Treating Dyslipidemia for the Primary and Secondary Prevention of Stroke

Abstract

Stroke is associated with a heavy burden of mortality and disability, underscoring the importance of effective primary and secondary prevention measures. Dyslipidemia as a risk factor for ischemic stroke has long been disputed. Nevertheless, accumulating epidemiological evidence supports a role of lipid abnormalities in increasing ischemic stroke risk and representing a potential target for therapeutic interventions. 3-hydroxy-3-methyl-glutaryl- (HMG-) CoA reductase inhibitors (i.e., statins) are currently the mainstay of therapy for the management of hypercholesterolemia in patients with cardiovascular disease and stroke. Although their beneficial effects on stroke risk have been attributed chiefly to their lipid-lowering capacity, they also have pleiotropic effects. Other lipid lowering modalities have been shown to reduce the risk of ischemic stroke in individuals at high cardiovascular risk, but data regarding their use in secondary stroke prevention are lacking.

Keywords

dyslipidemia - ischemic stroke - lipid-lowering treatment - prevention - statin

• References

• 1 Mozaffarian D, Benjamin EJ, Go AS. , et al; Writing Group Members; American Heart Association Statistics Committee; Stroke Statistics Subcommittee. Heart Disease and Stroke Statistics-2016 Update: A Report From the American Heart Association. Circulation 2016; 133 (04) e38-e360
• 2 Tell GS, Crouse JR, Furberg CD. Relation between blood lipids, lipoproteins, and cerebrovascular atherosclerosis. A review. Stroke 1988; 19 (04) 423-430
• 3 Oliver MF. Cholesterol and strokes. Cholesterol lowering is indicated for strokes due to carotid atheroma. BMJ 2000; 320 (7233): 459-460
• 4 Baigent C, Keech A, Kearney PM. , et al; Cholesterol Treatment Trialists' (CTT) Collaborators. Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins. Lancet 2005; 366 (9493): 1267-1278
• 5 Amarenco P, Labreuche J. Lipid management in the prevention of stroke: review and updated meta-analysis of statins for stroke prevention. Lancet Neurol 2009; 8 (05) 453-463
• 6 Hong KS, Lee JS. Statins in acute ischemic stroke: a systematic review. J Stroke 2015; 17 (03) 282-301
• 7 Ní Chróinín D, Asplund K, Åsberg S. , et al. Statin therapy and outcome after ischemic stroke: systematic review and meta-analysis of observational studies and randomized trials. Stroke 2013; 44 (02) 448-456
• 8 Reiner Z, Catapano AL, De Backer G. , et al; European Association for Cardiovascular Prevention & Rehabilitation; ESC Committee for Practice Guidelines (CPG) 2008-2010 and 2010-2012 Committees. ESC/EAS Guidelines for the management of dyslipidaemias: the Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS). Eur Heart J 2011; 32 (14) 1769-1818
• 9 Stone NJ, Robinson JG, Lichtenstein AH. , et al; American College of Cardiology/American Heart Association Task Force on Practice Guidelines. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation 2014; 129 (25) (Suppl. 02) S1-S45
• 10 De Caterina R, Scarano M, Marfisi R. , et al. Cholesterol-lowering interventions and stroke: insights from a meta-analysis of randomized controlled trials. J Am Coll Cardiol 2010; 55 (03) 198-211
• 11 Di Napoli P, Taccardi AA, Oliver M, De Caterina R. Statins and stroke: evidence for cholesterol-independent effects. Eur Heart J 2002; 23 (24) 1908-1921
• 12 Goldstein LB, Amarenco P, Szarek M. , et al; SPARCL Investigators. Hemorrhagic Stroke in the Stroke Prevention by Aggressive Reduction in Cholesterol Levels Study. Neurology 2008; 70 (24 Pt 2): 2364-2370
• 13 O'Regan C, Wu P, Arora P, Perri D, Mills EJ. Statin therapy in stroke prevention: a meta-analysis involving 121,000 patients. Am J Med 2008; 121 (01) 24-33
• 14 Cannon CP, Blazing MA, Giugliano RP. , et al; IMPROVE-IT Investigators. Ezetimibe added to statin therapy after acute coronary syndromes. N Engl J Med 2015; 372 (25) 2387-2397
• 15 Castilla-Guerra L, Fernandez-Moreno MC. PCSK9 inhibitors: a new era in stroke prevention?. Eur J Intern Med 2017; 37: e44
• 16 Goldstein LB, Adams R, Becker K. , et al. Primary prevention of ischemic stroke: a statement for healthcare professionals from the Stroke Council of the American Heart Association. Circulation 2001; 103 (01) 163-182
• 17 Koren-Morag N, Tanne D, Graff E, Goldbourt U. Low- and high-density lipoprotein cholesterol and ischemic cerebrovascular disease: the bezafibrate infarction prevention registry. Arch Intern Med 2002; 162 (09) 993-999
