Effectiveness of ezetimibe added to ongoing statin therapy in modifying lipid profiles and low-density lipoprotein cholesterol goal attainment in patients of different races and ethnicities: a substudy of the Ezetimibe add-on to statin for effectiveness trial.

OBJECTIVE: To examine whether the improvements in lipid profiles and low-density lipoprotein cholesterol (LDL-C) goal attainment found in the Ezetimibe Add-On to Statin for Effectiveness trial occurred equally in the black, Hispanic, and white patient populations enrolled in the study. PATIENTS AND METHODS: In this double-blind, placebo-controlled study, patients were recruited from 299 community-based practices across the United States (January to August 2003). Patients with, hypercholesterolemia and LDL-C levels exceeding National Cholesterol Education Program Adult Treatment Panel III goals were randomized (2:1) to receive either ezetimibe (10 mg/d) or placebo in addition to their ongoing statin therapy for 6 weeks. RESULTS: A total of 5802 patients were screened at baseline for the Ezetimibe Add-On to Statin for Effectiveness study. Of these, 2772 were excluded, and the remaining 3030 eligible patients were randomized. Ezetimibe, compared with placebo, added to statin therapy significantly reduced LDL-C levels from statin-treated baseline by 23.0% (white patients), 23.0% (black patients), and 21.0% (Hispanic patients). This effect was consistent across race and ethnicity groups (P > .50 for treatment-by-race interactions). Ezetimibe added to statin therapy also statistically significantly (P < .001) increased the percentage of patients attaining their LDL-C goal for their National Cholesterol Education Program Adult Treatment Panel III risk category in black (63.0%), Hispanic (64.8%), and white (72.3%) patients compared with placebo plus statin (32.9% black patients, 19.0% Hispanic patients, and 19.7% white patients). Ezetimibe treatment improved other lipid parameters across groups, including triglyceride, high-density lipoprotein cholesterol, non-high-density ilpoprotein cholesterol, and total cholesterol levels. Finally, the addition of ezetimibe reduced high-sensitivity C-reactive protein levels overall, and no significant interaction of treatment by race occurred (P = .83), Indicating a consistent effect across races. Ezetimibe was generally well tolerated, and no detectable differences occurred in the adverse event profile by race or ethnicity. CONCLUSION: Ezetimibe added to statin therapy is effective and well tolerated for improving the lipid profile and LDL-C goal attainment of patients regardless of race or ethnicity.

Dose-comparison study of the combination of ezetimibe and simvastatin (Vytorin) versus atorvastatin in patients with hypercholesterolemia: the Vytorin Versus Atorvastatin (VYVA) study.

BACKGROUND: Low-density lipoprotein cholesterol (LDL-C) is the primary therapeutic target in the National Cholesterol Education Program Adult Treatment Panel III (ATP III) guidelines. This study tested the hypothesis that ezetimibe/simvastatin, a lipid-lowering agent that inhibits both intestinal cholesterol absorption and cholesterol synthesis, provides greater LDL-C reductions than atorvastatin across dose ranges. METHODS: This multicenter, double-blind, 6-week parallel-group study randomized 1902 patients with LDL-C above ATP III goal to atorvastatin (10, 20, 40, or 80 mg) or to ezetimibe/simvastatin (10/10, 10/20, 10/40, or 10/80 mg). Patients were stratified by prerandomization LDL-C level. RESULTS: At each milligram-equivalent statin dose comparison, and averaged across doses, ezetimibe/simvastatin provided greater LDL-C reductions (47%-59%) than atorvastatin (36%-53%). Ezetimibe/simvastatin 10/40 and 10/80 mg also provided significantly greater high-density lipoprotein cholesterol (HDL-C) increases than atorvastatin 40 and 80 mg. Triglyceride reductions were similar for all comparisons. More ezetimibe/simvastatin than atorvastatin patients with coronary heart disease (CHD) or CHD risk equivalents attained the ATP III LDL-C goal of <100 mg/dL and the optional LDL-C target of <70 mg/dL. C-reactive protein reductions were similar between treatment groups. Consecutive elevations in alanine aminotransferase and/or aspartate aminotransferase occurred in significantly more atorvastatin patients than ezetimibe/simvastatin patients. No myopathy or liver-related adverse events led to study discontinuation with either drug. CONCLUSIONS: Ezetimibe/simvastatin was more effective than atorvastatin in lowering LDL-C at each dose comparison and provided greater increases in HDL-C at the 40- and 80-mg statin dose. Ezetimibe/simvastatin is a highly efficacious, well-tolerated treatment option for hypercholesterolemic patients.

Effectiveness and tolerability of simvastatin plus fenofibrate for combined hyperlipidemia (the SAFARI trial).

