Comparison of rosuvastatin versus atorvastatin in South-Asian patients at risk of coronary heart disease (from the IRIS Trial)

In a large randomized trial of statin therapy in patients of South-Asian origin with hypercholesterolemia, 740 patients in the United States and Canada received 6 weeks of treatment with rosuvastatin 10 or 20 mg or atorvastatin 10 or 20 mg. A total of 485 patients (66%) were categorized as being at high risk of coronary heart disease and had a National Cholesterol Education Program Adult Treatment Panel III treatment goal of low-density lipoprotein (LDL) cholesterol <100 mg/dl (<2.6 mmol/L). LDL cholesterol decreased by 45% with rosuvastatin 10 mg versus 40% with atorvastatin 10 mg (p = 0.0023) and by 50% with rosuvastatin 20 mg versus 47% with atorvastatin 20 mg (p = NS). National Cholesterol Education Program Adult Treatment Panel III LDL cholesterol goal achievement rates in high-risk patients (all patients) were 76% (79%) and 88% (89%) with rosuvastatin 10 and 20 mg, respectively, compared with 70% (76%) and 81% (85%) with atorvastatin 10 and 20 mg, respectively. Rosuvastatin and atorvastatin were well tolerated. There were no clinically relevant differences between statins in adverse events or incidence of creatine kinase >10 times the upper limit of normal, alanine aminotransferase >3 times the upper limit of normal on 2 consecutive occasions, or proteinuria or hematuria over the relatively short duration of treatment. In conclusion, statin therapy was well tolerated and effective in decreasing LDL cholesterol in patients of South-Asian origin, with the 10- and 20-mg doses of rosuvastatin and atorvastatin allowing most patients to reach recommended LDL cholesterol goals.     

Results of new statin trials: Should the low-density lipoprotein cholesterol treatment guidelines be revised?

In December 2002, the National Cholesterol Education Program published its third expert panel report on the detection, evaluation, and treatment of high blood cholesterol in adults (Adult Treatment Panel III). Since then, many new studies suggest that a more aggressive approach should be taken in cholesterol therapy. Based on these new clinical trials, the National Cholesterol Education Program published recommended modifications to the Adult Treatment Panel III guidelines in July 2004. There is good evidence to support the proposed modifications to Adult Treatment Panel III, but there is still much uncertainty in many patient subsets. More evidence is necessary to clarify if current treatment guidelines and low-density lipoprotein cholesterol goals are optimal for all patients within each risk category. These guidelines, and the proposed modifications, should be used as a tool to guide therapy that should be tailored to fit the overall risk assessment and needs of the individual patient.     

Combination lipid-lowering therapy in diabetes

Owing to the National Cholesterol Education Program Adult Treatment Panel III recommendations that patients with diabetes require a low-density lipoprotein (LDL) less than 100 mg/dL and a non-high-density lipoprotein (HDL) less than 130 mg/dL, frequently, combination lipid-lowering therapy is required. However, diabetic patients are commonly on multiple medications and have renal impairment. Therefore, the risk of myopathy with statin therapy is markedly increased. The safety of lipid-lowering therapy can be significantly improved by avoiding high-dose statins in combination with fibrates, especially gemfibrozil. To achieve non-HDL goals combining fenofibrate, or if glucose is well controlled, niacin, with a statin (not to exceed 40 mg), may significantly reduce the risk of myopathy. For diabetic patients who require additional LDL lowering, ezetimibe may provide a safe combination to a statin to achieve the LDL goal of less than 100 mg/dL.     

