Clinical trials: Evidence and unanswered questions--hyperlipidaemia

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.     

Drug insight: translating evidence on statin therapy into clinical benefits

The Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial showed that, in patients who had experienced a stroke or transient ischemic attack, treatment with high-dose atorvastatin over a 5-year period significantly reduced the risk of a subsequent stroke. SPARCL also showed that the benefits of an intensive statin regimen in these patients extended beyond reduction of secondary stroke to include significant reductions in future major vascular events. SPARCL has established statin treatment as a key component of a multimodal vascular risk reduction strategy after an ischemic stroke or transient ischemic attack. It is recommended that the vast majority of patients with ischemic cerebrovascular events should be started on statin therapy, preferably before discharge from acute hospitalization for their index event, with the goal of achieving and maintaining consensus guideline cholesterol targets as soon and for as long as possible.     

Stroke prevention, blood cholesterol and statins

Statins have a good overall safety profile to date, with no increase in haemorrhagic stroke or cancer. They have favourable effects in the primary prevention of cardiovascular disease in high-risk young as well as elderly populations. Statins reduce the incidence of stroke in high-risk populations (mainly CHD patients, diabetics and hypertensives) even with a normal baseline blood cholesterol level, which argues for a global cardiovascular risk-based treatment strategy. As for CHD, stroke reduction was mainly observed in studies with large between-group LDL cholesterol difference. In patients with prior strokes, statins reduce the incidence of coronary events, but it is not yet proven that they actually reduce the incidence of recurrent strokes in secondary prevention. From a practical point of view, since there was a favourable treatment effect overall in stroke and TIA patients in HPS, it seems reasonable to treat stroke patients with a statin and total cholesterol >135 mg/dL (3.5 mmol/dL). On-going research is aiming to refine patient selection. As anticipated by current US recommendations, patients who are likely to benefit most are those with carotid atherosclerosis, diabetes mellitus, previous coronary heart disease, hypertension, hypercholesterolaemia, or cigarette smoking and LDL cholesterol > 100 mg/dL.     

Meta-analysis of the cardiovascular benefits of intensive lipid lowering with statins

Chan DKY, O’Rourke F, Shen Q, Mak JCS, Hung WT. Meta‐analysis of the cardiovascular benefits of intensive lipid lowering with statins.
Acta Neurol Scand: 2011: 124: 188–195.
© 2010 John Wiley & Sons A/S. Objective – To evaluate the efficacy of intensive lipid lowering with higher‐dose statins. Methods – Meta‐analysis of seven randomized controlled trials comprising 50,972 participants. Results – Mean follow‐up was 3.1 years with mean age 63 years. Final LDL‐C levels in intensive lipid‐lowering group were 1.42–2.07 mmol/l compared to 2.1–3.5 mmol/l in the less intensive or control group. The intensive arm had significantly lower risks for stroke OR 0.80 (95% CI 0.71–0.89); major coronary events OR 0.74 (95% CI 0.65–0.83); cardiovascular disease (CVD) or coronary heart disease (CHD) deaths OR 0.84 (95% CI 0.74–0.95). Significantly higher liver enzyme abnormalities occurred in intensive group* (OR 3.96; 95% CI 2.08–7.53), but it was not associated with drug discontinuations (OR 1.20; 95% CI 0.88–1.64). Conclusion – In those at high risk of cardiovascular events, intensive lipid lowering with statins to LDL‐C level <2.1 mmol/l significantly reduces risk of stroke, major coronary events and CVD or CHD deaths compared to LDL‐C level ≥2.1 mmol/l. [*Correction added on 11 January 2011 after first online publication on 27 October 2010. The phrase, “Significantly higher liver enzyme abnormalities occurred in less intensive group”, was amended to “Significantly higher liver enzyme abnormalities occurred in intensive group”.]     

