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.     

Design and rationale of the ARBITER trial (Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol)--a randomized trial comparing the effects of atorvastatin and pravastatin on carotid artery intima-media thickness

BACKGROUND: As a class, statins are remarkably effective in reducing low-density lipoprotein (LDL) cholesterol, and several of these drugs have now been shown to reduce coronary heart disease morbidity and mortality. However, several important controversies in the use of statins remain to be answered by clinical trials. For example, it is controversial whether marked cholesterol reduction to levels below 100 mg/dL would further reduce the incidence of coronary heart disease. Furthermore, concerns about differences among statins for nonlipid effects has raised the concern that the assumption of a class effect is premature until head-to-head clinical trials are completed. METHODS: Arterial Biology for the Investigation for the Treatment Effects of Reducing Cholesterol (ARBITER) is a single-center, randomized, active-controlled study comparing the efficacy of high-dose atorvastatin (80 mg/d) and pravastatin (40 mg/d) in patients being treated for either the primary or secondary prevention of coronary heart disease. This trial will enroll up to 200 patients for the primary end point of the mean change in intima-media thickness of the common carotid artery. This effect will be evaluated over a treatment duration of 12 months. Secondary end points include the effects of statin therapy on inflammatory and hemostatic markers (C-reactive protein and fibrinogen). CONCLUSION: ARBITER will provide important data on the role of marked LDL reduction and the "class effect" theory of statin therapy in cardiovascular medicine.     

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.     

Cardiometabolic Impact of Non-Statin Lipid Lowering Therapies

There is evidence from epidemiology, pathophysiology, and clinical trials that high LDL cholesterol levels cause atherosclerotic heart disease. Current guidelines recommend an LDL cholesterol target of 70 mg/dL for patients at high or very high risk. The risk imposed by LDL cholesterol is modulated by the presence of additional risk factors such as age, smoking, and indices of inflammation. Epidemiologic studies as well as rare congenital conditions (e.g., hypobetalipoproteinemia) have shown that very low LDL cholesterol (lower than 70 mg/dL) levels are associated with a very low risk of cardiovascular disease. Analyses of randomized clinical trials have shown a greater benefit in reducing the risk of cardiovascular disease (without an increase in adverse events) among those with very low achieved LDL (below 40 mg/dL). In one study of patients with achieved LDL cholesterol below 30 mg/dL, there was no increase in the usual adverse events compared to patients with LDL cholesterol levels above 30 mg/dL. High-intensity statin therapy is associated with a higher rate of transaminase elevations, but no hepatic failure, a very small risk of myopathy, and an increased risk of developing diabetes. However, the small increase in the risk of developing diabetes is much smaller than the marked lowering of cardiovascular risk. The duration of statin therapy may be important in studies of primary prevention and early, probably low-dose statin therapy, may achieve primordial prevention of atherosclerotic disease.     

Low-density lipoprotein cholesterol reduction: the end is more important than the means

Many epidemiologic studies and clinical trials have demonstrated the linear relation between elevated serum levels of low-density lipoprotein (LDL) cholesterol and the risk for coronary heart disease. Conversely, for each 1% reduction in LDL cholesterol in clinical trials, there is a corresponding 1% reduction in coronary heart disease risk. Although the degree of reduction is more important in affecting risk than the means used to lower LDL, statins are considered the most consistently effective means of lowering LDL. The National Cholesterol Education Program now recommends an optional goal of <70 mg/dl for patients at very high risk for coronary heart disease. In conclusion, on the basis of completed clinical trials, there is no evidence that achieving and maintaining such low levels of LDL cholesterol result in adverse effects. The most potent statins, rosuvastatin and atorvastatin, are capable of getting most patients to their LDL cholesterol goals, but combinations of statins with other drugs may be necessary for patients who require additional lipid lowering.     

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.     

Optimal treatment of dyslipidemia in high-risk patients: intensive statin treatment or combination therapy?

