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.     

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.     

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.     

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.     

Are cholesterol-lowering medications and antihypertensive agents preventing stroke in ways other than by controlling the risk factor?

Statins and angiotensin-converting enzyme (ACE) inhibitors are an important component of our armamentarium for stroke prevention. Both of these classes of agents have a primary mechanism of action of reducing the level of the respective risk factor. They also have mechanisms of action that may confer benefits beyond what is believed to be the primary action of the agent. This has led to speculation that statins reduce stroke risk by means beyond cholesterol lowering, and ACE inhibitors reduce stroke risk by means beyond blood pressure lowering. We review the mounting evidence that suggests that statins and ACE inhibitors have so-called pleiotropic effects that may lead to stroke prevention.     

Statins and stroke prevention

Over the past decade, statins have been proven to significantly decrease coronary events in primary and secondary prevention of coronary artery disease. Recent clinical trials have indicated that statins significantly reduce stroke risk in patients with vascular disease. The Cholesterol Treatment Trialists' Collaborators in a meta-analysis including 90,056 patients found that the use of statins determined a significant 17% proportional reduction in the incidence of first-ever stroke of any type per 1 mmol/l low-density lipoprotein (LDL) cholesterol reduction. During an average of 5 years of treatment, the reduction in the overall incidence of stroke was about one sixth per 1 mmol/l LDL cholesterol decrease meaning that 8 fewer participants have any stroke per 1,000 among those with preexisting coronary artery disease at baseline, compared with 5 fewer per 1,000 among the participants with no such history. It is not known whether these findings might be due to the cholesterol reduction effect of statins or to pleiotropic effects of statins, such as improved endothelial function, decreased platelet aggregability, and reduced vascular inflammation. In secondary prevention of stroke, the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) study found that treatment with atorvastatin reduced the risk of recurrent cerebrovascular events in patients with recent stroke or transient ischemic attack but no history of heart disease. Combining the results of patients with no history of heart disease from the SPARCL study and Heart Protection Study in a mini meta-analysis, compared with placebo, statins were associated with a barely nonsignificant difference in recurrent stroke (OR = 0.87, 95% CI = 0.75-1.01, p = 0.07) and a significant difference in the occurrence of major vascular events (OR = 0.78, 95% CI = 0.68-0.88, p = 0.0001) at final follow-up.     

Cholesterol reduction and stroke occurrence: an overview of randomized clinical trials

We performed a meta-analysis of randomized clinical trials of more than 6 months duration to describe how fatal and nonfatal strokes are related to cholesterol lowering and to the type of intervention. A total of 41 individual trials including approximately 80,000 subjects and followed for an average of about 4 years were included in the overview. There was a 16% (95% CI, 7-25%) reduction in risk of stroke among treated patients compared to control patients (test for heterogeneity, p = 0.76). When trials that used different interventions were separately examined, a significant reduction in stroke occurrence was observed only for those using statins as active treatment (risk reduction 23%; 95% CI 13-33%). A variance-weighted regression analysis of the logarithmic odds ratios for stroke incidence against the percentage of cholesterol reduction indicated that a reduction of fatal and nonfatal stroke can be obtained for a cholesterol reduction of 9% (95% CI 6.8-13.6%). The combined data of primary and secondary prevention trials indicate that a large reduction of blood cholesterol, achievable with statin drugs, can reduce the incidence of stroke.     

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.     

Statins and stroke.

Inhibitors of HMG-CoA reductase (statins) are potent cholesterol-lowering drugs. Large clinical trials have shown that statins reduce the incidence of cerebrovascular events, which might be surprising because cholesterol is not an established risk factor for stroke. In addition to their cholesterol-lowering properties, statins exert a number of pleiotropic, vasculoprotective actions that include improvement of endothelial function, increased nitric oxide (NO) bioavailability, antioxidant properties, inhibition of inflammatory responses, immunomodulatory actions, regulation of progenitor cells, and stabilization of atherosclerotic plaques. In fact, statins augment cerebral blood flow and confer significant protection in animal models of stroke partly via mechanisms related to the upregulation of endothelial nitric oxide synthase. Retrospective clinical evidence suggests that long-term statin administration may not only reduce stroke risk but also improve outcome. Early secondary prevention trials are underway to test the hypothesis that statin treatment initiated immediately after an event improves short-term outcome. Lastly, recent evidence suggests that sudden discontinuation of statin treatment leads to a rebound effect with downregulation of NO production. Withdrawal of statin treatment may impair vascular function and increase morbidity and mortality in patients with vascular disease.     