Patients with combined hyperlipidemia (elevated triglyceride [TG] levels, elevated low-density lipoprotein [LDL] cholesterol, and multiple lipoprotein abnormalities) are at increased risk for coronary heart disease. We conducted a multicenter (in the United States), randomized, double-blind, active-controlled, 18-week study to determine if combination therapy with simvastatin plus fenofibrate is more effective in reducing elevated TG levels, thus improving the lipoprotein pattern in patients with combined hyperlipidemia compared with simvastatin monotherapy, and to evaluate safety and tolerability. Patients (aged 21 to 68 years) with a diagnosis of combined hyperlipidemia (fasting TG levels >/=150 and 130 mg/dl) received simvastatin monotherapy (20 mg/day, n = 207) or simvastatin 20 mg plus fenofibrate (160 mg/day) combination therapy (n = 411) for 12 weeks following a 6-week diet and placebo run-in period. From baseline to week 12, median TG levels decreased 43.0% (combination therapy) and 20.1% (simvastatin monotherapy [treatment difference -23.6%, p <0.001]). Mean LDL cholesterol levels decreased 31.2% and 25.8% (treatment difference -5.4%, p <0.001), and high-density lipoprotein cholesterol levels increased 18.6% and 9.7% (treatment difference 8.8%, p <0.001) in the combination therapy versus monotherapy groups, respectively. No drug-related serious adverse experiences were observed. No patient experienced clinical myopathy or severe abnormalities in liver function. Combination therapy with simvastatin 20 mg and fenofibrate 160 mg in patients with combined hyperlipidemia resulted in additional improvement in all lipoprotein parameters measured compared with simvastatin 20 mg monotherapy and was well tolerated. Thus, this combination therapy is a beneficial therapeutic option for managing combined hyperlipidemia.

A community-based, randomized trial of ezetimibe added to statin therapy to attain NCEP ATP III goals for LDL cholesterol in hypercholesterolemic patients: the ezetimibe add-on to statin for effectiveness (EASE) trial.

OBJECTIVE: To determine the extent of reduction in low-density lipoprotein cholesterol (LDL-C) level and improvement in National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) LDL-C goal attainment when ezetimibe was added to ongoing statin therapy in a diverse population of community-based patients. PATIENTS AND METHODS: In this multicenter, double-blind, placebo-controlled trial (from January 2003 to August 2003), hypercholesterolemic patients (from 299 US primary care and specialty practices) with LDL-C levels exceeding NCEP ATP III goals were randomized (2:1) to receive ezetimibe (10 mg/d) or placebo in addition to their ongoing statin therapy for 6 weeks. RESULTS: In a study of 3030 randomized patients, ezetimibe added to statin therapy significantly reduced the LDL-C level by an additional 25.8% in the total population, compared with an additional 2.7% reduction with placebo plus statin (treatment difference, -23.1%; P<.001); the treatment difference ranged from -19.9% to -24.0% (P<.001) in each NCEP ATP III risk category subgroup. Significantly (P<.001) more patients (71.0%) treated with ezetimibe added to statin reached their NCEP ATP III target LDL-C level compared with those treated with placebo plus statin (20.6%). The addition of ezetimibe also resulted in improvement in other lipid parameters and high-sensitivity C-reactive protein levels. These benefits were consistent across sex, race, age, statin brand, and dose subgroups. Ezetimibe plus statin therapy was well tolerated, with a safety profile similar to placebo plus statin. CONCLUSION: Across multiple subgroups, ezetimibe added to statin therapy consistently produced significant additional improvements in LDL-C levels and goal attainment, as well as in other lipoproteins, compared with addition of placebo. The addition of ezetimibe to statin therapy should be considered for patients not achieving their NCEP ATP III LDL-C goals while receiving statin therapy alone.

Lipid altering-efficacy of ezetimibe co-administered with simvastatin compared with rosuvastatin: a meta-analysis of pooled data from 14 clinical trials.

OBJECTIVE: Results of direct comparative studies between ezetimibe/simvastatin and rosuvastatin therapies have not been reported. Both of these treatment options offer significant reductions in LDL-C. To evaluate the lipid efficacy of each of these therapies relative to each other, a meta-analysis of data from 14 randomized, double-blind clinical trials that compared the effectiveness of two new options for cholesterol lowering was performed. DATA SOURCES: PubMed, EMBASE and BIOSIS databases were searched up to March 14, 2004. METHODS OF STUDY SELECTION: Efficacy results from clinical trials with the co-administration of ezetimibe 10 mg with simvastatin or with the ezetimibe/simvastatin combination product (ezetimibe/simvastatin 10/10 mg, 10/20 mg, 10/40 mg, and 10/80 mg) were compared with efficacy results from clinical trials of rosuvastatin 5 mg, 10 mg, 20 mg, and 40 mg in patients with primary hypercholesterolemia. Trials in healthy patients, heterozygous familial hypercholesterolemia or combined hyperlipidemia, and pharmacokinetic trials were excluded. DATA EXTRACTION AND SYNTHESIS: This analysis used pooled data for LDL-C, HDL-C, non-HDL-C, triglycerides, total cholesterol, apolipoprotein (apo) A-I, and apo B for the two therapies at their lowest doses (ezetimibe/simvastatin 10/10 mg and rosuvastatin 5 mg) through their highest doses (ezetimibe/simvastatin 10/80 mg and rosuvastatin 40 mg), and estimated within-treatment percentage changes in these parameters. Percentage reductions from baseline in LDL-C for the pooled data were 46.2% and 41.8% for ezetimibe/simvastatin 10/10 mg and rosuvastatin 5 mg, respectively; 50.6% and 47.4% for ezetimibe/simvastatin 10/20 mg and rosuvastatin 10 mg, respectively; 55.9% and 52.1% for ezetimibe/simvastatin 10/40 mg and rosuvastatin 20 mg, respectively; and 59.7% and 58.5% for ezetimibe/simvastatin 10/80 mg and rosuvastatin 40 mg, respectively. CONCLUSIONS: The results of this meta-analysis suggest greater LDL-C lowering with ezetimibe/simvastatin compared with rosuvastatin. These results need to be confirmed in a head-to-head comparison of both therapies.

