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Effect of niacin on lipid and lipoprotein levels and glycemic control in patients with diabetes and peripheral arterial disease: the ADMIT study: A randomized trial. Arterial Disease Multiple Intervention Trial. [...]

BACKGROUND: Hypercholesterolemic patients with metabolic syndrome (MS) are at high risk for coronary heart disease. The National Cholesterol Education Program (NCEP) Adult Treatment Panel III (ATP III) guidelines provide the option of aggressively lowering low-density lipoprotein cholesterol (LDL-C) in hypercholesterolemic patients with MS. OBJECTIVE: The lipid-modifying efficacy of simvastatin and atorvastatin in hypercholesterolemic patients with MS as defined by NCEP ATP III was assessed. METHODS: A post hoc subgroup analysis was performed on data from a 36-week, multicenter (54 sites worldwide), randomized, double-blind, parallel-group, dose-escalation (forced-titration) study designed to assess the effects of simvastatin (40-80 mg) and atorvastatin (20-80 mg) on high-density lipoprotein cholesterol (HDL-C) and apolipoprotein (apo) A-I levels in patients with LDL-C > or = 160 mg/dL. Patients were classified as having MS if they met >/=3 of the following criteria: (1) triglyceride (TG) level > or =150 mg/dL; (2) HDL-C <40 mg/dL (men) or <50 mg/dL (women); (3) secondary diagnosis of type 2 diabetes mellitus and/or taking antidiabetic medication and/or fasting serum glucose (FSG) level > or =110 mg/dL; (4) secondary diagnosis of hypertension and/or taking antihypertensive medication and/or systolic blood pressure (SBP)/diastolic blood pressure (DBP) > or =130/ > or =85 mm Hg; and (5) body mass index (BMI) > or =30 kg/m(2) (surrogate for waist circumference). RESULTS: Of 808 evaluable patients, 212 (26.2%) were classified as having MS at baseline. Compared with the non-MS subgroup, MS patients were slightly older and more likely to be female. They also had higher BMI, SBP/DBP, FSG, and TG levels, and lower HDL-C and apo A-I levels than non-MS patients. The simvastatin group contained 99 patients; the atorvastatin group, 113 patients. Both drugs produced large reductions in total cholesterol, LDL-C, non-HDL-C, TG, and apo B, with atorvastatin producing slightly greater reductions in TG. However, simvastatin consistently produced larger increases in HDL-C and apo A-I than atorvastatin, especially at higher doses. After 36 weeks of treatment, 47.7% and 48.5% in the simvastatin and atorvastatin groups, respectively, no longer met > or =3 of the MS criteria. CONCLUSIONS: In hypercholesterolemic patients with characteristics of MS, simvastatin and atorvastatin had comparable beneficial effects on apo B-containing atherogenic lipids and lipoproteins, and MS status was effectively modified by both drugs. However, although atorvastatin produced slightly larger decreases in TG, simvastatin produced larger increases in HDL-C. [ABSTRACT FROM AUTHOR]

Background: Animal and observational epidemiologic studies have reported that estrogens may increase the risk for gallstones. No major clinical trials have examined the effect of estrogen plus progestin therapy in postmenopausal women on the risk for biliary tract surgery.Objective: To determine the effect of estrogen plus progestin on the risk for biliary tract surgery in postmenopausal women with known coronary artery disease.Design: Randomized, double-blind placebo-controlled trial of postmenopausal hormone therapy for coronary heart disease.Setting: 20 U.S. clinical centers.Participants: 2253 postmenopausal women with a gallbladder, 44 to 79 years of age at baseline, in the Heart and Estrogen/progestin Replacement Study (HERS).Intervention: Conjugated equine estrogens, 0.625 mg, plus medroxyprogesterone acetate, 2.5 mg, daily in one tablet or identical placebo.Measurements: Documented biliary tract surgery.Results: A total of 147 women (7%) were hospitalized for biliary tract surgery in HERS. Treatment with estrogen plus progestin resulted in a marginally significant 38% increase in the relative risk for biliary tract surgery (P = 0.05). A small absolute difference in risk suggested that for every 185 women treated with estrogen plus progestin, one additional woman had biliary tract surgery per year. After adjustment for baseline and in-study statin use, the association was attenuated further (P = 0.09). After adjustment for treatment assignment and other variables, increased body mass index, fibric acid use, and a history of nonsurgical gallbladder disease were associated with an increased risk for biliary tract surgery, whereas statin use was associated with a decreased risk (for each comparison, P < 0.05).Conclusion: Estrogen plus progestin therapy among postmenopausal women with known coronary disease resulted in a marginally significant increase in the risk for biliary tract surgery. [ABSTRACT FROM AUTHOR]

Context: Although niacin increases low levels of high-density lipoprotein cholesterol (HDL-C), which frequently accompany diabetes, current guidelines do not recommend use of niacin in patients with diabetes because of concerns about adverse effects on glycemic control; however, this is based on limited clinical data.Objective: To determine the efficacy and safety of lipid-modifying dosages of niacin in patients with diabetes.Design and Setting: Prospective, randomized placebo-controlled clinical trial conducted in 6 clinical centers from August 1993 to December 1995.Participants: A total of 468 participants, including 125 with diabetes, who had diagnosed peripheral arterial disease.Interventions: After an active run-in period, participants were randomly assigned to receive niacin (crystalline nicotinic acid), 3000 mg/d or maximum tolerated dosage (n = 64 with diabetes; n = 173 without diabetes), or placebo (n = 61 with diabetes; n = 170 without diabetes) for up to 60 weeks (12-week active run-in and 48-week double-blind).Main Outcome Measures: Plasma lipoprotein, glucose, hemoglobin A(1c) (HbA(1c)), alanine aminotransferase, and uric acid levels; hypoglycemic drug use; compliance; and adverse events, in patients with diabetes vs without who were receiving niacin vs placebo.Results: Niacin use significantly increased HDL-C by 29% and 29% and decreased triglycerides by 23% and 28% and low-density lipoprotein cholesterol (LDL-C) by 8% and 9%, respectively, in participants with and without diabetes (P<.001 for niacin vs placebo for all). Corresponding changes in participants receiving placebo were increases of 0% and 2% in HDL-C and increases of 7% and 0% in triglycerides, and increases of 1% and 1% in LDL-C. Glucose levels were modestly increased by niacin (8.7 and 6.3 mg/dL [0.4 and 0.3 mmol/L]; P =.04 and P<.001) in participants with and without diabetes, respectively. Levels of HbA(1c) were unchanged from baseline to follow-up in participants with diabetes treated with niacin. In participants with diabetes treated with placebo, HbA(1c) decreased by 0.3% (P =.04 for difference). There were no significant differences in niacin discontinuation, niacin dosage, or hypoglycemic therapy in participants with diabetes assigned to niacin vs placebo.Conclusions: Our study suggests that lipid-modifying dosages of niacin can be safely used in patients with diabetes and that niacin therapy may be considered as an alternative to statin drugs or fibrates for patients with diabetes in whom these agents are not tolerated or fail to sufficiently correct hypertriglyceridemia or low HDL-C levels. JAMA. 2000;284:1263-1270 [ABSTRACT FROM AUTHOR]

