Cardiovascular basis for cholesterol therapy

The success of cholesterol treatment in reducing cardiovascular events has suggested addition of a cholesterol paradigm to previous clinical models of stenosis and occlusion in coronary artery disease. Risk factors for coronary artery disease now serve as guidelines for treatment goals for low-density lipoprotein cholesterol reduction. Oxidation of low-density lipoprotein cholesterol within the vessel wall initiates a variety of deleterious mechanisms contributing to atherosclerosis. Hepatic hydroxymethylglutaryl-coenzyme A reductase inhibitors or statin drugs exert a primary action on hepatic cholesterol metabolism, as well as influences on vascular reactivity, thrombus formation, inflammation, ischemia, and plaque stabilization. Trials with statin drugs have reported reduction of cardiovascular events in men and women without clinical evidence of coronary artery disease. Several trials have demonstrated angiographic stabilization with cholesterol lowering and a greater reduction in cardiovascular events, revascularization procedures, and strokes. Recent studies suggest benefits in lowering triglycerides and raising high-density lipoprotein cholesterol with drugs. A clinical approach with available cholesterol-lowering drugs is presented based on National Cholesterol Education Program guidelines and follow-up time tables. Thus, cholesterol therapy offers the opportunity to treat atherosclerotic vascular disease before, during, and after ischemic events.     

How aggressive should lipid lowering be among patients with acute coronary syndromes?

Results from recent clinical trials have advanced our understanding of the role of HMG-CoA reductase inhibitors (statins) in the management of patients following acute coronary syndrome (ACS) episodes. In aggregate, these trials have demonstrated the safety and efficacy associated with initiation of intensive statin therapy prior to hospital discharge following an ACS episode, independent of baseline low-density lipoprotein (LDL) cholesterol concentrations. Based on the results of these trials, there is now compelling evidence to support intensive lipid lowering with high-dose statins initiated prior to hospital discharge for all patients suffering ACS episodes with a target for LDL cholesterol of 70 mg/dL or lower, recommendations that have been incorporated into clinical practice guideline recommendations in the most recent position statement from the National Cholesterol Education Panel.     

Statin therapy: Is the percent reduction or the attained low-density lipoprotein cholesterol level more important?

Hyperlipidemia is a well-known risk factor for atherosclerosis. Several trials have demonstrated the importance of lowering low-density lipoprotein cholesterol (LDL-C) levels to reduce all-cause mortality, coronary ischemia, and cerebrovascular accidents. Although the optimal goal for LDL-C levels in patients with known coronary heart disease has been less than 100 mg/dL, more recent findings support achieving even lower LDL-C levels for very high-risk patients. As the target levels for LDL-C trend towards lower values, it is important to evaluate the status for optimal management with statin therapy. In this review article, we discuss the role of percent LDL-C reduction versus attained LDL-C levels as targets for statin therapy in order to maximize the preventive care provided to high-risk patients.     

"The lower the better" in hypercholesterolemia therapy: a reliable clinical guideline?

Since the publication of the second set of guidelines by the National Cholesterol Education Program, a solid body of data from landmark clinical studies has demonstrated that reduction in low-density lipoprotein (LDL) cholesterol with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor ("statin") therapy sharply diminishes the risk for coronary artery disease. These trials include the Scandinavian Simvastatin Survival Study, the West of Scotland Coronary Prevention Study, the Air Force/Texas Coronary Atherosclerosis Prevention Study, the Cholesterol and Recurrent Events investigation, and the Long-Term Intervention with Pravastatin in Ischaemic Disease trial. Coronary event rates and, in some cases, all-cause mortality decreased significantly after about 5 years of statin therapy in patients at risk for and those who had coronary artery disease at baseline. In contrast, recent subgroup analyses of these pivotal studies have in the aggregate challenged the premise that lower LDL cholesterol levels necessarily lead to further declines in risk for coronary artery disease, particularly among the patients most likely to be seen by the clinician: those with moderately elevated or normal cholesterol profiles. Indeed, when LDL cholesterol levels are in this range, further lowering with statin therapy elicits diminishing returns in terms of coronary event rates. These findings are readily accommodated by the curvilinear, or log-linear, model between serum cholesterol level and risk for coronary artery disease, which is predicated on data from large epidemiologic studies. In light of the current climate involving competing health care costs, the pursuit of progressively diminishing returns in terms of reductions in coronary artery disease risk through more aggressive lowering of LDL cholesterol levels appears to be unwarranted. Until data are published from ongoing randomized, clinical trials that can more effectively resolve the clinical utility of aggressive lipid-lowering strategies to improve coronary event rates, a prudent, evidence-based strategy seems warranted.     