Newer pharmaceutical agents to treat lipid disorders

The National Cholesterol Education Program Adult Treatment Panel III guidelines and the results of the Heart Protection Study have provided a stronger rationale to more aggressively treat high-risk patients to a low-density (LDL) cholesterol goal of less than 100 mL/dL. Two new therapies, ezetimibe and rosuvastatin, have recently been added to the lipid-lowering armamentarium to improve guideline adherence. Ezetimibe, a novel cholesterol absorption inhibitor, lowers LDL by 18% to 20% and can be used safely in combination with statins. Adding ezetimibe to a statin is comparable with the LDL-lowering efficacy of tripling the dose of the statin. Rosuvastatin is a highly efficacious statin providing 8% greater LDL reduction than equivalent doses of atorvastatin, and the starting dose of 10 mg/d provides nearly a 50% reduction in LDL cholesterol. There are several investigational drugs in development for the prevention and treatment of atherosclerosis. Of these investigational drugs, the most promising are the cholesterol ester transfer protein inhibitors, which have the potential to significantly raise high-density lipoprotein cholesterol and acetyl-coenzyme A: cholesterol acyltransferase inhibitors, which may directly inhibit the progression of atherosclerosis.     

The place of HDL in cholesterol management. A perspective from the National Cholesterol Educational Program

The guidelines developed by the Adult Treatment Panel of the National Cholesterol Education Program identified low density lipoprotein (LDL) as the major atherogenic lipoprotein, and high levels of LDL-cholesterol as the primary target for cholesterol-lowering therapy. Low levels of high density lipoprotein (HDL)-cholesterol were recognized as a major risk factor for coronary heart disease. This report reexamines in depth the recommendations of the Adult Treatment Panel on HDL-cholesterol. Two major questions are discussed: (1) Should HDL-cholesterol levels be measured in all adults, as recommended for total cholesterol? (2) Should patients found to have a low serum HDL [corrected]-cholesterol level (less than 35 mg/dL [less than 0.91 mmol/L]) enter medical therapy to raise the level? The guidelines of the Adult Treatment Panel are reaffirmed as appropriate from the current perspective. These guidelines recommend that HDL-cholesterol levels be determined in patients deemed to be at high risk for coronary heart disease and suggest that HDL measurement is optional for individuals with borderline-high total levels. The guidelines of the Adult Treatment Panel recommend that low HDL-cholesterol levels be raised mainly by hygienic means (ie, smoking cessation, weight loss, aerobic exercise). When drug therapy is required for high LDL-cholesterol levels in the presence of low HDL levels, cholesterol-lowering drugs that concomitantly raise HDL should be given first priority.     

Gap between guidelines and practice: attainment of treatment targets in patients with primary hypercholesterolemia starting statin therapy. Results of the 4E-Registry (Efficacy Calculation and Measurement of Cardiovascular and Cerebrovascular Events Including Physicians' Experience and Evaluation).

BACKGROUND: The aim of this study was to determine the achievement of National Cholesterol Education Program Adult Treatment Panel III goals in patients with primary hypercholesterolemia starting statin therapy in clinical practice. METHODS AND RESULTS: Data were collected by 4401 physicians in private practice on 52 848 patients aged 35-65 years (46.3% women, 53.7% men). 56.1% of patients had no manifested atherosclerosis (primary prevention) among whom 34.9% of men and 0.5% of women had a 10-year coronary heart disease risk over 20% (high-risk) as calculated using the Prospective Cardiovascular Münster study (PROCAM) algorithm. After 6 weeks of statins, only 6.9% of these high-risk men and 4.6% of these high-risk women reached their low-density lipoprotein (LDL) cholesterol target of 2.6 mmol/l or below (100 mg/dl). Even after 9 months, only 8.0% of these men and 6.2% of these women achieved their LDL target. No fewer than 57.3% of treated women had a coronary risk below 10%, and 18.8% of women were already at target before statins were prescribed. Of patients 43.9% had manifest atherosclerosis (secondary prevention). After 6 weeks of therapy, only 12.9% of the women and 16.3% of the men in this secondary prevention group reached LDL target levels of 2.6 mmol/l or below. Even after 9 months, only 21.3% of men and 17.3% of women with manifest atherosclerosis reached target LDL. CONCLUSIONS: Most high-risk patients do not achieve LDL targets. Overtreatment of low-risk groups is also very common.     

