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

The Adult Treatment Panel III (ATP III) of the National Cholesterol Education Program issued an evidence-based set of guidelines on cholesterol management in 2001. Since the publication of ATP III, 5 major clinical trials of statin therapy with clinical end points have been published. These trials addressed issues that were not examined in previous clinical trials of cholesterol-lowering therapy. The present document reviews the results of these recent trials and assesses their implications for cholesterol management. Therapeutic lifestyle changes (TLC) remain an essential modality in clinical management. The trials confirm the benefit of cholesterol-lowering therapy in high-risk patients and support the ATP III treatment goal of low-density lipoprotein cholesterol (LDL-C) less than 100 mg/dL. They support the inclusion of patients with diabetes in the high-risk category and confirm the benefits of LDL-lowering therapy in these patients. They further confirm that older persons benefit from therapeutic lowering of LDL-C. The major recommendations for modifications to footnote the ATP III treatment algorithm are the following. In high-risk persons, the recommended LDL-C goal is less than 100 mg/dL, but when risk is very high, an LDL-C goal of less than 70 mg/dL is a therapeutic option, ie, a reasonable clinical strategy, on the basis of available clinical trial evidence. This therapeutic option extends also to patients at very high risk who have a baseline LDL-C less than 100 mg/dL. Moreover, when a high-risk patient has high triglycerides or low high-density lipoprotein cholesterol (HDL-C), consideration can be given to combining a fibrate or nicotinic acid with an LDL-lowering drug. For moderately high-risk persons (2+ risk factors and 10-year risk 10% to 20%), the recommended LDL-C goal is less than 130 mg/dL, but an LDL-C goal less than 100 mg/dL is a therapeutic option on the basis of recent trial evidence. The latter option extends also to moderately high-risk persons with a baseline LDL-C of 100 to 129 mg/dL. When LDL-lowering drug therapy is employed in high-risk or moderately high-risk persons, it is advised that intensity of therapy be sufficient to achieve at least a 30% to 40% reduction in LDL-C levels. Moreover, any person at high risk or moderately high risk who has lifestyle-related risk factors (eg, obesity, physical inactivity, elevated triglycerides, low HDL-C, or metabolic syndrome) is a candidate for TLC to modify these risk factors regardless of LDL-C level. Finally, for people in lower-risk categories, recent clinical trials do not modify the goals and cutpoints of therapy

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

"The Adult Treatment Panel III (ATP III) of the National Cholesterol Education Program issued an evidence-based set of guidelines on cholesterol management in 2001. Since the publication of ATP III, 5 major clinical trials of statin therapy with clinical end points have been published. These trials addressed issues that were not examined in previous clinical trials of cholesterol-lowering therapy. The present document reviews the results of these recent trials and assesses their implications for cholesterol management. Therapeutic lifestyle changes (TLC) remain an essential modality in clinical management. The trials confirm the benefit of cholesterol-lowering therapy in high-risk patients and support the ATP III treatment goal of low-density lipoprotein cholesterol (LDL-C) less than 100 mg/dL. They support the inclusion of patients with diabetes in the high-risk category and confirm the benefits of LDL-lowering therapy in these patients. They further confirm that older persons benefit from therapeutic lowering of LDL-C. The major recommendations for modifications to footnote the ATP III treatment algorithm are the following. In high-risk persons, the recommended LDL-C goal is less than 100 mg/dL, but when risk is very high, an LDL-C goal of less than 70 mg/dL is a therapeutic option, ie, a reasonable clinical strategy, on the basis of available clinical trial evidence. This therapeutic option extends also to patients at very high risk who have a baseline LDL-C less than 100 mg/dL. Moreover, when a high-risk patient has high triglycerides or low high-density lipoprotein cholesterol (HDL-C), consideration can be given to combining a fibrate or nicotinic acid with an LDL-lowering drug. For moderately high-risk persons (2+ risk factors and 10-year risk 10% to 20%), the recommended LDL-C goal is less than 130 mg/dL, but an LDL-C goal less than 100 mg/dL is a therapeutic option on the basis of recent trial evidence. The latter option extends also to moderately high-risk persons with a baseline LDL-C of 100 to 129 mg/dL. When LDL-lowering drug therapy is employed in high-risk or moderately high-risk persons, it is advised that intensity of therapy be sufficient to achieve at least a 30% to 40% reduction in LDL-C levels. Moreover, any person at high risk or moderately high risk who has lifestyle-related risk factors (eg, obesity, physical inactivity, elevated triglycerides, low HDL-C, or metabolic syndrome) is a candidate for TLC to modify these risk factors regardless of LDL-C level. Finally, for people in lower-risk categories, recent clinical trials do not modify the goals and cutpoints of therapy.