Lipid lowering and coronary bypass graft surgery

This article reviews the rationale for lipid lowering in patients who have coronary heart disease, and specifically for post-bypass patients. It has been well demonstrated that after coronary artery bypass graft surgery, atherosclerosis continues to progress in the native circulation and develops at an accelerated rate in saphenous vein bypass grafts. During the last decade, numerous clinical trials based on angiographic or clinical outcomes have clearly shown the beneficial effect of lipid lowering in coronary heart disease. Three trials (CLAS, post-CABG, and CARE) have demonstrated delayed progression of atherosclerosis in SVGs and/or a reduction of cardiac deaths, nonfatal MI, and the need for revascularization after lowering LDL-cholesterol. The recommended target of LDL cholesterol level of more than 100 mg/dl can be safely reached with diet and monotherapy using one of the statin drugs (HMG-CoA reductase inhibitors). Despite this widely-circulated information, there appears to be inadequate public and professional awareness of the importance of properly managing hyperlipidemia after coronary artery bypass graft surgery.     

Intensive statin therapy for Indians: Part-I. Benefits

The underlying disorder in the vast majority of cases of cardiovascular disease (CVD) is atherosclerosis, for which low-density lipoprotein cholesterol (LDL-C) is recognized as the first and foremost risk factor. HMG-CoA reductase inhibitors, popularly called statins, are highly effective and remarkably safe in reducing LDL-C and non-HDL-C levels. Evidence from clinical trials have demonstrated that statin therapy can reduce the risk of myocardial infarction (MI), stroke, death, and the need for coronary artery revascularization procedures (CARPs) by 25-50%, depending on the magnitude of LDL-C lowering achieved. Benefits are seen in men and women, young and old, and in people with and without diabetes or prior diagnosis of CVD. Clinical trials comparing standard statin therapy to intensive statin therapy have clearly demonstrated greater benefits in CVD risk reduction (including halting the progression and even reversing coronary atherosclerosis) without any corresponding increase in risk. Numerous outcome trials of intensive statin therapy using atorvastatin 80 mg/d have demonstrated the safety and the benefits of lowering LDL-C to very low levels. This led the USNCEP Guideline Committee to standardize 40 mg/dL as the optimum LDL-C level, above which the CVD risk begins to rise. Recent studies have shown intensive statin therapy can also lower CVD events even in low-risk individuals with LDL-C <110 mg/dL. Because of the heightened risk of CVD in Asian Indians, the LDL-C target is set at 30 mg/dL lower than that recommended by NCEP. Accordingly, the LDL-C goal is < 70 mg/dL for Indians who have CVD, diabetes, metabolic syndrome, or chronic kidney disease. Intensive statin therapy is often required in these populations as well as others who require a > or = 50% reduction in LDL-C. Broader acceptance of this lower LDL-C targets and its implementation could reduce the CVD burden in the Indian population by 50% in the next 25 years. Clinical trial data support an extremely favorable benefit-to-risk ratio of intensive statin therapy with some but not all statins. Atorvastatin 80 mg/d is 100 times safer than aspirin 81 mg/d and 10 times safer than diabetic medications. Intensive statin therapy is more effective and safe compared to intensive control of blood sugar or blood pressure in patients with diabetes.     