Diet and drug therapy: a dynamic duo for reducing coronary heart disease risk

A large proportion of the United States population requires aggressive low-density lipoprotein (LDL) cholesterol-lowering therapy to meet the new treatment guidelines established by the National Cholesterol Education Program Adult Treamtent Panel III. This has further widened the gap between the number of people being treated compared with those who should be treated. Moreover, many people being treated do not meet their LDL cholesterol goal. Diet and healthy lifestyle practices remain the cornerstone of treatment to lower LDL cholesterol. Pharmacologic therapy has assumed an increasingly important role in reaching LDL cholesterol goals. Diet and healthy-lifestyle interventions have been shown to augment the benefits of cholesterol-lowering drugs. Together, this dynamic duo provides the most effective clinical means identified to date for maximally lowering LDL cholesterol levels.     

Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines

PURPOSE OF REVIEW: In 2001, the Adult Treatment Panel III of the National Cholesterol Education Program issued recommendations, which were updated in 2004 to reflect knowledge from five major clinical trials completed after 2001. This review discusses the results of key clinical trials released in 2005 and their potential impact on the guidelines. RECENT FINDINGS: Three major clinical trials, one subgroup analysis, and one meta-analysis were published in 2005 that can potentially affect the existing guidelines. The Treating to New Targets and the Incremental Decrease in End Points Through Aggressive Lipid Lowering trials demonstrated the incremental benefit of more aggressive low-density cholesterol lowering in stable coronary heart disease. The Cholesterol Treatment Trialists' Collaboration meta-analysis of statin trials supported the importance of low-density lipoprotein cholesterol reduction, irrespective of initial lipid profile, in reducing cardiovascular events. A subgroup analysis of the Anglo-Scandinavian Cardiac Outcomes Trial - Lipid-Lowering Arm demonstrated statin benefits in diabetes, whereas the Fenofibrate Intervention and Event Lowering in Diabetes study failed to show overall treatment benefits with a fibrate in diabetes. SUMMARY: Lowering of low-density lipoprotein cholesterol remains central in reducing cardiovascular risk; however, the recent trials support a target of less than 2.0 mmol/l (<80 mg/dl), rather than the less than 1.8 mmol/l (70 mg/dl) suggested by the 2004 update, for all high-risk patients and not, as recommended previously, just for those with additional factors. For individuals with diabetes, recent data support the use of statin therapy, even in those at less than high risk. First-line therapy should remain statins and not fibrates.     

Two approaches of coronary risk assessment--do they work?

The risk assessment method reported by the National Cholesterol Education Program, Adult Treatment Panel III, is used as a guide to define low-density lipoprotein cholesterol goals and cutpoints for intervention. Two approaches of this method are described by National Cholesterol Education Program, Adult Treatment Panel III and were used to compute coronary heart disease risk among participants in the National Health and Nutrition Examination Survey from 1999 to 2002. In conclusion, the low-density lipoprotein goals were not clear for a sizable proportion of participants, especially using the second approach, and may lead to less intensive intervention.     

The Role of Statin Therapy for Primary Prevention: What is the Evidence?

Almost one third of annual worldwide mortality is attributed to cardiovascular disease (CVD), making it the leading cause of global death. Dyslipidemia is a well-established risk factor for CVD and plays a pivotal role in the pathogenesis of atherosclerosis. Statins, which inhibit 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase and lower low-density lipoprotein cholesterol, have emerged as the most effective therapy to date against atherothrombotic CVD. Although their role in secondary prevention of CVD is undisputed, it remains a topic for debate as to how widely they should be used for primary prevention. The Framingham Risk Score and the National Cholesterol Education Program Adult Treatment Panel III guidelines are the cornerstones for the current guidelines for primary prevention statin therapy. Although these guidelines serve as help to evaluate cardiovascular risk and effectively identify many patients who will benefit from statin therapy, there is a growing population of “intermediate-risk” patients who may be undertreated. Additional noninvasive tests may complement the traditional risk scores, potentially expanding the indications for statins.     

