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Stroke. 2004;35:1121-1123
Published online before print April 8, 2004, doi: 10.1161/01.STR.0000126481.79085.47
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(Stroke. 2004;35:1121.)
© 2004 American Heart Association, Inc.

Original Contributions

Editorial Comment—Statins, Stroke Outcome, and Stroke Prevention: When Should We Start Treatment?

Jonathan Y. Streifler, MD

Neurology Department, Rabin Medical Center, Petach Tikva and Tel Aviv University, Israel

Statins or 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors are a group of potent hypocholesterolemic agents that are widely used throughout the world. Many long-term clinical studies have demonstrated that statin therapy is associated with a reduced risk of vascular events—mainly coronary—even in so-called normocholesterolemic patients. Accordingly, guidelines for cholesterol treatment have been and are being modified, particularly for patients with ischemic heart disease (IHD). The magnitude of the effects is large. A recent meta-analysis1 has demonstrated that a decrease in low-density lipoprotein cholesterol levels by 1.8 mmol/L reduces the risk of IHD by 61% and the risk of stroke by 17%, preventing thromboembolic but not hemorrhagic strokes. The benefit of statins treatment has also been shown for patients with hypertension,2 diabetes mellitus,3 severe aortic arch plaques,4 and for high-risk patients in general.5 For secondary stroke prevention, however, the data are still somewhat circumstantial6 and a specific study is underway.7 In many of the studies, the beneficial effects of the statins were not directly related to their lipid-lowering properties, and data on many other effects of statins is accumulating.8,9 On the vascular wall, statins exert vasodilatation and plaque stabilizing effects by many ways, such as upregulation of endothelial nitric oxide synthase (eNOS), suppression of heightened macrophage activity with subsequent reduced production of several matrix metalloproteins and proinflammatory cytokines TNF{alpha}, IL-6, CRP, and reduction of vascular expression of adhesion molecules. Because all these factors enhance the thrombogenic potential of the atherosclerotic plaque, statins have a role in ameliorating this risk. Antiatherogenic properties of statins were demonstrated in retarding intimal medial thickening of the carotid wall, coronary plaque volume, and aortic atherosclerosis.9 A more rapid clinical effect was recently reported in patients with acute coronary syndrome: early statin administration was associated with reduced ischemic events within the first month of treatment.10 This effect was explained, at least in part, by a reduction in local inflammation.11

For stroke, statin therapy is believed to be effective even earlier, leading to a better functional recovery; animal studies have recently shown the effects of statins on enhanced functional outcome and induction of brain plasticity when administered after stroke, probably by induction of angiogenesis, neurogenesis, and synaptogenesis.12 Lesion volumes have decreased regardless of cholesterol blood levels. Stroke protection is lost, however, within 2 to 4 days after withdrawal of statins treatment.13 These acute pleiotropic effects induce neuroprotection throughout several mechanisms including eNOS modulation (by augmenting regional cerebral blood flow), by inhibition of platelet aggregation, and by antiinflammatory effects.9,12

Are these effects also applicable to human beings? A pilot case-referent study14 has shown a trend for a favorable outcome (earlier discharge to home) in patients pretreated with statins, and a pilot randomized study on the acute effects of simvastatin in ischemic stroke (MISTICS trial) has demonstrated beneficial effects.15

In this issue, Marti-Fabregas et al16 present their experience with statin treatment and stroke outcome in 167 acute stroke patients, of which 18% were pretreated with statins. This was an open study in which patients were included prospectively and followed-up for 3 months.

Median National Institutes of Health Stroke Scale (NIHSS) scores at admission were lower in the statin group (5 versus 6) and neurological deterioration was less frequent in this group (3.3% versus 8.1% in the nonstatin group); yet, maybe because of the small sample size, these differences were not significant. At 3 months, statin treatment was found to be independently associated with a favorable outcome. The authors conclude that statins may provide long-term beneficial effects when given before the onset of acute stroke. They state that for maximum benefit, therapy should start within the first few hours of an acute stroke and declare that a randomized controlled study is needed to clarify the importance of statins on stroke outcome.

This article is important in strengthening previous observations; however, because of its nature (observational, unmatched), it still leaves some uncertainties. Apart from the limitations acknowledged by the authors in their discussion, there is also another concern, ie, the lack of information on concomitant treatment. It is possible that other medications confer neuroprotective properties, as has just recently been presented for angiotensin-converting enzyme (ACE) inhibitors.17 Also, the possibility that patients using statins are those that get, or can afford, better medical care was not ruled out.

Why were only 18% of the patients using statins? Given our current knowledge and the list of risk factors in the "control" group, this percent should have been higher. Alternatively, the fact that only 18% of the whole group were using statins suggests that a priori such patients are somewhat protected from stroke. Additionally, the higher rate of lacunar stroke in the treated group may imply that patients with large artery atherothrombosis are more protected because of the pleiotropic and plaque-stabilizing effects of statins.

This study provides information relating to the long-term beneficial effects of statins on stroke outcome, including, perhaps, an additional benefit at the subacute stage; however, this does not clarify the acute effects of statins and the importance of its administration in the hyperacute stage. Thus, the exact timing of statin administration in acute stroke remains open.

In the near future, however, with the completion of the SPARCL study,7 it may be possible to answer 2 major questions: (1) are statins beneficial in the secondary prevention of stroke in all patients regardless of their premorbid conditions; and (2) are stroke outcomes in the statin-treated group milder and/or associated with a better outcome once they have occurred? We will also be able to learn which subtypes of strokes are mostly influenced by statins.

