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.     

Statins in stroke prevention: what an internist should know

Historically, the etiological link between hypercholesterolemia and stroke has been less clear than for coronary heart disease. The lack of association between cholesterol levels and stroke in most epidemiological and observational studies has brought about this controversy. Many recent, long-term clinical studies have confirmed that statin therapy results in a reduced risk of strokes, even in so-called "normocholesterolemic" patients. The magnitude of the effect is great. A large-scale analysis of more than 90,000 individuals showed that every 10% reduction in the concentration of LDL-cholesterol reduces the risk of stroke by 15.6%. The positive effect of statins on stroke depends mainly on LDL cholesterol reduction, but other non-lipid mechanisms, so-called "pleiotropic" effects, have been shown to play a role. This review seeks to summarize the role of statins in stroke prevention. Despite the fact that our understanding of the benefits of statins in stroke prevention is still evolving, we find marked room for improvement in stroke risk factor management. Internists must face this challenge and integrate this new knowledge into their daily clinical practice.     

他汀类与非酒精性脂肪肝病患者的卒中预防

非酒精性脂肪肝病(non-alcoholic fatty liver disease,NAFLD)是慢性肝病中的一个重要类型,其发病率日益增高,是代谢综合征的肝脏表现,与心脑血管病的发生关系密切.对NAFLD患者的卒中预防十分重要.他汀类药物是最重要的一类降胆固醇药物,通过抑制羟甲基戊二酰辅酶A(hydroxy-methyl-glutaryl coenzyme A HMG-CoA)还原酶,减少胆固醇合成,上调肝脏低密度脂蛋白(low-density lipoprotein,LDL)受体,降低循环低密度脂蛋白胆固醇(low-density lipoprotein cholesterol,LDL-C)水平,有效降低卒中风险.此外,他汀类的多效性以及对胆同醇相关细胞信号通路的影响,能减缓或防止NAFLD的进展.由于他汀类药物对肝脏有一定的不良作用,是否能应用于慢性肝病患者存在较大争议.现有证据显示,他汀类药物可在NAFLD患者中安全使用,通常无需监测肝酶,过分关注他汀类药物的肝毒性反而可能采取不恰当的停药,导致心血管事件风险的增高.为此,他汀类对NAFLD患者的有效性及安全性尚需进一步评估.     

Statins and ischemic stroke

The 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase inhibitors or statins are potent inhibitors of cholesterol synthesis. Several large clinical trials have demonstrated that these agents reduce serum cholesterol levels and the incidence of cardiovascular diseases. However, overlap and meta-analyses of these clinical trials suggest that the beneficial effects of statins may extend beyond their effects on serum cholesterol levels. Because statins also inhibit the synthesis of isoprenoid intermediates in the cholesterol biosynthetic pathway, they may have pleiotropic effects on the vascular wall. In particular, the ability of statins to decrease the incidence of ischemic stroke highlights some of their non-cholesterol effects since serum cholesterol levels are poorly correlated with the risk for ischemic stroke.     

Statins for primary cardiovascular prevention in the elderly

The elderly population is increasing worldwide, with subjects > 65 years of age constituting the fastest-growing age group. Furthermore, the elderly face the greatest risk and burden of cardiovascular disease mortality and morbidity. Although elderly patients, particularly those older > 75, have not been well represented in randomized clinical trials evaluating lipid-lowering therapy, the available evidence supporting the use of statin therapy in primary prevention in older individuals is derived mainly from subgroup analyses and post-hoc data. On the other hand, elderly patients often have multiple co-morbidities that require a high number of concurrent medications; this may increase the risk for drug-drug interactions, thereby reducing the potential benefits of statin therapy. The aim of this review was to present the relevant literature regarding statin use in the elderly for their primary cardiovascular disease, with the associated risks and benefits of treatment.     

Statins and ischemic stroke severity: Cytoprotection

Cytoprotective or neuroprotective interventions would be of value if they could block the processes leading to delayed neuronal death or if they could delay the period between the onset of ischemia and irreversible necrotic injury, thereby lengthening the period for effective reperfusion therapy. Experimental studies in cell culture systems and laboratory animals show that statins have several potential cytoprotective actions, including promotion of angiogenesis, reduction of clot formation and facilitation of clot lysis, upregulation of endothelial nitric oxide synthase, downregulation of inducible nitric oxide synthase, reduction of excitotoxicity, and modulation of the inflammatory response. Clinically, statins appear to protect against vasospasm-related ischemic injury after subarachnoid hemorrhage. There have been no prospective randomized trials aimed at determining whether statins reduce acute stroke severity, and observational studies have had inconsistent results. Although a prospective, randomized trial assessing the effect of pre-or poststroke statin treatment on initial stroke severity would be the most appropriate study design to test for this type of effect, it is unlikely that such a trial will be conducted given the benefits of these drugs in reducing the risk of cardiovascular events and stroke in high-risk populations.     

