Stroke Prevention By Aggressive Reduction In Cholesterol Levels Research Articles

Intensive Statin Therapy After Stroke or Transient Ischemic Attack

Anyone aware of the conflicting data regarding the importance of circulating cholesterol in stroke will welcome the results of the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial.1 Unlike with coronary heart disease, epidemiological studies often failed to demonstrate an association between elevated cholesterol levels and stroke incidence.2 However, many studies did not take into account the distinct underlying pathophysiological mechanisms of stroke and instead examined conflated end points such as a combination of ischemic and hemorrhagic stroke, or total ischemic stroke without subtyping, and others did not evaluate cholesterol subfractions. In contrast, epidemiological studies that carefully distinguished ischemic and hemorrhagic strokes generally found both a modest association of elevated cholesterol with increased risk of ischemic events and of low cholesterol with an increased risk of intracerebral hemorrhage.3 HMG-CoA reductase inhibitors or “statins,” which inhibit the synthesis of cholesterol that contributes to atheroma development and progression, have been shown to reduce the risk of first stroke in patients with established coronary heart disease, diabetes, or multiple cardiovascular risk factors.4 Indeed, as our cardiology colleagues kept finding the benefit of lower and lower cholesterol targets for reducing the risk of coronary heart disease events,5 the jury remained out as to what role, if any, that statins played in stroke patients without established coronary heart disease. Subset analyses of prior clinical trials had suggested, but not definitely proved, a benefit of statin therapy in patients with prior strokes. A retrospective subset analysis of 3280 subjects with a remote (mean 4.3 years) history of symptomatic ischemic cerebrovascular disease enrolled in the Heart Protection Study (HPS) showed that simvastatin therapy yield a 20% reduction in major vascular events (0.80, 0.71 to 0.92).6 This benefit was driven by a reduction in myocardial infarction and vascular death end …

Atorvastatin

An association between hypercholesterolaemia and ischaemic stroke has not yet been clearly defined by observational studies. In clinical trials, however, cholesterol-lowering treatments appear to consistently reduce stroke risk. Data are now available from various primary prevention studies - ALLHAT-LLT (Antihypertensive and Lipid-Lowering treatment to prevent Heart Attack, Lipid-Lowering Therapy), ASCOT-LLA (Anglo-Scandinavian Cardiac Outcomes Trial, Lipid-Lowering Arm), CARDS (Collaborative Atorvastatin Diabetes Study, WOSCOPS (West of Scotland COronary Prevention Study) - and secondary prevention studies - 4S (Scandinavian Simvastatin Survival Study), CARE (Cholesterol and Recurrent Events), GREACE (GREek Atorvastatin and Coronary-heart-disease Evaluation), HPS (Heart Protection Study), LIPID (Long-term Intervention with Pravastatin in Ischaemic Disease), MIRACL (Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering), SPARCL (Stroke Prevention by Aggressive Reduction in Cholesterol Levels), TNT (Treating to New Targets) - confirming the ability of statins to reduce stroke risk. Regarding primary prevention, post hoc analyses showed pravastatin reduced the relative risk of stroke by 9-11% (not statistically significant) in the ALLHAT-LLT and WOSCOPS trials, whereas atorvastatin reduced this risk by 27-48% in the ASCOT-LLA (p = 0.024) and CARDS trials. It remains to be established in prospective studies whether cholesterol-lowering is effective in the primary prevention of stroke. Regarding secondary prevention, in five placebo-controlled studies (4S, CARE, HPS, LIPID, MIRACL) involving a total of >40 000 patients with coronary heart disease (CHD), statin therapy reduced the relative risk of fatal or nonfatal stroke by 19-50% (p < or = 0.048); the largest decrease was produced by atorvastatin in the MIRACL study (-50%, p = 0.045). In addition, high-dosage atorvastatin reduced stroke risk by 25% (p = 0.02) relative to lower-dosage therapy in the TNT trial, and by 47% (p = 0.034) relative to 'usual' care in the GREACE study. A post hoc analysis of data for 3280 HPS study participants who had had a previous stroke revealed that simvastatin reduced major vascular events by 20% (p = 0.001).The SPARCL study assessed the secondary preventive efficacy of atorvastatin versus placebo in 4731 patients with a history of stroke or transient ischaemic attack (TIA), but without CHD. Atorvastatin reduced the adjusted relative risk of fatal or nonfatal stroke by 16% (p = 0.03), and that of fatal stroke alone by 43% (p = 0.03). Among secondary study endpoints, atorvastatin reduced the relative risks of stroke and TIA (-23%; p < 0.001), TIA alone (-26%; p = 0.004), and ischaemic stroke (-22%; p = 0.01). Overall, SPARCL study findings suggest that intensive atorvastatin therapy should be started immediately after a stroke or TIA. In summary, atorvastatin has developed a well defined role in the primary and secondary prevention of cerebrovascular disease, and appears to have a particularly prominent place in preventing such disease in CHD patients, and in the post-stroke and post-TIA setting in patients without CHD.

