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.     

The endotoxin-lipoprotein hypothesis

The advent of 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (statins) has revolutionised the treatment of hypercholesterolaemia. Statin treatment, by lowering the atherogenic lipoprotein profile, reduces morbidity and mortality in patients with cardiovascular disease. Treatment with simvastatin causes a reduction of events of new-onset heart failure, but this may be attributable to properties other than its lipid-lowering effects. There is some evidence that lower serum cholesterol concentrations (as a surrogate for the totality of lipoproteins) relate to impaired survival in patients with chronic heart failure (CHF). Inflammation is a feature in patients with CHF and increased lipopolysaccharide may contribute substantially. We postulate that higher concentrations of total cholesterol are beneficial in these patients. This is potentially attributable to the property of lipoproteins to bind lipopolysaccharide, thereby preventing its detrimental effects. We hypothesise there is an optimum lipoprotein concentration below which lipid reduction would, on balance, be detrimental. We also propose that, in patients with CHF, a non-lipid-lowering statin (with ancillary properties such as immune modulatory and anti-inflammatory actions) could be as effective or even more beneficial than a lipid-lowering statin.     

Recommendations for management of dyslipidemia in high cardiovascular risk patients

Overwhelming evidence supports a causal relationship between elevated levels of plasma cholesterol, particularly low-density lipoprotein cholesterol, and increased risk of coronary artery disease, which remains the leading cause of death and morbidity worldwide. Low-density lipoprotein cholesterol lowering has been the main goal of therapy, and clinical trial results from recently published studies of intensive statin therapy confirm the benefits of more aggressive lipid-lowering targets, particularly in subjects at high risk for cardiovascular events. This management update will focus on the implications of risk reduction in patients at high cardiovascular risk, and will provide practical steps to help further risk stratify these patients and help them reach their target goals.     

In-hospital initiation of statin therapy in patients with acute coronary events

After acute coronary events, patients remain at high risk for recurrent cardiovascular events and mortality. Despite the compelling scientific and clinical trial evidence that statin therapy reduces mortality in patients after acute coronary events, this life-saving therapy continues to be underutilized. It is now recognized that the setting in which statin therapy is initiated has a major impact on patient adherence. In-hospital initiation of statin therapy has been demonstrated to result in a markedly increased treatment rate, improved long-term patient compliance, more patients reaching low-density lipoprotein levels less than 100 mg/dL, and improved long-term clinical outcomes. As long-term risk reduction is seen with statin therapy irrespective of baseline low-density lipoprotein cholesterol, virtually all acute coronary event patients are candidates for statin treatment. In-hospital initiation of statin therapy may also reduce early clinical events in acute coronary syndrome patients, but further research is required before this is fully established. The adoption of in-hospital initiation of statin therapy as the standard of care for patients hospitalized with acute coronary events will dramatically improve treatment rates and thus substantially reduce the risk of future coronary events and prolong life in the large number of patients hospitalized each year.     

Einfluss der Lipidstoffwechselparameter auf die Entstehung und Progression der koronaren Herzerkrankung

Disorders of lipid metabolism play a major role in the development and progression of coronary artery disease. Dyslipidemia therefore plays a central role in therapeutic approaches for prevention and treatment of cardiovascular events associated with coronary artery disease. Epidemiological studies have shown an association between various lipid metabolism parameters, the risk of developing coronary artery disease and progression of a pre-existing disease. In particular, increased levels of low-density lipoprotein cholesterol (LDL-C), reduced levels of HDL cholesterol (HDL-C), as well as high levels of triglycerides and increased lipoprotein(a) [Lp(a)] levels can be taken into account when assessing the risk stratification of patients for primary prevention of coronary artery disease. Lifestyle and dietary changes, intensified statin therapy and possibly the addition of ezetimibe remain the major interventions in both primary and secondary prevention of coronary artery disease, as they improve the prognosis particularly by lowering levels of LDL-C. Recently, genetic studies have contributed to extending our understanding of the relationship between lipid metabolism and coronary artery disease. A causal role for progression of coronary artery disease could be demonstrated for LDL-C, Lpa and triglyceride-rich lipoproteins (TRL), which could not be demonstrated for HDL-C in various studies. Furthermore, the effect of reduction of LDL-C by proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition and by the cholesteryl ester transfer protein (CETP) inhibitor anacetrapib on cardiovascular events is currently being investigated in large clinical outcome study programs.     