Statins and stroke prevention

Four randomized trials with a statin and one trial with a fibrate showed a modest but significant absolute reduction in the incidence of stroke in patients with a previous myocardial infarction. The reasons for the positive effect of statins on stroke end-point are unclear since, paradoxically, the link between serum cholesterol level and stroke has never been fully established. Furthermore, the positive results of statins trials were mainly obtained in patients with an average or a low serum cholesterol level. This suggests nonhypolipidemic effects of these drugs, so-called pleiotropic effects, acting on the biologic promoters of plaque instability. Statins have a good overall safety profile with no increase of hemorrhagic stroke and no increase in cancer. They have positive effects in primary prevention of cardiovascular disease in high-risk young as well as elderly populations. Statins reduced stroke incidence in high-risk (mainly CHD, diabetics and hypertensives) population even with a normal baseline blood cholesterol level, which argues for a global cardiovascular risk-based treatment strategy. In patients with prior strokes, statins likely reduce the incidence of cononary events, but it is not yet proven that statins actually reduce the incidence of recurrent strokes in secondary prevention. If current hypotheses are verified by ongoing trials, we may expect between 20 to 30 more stroke events avoided per 1,000 patients treated during 2 years with a lipid-lowering agent, which adds to the 28 stroke events prevented with an antiplatelet agent over the same time period. This would be one of the most significant advances in stroke and vascular dementia prevention since the era of aspirin therapy.     

Apolipoproteins as predictors of ischaemic stroke in patients with a previous transient ischaemic attack

BACKGROUND: Weak associations between total and LDL cholesterol and ischaemic stroke compared with coronary heart disease (CHD) are at odds with the similar effectiveness of statin drugs in preventing ischaemic stroke and CHD, suggesting that other lipid sub-fractions that are affected by statins might be better predictors of ischaemic stroke. Apolipoprotein B levels are reduced by statins and are a stronger predictor of CHD than total and LDL cholesterol in patients both on and off statins. However, there are very few published data on apolipoproteins and stroke risk and no studies in patients with previous transient ischaemic attack (TIA). METHODS: We performed a prospective cohort study of the associations of baseline total cholesterol, LDL, HDL, apolipoproteins A1 and B (apo A1; apo B) and risk of ischaemic stroke in 261 patients with previous TIA. Cox proportional hazards models were used to determine crude and multivariate-adjusted hazard ratios (HR) above versus below median values at 10-years follow-up. RESULTS: The apo B/apo A1 ratio was the strongest independent predictor of ischaemic stroke (HR=2.94, 95% CI 1.43-5.88, p=0.003) followed by apo B (HR=2.26, 95% CI 1.16-4.38, p=0.02). The associations between total cholesterol, LDL, HDL, LDL/HDL ratio and apo A1 and ischaemic stroke risk did not reach statistical significance. CONCLUSIONS: Apo B and the apo B/apo A1 ratio are predictive of ischaemic stroke in patients with previous TIA. Further studies are required to determine whether the prognostic value of apolipoprotein levels is maintained in patients on statins.     

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 4732 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.     

Inhibidores de la proproteína convertasa subtilisina/kexina tipo 9 (iPCSK9) en la prevención secundaria de episodios vasculares en pacientes con ictus isquémico: Documento de consenso y aplicaciones prácticas

IntroductionPatients with history of stroke or transient ischaemic attack present considerable risk of future vascular events. Reducing levels of low-density lipoprotein (LDL) cholesterol decreases the incidence of new vascular events, although in a substantial number of patients, the currently available lipid-lowering therapies fail to achieve the therapeutic goals recommended in clinical guidelines. The aim of this consensus statement is to provide updated information on the role of the proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors alirocumab and evolocumab in the secondary prevention of vascular events in patients with history of ischaemic stroke.MethodsA literature review was performed to identify the main evidence on the use of PCSK9 inhibitors in these patients and the recommended therapeutic targets of LDL cholesterol. The results were discussed in 2 consensus meetings that constituted the basis for the drafting of the document.ConclusionsPCSK9 inhibitors are effective in reducing vascular risk in secondary prevention; evolocumab specifically has achieved this reduction in patients with history of ischaemic stroke. Moreover, both alirocumab and evolocumab present good safety profiles, even in patients achieving LDL cholesterol levels < 20 mg/dL, and no signs of cognitive impairment have been observed in patients treated with evolocumab who achieved very low levels of LDL cholesterol. In the light of this evidence, we provide practical recommendations about the use of PCSK9 inhibitors in secondary prevention of vascular events in patients with history of ischaemic stroke and follow-up of these patients.     