The evolving role of statins in the management of atherosclerosis

Significant advances in the management of cardiovascular disease have been made possible by the development of 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitors--"statins." Initial studies explored the impact of statin therapy on coronary artery disease (CAD) progression and regression. Although the angiographic changes were small, associated clinical responses appeared significant. Subsequent large prospective placebo-controlled clinical trials with statins demonstrated benefit in the secondary and primary prevention of CAD in subjects with elevated cholesterol levels. More recently, the efficacy of statins has been extended to the primary prevention of CAD in subjects with average cholesterol levels. Recent studies also suggest that statins have benefits beyond the coronary vascular bed and are capable of reducing ischemic stroke risk by approximately one-third in patients with evidence of vascular disease. In addition to lowering low-density lipoprotein (LDL) cholesterol, statin therapy appears to exhibit pleiotropic effects on many components of atherosclerosis including plaque thrombogenicity, cellular migration, endothelial function and thrombotic tendency. Growing clinical and experimental evidence indicates that the beneficial actions of statins occur rapidly and yield potentially clinically important anti-ischemic effects as early as one month after commencement of therapy. Future investigations are warranted to determine threshold LDL values in primary prevention studies, and to elucidate effects of statins other than LDL lowering. Finally, given the rapid and protean effects of statins on determinants of platelet reactivity, coagulation, and endothelial function, further research may establish a role for statin therapy in acute coronary syndromes.     

Nonlipid-lowering effects of statins

Optional statement Statins have been shown to effectively reduce cardiovascular events in patients with hypercholesterolemia, diabetes, and coronary disease, and after an acute coronary syndrome in several large-scale clinical trials. Interestingly, numerous studies have suggested that statins exert potentially important effects independent of lipid lowering (ie, improve endothelial function, reduce oxidant stress), and have direct antiinflammatory, antithrombotic, and plaque-stabilizing effects. These beneficial effects may contribute to cardiovascular protection by statin therapy beyond low-density lipoprotein (LDL) cholesterol lowering. Therefore, it remains unclear at present to what extent the beneficial cardiovascular effects of statin treatment are dependent on LDL cholesterol lowering (ie, whether the same effect would be achieved by other modes of lipid lowering). Consequently, statins should be used as a first-line therapy for lipid lowering. Importantly, the observation of LDL cholesterol-independent effects of statins has stimulated clinical studies testing a wider use of statin treatment for diseases that are not thought to be related to increased LDL cholesterol levels, such as in patients with chronic heart failure (in particular dilated cardiomyopathy) and even in inflammatory diseases such as rheumatoid arthritis and multiple sclerosis.     

Therapeutic implications of recent ATP III guidelines and the important role of combination therapy in total dyslipidemia management

The Adult Treatment Panel III report reemphasized the importance of reducing elevated levels of low-density lipoprotein cholesterol as the most efficacious treatment target to reducing coronary heart disease morbidity and mortality, which is the leading cause of disability and death in the United States. Although the etiologic role of elevated levels of low-density lipoprotein cholesterol in atherosclerosis is well established, treatment with statins still leaves a large proportion of patients vulnerable to cardiovascular events. The role of high-density lipoprotein cholesterol in atherosclerosis is increasingly recognized because of its strong inverse association with coronary heart disease in epidemiologic studies, and the observed high prevalence of low high-density lipoprotein cholesterol that occurs in populations with coronary heart disease, with or without elevated low-density lipoprotein cholesterol, especially among patients with diabetes and metabolic syndrome. This report highlights some of the therapeutic implications of the Adult Treatment Panel III report and various therapeutic approaches to both lowering elevated low-density lipoprotein cholesterol and triglycerides as well as increasing low levels of high-density lipoprotein cholesterol to optimize clinical event rate reduction in patients with coronary heart disease. Among available dyslipidemic therapies, although statins remain the mainstay for lowering low-density lipoprotein cholesterol and clinical events, niacin is currently the most effective agent for increasing low high-density lipoprotein cholesterol levels. The importance of combination dyslipidemic therapy, such as a statin plus niacin, in treating more optimally the entire lipid profile has been demonstrated not only to decrease progression and increase regression of atherosclerotic lesions, but to enhance event-free survival compared with statin monotherapy. Combination dyslipidemic therapy affords the most efficacious approach to controlling the multiple lipid abnormalities associated with atherosclerotic cardiovascular disease and optimizing cardiovascular event rate reduction in patients with coronary heart disease.     