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.     

Statin therapy in acute coronary syndromes: mechanistic insight into clinical benefit

Randomized trials have established that statin treatment reduces coronary events in primary prevention and in patients with stable coronary artery disease. In unstable coronary artery disease, however, the pathophysiological background is distinct, and the potential benefits of statin therapy have not been evaluated until recently. Data from animal models and clinical studies indicate that statin treatment can influence a spectrum of molecular and cellular mechanisms that are intimately related to the pathogenesis of acute coronary syndromes; these include the reduction of circulating levels of atherogenic lipoproteins (very low density lipoprotein, very low density lipoprotein remnants, intermediate density lipoprotein, and low density lipoprotein) and thus of arterial lipid deposition and the attenuation of inflammation, modulation of thrombogenesis and thrombolysis, improvement of endothelial dysfunction, and reduction of ischemia/reperfusion injury. Indeed, findings from prospective and observational studies have demonstrated that statin treatment significantly improves clinical outcome after acute coronary syndromes. Therefore, early initiation of statin therapy after an acute coronary event not only enhances adherence to treatment but also preempts the occurrence of new events. In this review, we discuss recent important developments in our knowledge of the clinical evidence of the beneficial effects of early statin therapy in acute coronary syndromes and the biological mechanisms that underlie them.     

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.     

Hochdosierte Statintherapie für kardiovaskuläre Risikopatienten

Lowering LDL cholesterol (LDL-C) with statins decreases cardiovascular risk; therefore LDL-C is the primary target in lipid therapy. The amount of risk reduction is the greater, the lower the LDL-C values achieved by statin therapy are. Current guidelines therefore require an LDL-C as low as < 70 mg/dl in patients who are at a very high risk of cardiovascular events. This stringent treatment goal depending on the baseline LDL-C values typically can only be obtained with higher doses of potent statins. Randomised trials demonstrate the efficacy of high-dose therapy with atorvastatin 80 mg/day with regard to the prevention of cardiovascular events in patients after acute coronary syndromes (PROVE-IT TIMI 22 trial), in patients with stable coronary artery disease (TNT trial), and in patients after stroke or TIA (SPARCL trial). Moreover, potent statin treatment reduces the progression of coronary atherosclerosis (REVERSAL and ASTEROID trials). Furthermore, large meta-analyses of the efficacy of high-dose statin therapy confirm its safety; in particular, muscle-related adverse events are not more frequent than with standard statin doses. It is recommended that evidence-based statin doses be used in clinical practice; the dosages used in clinical trials should be given rather than titrating patients to LDL-C targets by increasing statin doses in a stepwise manner. Whether the strong LDL-C lowering combination of simvastatin plus ezetimibe will reduce cardiovascular events over and above simvastatin monotherapy is currently being tested in the ongoing IMPROVE-IT trial. Importantly, despite the large body of evidence in favour of high-dose statin therapy for patients at high cardiovascular risk, high-dose statin therapy is still underused and LDL-C goals are still not met in the majority of these patients.     

Effects of lipid-lowering therapy with strong statin on serum polyunsaturated fatty acid levels in patients with coronary artery disease