This study examined a ready-to-eat breakfast cereal, CHEERIOS, made of whole grain oats, containing 8 grams of oat bran per oz., for its cholesterol-lowering effect. This was a randomized, double-blind study, with forty-three subjects (21 men and 22 women) who had mild to moderate hypercholesterolemia (mean baseline value 5.94 +/- 0.65 mmol/L [230.8 +/- 25.3 mg/dL]). Subjects followed medical nutrition therapy and ate either 3 oz. of Country CORNFLAKES, with essentially no bran or germ or CHEERIOS for 4 weeks. Compared with the control, those consuming oat cereal achieved a 4.4 % reduction in total cholesterol and a 4.9% reduction in low-density lipoprotein cholesterol compared with baseline. Copyright © 2000 by Aspen Publishers, Inc. [ABSTRACT FROM AUTHOR]

Diabetic patients have greater risk for coronary heart disease (CHD) events after coronary artery bypass graft (CABG) surgery than nondiabetic patients. The Post CABG trial studied the effects of aggressive cholesterol lowering and low-dose anticoagulation in diabetic patients compared with nondiabetic patients. A double-blind, randomized clinical trial in 1,351 patients (1-11 years after CABG), the Post CABG trial consisted of two interventions (aggressive cholesterol-lowering versus moderate lowering and low-dose warfarin versus placebo) on angiographic end points. Angiographic changes in saphenous vein graft conduits 4.3 years after entry were compared in 116 diabetic and 1,235 nondiabetic patients. Seven clinical centers participated in the trial, as well as the National Institutes of Health project office (National Heart, Lung, and Blood Institute), the coordinating center (Maryland Medical Research Institute), and the Angiogram Reading Center (University of Minnesota). Baseline characteristics of the diabetic patients differed from the nondiabetic patients in the following ways: percentage of women participants, 15 vs. 7%, P = 0.002; mean baseline weight, 87.4 vs. 82.8 kg, P = 0.006; mean BMI, 29.5 vs. 27.6 kg/m2, P = 0.0002; mean systolic blood pressure, 141.7 vs. 133.6, P < 0.0001; mean triglyceride concentrations, 2.09 vs. 1.77 mmol/l, P < 0.0001; and mean HDL cholesterol concentrations, 0.93 vs. 1.02 mmol, P = 0.0001. The percentage of clinical events was higher in diabetic than nondiabetic patients (20.6 vs. 13.4, P = 0.033) and angiographic outcomes were not different. The benefits of aggressive cholesterol lowering were comparable in diabetic and nondiabetic patients for the angiographic end points. Warfarin use was not associated with clinical or angiographic benefit. Diabetic patients in the Post CABG trial had more CHD risk factors at study entry and higher clinical event rates during the study than nondiabetic patients. The benefits of aggressive cholesterol lowering in diabetic patients were comparable to those in nondiabetic patients for both angiographic and clinical end points. The small number of diabetic patients provided limited power to detect significant differences between diabetic and nondiabetic patients or between diabetic patients in the aggressive versus moderate cholesterol treatment strategies. [ABSTRACT FROM AUTHOR]

The effect of equivalent hypolipidaemic doses of cholestyramine (8 g) or colestipol (10 g) on the plasma concentrations of propranolol and 4′- hydroxypropranolol was studied in 12 normal volunteers following the oral administration of 120 mg of normal release propranolol tablets. When two doses of either cholestyramine or colestipol were administered prior to the propranolol, the peak plasma concentrations and area under the curve for both propranolol and the metabolite 4′-hydroxypropranolol were reduced significantly (P less than 0.05). We conclude that the drug interaction between cholestyramine or colestipol and propranolol leads to significant reductions in plasma concentrations of propranolol and 4′-hydroxypropranolol which may cause a clinically diminished effect for a given dosage. Therefore, patients should be observed when either of these resins are added to or deleted from a therapeutic regimen. [ABSTRACT FROM AUTHOR]

BACKGROUND: Combination lipid-lowering therapy may be desirable in patients with elevated low-density lipoprotein cholesterol, high triglycerides, and low high-density lipoprotein cholesterol. This study was conducted to determine the lipid-lowering efficacy of the combination of low-dose simvastatin and niacin in patients with combined hyperlipidemia and low high-density lipoprotein cholesterol. METHODS AND RESULTS: In this multicenter, prospective, randomized trial, 180 patients with hypercholesterolemia and hypertriglyceridemia and/or low high-density lipoprotein cholesterol were randomized to combination simvastatin (10 mg/day) and niacin (0.75 g/day) or to either drug alone for 9 weeks. The dose of niacin was doubled (from 0.75 g/day to 1.5 g/day) in both the combination and niacin arms for the remaining 8 weeks. The combination of simvastatin, 10 mg/day, and niacin, 1.5 g/day, reduced total, low-density lipoprotein, and very low-density lipoprotein cholesterol and triglycerides by 24%, 29%, 45%, and 31%, respectively, while increasing high-density lipoprotein cholesterol by 31%. The addition of niacin to simvastatin did not enhance the low-density lipoprotein cholesterol by 31%. The addition of niacin to simvastatin did not enhance the low-density lipoprotein cholesterol-lowering effect of simvastatin; however, the combination was more effective than either monotherapy at raising high-density lipoprotein cholesterol and lowering very low-density lipoprotein cholesterol (P <.05). More patients discontinued treatment because of an adverse event in the niacin (P <.03) and combination groups (P =.06) than the simvastatin group. CONCLUSIONS: Treatment of patients with combined hyperlipidemia and/or low high-density lipoprotein with combination low-dose simvastatin and niacin resulted in large reductions in total, low-density lipoprotein, and very low-density lipoprotein cholesterol and increases in HDL cholesterol. Although the combination was well tolerated in the current trial, its safety needs to be evaluated in larger trials of longer duration. [ABSTRACT FROM AUTHOR]