Therapeutic lifestyle changes and drug treatment for high blood cholesterol in China and application of the Adult Treatment Panel III guidelines

The prevalence of elevated blood cholesterol in China has increased during the past several decades. We estimated the percentage of the Chinese population for whom therapeutic lifestyle changes and drug therapy to lower blood cholesterol should be considered by applying the United States' National Cholesterol Education Panel's Adult Treatment Panel III guidelines to a nationally representative sample of the Chinese population from the International Collaborative Study of Cardiovascular Disease in Asia. Serum samples were collected for 14,919 Chinese adults, 35 to 74 years old, in 2000 and 2001, after an overnight fast of > or =8 hours and their low-density lipoprotein (LDL) cholesterol level was calculated using the Freidewald equation. Using the Adult Treatment Panel III guidelines, 85.9 million Chinese adults (18.2%) should initiate therapeutic lifestyle changes to lower their LDL cholesterol and 35.0 million (7.4%) should be considered for lifestyle changes and lipid-lowering drug therapy. Of those for whom drug therapy should be considered, 4.7 million (13.4%) reported having been told they had "high cholesterol" by a healthcare provider and 1.6 million (33.7% of those aware of their high cholesterol) were receiving lipid-lowering medication-leaving 33.4 million Chinese adults with untreated elevated LDL cholesterol (95.5% of those with elevated LDL cholesterol). A 10% population-wide reduction in LDL cholesterol would reduce the number of Chinese adults who should be considered for drug therapy by 45% to 19.3 million (4.1% of adults). In conclusion, most adults in China with an elevated LDL cholesterol remain untreated.     

Results of the National Cholesterol Education (NCEP) Program Evaluation ProjecT Utilizing Novel E-Technology (NEPTUNE) II survey and implications for treatment under the recent NCEP Writing Group recommendations

The most recent national survey of compliance with the National Cholesterol Education Program (NCEP) Adult Treatment Panel (ATP) guidelines was completed before ATP III and showed significant underachievement of low-density lipoprotein (LDL) cholesterol goals. The NCEP Evaluation ProjecT Utilizing Novel E-Technology (NEPTUNE) II was a national survey conducted in 2003. Of the 4,885 patients, 67% achieved their LDL cholesterol treatment goal, including 89%, 76%, and 57%, respectively, in the 0 or 1 risk factor, > or = 2 risk factors or coronary heart disease (CHD), and CHD risk equivalent categories. The percentage with triglyceride concentrations > or = 200 mg/dl (2.25 mmol/L) in each risk category who achieved their LDL cholesterol and non-high-density lipoprotein cholesterol goals was 64%, 52%, and 27%, respectively. Patients with diabetes (55%) and other CHD risk equivalents (40%) were less likely to have achieved their LDL cholesterol targets than those with CHD (62%). Of the 1,447 patients with cardiovascular disease, 75% could be classified as very high risk according to the new July 2004 NCEP Writing Group recommendations, and 17.8% of those at very high risk had an LDL cholesterol level of <70 mg/dl (<1.81 mmol/L). In conclusion, these results suggest improved lipid management compared with previous surveys. The largest treatment gaps were found for features new to ATP III as of July 2004, including goal achievement for patients with CHD risk equivalents and for non-high-density lipoprotein cholesterol targets. Most of those (75%) with cardiovascular disease in NEPTUNE II would be considered very high risk and candidates for aggressive therapy to reach the new optional treatment goals.     