Potential therapeutic role of statins in neurological disorders

Statins, the inhibitors of HMG-CoA reductase, are currently among the most commonly prescribed agents for the prevention of cardiovascular disease. It is well established that statins reduce cholesterol levels and prevent coronary heart disease. Moreover, evidence suggests that statins have additional properties such as endothelial protection via actions on the nitric oxide synthetase system as well as antioxidant, anti-inflammatory and antiplatelet effects. There is evidence that all these actions might have potential therapeutic implications not only in stroke, but also in various neurological disorders, such as Alzheimer's disease, Parkinson's disease, multiple sclerosis and primary brain tumors. In this review, we summarize the protective effects of statins on various neurological diseases. Currently available data suggest that statins are safe and effective in the treatment of these neurological disorders, although further experiments and new data are required.     

他汀类药对脑梗死的临床疗效和作用机制

多项研究已经提示他汀类药可以降低缺血性脑卒中发生率，具有神经保护作用。他汀类药除降血脂作用外，还有改善血管内皮功能，减少氧化应激，抑制炎性反应等作用。缺血性脑卒中患者使用他汀类药治疗后恢复较好，这不仅归因于他汀类药的调脂作用，其还有各种非降脂作用，称他汀类药具有多效性。本文总结了有关他汀类药多效性作用的实验研究，以及他汀类药预防缺血性脑卒中的临床试验研究。     

Stroke prevention

Stroke prevention is a crucial issue because (i) stroke is a frequent and severe disorder, and (ii) acute stroke therapies that are effective at the individual level have only a little impact in term of public health. Stroke prevention consists of the combination of 3 strategies: an optimal management of vascular risk factors, associated when appropriate with antithrombotic therapies, carotid surgery, or both. Primary prevention trials have shown that reducing blood pressure in hypertensive subjects reduces their vascular risk, including stroke. The association of perindopril plus indapamide reduces the vascular risk in patients who have had a stroke or TIA during the last 5 years, irrespective of their baseline blood pressure. Lowering serum cholesterol with statins or gemfibrozil in patients with hypercholesterolemia or coronary heart disease (CHD), reduces the risk of stroke. However, no trial of cholesterol-lowering therapy has been completed in stroke patients. A strict control of high cholesterol levels should be encouraged, because of benefits in terms of CHD. Statins should be prescribed for stroke patients with CHD, or increased cholesterol levels. Cigarette smoking is associated with an increased risk of stroke and should be avoided. Careful control of all risk factors, especially arterial hypertension in type 1 and type 2 diabetics is recommended, together with a strict glycemic control to reduce systemic microvascular complications. Estrogens prescribed in hormone replacement or oral contraceptive therapies are not recommended after an ischemic stroke. It is also recommended to reduce alcohol consumption and obesity, and to increase physical activity in patients at risk for first-ever or recurrent stroke. An optimal management of risk factors for stroke is crucial to reduce the risks of first-ever stroke, recurrent stroke, any vascular event after stroke and vascular death. One of the major public health issues for the coming years will be to focus more on risk factor recognition and management. Received: 29 November 2001, Accepted: 7 December 2001     

Neuroimmunomodulatory effects of transcranial laser therapy combined with intravenous tPA administration for acute cerebral ischemic injury

At present, the only FDA approved treatment for ischemic strokes is intravenous administration of tissue plasminogen activator within 4.5 hours of stroke onset. Owing to this brief window only a small percentage of patients receive tissue plasminogen activator. Transcranial laser therapy has been shown to be effective in animal models of acute ischemic stroke, resulting in significant improvement in neurological score and function. NEST-1 and NEST-2 clinical trials in human patients have demonstrated the safety and positive trends in efficacy of transcranial laser therapy for the treatment of ischemic stroke when initiated close to the time of stroke onset. Combining intravenous tissue plasminogen activator treatment with transcranial laser therapy may provide better functional outcomes. Statins given within 4 weeks of stroke onset improve stroke outcomes at 90 days compared to patients not given statins, and giving statins following transcranial laser therapy may provide an effective treatment for patients not able to be given tissue plasminogen activator due to time constraints.     

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.     

Marked elevation of liver transaminases after high-dose fluvastatin unmasks chronic hepatitis C: safety and re-challenge

The statins, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, have emerged as the drugs of choice for patients with dyslipidemia and have been shown to reduce major cardiovascular adverse events in large-scale clinical trials for both primary and secondary prevention. Statins are generally safe; however, the results of clinical trials do demonstrate possibilities of significant adverse effects in liver and muscle. Moreover, the numbers from the trials may not reflect the real situation in daily practice because individuals at increased risk for hepatotoxicity are usually deliberately and carefully excluded in clinical trials. We presented an 85-year-old woman who had a marked elevation of ALT (up to 409 U/L) after treatment with fluvastatin 80 mg/day for 6 weeks. Hepatitis C was identified after this episode. The elevation of ALT resolved 10 weeks after discontinuation of fluvastatin. Re-institution of fluvastatin from 40 to 80 mg/day for 2 months only cause mild elevation of ALT. This case suggests that elevation of transaminases during statin therapy may not be solely ascribed to statins. Re-challenge with the same statin at lower doses or with other statins may help to identify the patients who can still be treated with drugs of this category.     