• 18 Endres M, Heuschmann PU, Laufs U, Hakim AM. Primary prevention of stroke: blood pressure, lipids, and heart failure. Eur Heart J 2011; 32 (05) 545-552
• 19 Cholesterol, diastolic blood pressure, and stroke: 13,000 strokes in 450,000 people in 45 prospective cohorts. Prospective studies collaboration. Lancet 1995; 346 (8991-8992): 1647-1653
• 20 Zhang Y, Tuomilehto J, Jousilahti P, Wang Y, Antikainen R, Hu G. Total and high-density lipoprotein cholesterol and stroke risk. Stroke 2012; 43 (07) 1768-1774
• 21 Iso H, Jacobs Jr DR, 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. N Engl J Med 1989; 320 (14) 904-910
• 22 Imamura T, Doi Y, Arima H. , et al. LDL cholesterol and the development of stroke subtypes and coronary heart disease in a general Japanese population: the Hisayama study. Stroke 2009; 40 (02) 382-388
• 23 Tirschwell DL, Smith NL, Heckbert SR, Lemaitre RN, Longstreth Jr WT, Psaty BM. Association of cholesterol with stroke risk varies in stroke subtypes and patient subgroups. Neurology 2004; 63 (10) 1868-1875
• 24 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
• 25 Wannamethee SG, Shaper AG, Ebrahim S. HDL-cholesterol, total cholesterol, and the risk of stroke in middle-aged British men. Stroke 2000; 31 (08) 1882-1888
• 26 Milionis HJ, Winder AF, Mikhailidis DP. Lipoprotein (a) and stroke. J Clin Pathol 2000; 53 (07) 487-496
• 27 Milionis HJ, Filippatos TD, Loukas T, Bairaktari ET, Tselepis AD, Elisaf MS. Serum lipoprotein(a) levels and apolipoprotein(a) isoform size and risk for first-ever acute ischaemic nonembolic stroke in elderly individuals. Atherosclerosis 2006; 187 (01) 170-176
• 28 O'Donnell MJ, Xavier D, Liu L. , et al; INTERSTROKE investigators. Risk factors for ischaemic and intracerebral haemorrhagic stroke in 22 countries (the INTERSTROKE study): a case-control study. Lancet 2010; 376 (9735): 112-123
• 29 O'Donnell MJ, Chin SL, Rangarajan S. , et al; INTERSTROKE investigators. Global and regional effects of potentially modifiable risk factors associated with acute stroke in 32 countries (INTERSTROKE): a case-control study. Lancet 2016; 388 (10046): 761-775
• 30 Gorelick PB. Stroke prevention: windows of opportunity and failed expectations? A discussion of modifiable cardiovascular risk factors and a prevention proposal. Neuroepidemiology 1997; 16 (04) 163-173
• 31 Barkas F, Elisaf M, Milionis H. Statins decrease the risk of stroke in individuals with heterozygous familial hypercholesterolemia: a systematic review and meta-analysis. Atherosclerosis 2015; 243 (01) 60-64
• 32 Vaughan CJ, Delanty N. Neuroprotective properties of statins in cerebral ischemia and stroke. Stroke 1999; 30 (09) 1969-1973
• 33 Duval D. Effects of statins on ischemic stroke: neuroprotection and/or triggering of apoptotic damage?. Stroke 2000; 31 (04) 989-990
• 34 Liao JK, Laufs U. Pleiotropic effects of statins. Annu Rev Pharmacol Toxicol 2005; 45: 89-118
• 35 Shepherd J, Cobbe SM, Ford I. , et al; West of Scotland Coronary Prevention Study Group. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. N Engl J Med 1995; 333 (20) 1301-1307
• 36 Officers A; ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial. Major outcomes in moderately hypercholesterolemic, hypertensive patients randomized to pravastatin vs usual care: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT-LLT). JAMA 2002; 288 (23) 2998-3007
• 37 Sever PS, Dahlöf B, Poulter NR. , et al; 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 multicentre randomised controlled trial. Lancet 2003; 361 (9364): 1149-1158
• 38 Hitman GA, Colhoun H, Newman C. , et al; CARDS Investigators. Stroke prediction and stroke prevention with atorvastatin in the Collaborative Atorvastatin Diabetes Study (CARDS). Diabet Med 2007; 24 (12) 1313-1321
• 39 Everett BM, Glynn RJ, MacFadyen JG, Ridker PM. Rosuvastatin in the prevention of stroke among men and women with elevated levels of C-reactive protein: justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER). Circulation 2010; 121 (01) 143-150
• 40 Shepherd J, Blauw GJ, Murphy MB. , et al; PROSPER study group. PROspective Study of Pravastatin in the Elderly at Risk. Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomised controlled trial. Lancet 2002; 360 (9346): 1623-1630
• 41 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 (9326): 7-22