The Use of Fibric Acid Derivatives in Cardiovascular Prevention

Clinical trials have demonstrated the benefit of reduction of low-density lipoprotein (LDL) cholesterol levels in the prevention of atherosclerotic cardiovascular disease. Evidence is less robust for the effect of reduction of triglyceride levels and increase of high-density lipoprotein (HDL) cholesterol levels. In spite of the decrease of cardiovascular events in trials of LDL cholesterol–lowering medications, considerable residual risk remains, even with the use of high-dose statins. The fibric acid derivatives or fibrates reduce triglyceride and increase HDL cholesterol levels, effects that would be expected to affect cardiovascular events. However, clinical outcomes trials with fibrates have shown mixed results. Post-hoc analyses of fibrate trials as well as several meta-analyses suggest an overall decrease in primarily non-fatal coronary events without decrease in total mortality. The effects are most apparent in patients with elevated triglycerides and low HDL cholesterol levels. Statin therapy is the treatment of choice for most patients with dyslipidemia. The addition of a fibrate appears to be most beneficial in high-risk patients who continue to have significant dyslipidemia on statin therapy, most notably patients with diabetes mellitus or the metabolic syndrome. Thus, fibrates are not first-line drugs, but they do have a place in the management of the atherogenic lipid profile.     

High-density lipoprotein and coronary heart disease: lessons from recent intervention trials

Epidemiologic studies have consistently implicated low plasma high-density lipoprotein cholesterol as an important, independent risk factor for the development of coronary heart disease. However, clinical trials specifically designed to evaluate the role of lipid therapy in patients with low high-density lipoprotein cholesterol have only been recently reported. They include two trials with angiographic end points, the Lopid Coronary Angiography Trial and the Bezafibrate Coronary Atherosclerosis Intervention Trial, and three clinical end points trials, the Air Force/Texas Coronary Atherosclerosis Prevention study, the Department of Veterans Affairs High-Density Lipoprotein Intervention Trial, and the Bezafibrate Infarction Prevention study. These and other trials clearly indicate that persons with coronary heart disease and high low-density lipoprotein cholesterol (>130 mg/dL [3.36 mmol/L]), with or without low high-density lipoprotein cholesterol, benefit from statin therapy. The Air Force/Texas Coronary Atherosclerosis Prevention study showed that persons at high risk of coronary heart disease but without known disease, who have moderate levels of low-density lipoprotein cholesterol as well as low levels of high-density lipoprotein cholesterol, also appear to benefit from statin therapy although the cost effectiveness of this approach is unclear. The results from the Department of Veterans Affairs High Density Lipoprotein Intervention Trial provide convincing evidence that patients without high low-density lipoprotein cholesterol and with established coronary heart disease and low high-density lipoprotein cholesterol benefit from gemfibrozil. This drug may be particularly beneficial for patients who, in addition to low high-density lipoprotein cholesterol, present with other features of the metabolic syndrome, such as obesity, glucose intolerance, and high triglycerides. Whether other fibrates, niacin, or statins lower coronary heart disease risk in persons with low high-density lipoprotein cholesterol in the absence of high or moderately high low-density lipoprotein cholesterol is unknown. (c)2000 by CHF, Inc.     

Progression der Koronarsklerose als Monitoring des Therapieerfolgs bei Hperlipidämie

BACKGROUND: Coronary calcium represents an integral part of coronary atherosclerosis. It results from an actively regulated process and already appears in early stages of the disease. Studies using electron-beam computed tomography (EBCT) have demonstrated that an accelerated progression of coronary calcified atherosclerosis is associated with an increased rate of clinical events. In experimental animal models, effective lowering of LDL cholesterol stops the progression of coronary calcified atherosclerosis. LDL CHOLESTEROL AND PROGRESSION OF CORONARY CALCIUM: A number of EBCT-derived retrospective analyses have consistently reported that LDL cholesterol values are the most important factor influencing the progression of coronary calcified atherosclerosis. In high-risk patients with no clinical coronary artery disease who were not specifically treated, a mean annual progression of coronary calcium of 52% was observed. In the presence of statin drug therapy, progression ranged from -7% through 22%, depending on the LDL cholesterol levels during therapy. A preliminary prospective investigation has confirmed these results and, in particular, suggested that reaching low LDL cholesterol levels < 100 mg/dl effectively stops the progression of coronary calcified atherosclerosis. LDL cholesterol independent ("pleiotropic") effects of statin drugs could not be demonstrated by using EBCT. At present, two large prospective, randomized trials are being conducted which analyze the effects of intensified versus standard statin drug therapy on the progression of coronary calcified atherosclerosis by EBCT. CONCLUSIONS: Serial EBCT studies enable analysis of the interaction between therapeutic measures, progression of coronary calcified atherosclerosis and clinical course of the patients by virtue of direct visualization of the activity of coronary plaque disease. This has already been successfully implemented in small patients groups. Validation in the individual patient is pending. Prospective, randomized therapeutic trials are expected to yield valuable knowledge for clinical practice.     