Within a few years, it seems that most high-risk patients will be treated with statins (the introduction of a "polypill" including a statin has been recently suggested18 for those patients), and thus only for a minority of the stroke patients will we be facing the dilemma of when to start treatment.

Nonetheless, the importance of the pleiotropic effects of statins in acute stroke should be investigated in a prospective randomized study.


*    References
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 *References
 

  1. Law MR, Wald NJ, Rudnicka AR. Quantifying effect of statins on low density lipoprotein cholesterol, ischaemic heart disease, and stroke: systematic review and meta-analysis. BMJ. 2003; 326: 1423–1429.[Abstract/Free Full Text]
  2. Sever PS, Dahlof B, Poulter NR, Wedel H, Beevers G, Caulfield M, Collins R, Kjeldsen SE, Kristinsson A, Mclnnes GT, Mehlsen J, Nieminen M, O’Brien E, Ostergren J, for the ASCOT Investigators. 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 multicenter randomized controlled trial. Lancet. 2003; 361: 1149–1158.[CrossRef][Medline] [Order article via Infotrieve]
  3. Heart Protection Study Collaborative Group. MRC/BHF Heart Protection study of cholesterol lowering with simvastatin in 5963 people with diabetes: a randomized placebo-controlled trial. Lancet. 2003; 361: 2005–2016.[CrossRef][Medline] [Order article via Infotrieve]
  4. Tunick PA, Nayar AC, Goodkin GM, Mirchandani S, Francescone S, Rosenzweig BP, Freedberg RS, Katz ES, Applebaum RM, Kronzon I for the NYU Atheroma Group. Effect of treatment on the incidence of stroke and other emboli in 519 patients with severe thoracic aortic plaque. Am J Cardiol. 2002; 90: 1320–1325.[CrossRef][Medline] [Order article via Infotrieve]
  5. Heart Protection Study Collaborative Group. MRC/ BHF Heart Protection Study of cholesterol lowering with simvastatin in 20536 high-risk individuals: a randomized placebo-controlled trial. Lancet. 2002; 360: 7–22.[CrossRef][Medline] [Order article via Infotrieve]
  6. Sillesen H. Statin for secondary stroke prevention in patients without known coronary heart disease: the jury is still out. Cerebrovasc Dis. 2004; 18: 1–2.[Medline] [Order article via Infotrieve]
  7. The SPARCL Investigators. Design and baseline characteristics of the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) Study. Cerebrovasc Dis. 2003; 16: 389–395.[CrossRef][Medline] [Order article via Infotrieve]
  8. Koh KK. Effects of statins on vascular wall: vasomotor function, inflammation, and plaque stability. Cardiovasc Res. 2000; 47: 648–657.[Abstract/Free Full Text]
  9. Vaughan CJ. Prevention of stroke and dementia with statin: effects beyond lipid lowering. Am J Cardiol. 2003; 91: 23B–29B.[Medline] [Order article via Infotrieve]
  10. Schwartz GG, Olsson AG, Ezekowitz MD, Ganz P, Oliver MF, Waters D, Zeiher A, Chaitman BR, Leslie S, Stern t. Effects of atorvastatin on early recurrent ischemic events in acute coronary syndromes: the MIRACL study: a randomized controlled trial. JAMA. 2001; 285: 1711–1718.[Abstract/Free Full Text]
  11. Kinlay S, Schwartz GG, Olsson AG, Rifai N, Leslie SJ, Sasiela WJ, Szarek M, Libby P, Ganz P. High-dose atorvastatin enhances the decline in inflammatory markers in patients with acute coronary syndromes in the MIRACL study. Circulation. 2003; 108: 1560–1566.[Abstract/Free Full Text]
  12. 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]
  13. Gertz K, Laufs U, Lindauer U, Nickenig G, Bohm M, Dirnagl U, Endres M. Withdrawal of statin treatment abrogates stroke protection in mice. Stroke. 2003; 34: 551–557.[Abstract/Free Full Text]
  14. Jonsson N, Asplund K. Does pretreatment with statins improve clinical outcome after stroke? A pilot case-referent study. Stroke. 2001; 32: 1112–1115.[Abstract/Free Full Text]
  15. Montaner J, Chacon P, Krupinski J, Rubio F, Millan M, Escudero D, Hereu P, Molina C, Quintana M, Alvarez-Sabin J. Safety and efficacy of statin in the acute phase of ischemic stroke: the MISTICS Trial. Stroke. 2004; 35: 293. Abstract.
  16. Marti-Fabregas J, Gomis M, Arboix A, Aleu A, Pagonadarraga J, Belvis R, Cocho D, Roquer J, Rodriguez A, Garcia MD, Molina-Porcel L, Diaz-Manera J, Marti-Vilalta JL. Favorable outcome of ischemic stroke in patients pretreated with statins. Stroke. 2004; 35: 1117–1123.[Abstract/Free Full Text]
  17. Selim M, Savitz S, Gomes J, Caplan L, Linfante I, Leary M, Finely A, Schlaug G. Effects of prior use of angiotensin-converting enzyme inhibitors on stroke severity. Stroke. 2004; 35: 235. Abstract.[Free Full Text]
  18. Wald NJ, Law MR. A strategy to reduce cardiovascular disease by more than 80%. BMJ. 2003; 326: 1419.[Abstract/Free Full Text]



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