• 42 Sacks FM, Pfeffer MA, Moye LA. , et al. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. Cholesterol and Recurrent Events Trial Investigators. N Engl J Med 1996; 335 (14) 1001-1009
• 43 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
• 44 LaRosa JC, Grundy SM, Waters DD. , et al; Treating to New Targets (TNT) Investigators. Intensive lipid lowering with atorvastatin in patients with stable coronary disease. N Engl J Med 2005; 352 (14) 1425-1435
• 45 Athyros VG, Papageorgiou AA, Mercouris BR. , et al. Treatment with atorvastatin to the National Cholesterol Educational Program goal versus ‘usual’ care in secondary coronary heart disease prevention. The GREek Atorvastatin and Coronary-heart-disease Evaluation (GREACE) study. Curr Med Res Opin 2002; 18 (04) 220-228
• 46 Collins R, Armitage J, Parish S, Sleight P, Peto R. ; Heart Protection Study Collaborative Group. 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
• 47 Amarenco P, Bogousslavsky J, Callahan III A. , et al; Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) Investigators. High-dose atorvastatin after stroke or transient ischemic attack. N Engl J Med 2006; 355 (06) 549-559
• 48 Milionis HJ, Giannopoulos S, Kosmidou M. , et al. Statin therapy after first stroke reduces 10-year stroke recurrence and improves survival. Neurology 2009; 72 (21) 1816-1822
• 49 Ní Chróinín D, Callaly EL, Duggan J. , et al. Association between acute statin therapy, survival, and improved functional outcome after ischemic stroke: the North Dublin Population Stroke Study. Stroke 2011; 42 (04) 1021-1029
• 50 Martínez-Sánchez P, Fuentes B, Martínez-Martínez M. , et al. Treatment with statins and ischemic stroke severity: does the dose matter?. Neurology 2013; 80 (19) 1800-1805
• 51 Blanco M, Nombela F, Castellanos M. , et al. Statin treatment withdrawal in ischemic stroke: a controlled randomized study. Neurology 2007; 69 (09) 904-910
• 52 Hackam DG, Austin PC, Huang A. , et al. Statins and intracerebral hemorrhage: a retrospective cohort study. Arch Neurol 2012; 69 (01) 39-45
• 53 Moro C, Hernández-Madrid A, Matía R. Non-antiarrhythmic drugs to prevent atrial fibrillation. Am J Cardiovasc Drugs 2010; 10 (03) 165-173
• 54 Fang WT, Li HJ, Zhang H, Jiang S. The role of statin therapy in the prevention of atrial fibrillation: a meta-analysis of randomized controlled trials. Br J Clin Pharmacol 2012; 74 (05) 744-756
• 55 Fauchier L, Pierre B, de Labriolle A, Grimard C, Zannad N, Babuty D. Antiarrhythmic effect of statin therapy and atrial fibrillation a meta-analysis of randomized controlled trials. J Am Coll Cardiol 2008; 51 (08) 828-835
• 56 Yang Q, Qi X, Li Y. The preventive effect of atorvastatin on atrial fibrillation: a meta-analysis of randomized controlled trials. BMC Cardiovasc Disord 2014; 14: 99
• 57 Choi JY, Seo WK, Kang SH. , et al. Statins improve survival in patients with cardioembolic stroke. Stroke 2014; 45 (06) 1849-1852
• 58 Ntaios G, Papavasileiou V, Makaritsis K. , et al. Statin treatment is associated with improved prognosis in patients with AF-related stroke. Int J Cardiol 2014; 177 (01) 129-133
• 59 Wang D, Liu B, Tao W, Hao Z, Liu M. Fibrates for secondary prevention of cardiovascular disease and stroke. Cochrane Database Syst Rev 2015; (10) CD009580
• 60 Jun M, Foote C, Lv J. , et al. Effects of fibrates on cardiovascular outcomes: a systematic review and meta-analysis. Lancet 2010; 375 (9729): 1875-1884
• 61 Bloomfield Rubins H, Davenport J, Babikian V. , et al; 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 (23) 2828-2833
• 62 De Caterina R, Salvatore T, Marchioli R. Cholesterol-lowering interventions and stroke: insights from IMPROVE-IT. Atherosclerosis 2016; 248: 216-218
• 63 Milionis H, Barkas F, Ntaios G. , et al. Proprotein convertase subtilisin kexin 9 (PCSK9) inhibitors to treat hypercholesterolemia: effect on stroke risk. Eur J Intern Med 2016; 34: 54-57
• 64 Sabatine MS, Giugliano RP, Keech A. , et al. Rationale and design of the Further cardiovascular OUtcomes Research with PCSK9 Inhibition in subjects with Elevated Risk trial. Am Heart J 2016; 173: 94-101
• 65 Schwartz GG, Bessac L, Berdan LG. , et al. Effect of alirocumab, a monoclonal antibody to PCSK9, on long-term cardiovascular outcomes following acute coronary syndromes: rationale and design of the ODYSSEY outcomes trial. Am Heart J 2014; 168 (05) 682-689