Both the National Cholesterol Education Program (NCEP) Adult Treatment Panel (ATP) III and the Second Joint Task Force of European Societies guidelines have established low-density lipoprotein (LDL) cholesterol goals for lipid-lowering treatment to reduce the risk of coronary artery disease. Data from 3 trials that compared rosuvastatin 10 mg (n = 389) with atorvastatin 10 mg (n = 393) and 2 trials that compared rosuvastatin 10 mg (n = 226) with pravastatin 20 mg (n = 252) and simvastatin 20 mg (n = 249) were pooled separately to compare the achievement of LDL cholesterol goals over 12 weeks of treatment in hypercholesterolemic patients. Noncomparative pooling of rosuvastatin 10 mg results from all 5 trials (n = 615) showed that 80% achieved NCEP ATP III goals and 81% achieved the European goal of <3.0 mmol/L. Compared with atorvastatin 10 mg, significantly more patients treated with rosuvastatin 10 mg achieved their ATP III (76% vs 53%) and European (82% vs 51%) goals (p <0.001). Also, in comparisons with simvastatin 20 mg and pravastatin 20 mg, 86% of patients treated with rosuvastatin 10 mg achieved ATP III goals, compared with 64% of simvastatin-treated patients and 49% of pravastatin-treated patients (p <0.001). The proportions of patients who achieved the European goal were 80%, 48%, and 16% for rosuvastatin 10 mg, simvastatin 20 mg, and pravastatin 20 mg, respectively, in this comparison (all p <0.001). A total of 71% of patients treated with rosuvastatin 10 mg who had triglyceride levels > or =200 mg/dL met both their LDL cholesterol and their non-high-density lipoprotein cholesterol goals. [ABSTRACT FROM AUTHOR]

The National Cholesterol Education Program (NCEP) Adult Treatment Panel (ATP) III report outlines the management of hypercholesterolemia through guidelines. These guidelines call for more aggressive diagnosis and treatment of hypercholesterolemia, which will substantially increase the number of individuals in the United States considered to be at risk for heart disease and will expand the number who will receive dietary and drug treatment. The new features of ATP III add complexity to the guidelines, which will impact adherence as well as add challenges to the management of hypercholesterolemia. Following key recommendations and incorporating essential elements of adherence can improve implementation of the NCEP ATP III guidelines. The use of global risk scoring aids, including the Palm Pilot cholesterol risk calculators, can improve guideline adherence and provide education and motivation to patients to maintain compliance. [ABSTRACT FROM AUTHOR]

The metabolic syndrome (MS) is a constellation of coronary risk factors. Atherogenic dyslipidemia is an important factor in cardiovascular risk in these patients, and treatment of atherogenic dyslipidemia has been identified as an important goal of therapy in patients with MS. This post hoc analysis of data from a 6-week, randomized, open-label, parallel-group, comparative trial (Statin Therapies for Elevated Lipid Levels compared Across doses to Rosuvastatin [STELLAR]) assessed the effects of rosuvastatin 10, 20, and 40 mg, atorvastatin 10, 20, 40, and 80 mg, simvastatin 10, 20, 40, and 80 mg, and pravastatin 10, 20, and 40 mg on plasma lipids in hypercholesterolemic patients (low-density lipoprotein cholesterol >/=160 and <250 mg/dl; triglycerides <400 mg/dl) who had >/=3 of the 5 National Cholesterol Education Program Adult Treatment Panel III criteria for MS (body mass index >30 kg/m(2) substituted for waist circumference). Of 2,268 patients, 811 met criteria for MS. Percent reductions in low-density lipoprotein cholesterol ranged from 20% in the pravastatin 10-mg group to 55% in the rosuvastatin 40-mg group. In patients with MS, triglyceride reductions were 22% to 34% with rosuvastatin, 23% to 33% with atorvastatin, 15% to 23% with simvastatin, and 12% to 15% with pravastatin. High-density lipoprotein cholesterol increased by 8% to 11% with rosuvastatin, 5% to 9% with atorvastatin, 8% to 10% with simvastatin, and 3% to 7% with pravastatin. Rosuvastatin, atorvastatin, simvastatin, and pravastatin treatment had favorable effects in hypercholesterolemic patients on the atherogenic dyslipidemia associated with MS. Rosuvastatin had the most favorable effect on the atherogenic lipid profile of MS overall.

Smoking is a major cause of chronic obstructive pulmonary disease (COPD) and cardiovascular disorders, including coronary heart disease (CHD) and peripheral arterial disease. Smoking-induced inflammation and other risk factors like dyslipidemia cause vascular endothelial damage via oxidative stress, and a vicious cycle with the characteristics of atherosclerosis ensues. Inflammatory cytokines stimulate hepatic acute-phase protein production, and C-reactive protein is now used widely to assess inflammation in the arterial wall. Smoking is associated with many alterations in lipids and lipoproteins, and is also prothrombotic. Global risk assessment, which determines the absolute risk for developing CHD in 10 years, is used widely to determine who should receive lipid-lowering therapy. Major CHD risk factors include age, sex, smoking, blood pressure, lipoproteins, and cholesterol, but COPD is not among them. Future studies should determine the absolute risk for developing CHD in patients with COPD. The 3-hydroxy-3-methylglutaryl coenzyme-A reductase inhibitors (statins) are used widely to treat and prevent cardiovascular disease. The statins may also produce other beneficial pleiotropic effects, including increased nitric oxide and prostacyclin, antithrombosis, and decreased inflammation, perhaps indicating utility in the therapy for COPD. Efforts are currently underway to determine if such antiinflammatory effects are independent of or in addition to simply lowering low-density lipoprotein cholesterol.

