarction.7
While epidemiological studies fail to show a dramatic effect of hyperlipidemia on ischemic stroke risk, low cholesterol levels are associated with an increased risk of intracerebral hemorrhage (ICH).8,9 Importantly, statin therapy has not been associated with an increased risk of ICH in any of the studies done to date.4,5,7 Furthermore, statin use may be associated with lessened stroke severity in patients with ischemic stroke, and animal data points to a similar benefit in ICH.10,11 These observations, along with the disconnect between the epidemiologic data regarding the role of cholesterol in stroke risk and the benefit of statins in stroke prevention suggest that the benefits of statins may be related to nonlipid effects of the drugs. Indeed, statins affect multiple biological systems, including the immune system. Prevention of vascular outcomes in trials of statins is strongly linked to a decrease in C-reactive protein.12,13 These potent antiinflammatory effects also appear to translate into benefit in the treatment of multiple sclerosis and rheumatoid arthritis.14,15
Statins have both neuroprotective as well as neurorestorative effects in the treatment of experimental stroke and neural injury. Statins improve endothelial function and have anticoagulant, antiinflammatory, and antithrombogenic properties, all of which may foster neuroprotective effects.16,17 These therapeutic properties are independent of lipid lowering.18,19 Pretreatment of experimental stroke with simvastatin significantly reduces the volume of cerebral infarction.20 Treatment with simvastatin after stroke onset likewise has neuroprotective effects.21,22 The antiinflammatory effects of statins suggest that these agents may also be effective when used in combination with thrombolytic therapies, such as with recombinant tissue plasminogen activator, possibly extending the therapeutic window and reducing hemorrhagic transformation. The multiple therapeutic pathways activated by statins also include those associated with restorative therapies. Statins administered to animals 24 hours after stroke increase expression of neurotrophic factors such as vascular endothelial growth factor (VEGF) and brain-derived neurotrophic factor (BDNF), amplify endogenous brain plasticity, and reduce neurological deficits.23
Statins are widely useed to reduce cholesterol levels and have a well characterized and generally good safety profile. The pleiotropic effects of these agents in enhancing endothelial NO synthase, reducing vascular inflammation, promoting tissue perfusion, and in amplifying brain plasticity suggest that statins should be investigated as prophylactic, acute neuroprotective and delayed neurorestorative treatment for stroke.
The articles in this section explore some of the nonlipid effects of statins as they pertain to the treatment and prevention of stroke.
Received July 20, 2004; accepted August 5, 2004.
 |
References |
|---|
 Top References |
|---|
- Engstrom G, Lind P, Hedblad B, Stavenow L, Janzon L, Lindgarde F. Effects of cholesterol and inflammation-sensitive plasma proteins on incidence of myocardial infarction and stroke in men. Circulation. 2002; 105: 2632–2637.
[Abstract/Free Full Text] - Bowman TS, Sesso HD, Ma J, Kurth T, Kase CS, Stampfer MJ, Gaziano JM. Cholesterol and the risk of ischemic stroke. Stroke. 2003; 34: 2930–2934.
[Abstract/Free Full Text] - Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20 536 high-risk individuals: a randomised placebo-controlled trial. Lancet. 2002; 360: 7–22.[CrossRef][Medline] [Order article via Infotrieve]
- 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. 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: 1149–1158.[CrossRef][Medline] [Order article via Infotrieve]
- Byington RP, Davis BR, Plehn JF, White HD, Baker J, Cobbe SM, Shepherd J. Reduction of stroke events with pravastatin: the Prospective Pravastatin Pooling (PPP) Project. Circulation. 2001; 103: 387–392.
[Abstract/Free Full Text] - Cheung BM, Lauder IJ, Lau CP, Kumana CR. Meta-analysis of large randomized controlled trials to evaluate the impact of statins on cardiovascular outcomes. Br J Clin Pharmacol. 2004; 57: 640–651.[CrossRef][Medline] [Order article via Infotrieve]
- Collins R, Armitage J, Parish S, Sleight P, Peto R. Effects of cholesterol-lowering with simvastatin on stroke and other major vascular events in 20 536 people with cerebrovascular disease or other high-risk conditions. Lancet. 2004; 363: 757–767.[CrossRef][Medline] [Order article via Infotrieve]
- Ariesen MJ, Claus SP, Rinkel GJ, Algra A. Risk factors for intracerebral hemorrhage in the general population: a systematic review. Stroke. 2003; 34: 2060–2065.
[Abstract/Free Full Text] - Leppala JM, Virtamo J, Fogelholm R, Albanes D, Heinonen OP. Different risk factors for different stroke subtypes: association of blood pressure, cholesterol, and antioxidants. Stroke. 1999; 30: 2535–2540.