The beneficial effect of statins treatment by stroke subtype

Background and purpose:  Statins have shown some protective effect after ischaemic stroke in observational studies. However, this effect has never been assessed by etiological subtypes.
Methods:  Observational study using data from the Stroke Unit Data Bank from consecutive patients with cerebral infarction. Variables analyzed: demographic data, cardiovascular risk factors, treatment with statins at stroke onset, stroke severity, stroke subtype, in-hospital complications, length of stay, and functional status at discharge (modified Rankin Scale).
Results:  A total of 2742 patients were included, 1539 were men. Mean age was 69.17 years (SD 12.19). Of these, 281 patients (10.2%) were receiving statins when admitted. The logistic regression analyses showed that previous treatment with statins was an independent predictor for better outcome at discharge among all strokes (OR, 2.08; 95% CI, 1.39 to 3.1) as well as for the atherothrombotic (OR, 2.79; 95% CI, 1.33 to 5.84) and lacunar strokes (OR, 2.28; 95% CI, 1.15 to 4.52) after adjustment for demographic data, risk factors, previous treatments, stroke subtypes, stroke severity, in-hospital complications and length of stay. This benefit was not observed either in cardioembolic or in other etiology strokes.
Conclusions:  Previous treatment with statins is an independent factor associated with good outcomes in patients with ischaemic stroke. Atherothrombotic and small vessel strokes show the greatest benefit.     

Statins as novel immunomodulators: from cell to potential clinical benefit

In the last decades, substantial progress has been made in understanding the relationship between lipid disorders and prevention of cardiac ischemic disease. Statins competitively inhibit 3-hydroxyl-3-methylglutaryl coenzyme A (HMG-CoA) reductase, an enzyme crucial to cholesterol biosynthesis. Statins have long been thought to exert their benefits by reducing cholesterol synthesis, but the fact that mevalonate is the precursor of isoprenoids that regulate diverse cellular functions has led investigators to examine pleiotropic effects for these agents. Statins have never been shown to be involved in the immune response, although two clinical trials have suggested that in heart transplant patients, statin therapy has beneficial effects on the incidence of cardiac rejection, coronary vasculopathy, and survival. Major Histocompatibility Complex class II (MHC-II) molecules, which affect the immune response and organ rejection after transplantation, may be induced by the pro-inflammatory cytokine interferon gamma (IFN-gamma). Recently, it has been demonstrated that statins repress the induction of MHC-II by IFN-gamma in vitro, and thus may suggest a potential role for statins as immunosuppressive agents in vivo. Indeed, two recent in vivo studies performed on different animal models provide further evidence that statin-treatment positively influence immunological disorders.     

New horizons for stroke prevention: PROGRESS and HOPE

Inhibitors of angiotensin-converting enzyme (ACE) act by blocking the conversion of angiotensin I to angiotensin II, which is catalysed by this enzyme. ACE inhibitors also prevent the breakdown of bradykinin, a potent vasodepressor agent, and prevent the effects of angiotensin II, which include increase in blood pressure, peripheral vasoconstriction, and stimulation of aldosterone secretion from the adrenal cortex. Physiological and pathological studies have shown that ACE inhibitors have beneficial effects, such as increasing vascular compliance, regression of periarteriolar collagen area, improvement of coronary reserve, and regression of resistance-artery structure and left-ventricular hypertrophy. Information about the role of ACE inhibitors in stroke prevention has been limited. This review explores the epidemiological evidence for hypertension as a risk factor for stroke, a national guideline for blood-pressure control to reduce the incidence of stroke and cardiovascular disease, the findings of two recently published clinical trials on prevention of stroke and cardiovascular disease after administration of ACE inhibitors (PROGRESS and HOPE), and the implications of the findings for redefinition of future management of blood-pressure control for individuals at high risk of stroke and cardiovascular disease. The PROGRESS and HOPE trials have shown that ACE inhibitors have an important role in the prevention of stroke and cardiovascular-disease events.     

The role of pleiotropic effects of statins in dementia

High serum cholesterol is associated with ischemic heart disease. Recent reports also indicate that cholesterol modulates amyloid beta-peptide interactions in the brain. Statins are inhibitors of 3-hydroxy-3-methylglutaryl-Coenzyme A reductase (HMG-CoA reductase), the rate-limiting enzyme involved in cholesterol synthesis. Statin treatment significantly reduces the levels of low-density lipoproteins (LDL) and very low-density lipoproteins (VLDL). In the past decade, cardiovascular mortality and morbidity has been reduced by the use of statins. However, evidence from in vivo and in vitro research has indicated that statins may confer multiple effects because of the inhibition of the production of intermediates in the mevalonate pathway. The aim of this review was to discuss the biological effects of statins on regulation of processes involved in the pathogenesis of dementia.