Stroke prevention, blood cholesterol, and statins

The risk of stroke increases with age, and hence the disease particularly affects the elderly, who are also at high risk for coronary heart disease. Epidemiological and observational studies have not shown a clear association between cholesterol concentrations and all causes of stroke. Large, long-term statin trials in patients with established or high risk for coronary heart disease have shown that statins decrease stroke incidence. These statin trials in a combined total of 70,020 patients indicate relative and absolute risk reductions for stroke of 21% and 0.9%, respectively. By comparison, the number of strokes prevented per 1000 patients treated for 5 years in patients with coronary heart disease is nine for statins versus 17.3 for antiplatelet drugs and 17 for antihypertensive drugs. Although the Heart Protection Study showed that statins lower the risk of major coronary events in patients with a previous stroke, statins may not lower stroke recurrence in these patients. In this review, we discuss the potential reasons for the effects of statins on stroke and the mechanisms of action. Treatment strategies on the basis of global cardiovascular risk may be most effective. Additional studies in patients representative of the typical stroke population are needed.     

Advantages of lipid-lowering therapy in cerebral ischemia: role of HMG-CoA reductase inhibitors

Dyslipemia as a risk factor for ischemic stroke and indications for statins in the prevention of ischemic stroke are revised. The role of cholesterol levels as a risk factor for ischemic stroke is controversial. This could be due to failures in the design of early epidemiological studies. Recent studies, however, do suggest a clearer risk relationship between cholesterol levels and ischemic stroke. Studies conducted on the prevention of ischemic heart disease (IHD) with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins), using pravastatin and simvastatin, unequivocally show reductions in overall mortality, cardiovascular mortality, acute myocardial infarction and other coronary events. These studies show a reduction in the risk of ischemic stroke, and although relative risk reduction is great, absolute risk reduction is low; the reasons for this are analyzed. Apart from lipid mechanisms, statins act on the atheroma plaque; they have antithrombotic and possibly neuroprotecting properties. Statins reduce the number of strokes due to the decrease of atherothrombotic strokes, cardioembolic strokes secondary to IHD, and lacunar strokes related to atherothrombosis and probably to microatheromas. Although there are currently no specific studies available on the secondary prevention of stroke with statins, which are required to clarify certain points, according to European and American guidelines for prevention, statins would be indicated in the secondary prevention of atherothrombotic stroke, and in cardioembolic and lacunar stroke associated with clinical or silent atherosclerosis (IHD, peripheral artery disease). Patients with ischemic stroke of other etiologies, except for stroke in the young or other unusual causes, are patients with a high vascular risk (cardiac and cerebral) owing to the stroke itself, age and other vascular risk factors, and they should also be treated with statins, at least from the point of view of primary prevention of IHD. Natural statins (pravastatin and simvastatin) play an essential part in secondary prevention of ischemic stroke, together with antiaggregants, anticoagulants, angiotensin-converting enzyme inhibitors and the treatment of other vascular risk factors.     

HMG-CoA reductase inhibitors (statins): a promising approach to stroke prevention

Statins represent a promising class of agents to prevent stroke. In randomized trials of middle-aged patients with coronary artery disease, statins reduce the incidence of stroke. The reduction in stroke may not be solely related to cholesterol or low-density lipoprotein reduction but may involve nonsterol mechanisms effects on endothelial cells, macrophages, platelets, and smooth muscle cells. Statins also reduce the size of cerebral infarction in a murine stroke model, suggesting a neuroprotective effect. The best current evidence for stroke prevention is with pravastatin and simvastatin. Pravastatin reduces the risk of stroke in patients with coronary artery disease and average cholesterol levels; simvastatin reduces the risk of the combined endpoint of stroke and transient ischemic attack in hypercholesterolemic patients with coronary artery disease. Future studies of statins are needed in stroke populations, particularly the elderly.     