Effectiveness of the addition of ezetimibe to ongoing statin therapy in modifying lipid profiles and attaining low-density lipoprotein cholesterol goals in older and elderly patients: subanalyses of data from a randomized, double-blind, placebo-controlled trial.

BACKGROUND: The Ezetimibe Add-on to Statin for Effectiveness (EASE) trial examined the effectiveness and safety profile of ezetimibe (EZE) added to ongoing statin therapy in 3030 patients with low-density lipoprotein cholesterol (LDL-C) levels exceeding National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP 111) goals. OBJECTIVE: Because people aged > 65 years are at increased risk for development of coronary heart disease (CHD), these subgroup analyses of data from the EASE trial were conducted to determine the extent of change in LDL-C levels and attainment of NCEP ATP III LDL-C goals with the addition of EZE to ongoing statin therapy in patients aged 65 to 74 years (the older group) and > or = 75 years (the elderly group). METHODS: In the multicenter (299 sites), community-based, double-blind, placebo-controlled EASE trial, patients were randomly assigned in a 2:1 ratio to receive EZE 10 mg/d or placebo in addition to their ongoing statin therapy for 6 weeks. The primary efficacy end point was the percent reduction in LDL-C levels, and the principal secondary end point was the proportion of patients achieving NCEP ATP III target LDL-C levels. The effects of the addition of EZE on additional lipid and lipoprotein measures and high-sensitivity C-reactive protein were also examined, as was tolerability. Study analyses were performed in the modified intent-to-treat population. RESULTS: This subgroup analysis included data from 841 patients in the older age group (579 EZE + statin, 262 placebo + statin), which constituted 27.8% of the overall EASE population, and 466 in the elderly group (307 EZE + statin, 159 placebo + statin), which constituted 15.4% of the overall EASE population. The former group included 436 (51.8%) men and 405 (48.2%) women, with a mean (SD) age of 69.2 (3.0) years; the latter group included 227 (48.7%) men and 239 (51.3%) women, with a mean age of 78.5 (3.2) years. The characteristics of the 2 groups were comparable at baseline. In the older group, 717 (85.3%) had CHD or a CHD risk equivalent, as did 421 (90.3%) of those in the elderly group. Thirty-two patients in the older group and 17 in the elderly group discontinued the study. The reasons for discontinuation included clinical adverse events (n = 23), withdrawal of consent (n = 15), loss to follow-up (n = 4), protocol deviation (n = 2), and other reasons (n = 5). EZE + statin significantly reduced LDL-C compared with placebo + statin (older group: mean [SE] treatment difference, -25.1% [1.4]; P < 0.001; elderly group: treatment difference, -22.0% [1.8]; P < 0.001). The LDL-Glowering effects of treatment were consistent in the 2 groups. EZE + statin therapy significantly improved other lipid parameters (triglycerides, non high density lipoprotein cholesterol, and total cholesterol, P < 0.001 in both age groups; high-density lipoprotein cholesterol, P < 0.03 in the older group only) and high-sensitivity C-reactive protein levels compared with EZE + placebo (P < 0.03). The attainment of LDL-C goals also was significantly increased with EZE + statin compared with placebo + statin (older group: 72.3% vs 18.9%, respectively; odds ratio [OR] = 14.59; 95% CI, 9.55 to 22.28; P < 0.001; elderly group: 73.3% vs 18.9%; OR = 13.44; 95% CI, 7.72 to 23.41; P < 0.001). EZE + statin therapy was well tolerated by patients in both age groups, with a safety profile comparable to that of placebo + statin. CONCLUSIONS: In these older and elderly patients, many of them at high risk for CHD, EZE added to ongoing statin therapy was well tolerated and was an effective treatment option for improving lipid profiles and attainment of LDL-C goals. Adding EZE improved rates of attainment of NCEP ATP III LDL-C goals without increases in the dose or potency of statin therapy. Further studies are necessary to determine whether these results can be generalized to other older and elderly populations.

LDL-C goal attainment with ezetimibe plus simvastatin coadministration vs atorvastatin or simvastatin monotherapy in patients at high risk of CHD.

