It is now clear that the management of hypercholesterolaemia is important for the reduction of morbidity and mortality caused by cerebrovascular and coronary events. The landmark Scandinavian Simvastatin Survival Study was the first to show conclusively that lipid-lowering therapy with statins reduces the incidence of stroke. Subsequent trials, undertaken in a variety of different patient populations, have confirmed that statin therapy reduces the incidence of stroke by approximately one-third. This important benefit has been observed in men and women, the young and the elderly, and also in subjects with diabetes mellitus. In the recent Heart Protection Study, which recruited ‘high-risk’ vascular subjects, stroke risk reduction was demonstrated even among those subjects considered to have ‘low’ low-density lipoprotein (LDL) cholesterol levels. The benefits of statin therapy in stroke have been attributed to reductions in cholesterol and to other non-lipid-lowering effects of statins. Ongoing clinical trials such as TNT (Treating to New Targets) and IDEAL (Incremental Decrease in Endpoints through Aggressive Lipid lowering) will test the ‘lower is better’ hypothesis. Using statins to lower LDL cholesterol to levels that are below current guidelines will provide additional benefits in stroke risk reduction. Most of the data on cholesterol reduction and cerebrovascular events have been derived from studies of patients with documented coronary heart disease (CHD). The ongoing SPARCL (Stroke Prevention by Aggressive Reduction in Cholesterol Levels) trial will examine the benefits of LDL cholesterol lowering in patients with previous stroke or transient ischaemic attack (TIA), but no history of coronary problems.

Keywords:
Stroke, Hyperlipidaemia, Statin therapy, Low-density lipoprotein cholesterol
1.
Castelli WP, Anderson K, Wilson PW, Levy D: Lipids and risk of coronary heart disease. The Framingham study. Ann Epidemiol 1992;2:23–28.
2.
Stamler J, Vaccaro O, Neaton JD, Wentworth D: Diabetes, other risk factors, and 12-yr cardiovascular mortality for men screened in the Multiple Risk Factor Intervention Trial. Diabetes Care 1993;16:434–444.
3.
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;344:1383–1389.
4.
Sacks FM, Pfeffer MA, Moye LA, Rouleau L, Rutherford JD, Cole TG, Brown L, Warnica JW, Arnold JMO, Wun C-C, Davis BR, Braunwald E; the Cholesterol and Recurrent Events Trial Investigators: The effect of pravastatin on coronary events after MI in patients with average cholesterol levels. New Engl J Med 1996;335:1001–1009.
5.
White HD, Simes RJ, Anderson NE, Hankey GJ, Watson JD, Hunt D, Colquhoun DM, Glasziou P, MacMahon S, Kirby AC, West MJ, Tonkin AM: Pravastatin therapy and the risk of stroke. New Eng J Med 2000;343:317–326.
6.
Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults: Executive summary of the 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) J Am Med Assoc 2001;285:2486–2497.
7.
Prospective Studies Collaboration: Cholesterol, diastolic blood pressure, and stroke: 13,000 strokes in 450,000 people in 45 prospective cohorts. Lancet 1995;346:1647–1653.
8.
Iso H, Jacobs DR, Jr, Wentworth D, Neaton JD, Cohen JD: Serum cholesterol levels and six-year mortality from stroke in 350,977 men screened for the multiple risk factor intervention trial. New Engl J Med 1989;320:904–910.
9.
Pedersen TR, Kjekshus J, Pyörälä K, Olsson AG, Cook TJ, Musliner TA, Tobert JA, Haghfelt T: Effect of simvastatin on ischemic signs and symptoms in the Scandinavian Simvastatin Survival Study (4S). Am J Cardiol 1998;81:333–335.
10.
Plehn JF, Davis BR, Sacks FM, Rouleau JL, Pfeffer MA, Bernstein V, Cuddy TE, Moye LA, Piller LB, Rutherford J, Simpson LM, Braunwald E: Reduction of stroke incidence after myocardial infarction with pravastatin: the Cholesterol and Recurrent Events (CARE) study. The Care Investigators. Circulation 1999;99(2):216–223.
11.
The LIPID Study Group: Long-term effectiveness and safety of pravastatin in 9014 patients with coronary heart disease and average cholesterol concentrations: the LIPID trial follow-up. Lancet 2002;359:1379–1387.
12.
Byington RP, Davis BR, Plehn JF, White HD, Baker J, Cobbe SM, Shepherd J, for the Prospective Pravastatin Pooling Investigators: Reduction of stroke events with pravastatin. The Prospective Pravastatin Pooling (PPP) Project. Circulation 2001;103:387–392.
13.
Craven TE, Ryu JE, Espeland MA: Evaluation of the associations between carotid artery atherosclerosis and coronary artery stenosis: a case-control study. Circulation 1990;82:1230–1242.
14.
O’Leary DH, Polak JF, Kronmal RA, Kittner SJ, Bond MG, Wolfson SK, Jr, Bommer W, Price TR, Gardin JM, Savage PJ: Distribution and correlates of sonographically detected carotid artery disease in the Cardiovascular Health Study: the CHS Collaborative Research Group. Stroke 1992;23:1752–1760.