A review of high-dose statin therapy: targeting cholesterol and inflammation in atherosclerosis.

Lipid lowering with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors or 'statins' has dramatically reduced morbidity and mortality in patients with established cardiovascular disease. Recently, there have been multiple studies investigating the role of high-dose statin therapy with more aggressive lipid lowering in this setting. Concomitantly, there is increasing evidence implicating a role of inflammation in the pathogenesis of atherosclerosis. These high-dose statin trials and other studies have also provided a wealth of data suggesting that statins have anti-inflammatory and anti-oxidant properties that go beyond their lipid-lowering effects. In this review, we will provide a brief overview of recent, large-scale, randomized, placebo and active controlled trials of high-dose statin therapy in the setting of stable and unstable coronary artery disease and percutaneous coronary intervention. Further, we will discuss the evidence for effects of high-dose statin therapy on inflammation and C-reactive protein.     

Statins in heart failure. Beyond the lipid lowering effect

Statins, the most widely prescribed medications in patients with hyperlipidemia and coronary heart disease, have a number of pleiotropic actions beyond cholesterol lowering. They improve endothelial function, they have antioxidant and anti-inflammatory effects, they regulate neovascularization and have immunomodulatory activities. Experimental evidence suggests that statins may be beneficial in heart failure as they can inhibit myocardial hypertrophy, reduce cardiomyocyte loss by apoptosis, reduce oxidative stress and restore neurohormonal imbalance. Furthermore small randomised clinical trials showed that short term statin administration may improve key pathophysiological aspects of this syndrome. Finally retrospective analyses of large statin trials imply a long term profit on clinical outcome in this group of patients. These results however need to be reviewed with caution as certain studies have demonstrated that low serum cholesterol is associated with worse prognosis in HF and that ubiquinone levels, a micronutrient with antioxidant actions, reduces significantly following statin administration. Large prospective randomised controlled trials are needed to confirm the beneficial effect of statins on cardiovascular outcome in HF patients and further elucidate the contributing mechanisms. Finally the statin dose and the interaction with co-administered drugs need to be studied.     

他汀在冠心病二级预防中的作用

他汀类药物对冠心病二级预防拥有大量的临床循证医学数据。早期他汀类的研究主要是与安慰剂比较,对稳定性冠心病的疗效,结果令人振奋。进入新世纪以来,他汀对急性冠脉综合征的作用效果也充分得到研究。越早积极降脂,效果越佳。同时,对稳定性冠心病采取积极强化他汀降脂比常规他汀降脂可以取得更好的临床益处。除了临床终点性的研究之外,影像学研究上也发现强化他汀可以减缓粥样斑块进展,甚至可以逆转病变。对冠心病特殊人群如老年和女性患者,也应当进行积极降脂。     

Treatment of older persons with hypercholesterolemia with and without cardiovascular disease

Hypercholesterolemia is a risk factor for new coronary events in older men and women. Secondary prevention trials have demonstrated in persons with coronary artery disease (CAD) and hypercholesterolemia that statin drugs reduced in older persons all-cause mortality, cardiovascular mortality, coronary events, coronary revascularization, stroke, and intermittent claudication. Statins have also been shown to slow progression of coronary atherosclerotic plaques in persons with CAD, to reduce restenosis after coronary stent implantation, and to decrease myocardial ischemia in persons with CAD. Older men and women with CAD, prior atherothrombotic brain infarction, peripheral arterial disease, or extracranial carotid arterial disease and a serum low-density lipoprotein (LDL) cholesterol level higher than 125 mg/dl despite diet should be treated with statin drug therapy to lower the serum LDL cholesterol level below 100 mg/dl. Primary prevention trials have shown that statins were also effective in reducing cardiovascular events in older persons with hypercholesterolemia. On the basis of data from the Air Force/Texas Coronary Atherosclerosis Prevention Study, the physician should consider using statins in persons aged 65-80 years without cardiovascular disease with a serum LDL cholesterol level above 130 mg/dl and serum high-density lipoprotein cholesterol level below 50 mg/dl.     