Residual risk of cardiovascular events after treatment with stain might be explained in part because patients have low levels of n?3 polyunsaturated fatty acids (PUFA). We examined how lipid-lowering therapy with strong statin affected serum PUFA levels in patients with coronary artery disease. The study population consisted of 46 patients with coronary artery disease whose low-density lipoprotein (LDL) cholesterol was more than 100 mg/dl. Lipid-lowering therapy was performed with a strong statin including atorvastatin (n = 22), rosuvastatin (n = 9) or pitavastatin (n = 15). Serum PUFA levels were determined by gas chromatography. The treatment with strong statin decreased the sum of dihomo-γ-linolenic acid (DGLA) and arachidonic acid (AA) levels (195 ± 41 to 184 ± 44 μg/ml, P < 0.05) as well as the sum of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) levels (233 ± 71 to 200 ± 72 μg/ml, P < 0.001). These effects of strong statin resulted in a significant decrease in ratio of the sum of EPA and DHA levels to the sum of DGLA and AA levels (1.20 ± 0.27 to 1.10 ± 0.35, P < 0.05). The percent decrease in the LDL cholesterol level correlated significantly with that in the sum of EPA and DHA levels (r = 0.38, P < 0.01). In conclusion, our results showed that lipid-lowering therapy with strong statin mainly reduced n?3 PUFAs in proportion to the decrease in the LDL cholesterol level in patients with coronary artery disease.     

Recurrence of angina pectoris after percutaneous coronary intervention is reduced by statins in Japanese patients

Background

Statins have been reported to reduce cardiovascular events in patients with coronary artery disease (CAD). Percutaneous coronary intervention (PCI) is commonly used to relieve ischemic symptoms in patients with CAD. However, there is little information on the effect of statins on cardiovascular events after PCI, even in the era of coronary stent implantation.

Methods

A total of 1019 patients with acute or chronic CAD and modest total cholesterol levels (180–240 mg/dl) were enrolled and randomly assigned to treatment with or without statins. We evaluated the effect of any available statin on the incidence of cardiovascular events after PCI. The primary endpoint was a composite of cardiovascular death, nonfatal acute myocardial infarction (MI), recurrent angina pectoris requiring emergency rehospitalization (rAP), heart failure, and stroke.

Results

Indications for PCI were stable angina in 54%, ST-elevation MI in 41% and non-ST-elevation MI/unstable angina pectoris in 5%. After 2 years of statin treatment, low-density lipoprotein cholesterol (LDL-C) decreased from 133 to 96 mg/dl. Stents were implanted in 84% of all cases. The primary endpoint event rate was 9.5% in the statin group and 14.7% in the non-statin group (p = 0.0292). Of all primary endpoint events, only rAP was significantly suppressed by statins (p = 0.0027). In rAP patients, coronary angiography revealed that statins suppressed restenosis but not new lesions.

Conclusions

For Japanese CAD patients treated with PCI and stent implantation, statin therapy reduced the incidence of recurrent cardiovascular events, particularly rAP. Discretionary statin treatment to achieve LDL-C levels <100 mg/dl effectively reduced restenosis causing rAP.     

Lipid management beyond the guidelines

The 2018 AHA/ACC cholesterol guideline builds on the 2013 ACC/AHA cholesterol guideline statin recommendations to provide more detailed recommendations for the use of nonstatin therapy risk stratification for primary prevention statin use. New information has become available after the development of the 2018 AHA/ACC cholesterol guideline that can further inform clinical practice. Proprotein convertase subtilisin kexin type-9 (PCSK9) monoclonal antibodies are now a reasonable or even good value following over 60% reductions in their acquisition price, and the identification of high risk patient groups most likely to benefit from further low-density lipoprotein cholesterol (LDL-C) lowering. Meta-analyses and clinical trial data now show that patients with LDL-C ≥ 100 mg/dl are more likely to experience progressively greater reductions in the risk of cardiovascular and total mortality and coronary heart disease events for progressively higher LDL-C levels. Icosapent ethyl, a highly concentrated form of modified EPA has been shown to reduce cardiovascular events in high risk patients with moderate hypertriglyceridemia on statin therapy. Comparisons with other statin guidelines revealed that statin initiation for those with ≥7.5% 10-year atherosclerotic cardiovascular disease (ASCVD) risk is the most effective strategy for reducing the most ASCVD events for the proportion of the population treated. Data from younger populations finally became available for coronary artery calcium (CAC) scoring (mean age of 51 years) which confirmed the value of CAC > 0 for identifying individuals at increased ASCVD risk most likely to benefit from statin initiation. This analysis also found that statins could keep CAC = 0 in those with risk factors. Epidemiologic pooling studies now clearly show that LDL-C and non-high-density lipoprotein cholesterol levels in young adulthood confer excess risk for ASCVD later in life. Accumulating data support earlier risk factor intervention trials as the next research priority.     