A recent update to the National Cholesterol Education Program's Adult Treatment Panel III guidelines suggests low-density lipoprotein cholesterol (LDL-C) goals of <70 mg/dL in very-high-risk patients and <100 mg/dL in high-risk patients. Currently available 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) are not equal in their ability to lower LDL-C, and it is unlikely that the substantial LDL-C reductions that are often needed in high-risk persons can be achieved with starting doses of some of the older statins. Possible alternatives in such cases include the use of high-dose statin therapy, a more efficacious statin, or combination therapy. Recent clinical data have demonstrated a greater likelihood of coronary heart disease event reduction with aggressive statin therapy that lowers LDL-C in a robust fashion (>30%-40%) than with moderate therapy. Until data from ongoing trials of combination therapy are available, however, monotherapy with a potent statin should be initiated to lower LDL-C. Nonetheless, for residual elevation in triglycerides and/or reduced high-density lipoprotein cholesterol, adding a second agent (eg, fenofibrate, niacin) is a reasonable option.     

Comparison of PCSK9 Inhibitor Evolocumab vs Ezetimibe in Statin‐Intolerant Patients: Design of the Goal Achievement After Utilizing an Anti‐PCSK9 Antibody in Statin‐Intolerant Subjects 3 (GAUSS‐3) Trial

Statins are the accepted standard for lowering low‐density lipoprotein cholesterol (LDL‐C). However, 5% to 10% of statin‐treated patients report intolerance, mostly due to muscle‐related adverse effects. Challenges exist to objective identification of statin‐intolerant patients. Evolocumab is a monoclonal antibody that binds proprotein convertase subtilisin/kexin type 9 (PCSK9), resulting in marked LDL‐C reduction. We report the design of Goal Achievement After Utilizing an Anti‐PCSK9 Antibody in Statin‐Intolerant Subjects 3 (GAUSS‐3), a phase 3, multicenter, randomized, double‐blind, ezetimibe‐controlled study to compare effectiveness of 24 weeks of evolocumab 420 mg monthly vs ezetimibe 10 mg daily in hypercholesterolemic patients unable to tolerate an effective statin dose. The study incorporates a novel atorvastatin‐controlled, double‐blind, crossover phase to objectively identify statin intolerance. Eligible patients had LDL‐C above the National Cholesterol Education Project Adult Treatment Panel III target level for the appropriate coronary heart disease risk category and were unable to tolerate ≥3 statins or 2 statins (one of which was atorvastatin ≤10 mg/d) or had a history of marked creatine kinase elevation accompanied by muscle symptoms while on 1 statin. This trial has 2 co‐primary endpoints: mean percent change from baseline in LDL‐C at weeks 22 and 24 and percent change from baseline in LDL‐C at week 24. Key secondary efficacy endpoints include change from baseline in LDL‐C, percent of patients attaining LDL‐C <70 mg/dL (1.81 mmol/L), and percent change from baseline in total cholesterol, non–high‐density lipoprotein cholesterol, and apolipoprotein B. Recruitment of 511 patients was completed on November 28, 2014.     

Cholesterol, stroke risk, and stroke prevention

Serum cholesterol traditionally has been considered a poor predictor of total stroke risk; however, it is associated positively with ischemic stroke risk and associated negatively with hemorrhagic stroke risk. Although studies failed to demonstrate stroke reduction using older cholesterol-lowering medications, recent study of the statin class of medications shows both consistent stroke and other cardiovascular benefits. Ischemic stroke and coronary heart disease share similar underlying mechanisms, likely explaining much of the therapeutic benefit from statins. Current research is directed at further determining groups of patients most likely to benefit from lipid reduction in stroke prevention. In the interim, patients with established atherosclerosis should be treated with a statin to achieve a low-density lipoprotein cholesterol level less than 100 mg/dL.     

Low-density lipoprotein reduction: Is the risk worth the benefit?

Outcomes from recent lipid-lowering trials have led to an update of the third Report of the National Cholesterol Education Program (NCEP) Adult Treatment Panel’s guidelines for treatment of hypercholesterolemia in adults. The updated NCEP guidelines now offer an optional goal of low-density lipoprotein (LDL) cholesterol of less than 70 mg/dL for high-risk individuals. Epidemiologic and clinical trial data suggest that for every 30-mg/dL change in LDL, the relative risk for coronary heart disease changes by about 30%. Statin therapy effectively lowers LDL and has an overall excellent safety profile in clinical trials. However, the use of high-dose statin therapy also entails greater risk of adverse events, such as myopathy and liver function test abnormalities, and this must be carefully weighed against the potential benefit for each patient. Alternative approaches targeting high-density lipoproteins and triglycerides may offer yet another option for coronary heart disease prevention in high-risk patients.     

