The Many Roles of Statins in Ischemic Stroke

Stroke is the third leading cause of human death. Endothelial dysfunction, thrombogenesis, inflammatory and oxidative stress damage, and angiogenesis play an important role in cerebral ischemic pathogenesis and represent a target for prevention and treatment. Statins have been found to improve endothelial function, modulate thrombogenesis, attenuate inflammatory and oxidative stress damage, and facilitate angiogenesis far beyond lowering cholesterol levels. Statins have also been proved to significantly decrease cardiovascular risk and to improve clinical outcome. Could statins be the new candidate agent for the prevention and therapy in ischemic stroke? In recent years, a vast expansion in the understanding of the pathophysiology of ischemic stroke and the pleiotropic effects of statins has occurred and clinical trials involving statins for the prevention and treatment of ischemic stroke have begun. These facts force us to revisit ischemic stroke and consider new strategies for prevention and treatment. Here, we survey the important developments in the non-lipid dependent pleiotropic effects and clinical effects of statins in ischemic stroke.     

Benefits of statins in cerebrovascular disease

Although elevated cholesterol levels have been associated with coronary heart disease, the evidence for a role of cholesterol in stroke is less well defined. Epidemiological studies indicate that high lipid levels are linked with an increase in ischemic stroke, while low lipid levels may increase the risk of hemorrhagic stroke. Lipid lowering with statins reduces the incidence of ischemic stroke without increasing the frequency of hemorrhagic stroke. The benefits of statins on stroke may be due to a combination of mechanisms. Statins lower cholesterol levels and reduce the progression of atherosclerotic plaque formation in carotid arteries, and the incidence of emboli from cardiac, aortic and carotid sites. Furthermore, statins may produce cholesterol-independent effects such as improving cerebral blood flow and reducing inflammation and oxidative stress, which could limit the size of an ischemic lesion. Statins offer potential benefits for reducing the incidence and improving the prognosis of stroke.     

New drugs for the treatment of hypercholesterolaemia

Endogenous and exogenous pathways determine plasma levels of cholesterol and lipoproteins. Plasma cholesterol levels and coronary heart disease risk can be reduced pharmacologically by decreasing cholesterol synthesis, increasing its elimination and/or reducing its absorption from the intestine. The more profound knowledge about cholesterol homeostasis has allowed the development of several lipid-lowering drugs with different mechanisms of action, with the purpose of reducing both morbidity and mortality associated with coronary heart disease. Two new and more potent 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins), also called superstatins (rosuvastatin and pitavastatin), are being studied for their ability to improve lipid profiles. Rosuvastatin is a potent, hepato-selective and relatively hydrophilic statin with a low propensity for muscle toxicity and drug interactions. Pitavastatin is another statin with a high oral bioavailability and minimal propensity for cytochrome p450-mediated drug interactions. Rosuvastatin seems to be more potent than other available statins while pitavastatin presents with a similar potency to that of atorvastatin. Another promising approach for lowering total and low-density lipoprotein cholesterol levels is inhibition of cholesterol absorption. A wide variety of new agents with the capacity for inhibiting the intestinal cholesterol absorption is currently being investigated. Ezetimibe is a selective cholesterol absorption inhibitor whose clinical efficacy has been recently demonstrated both in monotherapy and in combination with other lipid-lowering drugs. Colesevelam, a new bile acid sequestrant, has shown a clinical efficacy similar to that of other resins, with minimal gastrointestinal side effects, improving tolerability and patient compliance. Other lipid-lowering drugs with the ability to act at the enterocyte level, such as avasimibe and implitapide, are currently being investigated in humans.     