Intracardiac devices for stroke prevention

Stroke is a significant cause of serious disability and death worldwide. A substantial proportion of strokes are related to an underlying cardiac embolic source, most commonly in association with atrial arrhythmias (fibrillation/flutter). Atrial fibrillation is considered a major risk factor for stroke. Although long-term prophylactic oral anticoagulation has been shown to be very effective in reducing stroke in patients with atrial fibrillation, it has a number of major limitations and is not feasible in all patients. In such cases, the use of percutaneously (transvenous) implanted left atrial appendage occlusive devices or surgical appendage obliteration is being explored. Similarly, the presence of a patent foramen ovale, especially in the presence of an atrial septal aneurysm, is now recognized as an important potential mediator of paradoxical cardiogenic embolism. Percutaneous patent foramen ovale closure is becoming increasingly established as a safe and effective means of preventing recurrent strokes in the presence of a patent foramen ovale. In this account, the authors discuss the intracardiac devices and techniques available and the relative merits of their use for stroke prevention.     

Hypolipemic agents for stroke prevention

An important issue for stroke prevention is identification and treatment of risk factors such as hypercholesterolemia. The four reasons to test hypolipidemic agents in stroke prevention are: (i) a statistical link between elevated low-density lipoprotein cholesterol (LDL-c) or decreased high-density lipoprotein cholesterol (HDL-c) and ischemic stroke; (ii) a reduction in vascular risk in randomized trials in patients with coronary heart disease; (iii) evidence of a decreased plaque progression under statins, (iv) pooled analyses of primary and secondary prevention trials showing that reduction of total serum cholesterol reduces the incidence of stroke, especially with the highest rate of cholesterol reduction, and in patients with the highest risk of stroke (i.e., with statins in secondary prevention trials), and (v) prophylactic neuroprotection induced by hypolipidemic agents in animal models of cerebral ischemia. Data provided by trials conducted in subjects with coronary heart disease and in asymptomatic individuals should now be confirmed in stroke patient.     

Antiplatelet therapy for stroke prevention

Recent trials of antiplatelet therapy for stroke prevention indicate that the combination of clopidogrel (75 mg/d) plus low-dose aspirin (75–162 mg/d) was not more effective than low-dose aspirin alone in the long-term prevention of major vascular events among patients at high risk of atherothrombotic events, nor was it more effective than oral anticoagulation in patients with atrial fibrillation. Furthermore, oral anticoagulation (International Normalized Ratio of 2.0–3.0) was not more effective than aspirin alone among patients with recent cerebral ischemia of presumed arterial origin. However, the addition of extended-release dipyridamole to aspirin was more effective than aspirin alone among patients with recent cerebral ischemia of presumed arterial origin. A large trial comparing clopidogrel with the combination of aspirin and extended-release dipyridamole in more than 20,000 patients with recent (< 120 days) atherothrombotic ischemic stroke is expected to report in 2008.     

Percutaneous devices for stroke prevention

The most important approaches to prevent cerebral ischemia by catheter technique are patent foramen ovale (PFO) closure in patients with a history of cryptogenic stroke and left atrial appendage (LAA) occlusion in atrial fibrillation (AF) patients. Over the past years, several new devices have been developed for these procedures. Results of randomized trials comparing device therapy, antiplatelet, or anticoagulation therapy are still not available. However, several nonrandomized studies have shown promising results. This article gives a review on the current results and techniques of the most commonly used devices as well as on new developments and approaches to catheter-based stroke prevention.     

Statins and the primary prevention of cardiovascular events

Cardiovascular disease remains the leading cause of death in both men and women in the United States. Treating elevated low-density lipoprotein (LDL) cholesterol has been shown to be very effective in reducing the rate of coronary heart disease (CHD) in primary prevention trials; however, the data are not as robust for treating individuals categorized at either lower risk for CHD or with below-average LDL cholesterol levels. The next frontier for investigation will include strategies to determine who in these lower risk categories should be treated with statins. The growing epidemics of obesity, diabetes, and metabolic syndrome also loom as major problems that need to be incorporated into any strategy that focuses on the prevention of cardiovascular disease. In individuals with multiple cardiovascular risk factors, combination therapies tailored to address each individual’s risk profile need to be considered to best decrease the likelihood of their first coronary event.