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.     

Hypercholesterolemia. The evidence supports use of statins

Using statins to treat older men and women with coronary artery disease (CAD) and hypercholesterolemia reduces the risk of all-cause mortality, cardiovascular mortality, coronary events, coronary revascularization, stroke, Intermittent claudication, and congestive heart failure. The target serum low-density lipoprotein (LDL) cholesterol level is < 100 mg in older patients with CAD, prior stroke, peripheral arterial disease, extracranial carotid arterial disease, abdominal aortic aneurysm, diabetes meilitus, and the metabolic syndrome. Statins are also effective in reducing cardiovascular events in older persons with hypercholesterolemia without cardiovascular disease. Consider using statins in older persons without cardiovascular disease but with a serum LDL cholesterol > or = 130 mg/dL, or a serum high-density lipoprotein cholesterol < 50 mg/dL. Data from the Heart Protection Study favor treating patients at high risk for vascular events with statins regardless of age or initial serum lipids.     

Approach to Lipid Therapy in the Patient With Atherosclerotic Vascular Disease

Hyperlipidemia increases the incidence of atherosclerotic vascular disease and is associated with greater rates of recurrent cardiovascular events among individuals with established vascular disease. Several large population studies have confirmed the link between all cholesterol components (including elevated low-density lipoprotein [LDL] cholesterol, total cholesterol, and triglyceride levels, and reduced high-density lipoprotein [HDL] levels) with coronary heart disease and other manifestations of systemic atherosclerosis. In addition, landmark clinical trials have clearly established that lowering LDL cholesterol levels with statins (HMG-CoA reductase inhibitors) can lower recurrent cardiovascular events by nearly 25%. The benefits of altering non-LDL cholesterol levels (eg, triglycerides and HDL) are less clear, but several other medications are often used in conjunction with statins for cholesterol lowering. First-line therapy for lipid lowering in patients with atherosclerotic vascular disease includes statins and a recommendation for lifestyle changes (including diet and exercise). Second-line options for lowering cholesterol include fibrates, nicotinic acid, bile acid sequestrants, and ezetimibe. Therapeutic goals for patients with vascular disease are to achieve an LDL cholesterol level < 100 mg/dL, or <70 mg/dL in individuals at particularly high risk.     

Prevalence of low high-density lipoprotein cholesterol in patients with documented coronary heart disease or risk equivalent and controlled low-density lipoprotein cholesterol

Current guidelines identify low-density lipoprotein (LDL) cholesterol as the primary target for cardiovascular prevention but also recognize low high-density lipoprotein (HDL) cholesterol as an important secondary target. This study was conducted to determine the prevalence of low HDL cholesterol in a contemporary ambulatory high-risk population across various LDL cholesterol levels, including patients taking statins. Screening of 44,052 electronic medical records from a primary care practice identified 1,512 high-risk patients with documented coronary heart disease (CHD) or CHD risk equivalents. Low HDL cholesterol (< or =40 mg/dl in men, < or =50 mg/dl in women) was present in 66% of the 1,512 patients. Low HDL cholesterol was prevalent across all LDL cholesterol levels but most prevalent in patients with LDL cholesterol < or =70 mg/dl (79% vs 66% in those with LDL cholesterol 71 to 100 mg/dl and 64% in patients with LDL cholesterol >100 mg/dl, p <0.01). Low HDL cholesterol was equally and highly prevalent in patients taking statins (67%) and those not taking statins (64%) (p = NS). HDL cholesterol and LDL cholesterol levels correlated poorly (R(2) = 0.01), and this was unaffected by gender or statin treatment. In conclusion, in high-risk patients with CHD or CHD risk equivalents, low HDL cholesterol levels remain prevalent despite statin treatment and the achievement of aggressive LDL cholesterol goals.     

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.     