New drugs for the treatment of hypercholesterolaemia

Endogenous and exogenous pathways determine plasma levels of cholesterol and lipoproteins. Plasma cholesterol levels and coronary heart disease risk can be reduced pharmacologically by decreasing cholesterol synthesis, increasing its elimination and/or reducing its absorption from the intestine. The more profound knowledge about cholesterol homeostasis has allowed the development of several lipid-lowering drugs with different mechanisms of action, with the purpose of reducing both morbidity and mortality associated with coronary heart disease. Two new and more potent 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins), also called superstatins (rosuvastatin and pitavastatin), are being studied for their ability to improve lipid profiles. Rosuvastatin is a potent, hepato-selective and relatively hydrophilic statin with a low propensity for muscle toxicity and drug interactions. Pitavastatin is another statin with a high oral bioavailability and minimal propensity for cytochrome P450-mediated drug interactions. Rosuvastatin seems to be more potent than other available statins while pitavastatin presents with a similar potency to that of atorvastatin. Another promising approach for lowering total and low-density lipoprotein cholesterol levels is inhibition of cholesterol absorption. A wide variety of new agents with the capacity for inhibiting the intestinal cholesterol absorption is currently being investigated. Ezetimibe is a selective cholesterol absorption inhibitor whose clinical efficacy has been recently demonstrated both in monotherapy and in combination with other lipid-lowering drugs. Colesevelam, a new bile acid sequestrant, has shown a clinical efficacy similar to that of other resins, with minimal gastrointestinal side effects, improving tolerability and patient compliance. Other lipid-lowering drugs with the ability to act at the enterocyte level, such as avasimibe and implitapide, are currently being investigated in humans.     

Neuroprotective properties of statins

Treatment with statins (3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors) reduces the risk of ischemic stroke among patients with increased risk of vascular disease. Recent experimental data point to neuroprotective properties of statins in acute cerebral ischemia. There is a proven link between bioavailability of nitric oxide and the activity of statins and ischemic stroke. Due to their ability to up-regulate nitric oxide synthase, statins have been considered in the therapy of a number of the central nervous system disorders, including cerebral ischemia, Alzheimer's disease, Parkinson's disease, tumors, and trauma. It has been claimed that they suppress inflammatory response and secondary injury after acute ischemia.     

Modulation of the inflammatory process by statins

Statins reduce cholesterol levels through competitive inhibition of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, the key enzyme that regulates cholesterol synthesis. The cholesterol-lowering effect of statins is also due to an increase in the uptake of cholesterol by cells as a result of intracellular cholesterol depletion and enhanced expression of low-density lipoprotein (LDL) receptors. The use of statins as lipid-lowering agents has lead to remarkable changes in the treatment and prevention of ischemic heart disease. Results of large clinical trials of patients with ischemic heart disease have demonstrated that statins reduce inflammatory markers such as C-reactive protein, an independent risk factor in the disease. Statins exhibit properties that are beyond their lipid-lowering effects. These non-lipid-lowering properties involve the inhibition of the isoprenoid pathway through decreased synthesis of many nonsteroidal isoprenoid compounds. The focus on the immunomodulatory effect of statins is the result of the positive outcome of pravastatin treatment in cardiac transplantation patients, as well as angiographic regression studies showing insignificant changes in the degree of coronary stenosis despite a large reduction in cardiac events. Statin treatment reduces the risk of ischemic stroke despite the fact that LDL cholesterol is not directly associated with the risk of stroke. This observation lead to the investigation of the role of statins in inflammation and the immune system. Recent research data demonstrated that statins inhibit the induction of the major histocompatibility (MHC) class II expression by interferon-gamma (IFN-gamma), leading to repression of MHC II-mediated T-cell activation. Furthermore, statins inhibit the expression of specific cell surface receptors on monocytes, adhesion molecules and also integrin-dependent leucocyte adhesion. While statins may stimulate the secretion of caspase-1, IL-1beta and IL-18 in peripheral mononuclear cells in response to Mycobacterium tuberculosis, they exhibit additional effects on inflammation by decreasing IL-6 synthesis in human vascular smooth muscle cells (VSMC) in vitro. The focus of this monograph is to highlight the role of statins in the modulation of the immune system and inflammatory processes.     