Are Statins Indicated in Senior Citizens? A Review of Statin Therapy in the Elderly

The use of statin therapy in atherosclerotic cardiovascular disease (ASCVD) has demonstrated substantial improvement in morbidity and mortality of the aging population. Despite exhaustive studies demonstrating the benefits of statin therapy linking lower cholesterol levels to decreased vascular events, statin guidelines vary greatly with age, and recommendations are unclear regarding initiation and discontinuation of statin therapy in patients 65 years and older. Data suggest that statins are highly effective at secondary prevention of major cardiovascular events and development of coronary heart disease in patients with a history of vascular disease or risk factors such as diabetes mellitus, hypertension, hypercholesterolemia, or smoking. Therefore, patients who meet these criteria, regardless of age, should begin statin therapy. There is also some evidence to suggest that statin therapy may be beneficial in primary prevention of major cardiovascular events, although these data are not as well studied as secondary prevention use of statin therapy, and should therefore be individualized for each patient.     

Statin Therapy for Vascular Failure

There is increasing evidence that statins reduce cardiovascular events such as coronary artery disease or stroke in hypercholesterolemic patients in both primary and secondary prevention. The striking benefit achieved with statin treatments in patients with a wide range of cholesterol levels cannot be attributed to their cholesterol lowering effect alone. Substantial data has recently accumulated showing that statins exert various effects on multiple targets, namely pleiotropic effects, especially targeting the concept of ‘vascular failure’, including the improvement of vascular endothelial function, inhibition of vascular smooth muscle cell proliferation and migration, anti-inflammatory actions, anti-oxidative effects or stabilization of vulnerable plaques. These effects have potential in the treatments of coronary artery disease in various settings, such as prevention of its onset as well as its progression, or plaque rupture. Statin therapy should be more extensively applied even in normolipidemic patients if there are additional risk factors such as hypertension, diabetes mellitus, or others. Furthermore, statins may be used to intervene in earlier stage risk conditions such as postprandial hyperlipidemia or hyperglycemia, insulin resistant state, masked hypertension, or metabolic syndrome to further reduce mortality or morbidity of coronary artery disease and heart failure.     

Lipid-Lowering Therapy in Patients 75 Years and Older: Clinical Priority or Superfluous Therapy?

The incidence and prevalence of cardiovascular (CV)-related morbidity and mortality significantly increase with age. In the elderly, hypercholesterolemia with elevated total and low-density-lipoprotein cholesterol is a significant predictor of incident and recurrent CV disease. Multiple lines of evidence have established the benefit of statin therapy to lower cholesterol levels and reduce the risk of CV events as well as prevent progression of subclinical atherosclerotic disease. Elderly patients, particularly those older than 75 years, have not been well represented in randomized clinical trials evaluating lipid lowering therapy. The limited available data from clinical trials do support the benefit of statin therapy in the elderly population. Based upon these data, cholesterol treatment guidelines endorse statin therapy as the primary treatment of hypercholesterolemia in elderly patients, though caution is recommended given the greater number of co-morbid conditions and concern for poly-pharmacy common in the elderly. Additional research is needed to better establish the benefit of statin therapy in the elderly within the context of reducing CV risk, minimizing side effects, and improving overall quality of life.     