Niacin for Stroke Prevention: Evidence and Rationale

Low levels of high‐density lipoprotein (HDL) cholesterol are associated with increased atherothrombotic events, including stroke. Niacin is a safe and effective means of raising HDL, yet its role in stroke prevention is not well characterized. The purpose of the study is to determine the role of niacin in stroke prevention. A search of the PUBMED database using the keywords niacin, stroke, atherosclerosis, and/or carotid artery was undertaken to identify studies for review. National guidelines from the American Heart Asssociation and National Cholesterol Education Program were reviewed. Treatment of low serum HDL (<40 mg/dL) is an identified goal of dyslipidemic therapy. Niacin is effective in raising HDL levels and reducing cardiovascular events in individuals with high vascular risk and can be used for treatment of stroke patients with low serum HDL. Niacin can be used safely in combination with statins, the first‐line dyslipidemic treatment for secondary stroke risk reduction, with increased efficacy. Studies are needed to better define the role for niacin in secondary stroke prevention. Treatment of stroke patients with extended‐release (ER) of niacin, alone or in combination with statins, should be considered in stroke patients with atherosclerotic mechanisms with low serum HDL‐C levels.     

Lipid profile,statin use,and outcome after intravenous thrombolysis for acute ischaemic stroke

BACKGROUND: Low cholesterol levels have been associated with an increased risk of haemorrhagic stroke. This study investigated whether lipid levels or prior statin use influence outcome in patients with acute ischaemic stroke treated with IV thrombolysis. METHODS: The relation between admission lipid levels or statin use and both the development of symptomatic intracerebral haemorrhage (sICH) and 3-months functional outcome was assessed in a prospective hospital-based stroke registry comprising 252 patients treated with IV tissue plasminogen activator (tPA). The fasting status of the patients was unknown. Favourable outcome at 3 months was defined as a modified Rankin scale score 相似文献   

Treatment with simvastatin and low-dose aspirin depresses thrombin generation in patients with coronary heart disease and borderline-high cholesterol levels

Aspirin and statins are beneficial in coronary heart disease across a broad range of cholesterol levels. We assessed the effects of low-dose aspirin (75 mg daily) on thrombin generation in patients with coronary heart disease and average blood cholesterol levels. We also investigated whether in patients with borderline-high cholesterol level who have been already taking aspirin, additional treatment with simvastatin would affect thrombin generation. Seven-day treatment with low-dose aspirin decreased thrombin generation ex vivo only in patients with total cholesterol < or = 5.2 mmol/L. In patients with higher cholesterol levels aspirin had no effect. In these patients, already taking low-dose aspirin, additional three-month simvastatin treatment resulted in a reduction of thrombin generation. This demonstrates that low-dose aspirin depresses thrombin generation only in subjects with desirable blood cholesterol levels, while in others, with borderline-high cholesterol, thrombin formation is being reduced following the addition of simvastatin.     

Effect of pretreatment with statins on the severity of acute ischemic cerebrovascular events

OBJECTIVE: Treatment with statins reduces the risk of ischemic stroke among patients at increased risk for vascular disease. Recent experimental data suggest neuroprotective properties of statins in acute cerebral ischemia. We investigated whether a premedication with statins is associated with a better outcome in patients with acute ischemic cerebrovascular events. METHODS: Within a cross-sectional study, nested in a cohort we identified 1691 patients with a recent ischemic stroke or transient ischemic attack. Clinical severity of the vascular event was evaluated by the modified Rankin Scale (mRS) after 1 week. By means of multivariate logistic regression modeling, we determined the influence of prior statin use on stroke severity with adjustment for potential confounding factors. RESULTS: Severe stroke, defined as a modified Rankin Scale of 5 or 6 (n=231; 14%), was less frequent in patients receiving statin treatment before the event (6% vs. 14%, OR=0.37; 95% CI 0.19 to 0.74; p=0.004). This association remained significant after adjustment for confounding factors. We found a significant interaction between the presence of diabetes and the effect of pretreatment with statins on stroke outcome. Of the patients with diabetes, none of those on statin treatment but 16% of those without a statin had a bad outcome. After exclusion of the group of diabetic patients with prior statin medication, the protective effect was reduced and not statistically significant anymore. CONCLUSIONS: Pretreatment with statins seems to be associated with reduced clinical severity in patients with acute ischemic cerebrovascular events, particularly in patients with diabetes.     