15.
MacMahon S, Sharpe N, Gamble G, Hart H, Scott J, Simes J, White H, on behalf of the LIPID trial research group: Effects of lowering average or below-average cholesterol levels on the progression of carotid atherosclerosis. Results of the LIPID Atherosclerosis Substudy. Circulation 1998;97:1784–1790.
16.
Lammie GA, Sandercock PA, Dennis MS: Recently occluded intracranial and extracranial carotid arteries. Relevance of the unstable atherosclerotic plaque. Stroke 1999;30:1319–1325.
17.
Rost NS, Wolf PA, Kase CS, Kelly-Hayes M, Silbershatz H, Massaro JM, D’Agostino RB, Franzblau C, Wilson PW: Plasma concentration of C-reactive protein and risk of ischemic stroke and transient ischemic attack: the Framingham study. Stroke 2001;32:2575–2579.
18.
Nesto RW, Rutter MK: Impact of the atherosclerotic process in patients with diabetes. Acta Diabetol 2002;39:S22–S28.
19.
Bellosta S, Bernini F, Ferri N, Quarato P, Canavesi M, Arnaboldi L, Fumagalli R, Paoletti R, Corsini A: Direct vascular effects of HMG-CoA reductase inhibitors. Atherosclerosis 1998;137:S101–S109.
20.
Aikawa M, Rabkin E, Sugiyama S, Voglic SJ, Fukumoto Y, Furukawa Y, Shiomi M, Schoen FJ, Libby P: An HMG-CoA reductase inhibitor, cerivastatin, suppresses growth of macrophages expressing matrix metalloproteinases and tissue factor in vivo and in vitro. Circulation 201;103:276–283.
21.
Williams JK, Sukhova GK, Herrington DM, Libby P: Pravastatin has cholesterol-lowering independent effects on the artery wall of atherosclerotic monkeys. J Am Coll Cardiol 1998;31:684–691.
22.
Corsini A, Bernini F, Quarato P, Donetti E, Bellosta S, Fumagalli R, Paoletti R, Soma VM: Non-lipid-related effects of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors. Cardiology 1996;87:458–468.
23.
Laufs U, La Fata V, Plutzky J, Liao JK: Upregulation of endothelial nitric oxide synthase by HMG CoA reductase inhibitors. Circulation 1998;97:1129–1135.
24.
Schwartz GG, Olsson AG, Ezekowitz MD, Ganz P, Oliver MF, Waters D, Zeiher A, Chaitman BR, Leslie S, Stern T; Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) study investigators: Effects of atorvastatin on early recurrent ischemic events in acute coronary syndromes: the MIRACL study: a randomized controlled trial. J Am Med Assoc 2001;285:1711–1718.
25.
Waters DD, Schwartz GG, Olsson AG, Zeiher A, Oliver MF, Ganz P, Ezekowitz M, Chaitman BR, Leslie SJ, Stern T; MIRACL Investigators. Effects of atorvastatin on stroke in patients with unstable angina or non-Q-wave myocardial infarction: a Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) substudy. Circulation 2002;106:1596–1598.
26.
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.
27.
Tanne D, Koren-Morag N, Graff E, Goldbourt U: Blood lipids and first-ever ischemic stroke/transient ischemic attack in the Bezafibrate Infarction Prevention (BIP) Registry: high triglycerides constitute an independent risk factor. Circulation 2001;104(24):2892–2897.
28.
Bloomfield Rubins H, Davenport J, Babikian V, Brass LM, Collins D, Wexler L, Wagner S, Papademetriou V, Rutan G, Robins SJ, for the VA-HIT Study Group: Reduction in Stroke With Gemfibrozil in Men With Coronary Heart Disease and Low HDL Cholesterol. The Veterans Affairs HDL Intervention Trial (VA-HIT). Circulation 2001;103:2828–2833.
29.
The Diabetes Atorvastin Lipid Intervention (DALI) Study Group: The effect of aggressive versus standard lipid lowering by atorvastatin on diabetic dyslipidemia: the DALI study: a double-blind, randomized, placebo-controlled trial in patients with type 2 diabetes and diabetic dyslipidemia. Diabetes Care 2001;24:1335–1341.
30.
Berenson GS, Srinivasan SR, Bao W, Newman WP III, Tracy RP, Wattigney WA, for the Bogalusa Heart Study: Association between multiple cardiovascular risk factors and atherosclerosis in children and young adults. N Engl J Med 1998;338:1650–1656.
31.
Smilde TJ, Van Wissen S, Wollersheim H, Trip MD, Kastelein JJP, Stalenhoef AHP: Effect of aggressive versus conventional lipid lowering on atherosclerosis progression in familial hypercholesterolaemia (ASAP): a prospective, randomised, double-blind trial. Lancet 2001;357:577–581.
© 2003 S. Karger AG, Basel
2003
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.