AIMS: To compare the proportion of patients at high risk for coronary heart disease (CHD) achieving the recommended low-density lipoprotein cholesterol (LDL-C) treatment goal of < 100 mg/dL and the optional LDL-C target of < 70 mg/dL with coadministration of ezetimibe and simvastatin (EZE/SIMVA) vs either atorvastatin or simvastatin monotherapy. PATIENTS: Patients with established CHD or CHD risk equivalent according to National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) criteria with baseline LDL-C = 130 mg/dL and triglycerides (TG) < or = 350 mg/dL. METHODS: A post hoc analysis from 2 separate studies assessed the percentage of high-risk patients achieving the LDL-C targets (< 100 and < 70 mg/dL) after 6 weeks on the usual recommended starting doses of the following treatments: EZE/SIMVA (10/20 mg) vs atorvastatin (10 mg) or simvastatin (20 mg). Depending on the study, EZE/SIMVA 10/10 or 10/40 mg was also compared with either atorvastatin 10 mg or simvastatin 20 mg. Percent change in other lipid parameters from baseline to study endpoint was also examined. RESULTS: In both studies, the proportions of patients achieving an LDL-C of < 100 mg/dL were significantly (P < .001) greater for EZE/SIMVA 10/10, 10/20, or 10/40 mg vs either atorvastatin 10 mg or simvastatin 20 mg after 6 weeks. The percentage reaching the optional LDL-C treatment target of < 70 mg/dL was also significantly higher with EZE/SIMVA compared with either atorvastatin or simvastatin. Percent reduction in LDL-C was significantly (P < .001) larger with all doses of EZE/SIMVA (46% to 59%) compared with either atorvastatin 10 mg (37%) or simvastatin 20 mg (38%) monotherapy after 6 weeks. Changes in other lipid parameters consistently favored EZE/SIMVA vs statin monotherapy. All treatments were well tolerated in both studies. CONCLUSION: Patients at high risk for CHD are more likely to attain LDL-C treatment targets with the usual recommended starting dose of EZE/SIMVA (10 or 20 mg) therapy than with that of atorvastatin (10 mg) or simvastatin (20 mg) monotherapy.

Effect on high-density lipoprotein cholesterol of maximum dose simvastatin and atorvastatin in patients with hypercholesterolemia: results of the Comparative HDL Efficacy and Safety Study (CHESS).

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.

Efficacy and safety of ezetimibe co-administered with simvastatin compared with atorvastatin in adults with hypercholesterolemia.

This study compared the efficacy and safety of co-administered ezetimibe + simvastatin with atorvastatin monotherapy in adults with hypercholesterolemia. Seven hundred eighty-eight patients were randomized 1:1:1 to 3 treatment groups; each group was force-titrated over four 6-week treatment periods: (1) 10 mg of atorvastatin as the initial dose was titrated to 20, 40, and 80 mg; (2) co-administration of 10 mg of ezetimibe and 10 mg of simvastatin (10/10 mg) was titrated to 10/20, 10/40, and 10/80 mg of ezetimibe + simvastatin; and (3) co-administration of 10/20 mg of ezetimibe + simvastatin was titrated to 10/40 mg (for 2 treatment periods) and 10/80 mg of ezetimibe + simvastatin. Key efficacy measures included percent changes in low-density lipoprotein cholesterol (LDL) and high-density lipoprotein cholesterol (HDL) from baseline to the ends of (1) treatment periods 1 and 2 (for LDL cholesterol) comparing co-administration of 10/20 mg and 10/10 mg of ezetimibe + simvastatin with 10 mg of atorvastatin and (2) treatment period 4 (for LDL cholesterol and HDL cholesterol) comparing co-administration of 10/80 mg of ezetimibe + simvastatin with 80 mg of atorvastatin. Baseline LDL and HDL cholesterol levels were comparable between treatment groups. At the end of treatment period 1, the mean decrease of LDL cholesterol was significantly (p

Tolerability of once-weekly alendronate in patients with osteoporosis: a randomized, double-blind, placebo-controlled study.

OBJECTIVE: To compare the upper gastrointestinal (GI) tract tolerability of once-weekly oral alendronate, 70 mg, and placebo. PATIENTS AND METHODS: This was a 12-week multicenter, randomized, double-blind, placebo-controlled study. The first patient initiated treatment on June 5, 2000, and the last patient completed treatment on March 1, 2001. The study enrolled 450 postmenopausal women and men with osteoporosis (224 took alendronate, 226 took placebo) who were ambulatory and community dwelling at 48 outpatient study centers in the United States. By design, approximately half of the patients were naive to bisphosphonates. The primary end point was upper GI tract tolerability based on the incidence of any upper GI tract adverse events. Secondary end points included the number of discontinuations due to drug-related upper GI tract adverse events and the change from baseline in bone resorption, assessed by the urinary N-telopeptide-creatinine ratio at 12 weeks. A subgroup analysis of the primary and secondary end points was performed on the patients stratified by prior bisphosphonate use. The safety and tolerability of the weekly alendronate and placebo regimens were captured as clinical and laboratory adverse events. RESULTS: A total of 11% of the alendronate patients and 13% of the placebo patients reported an upper GI tract adverse event. Discontinuations due to drug-related upper GI tract adverse events occurred in 3% of alendronate patients and 1% of placebo patients. The differences between the treatment groups for the primary and secondary end points were not significant. For the primary end point, the upper limit of the 95% confidence interval of the difference was well within the prespecified 14% comparability bound (-2.2%; 95% confidence interval, -8.3% to 3.9%). The overall incidence of upper GI tract adverse events was lower in the subgroup of patients with prior bisphosphonate exposure (8%) than in those who were bisphosphonate naive (16%). However, regardless of prior bisphosphonate exposure, the incidence of upper GI tract adverse events was similar between the alendronate and placebo patients. The urinary N-telopeptide-creatinine ratio showed a significant decrease in the alendronate patients (72% of baseline, P<.001) compared with a slight increase in the placebo patients (106% of baseline) at week 12. CONCLUSION: In this 3-month study, the incidence of upper GI tract adverse events in patients treated with once-weekly alendronate, 70 mg, was comparable to that with placebo.