C-reactive protein predicts the severity of coronary artery disease beyond low-density lipoprotein cholesterol

Prospective studies and clinical trials have shown that C-reactive protein (CRP) independently predicts the occurrence of cardiovascular events, even in individuals without hypercholesterolemia. We evaluated whether CRP can predict the severity of coronary artery stenosis in patients with lower low-density lipoprotein cholesterol (LDL-C) levels. A total of 418 patients with lower LDL-C (<3.37 mmol/L) who underwent coronary angiography were recruited. The median levels of CRP increased according to the number of stenotic vessels. Multivariable adjustment model indicated that CRP was associated with the severity of coronary artery disease (CAD) in the top to the bottom third comparison of CRP levels, yielding an odds ratio of 1.72 (95% confidence interval: 1.08-2.74); this trend was preserved after excluding the confounding effect of statin treatment. C-reactive protein may serve as a useful biomarker for improving the risk assessment and secondary prevention of CAD patients without hypercholesterolemia.     

Pharmacologic therapy of lipid disorders in the elderly

Older men and women with coronary artery disease, prior stroke, peripheral arterial disease, and extracranial carotid arterial disease with a serum low-density lipoprotein (LDL) cholesterol >125 mg/dL despite diet should be treated with lipid-lowering drug therapy, preferably with statins, to reduce the serum LDL cholesterol to <100 mg/dL. If statin drug therapy does not lower the serum LDL cholesterol to <100 mg/dL in older persons with coronary artery disease, a bile acid binding resin, such as cholestyramine, should be added, since this drug does not increase the incidence of myositis in persons taking statins. The physician should use statins to treat older persons without atherosclerotic cardiovascular disease with a serum LDL cholesterol=160 mg/dL plus one major risk factor, or a serum LDL cholesterol=130 mg/dL plus a serum high-density lipoprotein (HDL) cholesterol <50 mg/dL. Gemfibrozil may be useful in reducing the incidence of coronary events in persons with coronary artery disease whose primary lipid abnormality is a low serum HDL cholesterol level. There are no good data supporting treatment of hypertriglyceridemia unassociated with increased LDL cholesterol or decreased HDL cholesterol for prevention of cardiovascular disease.     

To statin or to non-statin in coronary disease--considering absolute risk is the answer

The newest guidelines for treating people with coronary artery disease (CAD) suggest benefit from statin-induced LDL cholesterol lowering regardless of baseline LDL cholesterol level. These guidelines were based on recent clinical trials that showed statistically significant statin-induced relative risk reductions (RRR) in cardiovascular events. However, there are proven "non-statin" anti-atherosclerotic treatments. This analysis was designed to allow the physician to decide which patients benefit from the various anti-atherosclerotic treatments available. Analysis is presented as absolute risk reduction (ARR) because ARR takes baseline risk into account. There was a large benefit from statin therapy in stable CAD when LDL cholesterol levels were high. There were diminishing returns, despite statistically significance, with statin treatment of people with chronic CAD and lower LDL cholesterol levels. People with chronic CAD and lower LDL cholesterol levels had at least as much and possibly twice the ARR when treated with niacin or gemfibrozil as that would occur with statin treatment. For the first year after the acute coronary syndrome, risk was higher than in stable CAD, and trials showed a benefit especially with a Mediterranean diet and also with statin therapy that reduced LDL cholesterol levels to approximately 80 mg dl(-1). The Mediterranean diet was also beneficial in chronic CAD. These results suggest that both statin and non-statin therapy are important for reducing the sequelae of atherosclerosis.     

Drugs Targeting High-Density Lipoprotein Cholesterol for Coronary Artery Disease Management

Many patients remain at high risk for future cardiovascular events despite levels of low-density lipoprotein cholesterol (LDL-C) at, or below, target while taking statin therapy. Much effort is therefore being focused on strategies to reduce this residual risk. High-density lipoprotein cholesterol (HDL-C) is a strong, independent, inverse predictor of coronary heart disease risk and is therefore an attractive therapeutic target. Currently available agents that raise HDL-C have only modest effects and there is limited evidence of additional cardiovascular risk reduction on top of background statin therapy associated with their use. It was hoped that the use of cholesteryl ester transfer protein (CETP) inhibitors would provide additional benefit, but the results of clinical outcome studies to date have been disappointing. The results of ongoing trials with other CETP inhibitors that raise HDL-C to a greater degree and also lower LDL-C, as well as with other emerging therapies are awaited.     

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.