Objectives: This study sought to determine if an aggressive, focused low-density lipoprotein cholesterol (LDL-C)-lowering strategy was superior to usual care for coronary heart disease (CHD) patients enrolled in health maintenance organization or Veterans Administration settings., Background: Statin therapy benefits are well established. No prospective, randomized studies have tested strategies to optimize these benefits in a "real-world" setting., Methods: A total of 2,442 CHD patients with hyperlipidemia were randomized to either an aggressive treatment arm using atorvastatin or usual care and followed for 51.5 months on average. Atorvastatin-group patients were titrated to LDL-C goals of <80 mg/dl (2.1 mmol/l) or a maximum atorvastatin dose of 80 mg/day. Usual-care patients received any treatment deemed appropriate by their regular physicians. End point assessments were complete in 958 atorvastatin-group and 941 usual-care patients. Partial assessments occurred in 259 patients in the atorvastatin group and 284 patients in the usual care group who did not complete four years of study participation because of adverse events, withdrawn consent, or follow-up loss. The primary efficacy parameter was time to first cardiovascular event., Results: A total of 289 (23.7%) patients in the atorvastatin group compared with 333 (27.7%) patients in the usual care group experienced a primary outcome (hazard ratio, 0.83; 95% confidence interval 0.71 to 0.97, p = 0.02). This reduction in morbidity was largely due to fewer non-fatal myocardial infarctions (4.3% vs. 7.7%, p = 0.0002). Levels of LDL-C were reduced more (34.3% vs. 23.3%, p < 0.0001) and National Cholesterol Education Program goals (LDL-C <100 mg/dl) more likely met at end-of-study visits (72.4% vs. 40.0%) in patients receiving atorvastatin compared with those receiving usual care., Conclusions: An aggressive, focused statin therapy management strategy outperformed usual care in health maintenance organization and Veterans Administration clinic patients with CHD.

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

Background: Non-high-density lipoprotein cholesterol (HDL-C), apolipoprotein (apo) B, and lipid and apolipoprotein ratios that include both atherogenic and antiatherogenic lipid components have been found to be strong predictors of coronary heart disease risk., Objective: The goal of this study was to examine prospectively the effects of rosuvastatin, atorvastatin, simvastatin, and pravastatin across dose ranges on non-HDL-C, apo B, apo A-I, and total cholesterol (TC):HDL-C, low-density lipoprotein cholesterol (LDL-C):HDL-C, non-HDL-C:HDL-C, and apo B:apo A-I ratios in patients with hypercholesterolemia (LDL-C > or =160 mg/dL and <250 mg/dL and triglycerides <400 mg/dL) in the Statin Therapies for Elevated Lipid Levels compared Across doses to Rosuvastatin (STELLAR) trial., Methods: In this randomized, Multicenter, parallel-group, open-label trial (4522IL/0065), patients > or =18 years of age received rosuvastatin 10, 20, 40, or 80 mg; atorvastatin 10, 20, 40, or 80 mg; simvastatin 10, 20, 40, or 80 mg; or pravastatin 10, 20, or 40 mg for 6 weeks. Pairwise comparisons were prospectively planned and performed between rosuvastatin 10, 20, and 40 mg and milligram-equivalent or higher doses of comparators., Results: A total of 2268 patients were randomized to the rosuvastatin 10- to 40-mg, atorvastatin, simvastatin, and pravastatin groups. Fifty-one percent of patients were women, the mean (SD) age was 57 (12) years, and 19% had a documented history of atherosclerotic disease. Over 6 weeks, rosuvastatin significantly reduced non-HDL-C, apo B, and all lipid and apolipoprotein ratios assessed, compared with milligram-equivalent doses of atorvastatin and milligram-equivalent or higher doses of simvastatin and pravastatin (all, P < 0.002). Rosuvastatin reduced non-HDL-C by 42.0% to 50.9% compared with 34.4% to 48.1% with atorvastatin, 26.0% to 41.8% with simvastatin, and 18.6% to 27.4% with pravastatin. Rosuvastatin reduced apo B by 36.7% to 45.3% compared with 29.4% to 42.9% with atorvastatin, 22.2% to 34.7% with simvastatin, and 14.7% to 23.0% with pravastatin. The highest increase in apo A-I (8.8%) was observed in the rosuvastatin 20-mg group, and this increase was significantly greater than in the atorvastatin 40-mg and 80-mg groups (both, P < 0.002)., Conclusion: Rosuvastatin 10 to 40 mg was more efficacious in improving the lipid profile of patients with hypercholesterolemia than milligram-equivalent doses of atorvastatin and milligram-equivalent or higher doses of simvastatin and pravastatin.

An increased prevalence of hyperhomocysteinemia has been observed among patients with end-stage renal disease, and numerous studies have demonstrated that kidney function is one of the most important determinants of plasma total homocysteine (tHcy) concentration. In an effort to understand the mechanism of hyperhomocysteinemia in renal disease, we chose, as our model, living kidney donors who had undergone uninephrectomy. We studied 10 living kidney donors and measured fasting plasma tHcy, plasma creatinine, folate, vitamins B(12) and B(6), and high-sensitivity C-reactive protein (hsCRP) 24 hours before nephrectomy and 2 days, 6 weeks, and 6 months after nephrectomy compared to the values 24 hours before nephrectomy. Mean fasting tHcy and creatinine concentrations were significantly higher in donors 2 days, 6 weeks and 6 months after nephrectomy they were 24 hours before nephrectomy. Both the increases in tHcy levels 2 days after nephrectomy and subsequent decreases 6 weeks and 6 months after are paralleled by the changes in plasma creatinine values, although neither returned to its presurgery value. Decreases in tHcy are significantly correlated with decreases in creatinine values. The B vitamins were unchanged, and the hsCRP level was increased 2 days after surgery but had returned to the baseline level after 6 weeks. We conclude that tHcy and creatinine levels parallel each other after uninephrectomy and that the gradual decrease in tHcy is accounted for by hypertrophy of the remaining kidney. Our results, the first to be obtained from living kidney donors, support the hypothesis that renal metabolism of tHcy is the mechanism responsible for the correlation between renal function and plasma tHcy level.