Once-weekly alendronate 70 mg and raloxifene 60 mg daily in the treatment of postmenopausal osteoporosis.

OBJECTIVE: To compare the efficacy and tolerability of once-weekly (OW) alendronate (ALN) 70 mg and raloxifene (RLX) 60 mg daily in the treatment of postmenopausal osteoporosis. DESIGN: This 12-month, randomized, double-blind study enrolled 456 postmenopausal women with osteoporosis (223 ALN, 233 RLX) at 52 sites in the United States. Efficacy measurements included lumbar spine (LS), total hip, and trochanter bone mineral density (BMD) at 6 and 12 months, biochemical markers of bone turnover, and percent of women who maintained or gained BMD in response to treatment. The primary endpoint was percent change from baseline in LS BMD at 12 months. Adverse experiences were recorded to assess treatment safety and tolerability. RESULTS: Over 12 months, OW ALN produced a significantly greater increase in LS BMD (4.4%, P < 0.001) than RLX (1.9%). The percentage of women with > or = 0% increase in LS BMD (ALN, 94%; RLX, 75%; P < 0.001) and > or =3% increase in LS BMD (ALN, 66%; RLX, 38%; P < 0.001) were significantly greater with ALN than RLX. Total hip and trochanter BMD increases were also significantly greater (P < or =0.001) with ALN. Greater (P < 0.001) reductions in N-telopeptide of type I collagen and bone-specific alkaline phosphatase were achieved with ALN compared with RLX at 6 and 12 months. No significant differences in the incidence of upper gastrointestinal or vasomotor adverse experiences were seen. CONCLUSION: ALN 70 mg OW produced significantly greater increases in spine and hip BMD and greater reductions in markers of bone turnover than RLX over 12 months. A greater percentage of women maintained or gained BMD on ALN than RLX. Both medications had similar safety and tolerability profiles.

A multicenter, randomized, double-blind clinical trial comparing the low-density lipoprotein cholesterol-lowering ability of lovastatin 10, 20, and 40 mg/d with fluvastatin 20 and 40 mg/d.

BACKGROUND: The available statin drugs have similar pharmacodynamic properties but are not equal in low-density lipoprotein cholesterol (LDL-C)-lowering efficacy. OBJECTIVE: The aim of this study was to compare the effects of lovastatin and fluvastatin in lowering LDL-C. METHODS: This was a prospective, randomized, double-blind study of patients aged >20 years with primary hypercholesterolemia conducted at 44 clinical sites across the United States. After a 6-week National Cholesterol Education Program (NCEP) Step I diet lead-in period in patients taking lipid-lowering drugs at screening, patients were randomized to receive lovastatin 10, 20, or 40 mg/d or fluvastatin 20 or 40 mg/d (the doses available at the time the study was conducted) for 6 weeks. Patients not taking lipid-lowering drugs at screening and who had been following the Step I diet for at least 6 weeks proceeded to the treatment phase. All patients received instruction for a Step I diet, which they followed throughout the treatment phase. After the treatment period, total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), LDL-C, and triglycerides were measured, and TC:HDL-C and LDL-C:HDL-C ratios were calculated. RESULTS: A total of 838 patients (476 men, 362 women; mean [SD] age, 59 [12] years) were included in the study. Lovastatin 20 and 40 mg/d significantly reduced mean LDL-C compared with the same dosages of fluvastatin. TC and the LDL-C:HDL-C ratio decreased more with lovastatin than with fluvastatin at a given dose level. Approximately 50% of patients treated with lovastatin 20 and 40 mg/d compared with approximately 25% treated with fluvastatin 20 and 40 mg/d reached NCEP Adult Treatment Panel II LDL-C goals. CONCLUSION: In this small study population of patients with primary hypercholesterolemia taking lipid-lowering drugs, short-term (6-week) treatment with lovastatin was more efficacious than fluvastatin in lowering cholesterol levels and reaching LDL-C treatment goals.

Patient preference for once-weekly alendronate 70 mg versus once-daily alendronate 10 mg: a multicenter, randomized, open-label, crossover study.