What Proportion of Patients Admitted with Stroke or Transient Ischemic Attack May Be Suitable for Newer Cholesterol-Lowering Treatment?

BackgroundProtein convertase subtilisin–kexin type 9 (PCSK9) inhibitors effectively clear low-density lipoprotein cholesterol (LDL-C) and non-high-density lipoprotein cholesterol (non-HDL-C). We evaluated stroke admissions potentially eligible for more intensive cholesterol treatment.MethodsRetrospective analysis of consecutive admissions to a hyperacute stroke unit over 5 months in 2017. Records were individually searched. Data were collected on diagnosis, risk factors, and stroke work-up. European Society of Cardiology and European Atherosclerosis Society guidelines for the management of dyslipidaemias were used for screening patients eligible for PCSK9 inhibitors.ResultsOf 650 patient admissions: 351 (54%) had acute ischemic stroke or transient ischemic attack (TIA), 80 (12%) hemorrhage, and 219 (34%) mimic syndromes. Patients with hemorrhage (n = 80), mimic syndromes (n = 219), and absent LDL-C, or non-HDL-C testing (n = 27) were subsequently excluded. 324 patients with acute ischemic stroke and TIA were further screened for PCSK9-inhibitor treatment eligibility. Forty-one (13%) patients with LDL-C greater than or equal to 1.8mmol/L (≥70 mg/dL) on maximal tolerated statin dose and with concomitant “very high vascular risk” were identified. “Very high vascular risk” was defined as a documented history of cardiovascular disease and/or peripheral arterial disease. Of 41 patients eligible for PCSK9 inhibitors, median age was 82 years (range 53-96); median vascular risk factors were 2 (range 1-5); 7 (17%) had TIA; 13 (31%) had history of preceding cerebrovascular events, 13 (31%) diabetes mellitus, 17 (42%) cardioembolic events, 9 (22%) lacunar syndrome, 11 (22%) symptomatic internal carotid artery stenosis (n = 9 were >70%), and 4 (10%) undetermined aetiology. Eighty-three percent patients eligible for PCSK9 inhibitors also had non-HDL-C values greater than or equal to 2.6 mmol/L.ConclusionsUp to 13% of unselected acute ischemic stroke or TIA patients admitted to a hyper-acute stroke unit were potentially suitable for more intensive cholesterol treatment. Our data may act as a useful guide for sample size selection in future stroke trials testing PCSK9 inhibitors.     

