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.     

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.     

Low-density lipoprotein in the setting of congestive heart failure: Is lower really better?

Hypercholesterolemia is a risk factor for coronary artery disease (CAD), CAD mortality, and incident heart failure (HF). Lipid-lowering therapy with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) has been shown to reduce the risk of developing HF in patients with CAD. However, in patients with chronic established HF, hypercholesterolemia has not been associated with an increased risk of mortality. Several studies have demonstrated that higher lipid and lipoprotein levels, including total cholesterol, low-density lipoprotein, high-density lipoprotein, and triglycerides, are associated with significantly improved outcomes in HF of both ischemic and nonischemic etiologies. In light of the association between high cholesterol levels and improved survival in HF, statin or other lipid-lowering therapy in HF remains controversial. To date, large outcome trials of statin therapy in HF of multiple etiologies have not demonstrated mortality benefit.     

Can intensive statin therapy halt the progression of atherosclerosis? Recent evidence and potential implications for patient management

A number of studies using various imaging techniques have demonstrated that intensive lipid lowering with statins can halt or delay the progression of atherosclerosis and even, in some cases, lead to plaque regression. Improvements in atheroma burden with intensive statin therapy appear to be related not just to decreasing low-density lipoprotein cholesterol but also to anti-inflammatory and antiproliferative effects. Clinical trial results also suggest that achieving low-density lipoprotein cholesterol levels even lower than those currently recommended can produce improved clinical outcomes across a range of patient types. Given this body of evidence, it appears appropriate to use intensive statin therapy to treat dyslipidemic patients at high risk for coronary heart disease.     

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.     

Efficacy and safety of intensive statin therapy in the elderly

Numerous epidemiologic and intervention trials, including many studying elderly cohorts, have demonstrated the importance of lipids in primary and secondary preventions of cardiovascular diseases, including coronary heart disease (CHD) and stroke. More recent studies have demonstrated that more intensive statin therapy that reduces low-density lipoprotein cholesterol levels to <70 to 80 mg/dL have resulted in more marked cardiovascular event reduction than less intensive statin treatment. The authors review the efficacy and safety of intensive vs less intensive statin therapy. Specifically, 4 such studies with sufficient data in elderly patients, including 2 trials of patients with stable CHD and 2 with acute coronary syndrome, demonstrating the efficacy and safety of intensive statin therapy with high-dose (80 mg) atorvastatin are reviewed in detail. Although elderly patients may be more susceptible to drug interactions when receiving high doses of statins, the present evidence supports the use of intensive statin therapy in most high-risk elderly patients both with stable CHD and following acute coronary syndrome.     

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.     

Lipid lowering therapy in atherosclerosis

Dyslipidemia plays critical roles in the pathogenesis of coronary atherosclerosis, a chronic inflammatory disease. Vascular inflammation also triggers the onset of acute complications of atherosclerosis, such as myocardial infarction. Advances in cardiovascular medicine demonstrate that lipid-lowering therapy by 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) likely prevents acute coronary complications by limiting vascular inflammation. In particular, recent clinical evidence indicates aggressive lipid-lowering treatment for patients at risk. Preclinical studies also support the concept of anti-inflammatory properties of lipid lowering by either diet or statins. Therefore, dyslipidemia is the primary target of therapy for the prevention of coronary atherosclerosis and its acute thrombotic complications. Nevertheless, even aggressive statin therapy does not forestall many adverse events. Thus, current cardiovascular medicine also seeks mechanisms to mitigate vascular inflammation and atherosclerosis other than addressing low-density lipoprotein, and new therapeutic strategies beyond lipid lowering.     

Coronary artery disease prognosis and C-reactive protein levels improve in proportion to percent lowering of low-density lipoprotein

This editorial outlines the data supporting aggressive lipid goals and options for treating low-density lipoprotein (LDL) cholesterol to a range of approximately 30 to 70 mg/dl. The physiologically normal cholesterol range is approximately 30 to 70 mg/dl for native hunter-gatherers, healthy human neonates, free-living primates, and virtually all wild mammals. Randomized statin trials in patients with recent acute coronary syndromes and stable coronary artery disease have demonstrated that cardiovascular events are reduced and cardiovascular survival optimized when LDL cholesterol is reduced to <70 mg/dl. Secondary prevention trials have shown a decrease in all-cause mortality in proportion to the magnitude of LDL cholesterol reduction. An original analysis of available data shows that the ability of a lipid-lowering therapy to reduce the C-reactive protein level is closely correlated with its efficacy in LDL cholesterol reduction. Randomized trial data have shown no relation between either percentage LDL cholesterol decrease or final LDL cholesterol level achieved and the risk for myopathy or hepatic transaminase elevations associated with statins. Therefore, intensive LDL cholesterol reduction to levels of 30 to 70 mg/dl should be pursued in subjects with or at high risk for coronary artery disease.     