Beneficial effects of the addition of fenofibrate to statin therapy in patients with acute coronary syndrome after percutaneous coronary interventions

OBJECTIVE: To find out whether the addition of fenofibrate to statin monotherapy produced any synergistic or additive beneficial effects in reducing risk factors, especially plasma fibrinogen, in patients with acute coronary syndrome (ACS) requiring percutaneous coronary interventions. METHODS: A randomized, non-blinded, prospective study with parallel group design. One hundred two ACS patients who underwent angioplasty were randomly assigned to atorvastatin (20 mg/day, n=25), simvastatin (40 mg/day, n=27), atorvastatin-fenofibrate (10 mg/day-200 mg/day) combination (n=25) or simvastatin-fenofibrate (20 mg/day-200 mg/day) combination (n=25). The serum lipid profile and plasma fibrinogen were recorded before initiation of therapy and after three months of the respective treatments. RESULTS: All patients already had desirable lipid levels as per the National Cholesterol Education Program - Adult Treatment Panel III guidelines. The addition of fenofibrate to statin monotherapy produced further benefits to the reduction in triglyceride and very low-density lipoprotein levels, and caused an increase in high-density lipoprotein levels. All the treatment groups showed a significant decrease in the plasma fibrinogen levels. Plasma fibrinogen did not correlate with study parameters such as age, body weight, hemo-dynamic characteristics and lipoprotein levels. Statin monotherapy as well as its combination with fenofibrate produced a significant decrease in the fibrinogen levels. CONCLUSIONS: The addition of fenofibrate to statins seems to be beneficial in patients with ACS. Statins decreased plasma fibrinogen significantly, contrary to results from various reports, and the addition of fenofibrate further enhanced this reduction of the novel risk factor fibrinogen.     

Small,dense low-density lipoprotein: Risk or myth?

Based on the particle diameter of the major subpopulation of low-density lipoprotein (LDL) in plasma, an individual may be classified either as having phenotype A (desirable phenotype; large, buoyant LDL) or phenotype B (high risk; small, dense LDL). This article reviews the clinical significance of LDL particle diameter determination and proposes a strategy for incorporating this information in the new guidelines of the National Cholesterol Education Program’s Adult Treatment Panel III.     

Use and monitoring of "statin" lipid-lowering drugs compared with guidelines

BACKGROUND: In patients with high cholesterol, 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (or "statins") have been shown to reduce overall mortality in primary and secondary prevention. The National Cholesterol Education Program expert panel's guidelines (Adult Treatment Panel II) recommend evaluation and treatment of high cholesterol based on stratification of patients according to cardiovascular risk. While evidence suggests that many patients are undertreated, comparatively few data are available regarding overtreatment. OBJECTIVES: To assess the appropriateness of statin therapy compared with national guidelines and to examine the appropriateness of monitoring for adverse effects. METHODS: For all patients at a tertiary medical center, electronic medical records were evaluated for presence or absence of statin use and for presence of established coronary heart disease or cardiac risk factors. Therapy was compared with the recommendations of the National Cholesterol Education Program guidelines. Our primary outcome measures included, for all patients taking statins, prevalence of appropriateness vs overuse, and for all patients with coronary heart disease, prevalence of appropriateness vs underuse. RESULTS: Overuse of statin therapy was found among 69% of patients undergoing primary prevention, and among 47% of patients undergoing secondary prevention. In addition, among patients with coronary heart disease who were not taking statins, 88% were undertreated. Monitoring of liver function varied widely, and did not correlate with the risk of adverse events secondary to statin use. CONCLUSIONS: Overtreatment and undertreatment for hyperlipidemia were frequent. Decision support may help physicians improve their performance compared with guidelines.     