BACKGROUND: Alendronate, an oral bisphosphonate, is available for the treatment of osteoporosis in a 70-mg once-weekly and a 10-mg once-daily formulation. OBJECTIVES: This study aimed to determine patient preference for once-weekly versus once-daily dosing with alendronate, and to determine which treatment regimen the patients believed was more convenient and would be easier to comply with for a long period. METHODS: This was a multicenter, randomized, open-label, preference study in which postmenopausal women with osteoporosis were enrolled to receive 9 weeks of treatment in crossover fashion (4 weeks with each study regimen separated by a 1-week washout period). The study regimens included once-weekly alendronate 70 mg and once-daily alendronate 10 mg. The primary and secondary end points were assessed with a questionnaire completed by the patient. Adverse events (AEs) were recorded to assess patient tolerability of the study medications. RESULTS: A total of 324 patients met the eligibility requirements; 288 were randomized to treatment, 287 (mean age, 64.8 years) received treatment, 272 completed the questionnaire, and 266 completed the study. Of the patients who completed the questionnaire, 235 patients preferred the 70-mg once-weekly dosing regimen compared with the 10-mg once-daily regimen (86.4% vs 9.2%; P < 0.001). Most patients also believed that once-weekly dosing was more convenient than once-daily dosing (89.0% vs 7.7%; P < 0.001) and would allow them to achieve better long-term compliance (87.5% vs 8.5%; P < 0.001). Clinical AEs were reported in 30.7% of patients treated with once-weekly alendronate and 30% of patients treated with once-daily alendronate, with no significant differences between treatments. CONCLUSION: When once-weekly alendronate 70 mg was compared with once-daily alendronate 10 mg in this study, 70-mg once-weekly alendronate was the preferred dosing regimen.

Effectiveness of simvastatin therapy in raising HDL-C in patients with type 2 diabetes and low HDL-C.

OBJECTIVE: To evaluate the efficacy of high and moderate doses of simvastatin (80 and 40 mg), for raising high density lipoprotein-cholesterol (HDL-C), improving HDL sub-fractions, and affecting other parameters, including high sensitivity C-reactive protein (hs-CRP), in patients with type 2 diabetes mellitus (DM) and low HDL-C. RESEARCH DESIGN AND METHODS: This double-blind, placebo-controlled, randomized, 3-period, complete block, 6-week crossover study examined the efficacy of simvastatin in adult men and women (N = 151) with stable type 2 DM (HbA(1C) < 9%), low density lipoprotein-cholesterol (LDL-C) > 100 mg/dL (2.6 mmol/L), HDL-C < 40 mg/dL (< 1 mmol/L), and fasting triglyceride level > 150 (> 1.7 mmol/L) and < 700 mg/dL (< 7.9 mmol/L). This study included adult men (71%) and women (29%) of various races (89% white, 6% black, 1% Asian, 3% other) enrolled from 29 practice-based sites in the United States. MAIN OUTCOME MEASURES: Percentage change in HDL-C from baseline at the end of each 6-week treatment interval. RESULTS: Both simvastatin 80 and 40 mg significantly increased total HDL-C from baseline (mean increases of 8% +/- 1 [SE] and 5% +/- 1, respectively; p < 0.001) compared with placebo, and significantly reduced plasma concentrations of LDL-C (p < 0.001), triglycerides (p < 0.001), apolipoprotein B (p < 0.001), and hs-CRP (p < or = 0.012). Compared with simvastatin 40 mg, the 80 mg dose provided additional efficacy. Simvastatin 80 mg also significantly (p < 0.001) increased HDL(2) from baseline (14% +/- 3[SE]) and placebo phases (10 +/- 3). An exploratory analysis showed 87% (simvastatin 80 mg) and 82% (simvastatin 40 mg) of patients reached the NCEP ATP III treatment goals for LDL-C compared with 14% on placebo. CONCLUSIONS: Both simvastatin 80 and 40 mg raise HDL-C and improve other measures associated with elevated coronary risk in patients with type 2 DM and low HDL-C.

Efficacy and tolerability of finasteride 1 mg in men aged 41 to 60 years with male pattern hair loss.

A 24-month double-blind, randomized, placebo-controlled, parallel-group, multicenter study of 424 men was conducted to determine the efficacy and tolerability of finasteride 1 mg on hair growth/loss in men aged 41 to 60 years with mild-to-moderate, predominantly vertex male pattern hair loss. Efficacy was evaluated by review of global photographs of the vertex scalp taken at baseline and at Months 6, 12, 18, and 24 and by patient self-assessments and investigator clinical assessments of change from baseline in hair growth/loss collected at Months 6, 12, 18, and 24. Safety analyses included assessment of clinical and laboratory adverse experiences, including sexual adverse experiences. Analysis of global photographic assessment data showed significant improvement in hair growth for men in the finasteride group compared with those taking placebo beginning at Month 6 (p < 0.001) and maintained through Month 24 (p < 0.001). Results of the patient self-assessment and investigator assessments were consistent with those from the global photographic assessment. Finasteride 1 mg improved scalp hair growth in men aged 41 to 60 years with predominantly vertex male pattern hair loss compared with results seen with placebo. Improvement was evident by 6 months of treatment and continued through 24 months. Treatment with finasteride 1 mg was generally well tolerated.