Statins and Their Role in Pre-Percutaneous Coronary Intervention

Lipid-lowering therapy with statins reduces the risk of cardiovascular events in patients with coronary artery disease. Recent in vitro and in vivo studies demonstrated a low-density lipoprotein-independent action of this class of drugs, which appears to modulate endothelial function, inflammation, and thrombosis. Randomized studies showed a beneficial effect of short-term statin pretreatment in reducing periprocedural cardiac marker release in patients undergoing percutaneous coronary intervention (PCI). In particular, the ARMYDA (Atorvastatin for Reduction of Myocardial Damage During Angioplasty) investigators—initially in stable angina patients, then in patients with acute coronary syndrome, and then in patients already on chronic statin therapy—demonstrated an improvement in 30-day major adverse cardiac event rates, which were driven by a reduced rate of periprocedural myocardial infarction. Moreover, statin therapy at the time of PCI significantly decreased the incidence of contrast-induced nephropathy. These observations support high-dose statin pretreatment in all patients who are candidates for PCI.     

Comparison of effects of high (80 mg) versus low (20 mg) dose of simvastatin on C-reactive protein and lipoproteins in patients with angiographic evidence of coronary arterial narrowing

Although previous studies have demonstrated that various "statins" decrease levels of high-sensitivity C-reactive protein (hs-CRP), the dose-response relation for lowering hs-CRP by the clinically important drug simvastatin compared with lipid lowering is unclear. A 16-week, randomized, double-blind study was performed in patients with stable coronary artery disease and high hs-CRP levels (>3 mg/L). Subjects were randomized to placebo, 20 mg of simvastatin, or 80 mg of simvastatin for 12 weeks. Those currently on a statin first underwent a 4-week washout. Of the 107 total patients randomized, 96 completed the trial, and 89 were able to be evaluated for efficacy. Changes in hs-CRP differed across simvastatin and placebo groups (change score +1.6 vs -0.6 mg/L, p = 0.004), but no dose response was observed when comparing 80 with 20 mg/day (-0.6 vs -0.5 mg/L, respectively). A strong dose response was observed for changes in total (p <0.01) and low-density lipoprotein (p <0.001) cholesterol. hs-CRP changes did not correlate with low-density lipoprotein changes. In conclusion, this randomized trial in patients with chronic stable coronary artery disease showed a strong dose response for simvastatin for total and low-density lipoprotein cholesterol lowering but not for hs-CRP.     

Clinical relevance of statins: instituting treatment early in acute coronary syndrome patients

The efficacy of statins in lowering the total and low-density lipoprotein cholesterol and reducing the risk of cardiac events is now well established. The secondary prevention studies started treatment several months after the acute event. However, the greatest risk of recurrence is shortly after the index event. Recent evidence from small-scale clinical trials shows that standard doses of statins can be both safe and effective when given early after an acute coronary event, including early after thrombolytic therapy for myocardial infarction. Angiographic studies have shown beneficial effects of pravastatin on coronary stenosis when initiated after a coronary event. While none of these studies have been powered to demonstrate an effect on outcome, each has shown a reduction in major cardiovascular events. Two large observational studies have shown a reduction in 6- and 12-month risk-adjusted mortality among post-MI patients treated early with statins. Large-scale trials of all statins are now in progress to evaluate further the efficacy of early initiation of statin therapy in acute coronary syndromes. The largest of these is the Australian Pravastatin Acute Coronary Treatment (PACT) study, which will compare early outcomes in patients treated with pravastatin versus placebo prescribed within the first 24 h of an acute coronary event.     

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.     

Statin therapy, lipid levels, C-reactive protein and the survival of patients with angiographically severe coronary artery disease