Effects of colesevelam hydrochloride on low-density lipoprotein cholesterol and high-sensitivity C-reactive protein when added to statins in patients with hypercholesterolemia

Elevated high-sensitivity C-reactive protein (hs-CRP) levels are associated with an increased risk of atherosclerotic coronary heart disease (CHD). The addition of the bile acid sequestrants, such as colesevelam hydrochloride (HCl), to statins further reduces low-density lipoprotein (LDL) cholesterol levels. However, the effects of approved cholesterol-lowering bile acid sequestrants on hs-CRP have not previously been reported. Three randomized, double-blind, placebo-controlled, parallel, 6-week clinical trials of similar design investigated the efficacy of adding colesevelam HCl to stable simvastatin, atorvastatin, or pravastatin treatment in 204 patients with primary hypercholesterolemia. The primary end point was the mean percent change in the LDL cholesterol levels. Secondary end points included the effects on other lipid parameters and hs-CRP levels. A pooled analysis showed that adding colesevelam HCl to statin therapy significantly lowered LDL cholesterol levels (21 mg/dl or 16% mean reduction from baseline, p = 0.0013, and 11 mg/dl or 9% mean reduction compared with placebo, p = 0.0003). Four times as many patients receiving colesevelam HCl plus a statin achieved a LDL cholesterol target of <100 mg/dl compared with patients receiving a statin plus placebo (39% vs 10%, respectively, p <0.0001). The incidence of mild gastrointestinal adverse effects was slightly higher in the colesevelam HCl plus statin group than in the placebo plus statin group. Finally, the differences in the change in hs-CRP levels with colesevelam HCl plus statin therapy were significant compared with the changes with placebo plus statin (median change -23%, p = 0.0069). In conclusion, this is the first report suggesting that an approved cholesterol-lowering bile acid sequestrant, specifically colesevelam HCl, decreases hs-CRP levels when added to statin therapy.     

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.     

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.     

Cholesterol 2001. Rationale for lipid-lowering in older patients with or without CAD

Statin treatment of men and women age > or = 50 with coronary artery disease (CAD) and hypercholesterolemia reduces the risk of all-cause mortality, cardiovascular mortality, coronary events, coronary revascularization, stroke, and intermittent claudication. The target serum low-density lipoprotein (LDL) cholesterol level is < 100 mg/dL in older patients with CAD, prior stroke, peripheral arterial disease, or extracranial carotid arterial disease and serum LDL cholesterol > 125 mg/dL despite diet therapy. Statins are also effective in reducing cardiovascular events in older persons with hypercholesterolemia but without cardiovascular disease. Consider using statins in patients age 50 to 80 without cardiovascular disease, serum LDL cholesterol > 130 mg/dL, and serum high-density lipoprotein (HDL) cholesterol < 50 mg/dL.     

Ten-year follow-up of familial hypercholesterolemia patients after intensive cholesterol-lowering therapy

To prevent coronary artery disease, it is necessary for patients with familial hyper-cholesterolemia (FH) to maintain a low cholesterol level. Recently a combination therapy of low-density lipoprotein (LDL) apheresis and statins has been used for FH patients, but their long-term prognosis over 10 years is unknown. In this single center prospective report, 18 FH patients with severe coronary stenosis received LDL apheresis every 2 or 4 weeks and statin therapy for 9.8 +/- 3.0 years. Probucol was given to 17 of the 18 patients. We observed their clinical events as well as coronary stenosis findings and ejection fractions for 10.7 +/- 2.6 years. Total and LDL cholesterol levels before therapy were 345 +/- 46 and 277 +/- 48 mg/dL, respectively. Immediately following LDL-apheresis, these levels decreased to 104 +/- 7.5 and 66 +/- 16 mg/dL, respectively. There were no cardiac deaths and 4 patients were free from any coronary events. There was one noncardiac death. Nonfatal myocardial in-farction occurred in 2 patients and coronary bypass surgery was required in one patient. Twelve patients received additional coronary angioplasty. There was little change in coronary stenosis and ejection fraction following 10 years of the combination therapy. Univariate Cox regression analysis revealed that the calculated mean LDL cholesterol level was the predictive value of treatment efficacy (mean LDL cholesterol < 140 mg/dL, hazard ratio 0.23, P = 0.028). The combination therapy of LDL-apheresis and antilipid drugs delayed the progression of coronary atherosclerosis and prevented a major cardiac event, although complete inhibition was limited to a small group. Additional coronary angioplasty is likely to be required for a favorable clinical outcome in FH patients.