Cystatin C Is an Independent Predictor of Fasting and Post-Methionine Load Total Homocysteine Concentrations among Stable Renal Transplant Recipients

Background: An increased prevalence of hyperhomo-cysteinemia with an increased incidence of cardiovascu-lar disease events has been reported among stable renal transplant recipients (RTRs). Preliminary studies in a small number of these individuals have shown that serum creatinine and cystatin C, both markers of kidney function and glomerular filtration rate, are independent determinants of fasting tHcy concentrations; however, determinants of tHcy concentrations after a methionine load have not been studied. Methods: We determined the prevalence of both fasting and 4-h post-methionine load (PML) tHcy concentra-tions in 78 stable RTRs and compared the role of cystatin C with the role of serum creatinine as determi-nants of fasting and PML tHcy. Results: Of the 78 RTRs, 21 (26.9%) had fasting and PML tHcy within the respective reference intervals, and 57 (73.1%) had increased plasma tHcy. Of these 57 RTRs, 22 had fasting hyperhomocysteinemia, 9 had PML hy-perhomocysteinemia, and 26 had combined hyperhomo-cysteinemia (both fasting and PML). Unadjusted Pear-son correlations showed that fasting plasma tHcy correlated with both cystatin C (r 5 0.564; P <0.001) and creatinine (r 5 0.519; P <0.001) and that increases in PML tHcy modestly correlated with cystatin (r 5 0.205; P 5 0.072), but not creatinine (r 5 0.057; P 5 0.624). General linear regression modeling with stepwise anal-ysis of covariance showed that both cystatin C (partial R 5 0.554; P <0.001) and creatinine (partial R 5 0.535; P <0.001) were independent predictors of fasting tHcy, but of the two, only cystatin C (partial R 5 0.242; P 5 0.035) was an independent predictor of increased PML tHcy. Conclusions: Clinically stable RTRs have an excess prevalence of moderate hyperhomocysteinemia, and ad-ditional cases can be detected by methionine loading. Both creatinine and cystatin C are independent predic-tors of fasting tHcy in these individuals; however, only cystatin C is a determinant of tHcy concentration after a methionine load, probably because cystatin C is a more sensitive marker of glomerular filtration rate than se-rum creatinine

Guidelines for lowering lipids to reduce coronary artery disease risk: a comparison of rosuvastatin with atorvastatin, pravastatin, and simvastatin for achieving lipid-lowering goals

Copyright © 2003 Excerpta Medica Inc. All rights reserved.James Shepherd, Donald B. Hunninghake, Philip Barter, James M. McKenney and Howard G. Hutchinso

Safety of rosuvastatin

The safety and tolerability of rosuvastatin were assessed (as of August 2003) using data from 12,400 patients who received 5 to 40 mg of rosuvastatin in a multinational phase II/III program, which represented 12,212 patient-years of continuous exposure to rosuvastatin. An integrated database was used to examine adverse events and laboratory data. In placebo-controlled trials, adverse events, irrespective of causality assessment, occurred in 57.4% of patients who received 5 to 40 mg of rosuvastatin (n = 744) and 56.8% of patients who received placebo (n = 382). In fixed-dose trials with comparator statins, 5 to 40 mg of rosuvastatin showed an adverse event profile similar to those for 10 to 80 mg of atorvastatin, 10 to 80 mg of simvastatin, and 10 to 40 mg of pravastatin. Clinically significant elevations in alanine aminotransferase (>3 times the upper limit of normal) and creatine kinase (>10 times the upper limit of normal) were uncommon ( 10 times the upper limit of normal with muscle symptoms) that was possibly related to treatment occurred in <or=0.03% of patients who took rosuvastatin at doses <or=40 mg. A positive finding of proteinuria with dipstick testing at rosuvastatin doses <or=40 mg was comparable to that seen with other statins, and the development of proteinuria was not predictive of acute or progressive renal disease. No deaths in the program were attributed to rosuvastatin, and no rhabdomyolysis occurred in patients who received 5 to 40 mg of rosuvastatin. Rosuvastatin was well tolerated by a broad range of patients who had dyslipidemia, and its safety profile was similar to those of the comparator statins investigated in this extensive clinical progra