Current and Future Pharmacologic Options for the Management of Patients Unable to Achieve Low-Density Lipoprotein-Cholesterol Goals with Statins

Low-density lipoprotein-cholesterol (LDL-C) lowering is the mainstay of the current treatment guidelines in the management of cardiovascular risk. HMG-CoA reductase inhibitors (statins) are currently the most effective LDL-C-lowering drugs. However, a substantial number of patients do not reach treatment targets with statins. Therefore, an unmet medical need exists for lipid-lowering drugs with novel mechanisms of action to reach the recommended cholesterol target levels, either by monotherapy or combination therapy. Upregulation of the LDL receptor with squalene synthase inhibitors has shown promising results in animal studies but the clinical development of the lead compound lapaquistat (TAK-475) has recently been discontinued. Ezetimibe combined with statins allowed significantly more patients to reach their LDL-C targets. Other inhibitors of intestinal cholesterol absorption such as disodium ascorbyl phytostanol phosphate (FM-VP4) and bile acid transport inhibitors have shown positive results in early development trials, whereas the prospect of acyl coenzyme A: cholesterol acyltransferase inhibition in cardiovascular prevention is dire. Selective inhibition of messenger RNA (mRNA) by antisense oligonucleotides is a new approach to modify cholesterol levels. The inhibition of apolipoprotein B mRNA is in advanced development and mipomersen sodium (ISIS 301012) has shown striking results in phase II studies both as monotherapy as well as in combination with statins.     

Statins for the prevention of first or recurrent stroke

This review considers the evidence showing that statins can prevent first or recurrent stroke or improve its outcome in subjects at moderate or high risk for cardiovascular disease (CVD). Data are reviewed according to trial design (observational or prospective) and baseline CVD risk. Two (ASCOT, CARDS) out of five primary CVD prevention statin trials showed a considerable reduction in stroke rates. In two (MIRACL and PROVE IT) out of five acute coronary syndrome trials, the prevention of first stroke was significant. Most secondary prevention trials (4S, CARE, LIPID, HPS, GREACE and TNT) showed a beneficial effect of statins in stroke prevention. Finally, SPARCL, the only secondary stroke prevention trial in subjects without overt coronary heart disease (CHD), showed a significant reduction in total and ischaemic (fatal and nonfatal) stroke rate, although a small but significant increase in nonfatal haemorrhagic stroke was noted. There was also a significant reduction in CHD-related events. The possible mechanisms responsible for statin-associated stroke prevention are discussed. The evidence suggests the need to consider early and long-term statin treatment (with substantial low-density lipoprotein cholesterol reduction) in all patients at high risk of any type of major vascular event, without discriminating CHD from stroke. Thus, statins may be beneficial to both the heart and the brain.     

Treating acute ischemic stroke

Acute ischemic stroke (AIS) is a common disorder that has only one associated approved therapy: intravenous tissue plasminogen activator (iv t-PA). A limiting factor to the use of iv t-PA is that it must be initiated within 3 h of stroke onset. Efforts to expand the therapeutic time window are underway and include image evaluation of the ischemic penumbra to target those patients who are most appropriate for treatment. Intra-arterial t-PA is also used only in some treatment centers despite convincing proof of efficacy of this therapy. Devices to restore perfusion that have been approved in the US for recanalization exist, but these are not approved for use in stroke therapy. Many neuroprotective drugs have been evaluated as potential acute stroke therapies, but none have shown efficacy, hence the future of neuroprotection as a strategy for acute ischemic stroke therapy remains uncertain.     