Safety and efficacy of enoxaparin vs unfractionated heparin in patients with non-ST-segment elevation acute coronary syndromes who receive tirofiban and aspirin: a randomized controlled trial.

CONTEXT: Enoxaparin or the combination of glycoprotein IIb/IIIa inhibitor tirofiban with unfractionated heparin independently have shown superior efficacy over unfractionated heparin alone in patients with non-ST-elevation acute coronary syndromes (ACS). It is not clear if combining enoxaparin with glycoprotein IIb/IIIa inhibitors is as safe or as effective as the current standard combination of unfractionated heparin with glycoprotein IIb/IIIa inhibitors. OBJECTIVE: To assess efficacy and safety of the combination of enoxaparin and tirofiban compared with unfractionated heparin and tirofiban in patients with non-ST-elevation ACS. DESIGN, SETTING, AND PARTICIPANTS: A prospective, international, open-label, randomized, noninferiority trial of 1 mg/kg of enoxaparin every 12 hours (n = 2026) compared with weight-adjusted intravenous unfractionated heparin (n = 1961) in patients with non-ST-elevation ACS receiving tirofiban and aspirin. Phase A of the A to Z trial was conducted between December 1999 and May 2002. MAIN OUTCOME MEASURES: Death, recurrent myocardial infarction, or refractory ischemia at 7 days in the intent-to-treat population with boundaries set for superiority and noninferiority. Safety based on measures of bleeding using the Thrombolysis in Myocardial Infarction (TIMI) classification system. RESULTS: A total of 169 (8.4%) of 2018 patients randomized to enoxaparin experienced death, myocardial infarction, or refractory ischemia at 7 days compared with 184 (9.4%) of 1952 patients randomized to unfractionated heparin (hazard ratio [HR], 0.88; 95% confidence interval [CI], 0.71-1.08). This met the prespecified criterion for noninferiority. All components of the composite primary and secondary end points favored enoxaparin except death, which occurred in only 1% of patients (23 for enoxaparin and 17 for unfractionated heparin). Rates for any TIMI grade bleeding were low (3.0% for enoxaparin and 2.2% for unfractionated heparin; P =.13). Using a worst-case approach that combined 2 independent bleeding evaluations, use of enoxaparin was associated with 1 additional TIMI major bleeding episode for each 200 patients treated. CONCLUSIONS: In patients receiving tirofiban and aspirin, enoxaparin is a suitable alternative to unfractionated heparin for treatment of non-ST-elevation ACS. The 12% relative and 1% absolute reductions in the primary end point in favor of enoxaparin met criterion for noninferiority and are consistent with prior trials performed without the use of glycoprotein IIb/IIIa inhibitors.

Early intensive vs a delayed conservative simvastatin strategy in patients with acute coronary syndromes: phase Z of the A to Z trial.

CONTEXT: Limited data are available evaluating how the timing and intensity of statin therapy following an acute coronary syndrome (ACS) event affect clinical outcome. OBJECTIVE: To compare early initiation of an intensive statin regimen with delayed initiation of a less intensive regimen in patients with ACS. DESIGN, SETTING, AND PARTICIPANTS: International, randomized, double-blind trial of patients with ACS receiving 40 mg/d of simvastatin for 1 month followed by 80 mg/d thereafter (n = 2265) compared with ACS patients receiving placebo for 4 months followed by 20 mg/d of simvastatin (n = 2232), who were enrolled in phase Z of the A to Z trial between December 29, 1999, and January 6, 2003. MAIN OUTCOME MEASURE: The primary end point was a composite of cardiovascular death, nonfatal myocardial infarction, readmission for ACS, and stroke. Follow-up was for at least 6 months and up to 24 months. RESULTS: Among the patients in the placebo plus simvastatin group, the median low-density lipoprotein (LDL) cholesterol level achieved while taking placebo was 122 mg/dL (3.16 mmol/L) at 1 month and was 77 mg/dL (1.99 mmol/L) at 8 months while taking 20 mg/d of simvastatin. Among the patients in the simvastatin only group, the median LDL cholesterol level achieved at 1 month while taking 40 mg/d of simvastatin was 68 mg/dL (1.76 mmol/L) and was 63 mg/dL (1.63 mmol/L) at 8 months while taking 80 mg/d of simvastatin. A total of 343 patients (16.7%) in the placebo plus simvastatin group experienced the primary end point compared with 309 (14.4%) in the simvastatin only group (40 mg/80 mg) (hazard ratio [HR], 0.89; 95% confidence interval [CI] 0.76-1.04; P =.14). Cardiovascular death occurred in 109 (5.4%) and 83 (4.1%) patients in the 2 groups (HR, 0.75; 95% CI, 0.57-1.00; P =.05) but no differences were observed in other individual components of the primary end point. No difference was evident during the first 4 months between the groups for the primary end point (HR, 1.01; 95% CI, 0.83-1.25; P =.89), but from 4 months through the end of the study the primary end point was significantly reduced in the simvastatin only group (HR, 0.75; 95% CI, 0.60-0.95; P =.02). Myopathy (creatine kinase >10 times the upper limit of normal associated with muscle symptoms) occurred in 9 patients (0.4%) receiving simvastatin 80 mg/d, in no patients receiving lower doses of simvastatin, and in 1 patient receiving placebo (P =.02). CONCLUSIONS: The trial did not achieve the prespecified end point. However, among patients with ACS, the early initiation of an aggressive simvastatin regimen resulted in a favorable trend toward reduction of major cardiovascular events.