Background: Women undergoing coronary artery bypass graft (CABG) surgery have a worse medical condition and fewer social and financial resources than men. Some studies have found that women recover less well than men after CABG, whereas others have found women's outcomes comparable to those of men. Past studies of health-related quality of life after CABG have too few women for adequate comparison with men and have not included patients whose data are not available at baseline (eg, emergency CABG), limiting generalizability., Methods: A longitudinal study of symptoms and health-related quality of life was conducted among patients from four clinical centers enrolling both men (n = 405) and women (n = 269) in the Post CABG Biobehavioral Study in the United States and Canada., Results: After 6 weeks from CABG (average 81 days), both men and women had less anxiety and symptoms related to depression than before surgery (P <.001). After 6 months (average 294 days), both men and women improved in physical and social functioning (P <.001). Although changes in scale scores were similar for men and women at each time point, women scored lower than men on these domains (P <.001, adjusted for baseline medical and sociodemographic differences) and had more symptoms related to depression through 1 year after CABG (P =.003)., Conclusions: Both male and female patients improve in physical, social, and emotional functioning after CABG, and recovery over time is similar in men and women. However, women's health-related quality-of-life scale scores remained less favorable than men's through 1 year after surgery.

Background: Previous studies have shown that effects on high-density lipoprotein cholesterol (HDL-C) may differ among statins., Methods: A multicenter, randomized, double-blind, parallel-dose study was conducted in 917 hypercholesterolemic patients to compare the efficacy of 80 mg/d simvastatin versus 80 mg/d atorvastatin on HDL-C and apolipoprotein (apo) A-I for 24 weeks. Efficacy was assessed as the means of weeks 6 and 12 and weeks 18 and 24. Prespecified subgroups analyzed were patients with low HDL-C levels and with the metabolic syndrome., Results: Simvastatin increased HDL-C and apo A-I values significantly more than did atorvastatin for the mean of weeks 6 and 12 (8.9% vs 3.6% and 4.9% vs -0.9%, respectively) and the mean of weeks 18 and 24 (8.3% vs 4.2% and 3.7% vs -1.4%). These differences were observed across both baseline HDL-C subgroups (<40 mg/dL, > or =40 mg/dL) and in patients with the metabolic syndrome. Low-density lipoprotein cholesterol and triglyceride reductions were greater with atorvastatin. Consecutive elevations >3x the upper limit of normal in alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) occurred in significantly fewer patients treated with simvastatin than with atorvastatin (2/453 [0.4%] vs 13/464 [2.8%]), with most elevations observed in women taking atorvastatin (11/209 [5.3%] vs 1/199 [0.5%] for simvastatin)., Conclusions: Simvastatin (80 mg) increased HDL-C and apo A-I significantly more than did atorvastatin (80 mg) in patients with hypercholesterolemia. This advantage was observed regardless of HDL-C level at baseline or the presence of the metabolic syndrome. Significantly fewer consecutive elevations >3x the upper limit of normal in ALT and/or AST occurred in patients receiving simvastatin.

Background: Combination therapy for dyslipidemia holds promise as effective treatment for patients with multiple lipid disorders, especially those at high risk., Hypothesis: This study evaluated dose-response relationships and safety of a new dual-component drug product containing niacin extended-release (niacin ER) and lovastatin., Methods: The 28-week double-blind multicenter trial randomized 237 patients with type IIA or IIB hyperlipidemia to one of four escalating-dose treatment groups: niacin ER/lovastatin 1,000/20 mg, niacin ER/lovastatin 2,000/40 mg, niacin ER 2,000 mg, or lovastatin 40 mg., Results: Niacin ER/lovastatin was more effective than each of its components for improving levels of low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides (TG), and exhibited a clear dose-response effect and additivity across the dosage range. The 2,000/40 dose achieved greater mean reductions in LDL-C (-42%) than 1,000/20 (-28%, p < 0.001), lovastatin 40 mg (-32%, p < 0.05), or niacin ER 2,000 mg (-14%, p < 0.05). The 2,000/40 dose was significantly more effective in increasing HDL-C levels (+30%) than the 1,000/20 dose (+21%, p = 0.016). The decrease in TG was greater with 2,000/40 (-43%) than with 1,000/20 (-26%, p = 0.009). All three niacin-containing treatments were more effective than lovastatin monotherapy in reducing lipoprotein (a) [Lp(a)] levels. Flushing caused 12 (11%) patients receiving niacin ER/lovastatin and I patient receiving lovastatin alone to withdraw. No drug-related myopathy was noted. One patient each in the 2,000/40 group and the lovastatin 40-mg group had reversible elevations in liver transaminases., Conclusions: Niacin ER/lovastatin is well tolerated and effective for patients with multiple lipid disorders.

Background: Previous studies have suggested that angiographic evidence of disease progression in coronary arteries increases the risk of subsequent coronary clinical events. This study ascertained whether patients enrolled in the Post Coronary Artery Bypass Graft Clinical Trial (POST CABG) who had substantial progression of atherosclerosis in >or=1 saphenous vein grafts (on the basis of assessment of baseline and follow-up angiograms obtained 4-5 years after study entry), but who had not reported clinical symptoms before follow-up angiography, were at a higher risk of subsequent events than patients who did not have substantial progression of atherosclerosis (decrease >or=0.6 mm in lumen diameter at site of greatest change from baseline)., Methods: All 1351 patients enrolled in the trial underwent baseline angiography; only the 961 patients who had follow-up angiography and no coronary events before the follow-up study were included in this analysis. The clinical center staff contacted patients to ascertain the events that had occurred after follow-up angiography (approximately 3.4 years later)., Results: Sixty-nine patients had died; 870 patients or relatives were interviewed, and 22 patients could not be contacted. Univariable estimates of relative risk associated with substantial progression ranged from 2.2 (P <.001) for cardiovascular death or nonfatal myocardial infarction to 3.3 (P <.001) for revascularization. Multivariable and univariable estimates of risk were similar., Conclusions: The findings provide evidence that patients who had substantial progression of atherosclerosis in vein grafts are at an increased risk for subsequent coronary events and suggest that angiographic changes in vein grafts are appropriate surrogate measures for clinical outcomes.

The Post-CABG trial was designed to assess the effects of 2 different lipid lowering strategies and low dose warfarin vs placebo (2 x 2 factorial) design on the progression of atherosclerosis in saphenous vein grafts. Atherosclerotic progression was determined by comparing baseline and follow-up angiograms (mean interval: 4.3 years) using quantitative angiography. Significant progression of disease in SVG's was reduced with the aggressive lipid lowering strategy compared to the moderate strategy; significant progression in SVG's was not altered by low dose warfarin. The beneficial effects on angiographic changes were demonstrated in multiple subgroups of participants in the trial. The composite clinical end point of death, MI, stroke, PTCA or repeat CABG was analyzed at the end of the trial and 3 years (extended follow-up) after closure of the angiographic trial. At the time of the extended follow-up the aggressive lipid strategy was associated with reduced clinical events; low dose warfarin was also associated with reduced clinical events.