Statins, ACE inhibitors and ARBs in cardiovascular disease

Several trials have indicated that classical cardiovascular risk factors, including hyperlipidemia and hypertension, are not associated with a great number of acute cardiovascular events. Given the crucial role of inflammation in atherogenesis, inflammatory factors have been proposed to better define and predict acute cardiovascular events. In this promising context, treatments with lipid-lowering drugs (statins) and anti-hypertensive drugs (ACE inhibitors and ARBs) have been also investigated from an ‘anti-inflammatory’ point of view, with some encouraging results. At present, statins are recommended by the National Cholesterol Education Program (NCEP) Adult Treatment Panel (ATP) III guidelines as the first-line choice for drug therapy lowering LDL cholesterol in high-risk patients (LDL goal <70 mg/dL, <1.8 mmol/L). In moderate-risk patients (LDL goal <100 mg/dL, <2.6 mmol/L), statin therapy is indicated mainly in metabolic syndrome and in diabetic patients. Treatment with ACE inhibitors or ARBs is recommended in both hypertension and cardiovascular diseases, particularly in diabetic patients. The use of ACE inhibitors is recommended in all patients with ST-elevation myocardial infarction with LVEF ≤40%, with normal LVEF in the presence of well-controlled cardiovascular risk factors and revascularization, hypertension, diabetes or chronic kidney disease. On the other hand, the use of ARBs is recommended in patients intolerant of ACE inhibitors or who have heart failure or hypertension. In the future, these recommendations will probably be frequently updated as the pleiotropic activities of statins, ACE inhibitors and ARB are also taken into account.     

Efficacy and safety of ezetimibe added to ongoing statin therapy for treatment of patients with primary hypercholesterolemia

Ezetimibe is a lipid-lowering drug that inhibits the intestinal absorption of dietary and biliary cholesterol by blocking passage across the intestinal wall. The efficacy and safety of adding ezetimibe to ongoing statin therapy in patients with primary hypercholesterolemia was evaluated in a randomized, double-blind, placebo-controlled study. The study group included 769 adults (aged > or =18 years) with primary hypercholesterolemia who had not achieved National Cholesterol Education Program (NCEP) Adult Treatment Panel II goals with dietary alteration and statin monotherapy. Patients receiving a stable dose of a statin for > or =6 weeks were randomized to receive concurrent treatment with placebo (n = 390) or ezetimibe (n = 379), 10 mg/day, in addition to continuing their open-label statin for 8 weeks. The primary efficacy variable was the percent change in low-density lipoprotein (LDL) cholesterol from baseline with statin monotherapy to end point after intervention (secondary variables: high-density lipoprotein [HDL] cholesterol and triglycerides). Ongoing statin therapy plus ezetimibe led to changes of -25.1% for LDL cholesterol (HDL cholesterol +2.7%; triglycerides -14.0%) compared with LDL cholesterol -3.7% (p <0.001), HDL cholesterol +1.0% (p <0.05), and triglycerides -2.9% (p <0.001) for placebo added to ongoing statin therapy. Among patients not at LDL cholesterol goal at on-statin baseline, 71.5% receiving statin plus ezetimibe versus 18.9% receiving statin plus placebo reached goal at end point (odds ratio 23.7; p <0.001). The co-administration of statin and ezetimibe was generally well tolerated. Adding ezetimibe to ongoing statin therapy led to substantial additional reduction in LDL cholesterol levels, facilitating attainment of NCEP goals. Ezetimibe offers a new therapeutic option for patients receiving statins who require further reduction in LDL cholesterol.     

Rationale for intensive statin treatment in high-risk patients

Intensive lipid-lowering therapy with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) is now an established regimen for patients at high risk for cardiovascular events, regardless of baseline low-density lipoprotein cholesterol levels. Treatment with statins to reduce low-density lipoprotein cholesterol levels significantly below 100 mg/dL has been shown to further reduce the risk of cardiovascular morbidity and mortality in high-risk patients and has provided the necessary data for an update to the National Cholesterol Education Program's Third Adult Treatment Panel (ATP III) guidelines. Intensive statin therapy is also well tolerated, with no increased risk of noncardiovascular adverse events and a low incidence of clinically significant liver or muscle enzyme abnormalities. Results of recent clinical and surrogate end point trials confirm that intensive lowering of low-density lipoprotein cholesterol is beneficial and safe in a majority of high-risk patients.     

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.