Novel agents to manage dyslipidemias and impact atherosclerosis

Strong epidemiological evidence linked elevated levels of low-density lipoprotein cholesterol (LDL-C) to risk of atherosclerotic heart disease. As a consequence, LDL-C lowering has been the main goal of therapy to reduce cardiovascular risk for the past few decades and hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins) have become some of the most commonly prescribed drugs. In spite of the proven efficacy of these drugs, statins reduce cardiovascular events by only 30-40%. Epidemiological analyses clearly indicate that a significant portion of risk is linked to other particles such as low high-density lipoprotein cholesterol (HDL-C), high triglycerides and others. Furthermore, several quantitative coronary angiography studies showing regression of atherosclerosis and reduction in subsequent events utilized a combination of drugs effective on LDL-C as well as other lipoproteins. Hence, several new drugs are being investigated that affect more than the traditional LDL-C pathways. In this article, we review lipoprotein-modifying agents that have either been recently released, or are still in various phases of development. They include agents that reduce LDL-C levels by mechanisms other than HMG-CoA inhibition (such as cholesterol absorption inhibitors, Acyl-CoA cholesterol acyl transferase inhibitors, sterol-regulating binding protein cleavage activating protein ligands, microsomal triglyceride transfer protein inhibitors, LDL-C receptor activators and farnesoid X receptor antagonists) and agents that raise HDL-C cholesterol or improve cholesterol efflux (such as cholesterol ester transfer protein inhibitors, retinoid X receptor selective agonists, specific peroxisome proliferator-activated receptor (PPAR) agonists and estrogen like compounds).     

Contemporary management of transient ischemic attack: role of the pharmacist

Transient ischemic attacks (TIAs) have been redefined recently. The new tissue-based definition of TIA abandons the 24-hour restriction on symptom duration previously used to differentiate TIA from acute ischemic stroke and requires neuroimaging studies to identify the cause of the ischemia and to determine the presence and extent of brain injury. This new definition brings to light the need for urgent diagnostic testing and timely initiation of treatment, as well as secondary prevention measures to reduce the increased risk of stroke, cardiovascular complications, and death in the days and weeks after a TIA. Pharmacists play a key role in identifying patients at risk for a first or recurrent TIA or stroke, educating high-risk patients on the signs and symptoms of TIA or stroke and the need for urgent evaluation and treatment, overcoming barriers to timely diagnosis and treatment, and ensuring that appropriate primary or secondary prevention strategies are in place. Furthermore, studies have shown that pharmacist-led interventions can lead to significant improvements in modifiable risk factors, such as blood pressure and cholesterol levels, as well as drug adherence, and may reduce the occurrence of strokes. These interventions may also help maintain patients' health-related quality of life and improve patients' satisfaction with care.     

Clopidogrel in secondary ischemic stroke prevention

The results obtained in the CAPRIE study in 1996 led to the introduction of the clopidogrel as a new antiplatelet drug in the secondary prevention of acute myocardial infarct (AMI), ischemic stroke (IS) and symptomatic peripheral artery disease (PAD). Clopidogrel showed a similar efficacy and safety than acetylsalicylic acid (ASA). More recently, the combined use of clopidogrel with ASA has evidenced a better protection than ASA alone in some patients: patients with past history of AMI, angina pectoris, intermittent claudication or PAD, IS or TIA, coronary bypass, and diabetes mellitus, patients on treatment with statins, and patients with symptomatic carotid stenosis >/=50%. We review the reported evidence on the efficacy of clopidogrel in the secondary prevention of ischemic stroke.     

Defining the Role of High-Dose Statins in PCI

Several studies have reported a significant reduction in morbidity and mortality in patients with acute coronary syndrome (ACS) or in patients with stable ischemic heart disease with the use of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins). Based on these findings, current guidelines recommend the use of statin therapy before hospital discharge for all patients with ACS regardless of the baseline low-density lipoprotein level. Statins are also recommended to patients at high risk for cardiovascular disease. Statins have been introduced in the clinical arena to reduce the low-density lipoprotein (LDL) cholesterol level that is associated with coronary atherosclerosis; however, a growing body of evidence suggests that other mechanisms of action beyond the modification of the lipid profile may come into action. In particular, statins exert antiinflammatory effects, modulate endothelial function, and inhibit the thrombotic signaling cascade. All together the non-LDL cholesterol-lowering effects of statins are called pleiotropic effects. In this article we will review the evidence supporting the use of high-dose statins in patients undergoing percutaneous coronary intervention, and we will also attempt to highlight the possible mechanisms of action.     