The highest risk of a recurrent event in patients with acute coronary syndromes (ACS) occurs in the first month, with the rates of reported events ranging from 10% to 25%. Statins are the cornerstone of lipid-lowering therapy for the long-term care of patients with stable atherosclerotic disease. More recent accumulated data from several trials now show that statin therapy can also help reduce cardiovascular risk in unstable disease. These studies evaluated the effects of statin therapy begun before discharge, with the Myocardial Ischemia with Aggressive Cholesterol Lowering (MIRACL) trial showing that therapy could be started as early as 24 hours after onset with measurable clinical benefit. Registry data also suggest that long-term compliance may be improved in patients with a predischarge statin prescription compared with a postdischarge statin prescription. This is because many patients discharged without a statin prescription are either lost to further medical follow-up or do not receive a statin prescription from their primary care provider. The Third Report of the Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (ATP III), which constitutes the updated clinical guidelines of the National Cholesterol Education Program (NCEP), recommends that lipid-lowering drug therapy be initiated at hospital discharge. ATP III also provides important information on the goals of lipid-lowering therapy in patients after ACS. The challenge for the specialist is to establish a predischarge plan that includes maximal dosing to achieve aggressive target goals and to work with the patient's primary care provider to maintain these goals long-term.

Context: Peripheral arterial disease (PAD) is a manifestation of systemic atherosclerosis that is common and is associated with an increased risk of death and ischemic events, yet may be underdiagnosed in primary care practice., Objective: To assess the feasibility of detecting PAD in primary care clinics, patient and physician awareness of PAD, and intensity of risk factor treatment and use of antiplatelet therapies in primary care clinics., Design and Setting: The PAD Awareness, Risk, and Treatment: New Resources for Survival (PARTNERS) program, a multicenter, cross-sectional study conducted at 27 sites in 25 cities and 350 primary care practices throughout the United States in June-October 1999., Patients: A total of 6979 patients aged 70 years or older or aged 50 through 69 years with history of cigarette smoking or diabetes were evaluated by history and by measurement of the ankle-brachial index (ABI). PAD was considered present if the ABI was 0.90 or less, if it was documented in the medical record, or if there was a history of limb revascularization. Cardiovascular disease (CVD) was defined as a history of atherosclerotic coronary, cerebral, or abdominal aortic aneurysmal disease., Main Outcome Measures: Frequency of detection of PAD; physician and patient awareness of PAD diagnosis; treatment intensity in PAD patients compared with treatment of other forms of CVD and with patients without clinical evidence of atherosclerosis., Results: PAD was detected in 1865 patients (29%); 825 of these (44%) had PAD only, without evidence of CVD. Overall, 13% had PAD only, 16% had PAD and CVD, 24% had CVD only, and 47% had neither PAD nor CVD (the reference group). There were 457 patients (55%) with newly diagnosed PAD only and 366 (35%) with PAD and CVD who were newly diagnosed during the survey. Eighty-three percent of patients with prior PAD were aware of their diagnosis, but only 49% of physicians were aware of this diagnosis. Among patients with PAD, classic claudication was distinctly uncommon (11%). Patients with PAD had similar atherosclerosis risk factor profiles compared with those who had CVD. Smoking behavior was more frequently treated in patients with new (53%) and prior PAD (51%) only than in those with CVD only (35%; P <.001). Hypertension was treated less frequently in new (84%) and prior PAD (88%) only vs CVD only (95%; P <.001) and hyperlipidemia was treated less frequently in new (44%) and prior PAD (56%) only vs CVD only (73%, P<.001). Antiplatelet medications were prescribed less often in patients with new (33%) and prior PAD (54%) only vs CVD only (71%, P<.001). Treatment intensity for diabetes and use of hormone replacement therapy in women were similar across all groups., Conclusions: Prevalence of PAD in primary care practices is high, yet physician awareness of the PAD diagnosis is relatively low. A simple ABI measurement identified a large number of patients with previously unrecognized PAD. Atherosclerosis risk factors were very prevalent in PAD patients, but these patients received less intensive treatment for lipid disorders and hypertension and were prescribed antiplatelet therapy less frequently than were patients with CVD. These results demonstrate that underdiagnosis of PAD in primary care practice may be a barrier to effective secondary prevention of the high ischemic cardiovascular risk associated with PAD.

Background: Since coronary artery bypass graft patients remain at risk of coronary artery and bypass graft occlusion after successful surgery, adjunct treatment regimens are under investigation. In a study of the patients of the multicenter Post Coronary Artery Bypass Graft (Post CABG) Trial, 1 mg warfarin was found to have no important effect on coagulation parameters., Study Design: The effects of 1, 2 and 3 mg warfarin were evaluated at six-week intervals in 20 Post CABG Trial patients receiving titrated dose increases in comparison to 20 patients of similar age, gender and time from CABG treated with placebo., Results: International normalized ratio (INR) values increased with warfarin dose increments for 1, 2, and 3 mg, respectively (0.95+/-0.16, 1.08+/-0.19, and 1.34+/-0.39) and in comparison to placebo treated patients (dosextreatment p<0.001). Factor VII coagulant activity decreased with warfarin titration (1 mg, 119.0+/-18.3 %; 2 mg, 100.6+/-32.8 %; 3 mg, 95.0+/-27.8 %) and in comparison to placebo (dosextreatment p=0.008). Levels of prothrombin fragment F1.2, tissue plasminogen activator, fibrinogen and von Willebrand factor were unchanged with warfarin dose increments and in comparison to placebo., Conclusions: At doses up to 3 mg, warfarin acts on the INR through a reduction of factor VII with no effect on the fibrinolytic system, fibrinogen or von Willebrand factor. At these doses F1.2 did not document reduced coagulation activity. The observations of this study were consistent with the decision in the Post CABG Trial to increase the warfarin dose above 1 mg to achieve a distinct effect of warfarin that was less than full anticoagulation.