Women Versus Men: Is There Equal Benefit and Safety from Statins?

Coronary heart disease (CHD) is the leading cause of death in the United States. CHD risk differs between genders, with coronary events lagging behind ten years for women in comparison to men. Low-density lipoprotein cholesterol lowering with statin therapy is a major target for cardiovascular risk reduction. The benefit of statin therapy has been well established in men, for both primary and secondary prevention. However, the same has not been shown for women. While studies have demonstrated benefit in women for secondary prevention, their role in primary prevention of cardiovascular disease remains controversial. Data released over the past several years regarding statin efficacy and safety in men and women has been inconsistent, given that these studies had small sample sizes with numerous study limitations. A recent large scale meta-analysis of both primary and secondary statin prevention trials with sex-specific outcomes demonstrated a similar benefit in both men and women. Statins demonstrated a decrease in cardiovascular events and all-cause mortality in both sexes. In regards to statin safety, additional trials investigating the difference in adverse events of statins in men versus women, particularly new onset of diabetes, myalgias, and liver dysfunction, are warranted. Increased awareness and monitoring of female patients for myalgias and hyperglycemia should be considered as a precaution. Overall, women need to be better represented in prospective clinical trials powered to evaluate gender-specific differences in statin safety and efficacy in the management of cardiovascular disease.     

冠状动脉斑块消退的调脂治疗策略

4项他汀类药物治疗冠心病患者,以血管内超声评价冠状动脉(冠脉)斑块变化的临床试验(RE-VERSAL、ASTEROID、COSMOS和SATURN)结果一致显示,他汀治疗显著降低LDL-C,同时升高Apo-A1和HDL-C,才能观察到冠脉粥样硬化斑块的消退。适度调脂指通过他汀类药物治疗,达到减少胆固醇流入斑块的目标值:降低LDL-C>45%(达到1.81～2.46mmol/L),同时达到增加胆固醇流出斑块的目标值:升高Apo-A1>9%(达到3.50～3.89mmol/L)和HDL-C>8%(达到1.17～1.42mmol/L),实现冠脉斑块的消退。     

Statins and coronary artery disease: clinical evidence and future perspective

Many clinical trials have demonstrated the beneficial effects of statins on cardiovascular risk, both in patients with history of coronary heart disease and in healthy subjects with risk factors, because of a significant reduction in acute coronary events. The introduction of more powerful statins in the market offered the opportunity to study whether an intensive lipid lowering treatment could yields even better cardiovascular outcomes than a moderate statin therapy and several clinical trial confirmed this hypothesis. Statins have also pleiotropic effect behind their lipid lowering function: they reduce inflammation, which plays an important role in the atherosclerotic process.     

Women do benefit from lipid lowering: latest clinical trial data

Cardiovascular disease is the leading cause of morbidity and mortality among women in industrialized nations. Optimizing cardiovascular risk reduction is therefore of paramount importance, particularly among postmenopausal women, in whom the incidence of cardiovascular disease is highest. Accumulated data from a series of landmark trials unequivocally demonstrate the efficacy of statin therapy in the primary and secondary prevention of cardiovascular outcomes in both men and women. Moreover, the recently released Heart Protection Study provides substantive evidence that lowering low-density lipoprotein cholesterol below levels currently defined as optimal by National Cholesterol Educational Program guidelines is strongly associated with further cardiovascular risk reduction, and that this benefit accrues in all subgroups of patients, including women and the elderly. Despite the ability of hormone replacement therapy to improve serum lipid profiles, randomized trials of hormone therapy have demonstrated no benefit in reducing coronary outcomes among postmenopausal women. In contrast, data from over 8,000 women enrolled in the statin trials demonstrate that lipid lowering with statins is as effective at reducing cardiovascular outcomes in women as it is in men and suggest that statins should be considered standard of care for the prevention of adverse cardiovascular events in women at risk for coronary heart disease.