Peripheral arterial disease: a missed opportunity to administer statins so as to reduce cardiac morbidity and mortality

Peripheral arterial disease (PAD) is a common condition associated with an increased risk of coronary heart disease, myocardial infarction and stroke. It follows that PAD merits aggressive preventive treatment that includes lipid lowering drugs (mainly statins). This review summarises the current knowledge concerning the use and mechanisms of action of statins in patients with PAD. Statins not only lower the risk of vascular events, but they also improve the symptoms associated with PAD. There is also evidence that statins reduce surgical mortality and improve graft patency and limb salvage. Because of the high risk, a more aggressive goal [i.e. low density lipoprotein cholesterol (LDL-C) of 70 mg/dl; 1.8 mmol/l] [National Cholesterol Education Program (NCEP) Adult Treatment Panel III (ATP III), revised guidelines 2004] should be considered to maximally reduce the atheroma burden and related events. Not all statins can achieve this LDL-C target. Furthermore, there may be a need to use an additional lipid lowering drug so as to achieve the LDL-C goal and benefit from the different modes of action. Statins exert beneficial pleiotropic effects on haemostasis, the vasculature and inflammatory markers. There is also evidence that statins improve renal function (the plasma creatinine level is considered as an emerging vascular risk factor). Since PAD patients often take several drugs, there is a need to carefully consider their selection so as to maximize benefits and minimize adverse effects. Patients with PAD often do not receive adequate lipid lowering treatment. This situation needs to change.     

他汀类药物在缺血性卒中及短暂性脑缺血发作二级预防中的作用

目的对他汀类药物在缺血性卒中及短暂性脑缺血发作二级预防中的作用进行评价分析,为今后的临床预防以及合理用药工作提供可靠的参考依据。方法 抽取在2010年1月至2012年12月间本院收治的缺血性卒中/短暂性脑缺血发作患者218例,将其按照病情程度分成高危组、极高危Ⅱ组、极高危Ⅰ组,对这三组患者入院后与随访3个月的临床用药情况进行统计分析。结果本组218例患者中在住院期间预防性应用他汀类药物者115例,应用率为52.75%,其中极高危Ⅰ组他汀类药物应用与指南的符合率较高危组与极高危Ⅱ组高(P<0.05);随访3个月后,他汀类药物应用者为49例,应用率为22.48%,较住院期间发生显著降低(P<0.05)。结论在预防缺血性脑卒中和短暂性脑缺血发作时他汀类药物发挥了重要作用,降低了复发率,然其二级预防中用药依从性较差,与应用指南符合率较低,临床应予以注意,做好预防工作,合理用药,以改善患者预后。     

HMG-CoA reductase inhibitors: effects on chronic subacute inflammation and onset of atherosclerosis induced by dietary cholesterol

Besides classical risk factors such as hypercholesterolemia and hypertension, chronic subacute inflammation has recently been recognized as an important force driving the development of atherosclerosis, the most common underlying cause of myocardial infarction and stroke. There is compelling evidence that a disturbance of cholesterol homeostasis contributes to the development of a chronic inflammatory state and that inhibitors of HMG-CoA reductase (statins) may dampen inappropriate inflammatory responses. We review the evidence and suggest mechanisms by which dietary cholesterol can induce an atherogenic inflammatory response in liver and vessel wall, with particular emphasis on the time course of this inflammatory response during atherogenesis and the interplay between these tissues. We discuss how statins interfere in this process, and whether they may reduce chronic subacute inflammation via a) their cholesterol-lowering effect, and/or b) their cholesterol-independent (pleiotropic) vasculoprotective activities. Recent studies performed in (humanized) animal models allow us to distinguish the lipid-lowering-dependent from the lipid-lowering-independent functions of statins. Using these data, we discuss the degree to which the lipid-lowering-dependent and lipid-lowering-independent effects of statins contribute to a reduction of inflammation, allowing estimation of the relevance of pleiotropic statin effects for the human situation.     