The Minnesota Regional Peripheral Arterial Disease Screening Program was designed to define the efficacy of community PAD detection efforts, to assess the disease-specific and health-related morbidity, to assess PAD awareness rates, and to determine the magnitude of atherosclerosis disease risk factors and the intensity of their management. The target population was recruited via mass media efforts directed at individuals over 50 years of age and those with leg pain with ambulation. Screening sessions included assessments of the ankle-brachial index, blood pressure, fasting lipid profile, and use of validated tools to detect symptomatic claudication (by the Modified WHO-Edinburgh Claudication Questionnaire), walking impairment (Walking Impairment Questionnaire - WIQ), quality of life (MOS SF-36), PAD awareness, and the intensity of PAD medical therapeutic interventions. PAD was defined as any ankle-brachial index < or =0.85 or a history of lower extremity revascularization. The program evaluated 347 individuals and identified 92 subjects with PAD and 255 subjects without PAD, yielding a detection rate of 26.5%. Individuals with PAD were older, tended to have higher blood pressures, and had a significant walking impairment and an impaired health-related quality of life compared with the non-PAD subjects. Current rates of tobacco use were low. Lipid-lowering, estrogen replacement, anti-platelet, and antihypertensive medications and exercise therapies were underutilized in the PAD cohort. Peripheral arterial disease awareness was low in these community-identified patients. This Program demonstrated that individuals with PAD can be efficiently identified within the community, but that current standards of medical care are low. These data can assist in the future development of PAD awareness, education, and treatment programs.

Objective: At higher doses, simvastatin has been shown to produce significantly greater increases in high-density lipoprotein (HDL) cholesterol and apolipoprotein (apo) A-I than atorvastatin. To extend and confirm these findings, a 36-week, randomized, double-blind, dose-titration study was performed in 826 hypercholesterolemic patients to compare the effects of simvastatin and atorvastatin on HDL cholesterol, apo A-I, and clinical and laboratory safety. PRIMARY HYPOTHESIS: Simvastatin, across a range of doses, will be more effective than atorvastatin at raising HDL cholesterol and apo A-I levels., Methods: A total of 826 hypercholesterolemic patients were enrolled in this double-blind, randomized, parallel, 36-week, dose-escalation study. Patients randomized to simvastatin received 40 mg/day for the first 6 weeks, 80 mg/day for the next 6 weeks, and remained on 80 mg/day for the final 24 weeks. Patients randomized to atorvastatin received 20 mg/day for the first 6 weeks, 40 mg/day for the next 6 weeks, and 80 mg/day for the remaining 24 weeks., Results: During the first 12 weeks of the study, simvastatin increased HDL cholesterol and apo A-I more than the comparative doses of atorvastatin, while producing slightly lower reductions in low-density lipoprotein (LDL) cholesterol and triglycerides. At the maximal dose comparison, simvastatin 80 mg and atorvastatin 80 mg, the HDL cholesterol and apo A-I differences favoring simvastatin were larger than at the lower doses. In addition, at the maximal dose comparison, the incidence of drug-related clinical adverse experiences was approximately two-fold higher with atorvastatin 80 mg than with simvastatin 80 mg (23 versus 12%, p < 0.001), due predominantly to a greater incidence of gastrointestinal symptoms with atorvastatin (10 versus 3%, p < 0.001). The incidence of clinically significant alanine aminotransferase elevations was also higher with atorvastatin 80 mg than with simvastatin 80 mg (3.8 versus 0.5%, p < 0.010), especially in women (6.0 versus 0.6%)., Conclusions: At the doses compared in this study, simvastatin led to greater increases in HDL cholesterol and apo A-I levels than atorvastatin. At the maximum dose comparison, there were fewer drug-related gastrointestinal symptoms and clinically significant aminotransferase elevations with simvastatin.

Background: An increased prevalence of hyperhomocysteinemia with an increased incidence of cardiovascular 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 concentrations in 78 stable RTRs and compared the role of cystatin C with the role of serum creatinine as determinants 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 hyperhomocysteinemia, and 26 had combined hyperhomocysteinemia (both fasting and PML). Unadjusted Pearson correlations showed that fasting plasma tHcy correlated with both cystatin C (r = 0.564; P <0.001) and creatinine (r = 0.519; P <0.001) and that increases in PML tHcy modestly correlated with cystatin (r = 0.205; P = 0.072), but not creatinine (r = 0.057; P = 0.624). General linear regression modeling with stepwise analysis of covariance showed that both cystatin C (partial R = 0.554; P <0.001) and creatinine (partial R = 0.535; P <0.001) were independent predictors of fasting tHcy, but of the two, only cystatin C (partial R = 0.242; P = 0.035) was an independent predictor of increased PML tHcy., Conclusions: Clinically stable RTRs have an excess prevalence of moderate hyperhomocysteinemia, and additional cases can be detected by methionine loading. Both creatinine and cystatin C are independent predictors 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 serum creatinine.

Although many investigators have evaluated the technical variability of quantitative angiographic techniques used to study atherosclerosis regression in native coronary arteries, few have studied the variability inherent in repeated studies of atherosclerotic saphenous vein grafts. This study describes 2 studies performed during the course of the Post Coronary Artery Bypass Graft (CABG) Clinical Trial that were designed to assess the reproducibility of: (1) repeated angiographic views within a short time period; and (2) reproducibility of the total process of quantitative analysis of saphenous vein graft angiograms. Statistical methods are described that provide a more meaningful assessment of the impact of measurement variability in the analytic process versus the variability related to changes induced by pharmacologic interventions. One such method, the increase in standard deviation (SD) among patients (ISDP), showed that repeated angiographic views increased the variability of calculation of lesion minimal diameter by 1.5%, whereas the ISDP for repetition of the entire process of quantitative angiographic readings increased variability 6.4%. These data from the Post CABG trial reveal that technical variability is small and has negligible impact on the conclusions of the study.