Sequence variation in NPC1L1 and association with improved LDL-cholesterol lowering in response to ezetimibe treatment.

Niemann-Pick C1-like 1 (NPC1L1) is an intestinal cholesterol transporter and the molecular target of ezetimibe, a cholesterol absorption inhibitor demonstrated to reduce LDL-cholesterol (LDL-C) both as monotherapy and when co-administered with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins). Interestingly, significant interindividual variability has been observed for rates of intestinal cholesterol absorption and LDL-C reductions at both baseline and post ezetimibe treatment. To test the hypothesis that genetic variation in NPC1L1 could influence the LDL-C response to ezetimibe, we performed extensive resequencing of the gene in 375 apparently healthy individuals and genotyped hypercholesterolemic patients from clinical trial cohorts. No association was observed between NPC1L1 single-nucleotide polymorphism and baseline cholesterol. However, significant associations to LDL-C response to treatment with ezetimibe were observed in patients treated with ezetimibe in two large clinical trials. Our data demonstrate that DNA sequence variants in NPC1L1 are associated with an improvement in response to ezetimibe pharmacotherapy and suggest that detailed analysis of genetic variability in clinical trial cohorts can lead to improved understanding of factors contributing to variable drug response.

Dyslipidemia in patients with type 2 diabetes. relationships between lipids, kidney disease and cardiovascular disease.

Type 2 diabetes mellitus is a leading cause of morbidity and mortality. Cardiovascular disease (CVD) is the most prevalent complication and primarily accounts for the excess morbidity and mortality in diabetic patients, but microvascular complications, such as kidney disease and retinopathy, are frequent and contribute to the total disease burden. Lipid abnormalities in patients with type 2 diabetes are a major problem and associated with the increased risk of CVD. The most common pattern of dyslipidemia in these patients consists of elevated levels of triglycerides and low levels of high-density lipoprotein cholesterol. Low-density lipoprotein levels in these patients are often similar to that of the nondiabetic population, although there may be important qualitative differences in the pattern that contribute to the increased risk of CVD. Abnormal levels of urinary albumin occur in 30-40% of patients with type 2 diabetes and the presence of kidney disease enhances the mortality from CVD. Microalbuminuria, an early marker of diabetic nephropathy, is an independent risk factor for CVD. The increased levels of urinary albumin secretion may represent a more generalized vascular damage than renal microvascular injury alone. This Review focuses on the significance of diabetic dyslipidemia and microalbuminuria to CVD risk as well as to kidney complications. We also discuss the role of aggressive therapy to ameliorate vascular injury in the diabetic patient and reduce or prevent the cardiovascular and renal consequences of the disease.

Enoxaparin versus unfractionated heparin in patients treated with tirofiban, aspirin and an early conservative initial management strategy: results from the A phase of the A-to-Z trial.

AIMS: In high risk patients with non-ST elevation acute coronary syndromes (ACS), enoxaparin is generally preferred to unfractionated heparin (UFH). However, less is known about the relative merits of these two forms of heparin in patients receiving concomitant glycoprotein IIb/IIIa inhibitors. METHODS AND RESULTS: The A phase of the A-to-Z trial was an open label non-inferiority trial in which 3987 patients with non-ST elevation ACS were randomised to receive either enoxaparin or UFH in combination with aspirin and tirofiban. Inclusion required either ST depression or cardiac biomarker elevation. While the selection of an early management strategy (invasive or conservative) was at the discretion of the local investigator, investigators were asked to designate their plans for an invasive or conservative strategy on the case record form. An early conservative strategy was specified for 1778 patients (45%); this subgroup forms the population for the present analyses. Among patients with a planned conservative strategy, baseline characteristics were similar between those randomised to UFH (n = 872) and those randomised to enoxaparin (n = 906). The primary endpoint of death, new MI, or documented refractory ischaemia within 7 days of randomisation occurred in 10.6% of patients randomised to UFH and 7.7% of patients randomised to enoxaparin (HR 0.72; 95% CI 0.53-0.99; p = 0.04). The combined rate of TIMI major, minor, or loss no-site bleeding was 1.3% in patients treated with UFH and 1.8% in those treated with enoxaparin (p = ns). CONCLUSIONS: When a conservative approach to catheterisation and PCI was planned for ACS patients receiving tirofiban and aspirin, enoxaparin was associated with superior efficacy and similar bleeding vs UFH.