Evidence with antiplatelet therapy and ADP-receptor antagonists

Antiplatelet drugs have been shown to prevent a range of atherothrombotic events, including transient ischaemic attack (TIA) and ischaemic stroke. Clopidogrel and ticlopidine are adenosine diphosphate (ADP)-receptor antagonists that inhibit ADP-induced fibrinogen binding to platelets, a necessary step in the platelet aggregation process. The Antithrombotic Trialists' Collaboration recently published a major meta-analysis that assessed the effect of antiplatelet therapy in patients with various manifestations of atherosclerosis. In total, this analysis included 135,000 patients in comparisons of antiplatelet agents versus control and 77,000 patients in comparisons of different antiplatelet regimens. This meta-analysis found that overall, antiplatelet therapy reduces the combined odds of stroke, myocardial infarction (MI) or vascular death by 22%, and that antiplatelet agents reduce the odds of a non-fatal stroke by 25% over a wide range of patients with or without a history of cerebrovascular disease. In the CAPRIE trial of clopidogrel versus acetylsalicylic acid (ASA), there was a 10% odds reduction for stroke, MI or vascular death in favour of clopidogrel (p = 0.03). In a meta-analysis performed by the Cochrane Stroke Group, ADP-receptor antagonist therapy significantly reduced the odds of a serious vascular event (stroke, MI or vascular death) by 9% (2p = 0.01) and of any stroke by 12%. The safety/tolerability profile of clopidogrel was superior to that of ticlopidine, and at least as good as that of ASA. In CURE, a long-term benefit was observed with the use of clopidogrel on top of standard therapy (including ASA in all patients), with a 20% relative risk reduction for the primary endpoint of cardiovascular death, MI or stroke (p < 0.001) in patients with unstable angina and non-Q-wave MI. A consistent benefit was seen across all patient subgroups, including patients with a previous history of stroke. More recently, CREDO has demonstrated the incremental benefit of prolonged use of clopidogrel on top of ASA in patients undergoing elective PCI, with a 27% reduction in the combined risk of death, MI or stroke after 12 months of therapy (p = 0.02) and a 25% reduction in stroke over the same time period. The MATCH trial is currently being conducted to test the hypothesis that long-term administration of clopidogrel on top of ASA is superior to clopidogrel alone for the reduction of major ischaemic events in patients with recent TIA or ischaemic stroke who are at high risk of atherothrombotic recurrence. Further trials of clopidogrel on top of standard therapy (including ASA) are planned in neurology; these include SPS3, in patients with small subcortical strokes, and ATARI, in patients who have recently recovered from a TIA.     

Family History is Related to High Risk of Recurrent Events after Ischemic Stroke or Transient Ischemic Attack

ObjectivePrior data suggest paternal or sibling stroke was associated with increased risk of offspring stroke. Whether family history of cardiovascular disease (FHc) predicts risk of stroke recurrence remains unclear, we aim to determine this issue on patients with ischemic stroke (IS) or transient ischemic attack (TIA).Materials and MethodsThis is a post hoc analysis based on the Third China National Stroke Registry III. IS/TIA patients with data of FHc status were included. FHc was defined as family history of coronary heart disease (CHD) or stroke among first-degree relatives (include parents, children, and siblings (same parents)). Cox proportional hazards regression models were performed to assess the association between FHc and recurrent events at 1 year follow-up.ResultsTotally 14,208 patients with verified FHc status were included, 4,454 (31.3%) were female and the median (IQR) age was 62.0 (54.0, 70.0) years. Of these, 294 (2.1%), 726 (5.1%) and 1936 (13.6%) had family history of both CHD and stroke, family history of CHD, and family history of stroke only, respectively. Using multivariable Cox models adjusted for age, sex, and vascular risk factors, we found that patients with FHc experienced higher risk of stroke recurrence (HR=1.151, 95%CI=1.000-1.324) and combined vascular events (HR=1.186, 95%CI=1.036-1.358) at 1 year compared with those without FHc. In sensitivity analysis on patients who received primary secondary prevention treatment of antiplatelet and statins, the association persisted.ConclusionsFHc is associated with increased risk of stroke recurrence even under primary secondary prevention treatment.     

Use of statins in CNS disorders.

It is well established that 3-hydroxy-3-methyglutaryl coenzyme A (HMG-CoA) reductase inhibitors ("statins") reduce cholesterol levels and prevent coronary heart disease (CHD). Although a causal relation between elevated cholesterol levels and stroke has not been well defined, a number of large secondary prevention studies and meta-analyses have shown that statin therapy reduces stroke in patients with CHD and hypercholesterolemia. In addition to the vascular effects of statins (stabilization of atherosclerotic plaques, decreased carotid intimal-medial thickness), there are increasing data to suggest that these agents have additional properties that are potentially neuroprotective. These include endothelial protection via actions on the nitric oxide synthase system, as well as antioxidant, anti-inflammatory and anti-platelet effects. These actions of statins might have potential uses in other neurological disorders such as Alzheimer's disease and certain types of brain tumors.