[Abstract/Free Full Text] - Greisenegger S, Mullner M, Tentschert S, Lang W, Lalouschek W. Effect of pretreatment with statins on the severity of acute ischemic cerebrovascular events. J Neurol Sci. 2004; 221: 5–10.[CrossRef][Medline] [Order article via Infotrieve]
- Yoon SS, Dambrosia J, Chalela J, Ezzeddine M, Warach S, Haymore J, Davis L, Baird AE. Rising statin use and effect on ischemic stroke outcome. BMC Med. 2004; 2: 4.[CrossRef][Medline] [Order article via Infotrieve]
- Ridker PM, Rifai N, Pfeffer MA, Sacks FM, Moye LA, Goldman S, Flaker GC, Braunwald E. Inflammation, pravastatin, and the risk of coronary events after myocardial infarction in patients with average cholesterol levels. Cholesterol and Recurrent Events (CARE) Investigators. Circulation. 1998; 98: 839–844.
[Abstract/Free Full Text] - Ridker PM, Rifai N, Pfeffer MA, Sacks F, Braunwald E. Long-term effects of pravastatin on plasma concentration of C-reactive protein. The Cholesterol and Recurrent Events (CARE) Investigators. Circulation. 1999; 100: 230–235.
[Abstract/Free Full Text] - Vollmer T, Key L, Durkalski V, Tyor W, Corboy J, Markovic-Plese S, Preiningerova J, Rizzo M, Singh I. Oral simvastatin treatment in relapsing-remitting multiple sclerosis. Lancet. 2004; 363: 1607–1608.[CrossRef][Medline] [Order article via Infotrieve]
- McCarey DW, McInnes IB, Madhok R, Hampson R, Scherbakov O, Ford I, Capell HA, Sattar N. Trial of Atorvastatin in Rheumatoid Arthritis (TARA): double-blind, randomised placebo-controlled trial. Lancet. 2004; 363: 2015–2021.[CrossRef][Medline] [Order article via Infotrieve]
- Dangas G, Smith DA, Unger AH, Shao JH, Meraj P, Fier C, Cohen AM, Fallon JT, Badimon JJ, Ambrose JA. Pravastatin: an antithrombotic effect independent of the cholesterol-lowering effect. Thromb Haemost. 2000; 83: 688–692.[Medline] [Order article via Infotrieve]
- Honjo M, Tanihara H, Nishijima K, Kiryu J, Honda Y, Yue BY, Sawamura T. Statin inhibits leukocyte-endothelial interaction and prevents neuronal death induced by ischemia-reperfusion injury in the rat retina. Arch Ophthalmol. 2002; 120: 1707–1713.
[Abstract/Free Full Text] - Delanty N, Vaughan CJ, Sheehy N. Statins and neuroprotection. Expert Opin Investig Drugs. 2001; 10: 1847–1853.[CrossRef][Medline] [Order article via Infotrieve]
- Eto M, Kozai T, Cosentino F, Joch H, Luscher TF. Statin prevents tissue factor expression in human endothelial cells: role of Rho/Rho-kinase and Akt pathways. Circulation. 2002; 105: 1756–1759.
[Abstract/Free Full Text] - Laufs U, Gertz K, Huang P, Nickenig G, Bohm M, Dirnagl U, Endres M. Atorvastatin upregulates type III nitric oxide synthase in thrombocytes, decreases platelet activation, and protects from cerebral ischemia in normocholesterolemic mice. Stroke. 2000; 31: 2442–2449.
[Abstract/Free Full Text] - Amin-Hanjani S, Stagliano NE, Yamada M, Huang PL, Liao JK, Moskowitz MA. Mevastatin, an HMG-CoA reductase inhibitor, reduces stroke damage and upregulates endothelial nitric oxide synthase in mice. Stroke. 2001; 32: 980–986.
[Abstract/Free Full Text] - Sironi L, Cimino M, Guerrini U, Calvio AM, Lodetti B, Asdente M, Balduini W, Paoletti R, Tremoli E. Treatment with statins after induction of focal ischemia in rats reduces the extent of brain damage. Arterioscler Thromb Vasc Biol. 2003; 23: 322–327.
[Abstract/Free Full Text] - Chen J, Zhang ZG, Li Y, Wang Y, Wang L, Jiang H, Zhang C, Lu M, Katakowski M, Feldkamp CS, Chopp M. Statins induce angiogenesis, neurogenesis, and synaptogenesis after stroke. Ann Neurol. 2003; 53: 743–751.[CrossRef][Medline] [Order article via Infotrieve]
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||