SCH 48461, an inhibitor of gastrointestinal absorption of cholesterol, was evaluated for its effects on lipid parameters in patients with primary hypercholesterolemia in a multicenter, double-blind, randomized, parallel-group study. Following the baseline phase, which consisted of a 2- to 10-week drug washout and dietary stabilization phase and a 4-week placebo lead-in (placebo baseline phase), 190 patients were randomized to an 8-week double-blind active drug (SCH 48461 1, 6.25, 25, 100, 200, or 400 mg) or 40 mg lovastatin once daily each morning or placebo treatment phase. By week 2, patients who received SCH 48461 6.25 to 400 mg or lovastatin demonstrated greater reduction from baseline in directly measured low-density lipoprotein cholesterol (LDL-C) levels than patients in the placebo group (p < or = 0.03). Overall, the percent reductions in LDL-C from baseline increased as the dose of SCH 48461 increased, with 0.6% to 15.5% reductions from the minimum dose of 1 mg to the maximum dose of 400 mg. Lovastatin 40 mg/day reduced LDL-C by 30.7% (p < 0.01). Statistically significant decreases were also seen for total cholesterol and apolipoprotein B (apo B) with doses of 25 mg to 400 mg of SCH 48461 and lovastatin. SCH 48461 was well tolerated. There was a similar incidence of adverse events in each SCH 48461- or lovastatin-treated group compared to placebo. This study demonstrated a clinically and statistically significant cholesterol-lowering effect of SCH 48461 in patients with primary hypercholesterolemia.

Background: Patients with peripheral arterial disease (PAD) are at an increased risk of cardiovascular mortality and morbidity and thus are an excellent group in whom to evaluate the feasibility and the effect of an aggressive multifactorial intervention on atherosclerotic vascular disease risk factors. The Arterial Disease Multiple Intervention Trial (ADMIT) was designed to determine the efficacy, safety, and compliance of an multifactorial therapy on selected atherosclerotic disease risk factors in patients with PAD., Methods: By a 2 x 2 x 2 factorial design, eligible participants (N = 468) were randomly assigned to low-dose warfarin, antioxidant vitamins, and niacin or its corresponding placebo, and followed up for 1 year. All participants were encouraged to use aspirin. Pravastatin was added to the drug regimen for those who needed to reduce LDL cholesterol to recommended levels., Results: Niacin increased HDL cholesterol levels by 30%, with the majority of effect achieved at a dosage of 500 mg twice daily. Warfarin had an anticoagulant effect. The antioxidant vitamins resulted in a significant increase in vitamin E, C, and beta-carotene plasma levels. Overall, compliance was high and few adverse effects were reported., Conclusions: ADMIT demonstrates that it is both feasible and safe to modify multiple atherosclerotic disease risk factors effectively with intensive combination therapy in patients with PAD.

Background: A fairly immediate reduction in angina pectoris symptoms after cholesterol lowering has been described. Our previous findings in rabbits and in a four-patient human pilot study indicated the existence of an RBC membrane barrier to oxygen (O2) transport in the presence of hypercholesterolemia. Our current objective was to determine whether, and to what extent, the plasma cholesterol concentration is an influencing factor in RBC O2 release and cellular O2 availability., Study Design: In an unique O2 diffusion analysis system, blood samples from 100 patients referred for lipid modification were analyzed. After 1 to 2 minutes of mixing in our diffusion analysis system, the next 1 to 2 minutes of circulation is comparable with 1 to 2 seconds of myocardial capillary flow. RBC O2 diffusion was defined by the depletion rate of total O2 content in blood from full O2 saturation (98%) to desaturation (approximately 60%). Relative tissue O2 availability was defined as the percentage decrease in O2 availability between the high-cholesterol group and the low-cholesterol group., Results: The 100 patients were divided almost equally into two groups on the basis of plasma cholesterol ranges of 175 to 229 mg/dL (n=49) and 230 to 299 mg/dL (n = 51). The mean cholesterol concentrations and percentage increases in the high-cholesterol group over the low-cholesterol group were: for plasma, 206 +/- 0.3 and 256 +/- 0.4 mg/dL, 24.3% (p < 0.001); for RBCs, 93 +/- 0.2 and 106 +/- 0.2mg/dL, 14.0% (p < 0.001); and for RBC membranes, 41 +/- 0.1 and 54 +/- 0.2mg/dL, 31.7% (p < 0.001). The blood O2 diffusion curves were distinctly different between the high- and the low-cholesterol groups (p < 0.05). Blood O2 diffusion, defined by the blood O2 diffusion curves, was inversely proportional to the plasma, RBC, and RBC-membrane cholesterol concentrations. The relative tissue O2 availability, after a circulation period of more than 3 minutes in the diffusion system, showed a decrease of 17.5% (p < 0.05) between the plasma cholesterol groups. In comparing the two plasma cholesterol concentration extremes of less than 200mg/dL (n= 14) and greater than 275 mg/dL (n= 11) after a circulation period of more than 3 minutes in the diffusion system, we found a decrease in relative tissue O2 availability of 35.8% (p < 0.05)., Conclusions: The plasma cholesterol concentration may be an influencing factor in RBC-membrane cholesterol content, which, in turn, may regulate RBC-membrane O2 transport, RBC O2 release, and cellular O2 availability. The implications of this work include the addition of angina pectoris control to the indications for appropriate lipid modification and the development of an in vitro blood stress test to replace patient cardiac stress testing.

Background and Aim: Clinical data suggesting that larger decreases in low density lipoprotein cholesterol (LDL-C) result in greater reductions in coronary heart disease events have led to the establishment of aggressive LDL-C targets for the treatment of hypercholesterolemia. In view of this, the efficacy and safety of a new maximum dose of simvastatin, 80 mg, were evaluated in 9 studies involving 2819 hypercholesterolemic patients. This report focuses on the combined results from the 4 main or Pivotal studies in which a total of 1936 patients received simvastatin 40 or 80 mg for 36 to 48 weeks., Methods and Results: The Pivotal studies had similar randomized, multicenter, controlled, double-blind, parallel-group designs. Their combined results demonstrated a significant advantage in the LDL-C-lowering effect for the 80 mg dose. At week 24, the mean percentage reductions (95% confidence intervals) from baseline in LDL-C for the 40 and 80 mg groups were -39.8% (-40.9, -38.7) and -45.7% (-46.5, -45.0) respectively (p < 0.001, between groups), and larger reductions in total cholesterol and triglycerides were also observed in the 80 mg group. Both doses were well tolerated. No new or unexpected adverse events were observed and the overall clinical event profiles were similar in the two groups. Clinically significant hepatic transaminase increases (> 3 times the upper limit of normal/ULN) and myopathy (muscle symptoms plus creatine kinase increase > 10 times ULN) occurred infrequently with both doses. Simvastatin 80 mg had a comparable efficacy and safety profile in women and men as well as in non-elderly and elderly patients., Conclusions: Simvastatin 80 mg provides additional LDL-C and triglyceride reductions compared to the 40 mg dose and has an excellent safety and tolerability profile.