Statins – Are they anticonvulsant?

Statins are the most popular and effective lipid-lowering medications beneficial in hypercholesterolemias and prevention of cardiovascular diseases. Growing evidence supports theory that statins exhibit neuroprotective action in acute stroke, Alzheimer's disease, Parkinson's disease, multiple sclerosis or epilepsy. Hereby, we present available experimental data regarding action of this group of drugs on seizure activity and neuronal cell death. The most commonly examined statins, such as atorvastatin and simvastatin, display anticonvulsant action with only inconsiderable exceptions. However, the mechanism of this effect remains unexplained. Simvastatin, as a lipophilic statin, which can pass blood–brain barrier easily, was recommended as the best candidate for an anticonvulsant agent. Nevertheless, it is still indistinct, whether the protective activity of statins depends on cholesterol lowering properties or its pleiotropic characteristics. One of the most interesting of 3-hydroxy-3-methylglutaryl-coenzyme A inhibitor's actions involves influence on nitric oxide metabolism.     

Intensive Reduction of Low-Density Lipoprotein-Cholesterol

Strong evidence supports the use of HMG-CoA reductase inhibitors (statins) for preventing ischemic events in a variety of clinical settings. Benefits have been documented in primary and secondary prevention, across a range of baseline cholesterol levels, in the young and old, and in patients with varying manifestations of cardiovascular disease. Epidemiologic evidence suggests that risk is associated with serum cholesterol in a continuous, graded fashion with no clear threshold below which further reductions in risk do not occur. In aggregate, the placebo-controlled statin trials strongly suggest that the magnitude of risk reduction is related to the degree of cholesterol lowering achieved. However, until recently, it was unknown whether intensified cholesterol lowering with higher doses of newer, more potent statins could bring further gains over a policy of moderate or conventional lipid lowering. This article summarizes the results of randomized trials comparing these two strategies in patients with a history of coronary artery disease.     

他汀类药物的研究进展与临床应用评价

目的:评价他汀类药物的研究进展,以供临床医师合理用药参考.方法:查阅近年来国内外的相关文献资料,进行归纳和分析.结果与结论:他汀类药物不仅能降低血清胆固醇水平,还通过改善血管内皮功能、抗炎及抗氧化作用、抗血小板聚集和抑制血栓形成、稳定粥样硬化斑块、抑制平滑肌细胞增殖及迁移等其他多效性,在冠状动脉粥样硬化性心脏病、缺血性...     

Statins and stroke

Pharmacological studies highlighted pleiotropic effects of statins, that seem to influence atherogenesis not only by increasing atherosclerotic plaque stability but also by modulating endothelial function and inflammation and acting on platelet aggregation and thrombosis. Despite a strong association between increased levels of low-density lipoprotein cholesterol (LDL-C) and the incidence of coronary heart disease (CHD) has been well proven, it not yet established whether serum LDL-C levels are related to stroke incidence. The major aim of this paper is to perform a comprehensive up-to-date review of research papers, meta-analyses and randomized controlled clinical trials reporting the effects of statins in primary and secondary stroke prevention strategies. In addition, our work provides an overview on statin chemical structure, mechanism of action and pharmacological properties, investigating also most common adverse effects and relationship between statin therapy and haemorrhagic stroke risk, in order to assess drugs safety. Although studies are heterogeneous, our analysis shows that statins reduce the risk of stroke occurrence in high risk patients and seem also to reduce stroke recurrence. Moreover, the low incidence and reversibility of adverse effects, and the unclear association with hemorrhagic events, support the safe use of these drugs.