Stroke — An Equal Opportunity for the Initiation of Statin Therapy

Given the disparity in the numbers of cerebrovascular and cardiovascular clinical trials and the similarities in the interventions tested, it seems that stroke neurologists have had to peer at clinical-trial results over the shoulders of their cardiologist colleagues so often that they are at risk for chronic neck ailments. If only for evening the score a little, the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) investigators deserve our gratitude. In their randomized clinical trial that was specifically designed to test statin therapy for the prevention of stroke recurrence in patients who had had a stroke or transient ischemic . . .

Effect of statins in stroke prevention

This paper reviews recent studies into the outcomes of clinical trials in which statin therapy has been used in the prevention and treatment of strokes. Epidemiologic studies found no or little association between blood cholesterol levels and stroke. Randomized trials have confirmed that LDL lowering decreased the risk of stroke, in diabetic or hypertensive patients with 'normal' LDL cholesterol at baseline, and in patients with coronary artery disease, with respectively 48, 27 and 25% reduction in stroke incidence. A meta-analysis of trials showed that the greater the LDL cholesterol reduction, the greater the intima-media thickness and stroke risk reductions. Even if statins also have 'pleiotropic' effects, their main action seems to be through LDL reduction. The Heart Protection Study only included strokes that occurred 4.6 years before--a time when the stroke event rate is low and the cardiac event rate is high, and so may not have had the power to find a true effect of LDL cholesterol lowering in preventing recurrent stroke. The Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial may give a definite answer because SPARCL investigators included 4732 patients with brain infarction or transient ischemic attacks and no history of myocardial infarction within 6 months of their stroke event, at a time when the expected stroke rate is very high and the myocardial infarction rate is very low. The results should be announced by mid-2006. The positive effect of statins on stroke observed in trials of patients with coronary heart disease depended mainly on between-group LDL reduction, but other mechanisms could be involved. Though effective in prevention of major coronary events after a first stroke, statins have not yet been proven effective in prevention of recurrent stroke.

HMG-CoA Reductase Inhibitors Improve Acute Ischemic Stroke Outcome

HomeStrokeVol. 36, No. 11HMG-CoA Reductase Inhibitors Improve Acute Ischemic Stroke Outcome Free AccessLetterPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessLetterPDF/EPUBHMG-CoA Reductase Inhibitors Improve Acute Ischemic Stroke Outcome Bruce Ovbiagele, MD Bruce OvbiageleBruce Ovbiagele UCLA Stroke Center, Los Angeles, Calif Search for more papers by this author Originally published20 Oct 2005https://doi.org/10.1161/01.STR.0000185700.38737.5eStroke. 2005;36:2344Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: October 20, 2005: Previous Version 1 To the Editor:Dr. Moonis and colleagues are to be congratulated on an important study that provides further insight into the usefulness of statins in improving ischemic stroke outcome.1However, I disagree with the premise of the first sentence of the introductory section of their article, which reads as follows: “Prospective studies have demonstrated that HMG-CoA reductase inhibitors (statins) reduce stroke recurrence by 20% to 25%.”2,3 Indeed, there is little basis for drawing this conclusion from the studies cited to support this statement.The Scandinavian Simvastatin Survival Study demonstrated that statin treatment reduced the risk of primary stroke in a cohort of patients with coronary disease and high low-density lipoprotein cholesterol.2 Furthermore, although a post hoc analysis, not prespecified, of subjects entered into the Heart Protection Study with a history of symptomatic ischemic cerebrovascular disease revealed a significant reduction in major vascular events in favor of simvastatin, there was no beneficial treatment effect for stroke prevention by the statin agent.4 As such, currently there remains no convincing data that statins are beneficial in reducing recurrent stroke. The ongoing SPARCL study will likely shed further light on this issue.51 Moonis M, Kane K, Schwiderski U, Sandage BW, Fisher M. HMG-CoA reductase inhibitors improve acute ischemic stroke outcome. Stroke. 2005; 36: 1298–1300.LinkGoogle Scholar2 Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet. 1994; 344: 1383–1389.MedlineGoogle Scholar3 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.CrossrefMedlineGoogle Scholar4 Heart Protection Study Collaborative Group. 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.CrossrefMedlineGoogle Scholar5 Amarenco P, Bogousslavsky J, Callahan AS, Goldstein L, Hennerici M, Sillsen H, Welch MA, Zivin J. Design and baseline characteristics of the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) study. Cerebrovasc Dis. 2003; 16: 389–395.CrossrefMedlineGoogle ScholarstrokeahaStrokeStrokeStroke0039-24991524-4628Lippincott Williams & WilkinsResponse:Moonis Majaz, , MD, MRCPI, DM01112005I want to thank the Dr. Bruce Ovbiagele for his thoughtful comments and his interest in our article.1 I agree that the data on risk reduction of recurrent ischemic stroke is largely based on studies in patients with ischemic heart disease.2 Interestingly, the American Stroke Association still recommends using statins in patients with ischemic stroke with or without ischemic heart disease with the aim of secondary prevention. Space limitation and the fact that the objective of this research report was to assess the effects of statins on stroke outcome and not stroke recurrence did not allow room for a more detailed discussion on statins and risk reduction of recurrent ischemic stroke. Results of the SPARCL trial should be helpful in answering this question.3 Previous Back to top Next FiguresReferencesRelatedDetailsCited By Li A, Lv S, Yu Z, Zhang Y, Ma H, Zhao H, Piao H, Li S, Zhang N and Sun C (2013) Simvastatin attenuates hypomyelination induced by hypoxia–ischemia in neonatal rats, Neurological Research, 10.1179/016164110X12670144737774, 32:9, (945-952), Online publication date: 1-Nov-2010. November 2005Vol 36, Issue 11 Advertisement Article InformationMetrics https://doi.org/10.1161/01.STR.0000185700.38737.5ePMID: 16239633 Originally publishedOctober 20, 2005 PDF download Advertisement