OBJECTIVES: The joint predictive value of lipid and C-reactive protein (CRP) levels, as well as a possible interaction between statin therapy and CRP, were evaluated for survival after angiographic diagnosis of coronary artery disease (CAD). BACKGROUND: Hyperlipidemia increases risk of CAD and myocardial infarction. For first myocardial infarction, the combination of lipid and CRP levels may be prognostically more powerful. Although lipid levels are often measured at angiography to guide therapy, their prognostic value is unclear. METHODS: Blood samples were collected from a prospective cohort of 985 patients diagnosed angiographically with severe CAD (stenosis > or =70%) and tested for total cholesterol (TC), low-density lipoprotein (LDL), high-density lipoprotein (HDL), and CRP levels. Key risk factors, including initiation of statin therapy, were recorded, and subjects were followed for an average of 3.0 years (range: 1.8 to 4.3 years) to assess survival. RESULTS: Mortality was confirmed for 109 subjects (11%). In multiple variable Cox regression, levels of TC, LDL, HDL and the TC:HDL ratio did not predict survival, but statin therapy was protective (adjusted hazard ratio [HR] = 0.49, p = 0.04). C-reactive protein levels, age, left ventricular ejection fraction and diabetes were also independently predictive. Statins primarily benefited subjects with elevated CRP by eliminating the increased mortality across increasing CRP tertiles (statins: HR = 0.97 per tertile, p-trend = 0.94; no statins: HR = 1.8 per tertile, p-trend < 0.0001). CONCLUSIONS: Lipid levels drawn at angiography were not predictive of survival in this population, but initiation of statin therapy was associated with improved survival regardless of the lipid levels. The benefit of statin therapy occurred primarily in patients with elevated CRP.     

Statin loading before percutaneous coronary intervention: proposed mechanisms and applications

Statin therapy reduces the risk of cardiovascular events in patients with coronary artery disease. Recent in vitro and in vivo studies demonstrated a LDL-independent action of these class of drugs, which appears in modulating endothelial function, inflammation and thrombosis. Periprocedural myocardial infarction and contrast-induced nephropathy after percutaneous coronary intervention (PCI), associated with worse outcome on long-term follow-up, are both complications related to inflammatory pathogenetic mechanisms. Randomized studies demonstrated a beneficial effect of short-term statin pretreatment in reducing periprocedural cardiac marker release in patients undergoing PCI. Statin therapy before elective PCI reduces periprocedural myocardial infarction in patients with stable angina. Furthermore, an acute loading with a high dose of atorvastatin prevents myocardial damage in patients with acute coronary syndromes undergoing early PCI (<48 h). In patients already on chronic statin therapy, a reload with high-dose statins was associated with a significant improvement on 30-day major adverse cardiac event rates. Furthermore, statin therapy at the time of PCI significantly decreased the incidence of contrast-induced nephropathy. This evidence suggests an 'upstream administration' of short-term, high-dose statins in all patients undergoing PCI.     

The role of cholesterol and statins in stroke

Flawed observational studies find weak associations between high cholesterol and ischemic stroke, and low cholesterol and hemorrhagic stroke. Low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and triglycerides each appear to have individual effects on stroke risk and type. Statins decrease the risk of cerebral infarction in patients with coronary disease, diabetes, hypertension, and hypercholesterolemia. They also significantly decrease the risk of ischemic stroke in patients with recent cerebrovascular disease, while potentially increasing the risk of intracerebral hemorrhage. Lower achieved cholesterol values are associated with greater reductions in stroke risk. Besides their cholesterol-lowering properties, statins are also pleiotropic agents with various neuroprotective mechanisms. Neurologic disability and infarct size are decreased in patients administered statins during stroke. Mortality and neurologic deterioration are higher in patients with statin cessation during acute ischemic stroke. Cholesterol is a modifiable risk factor for stroke, and statins are excellent agents for prophylaxis and acute therapy.     

New and emerging data from clinical trials of statins

Recent clinical trials of statins have clearly demonstrated the benefit of statin therapy in preventing both coronary and cerebral vascular events. These benefits have been demonstrated to be present without reference to older age, sex, or comorbid conditions, including hypertension and diabetes. Future trials will test the value of more aggressive low-density lipoprotein cholesterol lowering, the value of immediate statin intervention during acute coronary syndromes, the role of cholesterol lowering with or without angioplasty, and the role of cholesterol lowering in stroke prevention.     

Effect of statin use in patients with acute coronary syndromes and a serum low-density lipoprotein<or=80 mg/dl

We identified 155 patients who were admitted with an acute coronary syndrome and a low-density lipoprotein cholesterol level相似文献   

Do statins prevent heart failure in patients after myocardial infarction?

3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, or statins, reduce morbidity and mortality in patients with coronary artery disease (CAD). Because CAD is the major cause of heart failure (HF) in developed countries, prevention of CAD may result in reduced HF. Evidence from randomized trials on lipid reduction (Cholesterol and Recurrent Events and the Scandinavian Simvastatin Survival Study) has shown statins to decrease progression to HF. Recently, many beneficial effects of statins have been demonstrated beyond cholesterol lowering. These agents improve endothelial function, exhibit anti-inflammatory properties, and prevent cardiac hypertrophy. Experimental studies have shown attenuation of left ventricular remodeling after myocardial infarction, possibly through reduced oxidative stress. However, no clinical evidence exists to support an effect on ventricular remodeling. Small, short-lasting clinical studies have also suggested that statin therapy might be associated with improved survival in ischemic and nonischemic HF.