Response

HomeStrokeVol. 36, No. 11HMG-CoA Reductase Inhibitors Improve Acute Ischemic Stroke Outcome Free AccessLetterPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessLetterPDF/EPUBHMG-CoA Reductase Inhibitors Improve Acute Ischemic Stroke Outcome Bruce Ovbiagele, MD Bruce OvbiageleBruce Ovbiagele UCLA Stroke Center, Los Angeles, Calif Search for more papers by this author Originally published20 Oct 2005https://doi.org/10.1161/01.STR.0000185700.38737.5eStroke. 2005;36:2344Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: October 20, 2005: Previous Version 1 To the Editor:Dr. Moonis and colleagues are to be congratulated on an important study that provides further insight into the usefulness of statins in improving ischemic stroke outcome.1However, I disagree with the premise of the first sentence of the introductory section of their article, which reads as follows: “Prospective studies have demonstrated that HMG-CoA reductase inhibitors (statins) reduce stroke recurrence by 20% to 25%.”2,3 Indeed, there is little basis for drawing this conclusion from the studies cited to support this statement.The Scandinavian Simvastatin Survival Study demonstrated that statin treatment reduced the risk of primary stroke in a cohort of patients with coronary disease and high low-density lipoprotein cholesterol.2 Furthermore, although a post hoc analysis, not prespecified, of subjects entered into the Heart Protection Study with a history of symptomatic ischemic cerebrovascular disease revealed a significant reduction in major vascular events in favor of simvastatin, there was no beneficial treatment effect for stroke prevention by the statin agent.4 As such, currently there remains no convincing data that statins are beneficial in reducing recurrent stroke. The ongoing SPARCL study will likely shed further light on this issue.51 Moonis M, Kane K, Schwiderski U, Sandage BW, Fisher M. HMG-CoA reductase inhibitors improve acute ischemic stroke outcome. Stroke. 2005; 36: 1298–1300.LinkGoogle Scholar2 Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet. 1994; 344: 1383–1389.MedlineGoogle Scholar3 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.CrossrefMedlineGoogle Scholar4 Heart Protection Study Collaborative Group. 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.CrossrefMedlineGoogle Scholar5 Amarenco P, Bogousslavsky J, Callahan AS, Goldstein L, Hennerici M, Sillsen H, Welch MA, Zivin J. Design and baseline characteristics of the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) study. Cerebrovasc Dis. 2003; 16: 389–395.CrossrefMedlineGoogle ScholarstrokeahaStrokeStrokeStroke0039-24991524-4628Lippincott Williams & WilkinsResponse:Moonis Majaz, , MD, MRCPI, DM01112005I want to thank the Dr. Bruce Ovbiagele for his thoughtful comments and his interest in our article.1 I agree that the data on risk reduction of recurrent ischemic stroke is largely based on studies in patients with ischemic heart disease.2 Interestingly, the American Stroke Association still recommends using statins in patients with ischemic stroke with or without ischemic heart disease with the aim of secondary prevention. Space limitation and the fact that the objective of this research report was to assess the effects of statins on stroke outcome and not stroke recurrence did not allow room for a more detailed discussion on statins and risk reduction of recurrent ischemic stroke. Results of the SPARCL trial should be helpful in answering this question.3 Previous Back to top Next FiguresReferencesRelatedDetailsCited By Li A, Lv S, Yu Z, Zhang Y, Ma H, Zhao H, Piao H, Li S, Zhang N and Sun C (2013) Simvastatin attenuates hypomyelination induced by hypoxia–ischemia in neonatal rats, Neurological Research, 10.1179/016164110X12670144737774, 32:9, (945-952), Online publication date: 1-Nov-2010. November 2005Vol 36, Issue 11 Advertisement Article InformationMetrics https://doi.org/10.1161/01.STR.0000185700.38737.5ePMID: 16239633 Originally publishedOctober 20, 2005 PDF download Advertisement

Statins and stroke prevention

Data from studies on the benefits of statins in coronary artery disease patients in preventing recurrent primary and secondary cardiac endpoints, as well as ischemic strokes, imply the potential value of statins in recurrent ischemic stroke prevention without coronary artery disease symptoms or, by extension, primary ischemic stroke prevention. However, data on the latter are lacking, although the ongoing Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) study is designed to answer that question. Until these data become available, clinicians are justified in using statins to avert recurrent ischemic strokes due to atherosclerosis, especially if elevated total cholesterol, increased low-density lipoprotein cholesterol, and/or reduced high-density lipoprotein cholesterol, as specified in the National Cholesterol Education Program Third Adult Treatment Panel, are present. This article reviews the pathophysiology of atherosclerosis, particularly the major components of atheromas of cholesterol, smooth muscle cells, inflammation, "foam cells," and connective tissue elements. Emphasis is placed on the first three and the results of statin trials in coronary artery disease, as well as the beneficial pleiotrophic effects of statins in ischemic strokes.

Prevention and Health Services Delivery

The burden of stroke to the health care system in the United States continues to increase. Stroke-related hospital admissions grew from 580 000 in 1988 to 820 000 in 1997, an 18.6% increase after age adjustment.1 More effective stroke prevention provides the primary means of reducing these alarming statistics. This can be accomplished through better implementation of known preventive strategies2 and through research into new approaches to stroke prevention. Diet can affect stroke risk, with epidemiological studies indicating an inverse relationship between fruit and vegetable consumption and cardiovascular events.2 For example, one study including individuals free of cardiovascular disease at baseline found that the relative risk (RR) of stroke was reduced by 31% (RR, 0.69; 95% CI, 0.52 to 0.92) for persons in the highest quintile of fruit and vegetable intake.3 Analysis of data from the National Health and Nutrition Examination Survey (NHANES) Epidemiologic Follow-up Study supports these results.4 The study included 9608 adults aged 25 to 74 years who were free of cardiovascular disease at a baseline evaluation between 1971 and 1975. Consumption of fruits and vegetables ≥3 times per day compared with <1 time per day was associated with a 27% lower stroke incidence (RR, 0.73; 95% CI, 0.57 to 0.95) after adjustment for potential confounders, suggesting the benefit is not attributable to a healthy-user effect. The results reinforce present recommendations for an intake of 5 servings of fruits and vegetables daily. Because fruits and vegetables contain antioxidants, antioxidant food supplements might be expected to have similar benefits. However, a 3-year study of patients with coronary heart disease, low levels of high-density lipoprotein cholesterol, and normal levels of low-density lipoprotein cholesterol found no reduction in cardiovascular end points (death, myocardial infarction, stroke, and revascularization procedures) with the use of antioxidant supplements (800 IU …

Lipid and Stroke

1) Amarenco P, Labreuche J, Lavallee P, et al. Statins in stroke prevention and carotid atherosclerosis: systematic review and up-to-date meta-analysis. Stroke 2004; 35:2902-2909.2) 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; 364:685-696.3) Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterollowering with simvastatin in 5963 people with diabetes: a randomised placebo-controlled trial. Lancet 2003; 361:2005-2016.4) 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; 361:1149-1158.5) Amarenco P, Bogousslavsky J, Callahan AS, et al. Design and baseline characteristics of the stroke prevention by aggressive reduction in cholesterol levels (SPARCL) study. Cerebrovasc Dis 2003; 16:389-395.

Design and Baseline Characteristics of the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) Study

Evidence suggests that statin therapy reduces the risk of stroke in patients with coronary heart disease (CHD), but its benefit for patients with cerebrovascular disease and no history of CHD remains uncertain. The Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) Study is a prospective, multi-centre, double-blind, randomised, placebo-controlled trial designed to evaluate the effects of atorvastatin 80 mg/day in patients who previously experienced a stroke or transient ischaemic attack, but who have no known CHD. A total of 4,732 patients have been enrolled, and the data collection phase of the study is expected to be completed by October 2004. SPARCL is the first study primarily designed to prospectively evaluate the effect of statin treatment in secondary stroke prevention.