Evaluation of a novel antiplatelet agent for secondary prevention in patients with a history of atherosclerotic disease: design and rationale for the Thrombin-Receptor Antagonist in Secondary Prevention of Atherothrombotic Ischemic Events (TRA 2 degrees P)-TIMI 50 trial.

Background: Thrombin potently activates platelets via interaction with the protease-activated receptor 1. SCH 530348 is a novel antiplatelet agent that selectively inhibits the cellular actions of thrombin via antagonism of the protease-activated receptor 1. Because SCH 530348 does not interfere with other pathways for hemostasis, it is possible that SCH 530348 reduces thrombosis with less increase in bleeding than do other potent antiplatelet agents.

Early versus delayed, provisional eptifibatide in acute coronary syndromes.

Background: Glycoprotein IIb/IIIa inhibitors are indicated in patients with acute coronary syndromes who are undergoing an invasive procedure. The optimal timing of the initiation of such therapy is unknown.

Methods: We compared a strategy of early, routine administration of eptifibatide with delayed, provisional administration in 9492 patients who had acute coronary syndromes without ST-segment elevation and who were assigned to an invasive strategy.

Safety and tolerability of SCH 530348 in patients undergoing non-urgent percutaneous coronary intervention: a randomised, double-blind, placebo-controlled phase II study.

Background: An antithrombotic drug is needed that safely reduces cardiovascular events in patients undergoing percutaneous coronary intervention (PCI). We therefore assessed the tolerability and safety of SCH 530348-an oral platelet protease-activated receptor-1 antagonist.

Methods: We randomly assigned patients aged 45 years or older and undergoing non-urgent PCI or coronary angiography with planned PCI to an oral loading dose of SCH 530348 (10 mg, 20 mg, or 40 mg) or matching placebo in a 3:1 ratio in a multicentre international study.

Tolerability and effects on lipids of ezetimibe coadministered with pravastatin or simvastatin for twelve months: results from two open-label extension studies in hypercholesterolemic patients.

Objective: The aim of these studies was to assess the long-term tolerability and effects on lipids of ezetimibe coadministered with pravastatin or simvastatin during treatment of hypercholesterolemic patients.

Methods: Two separate 12-month, open-label extension studies enrolled patients who had successfully completed one of three 12-week, double-blind, placebo-controlled trials of ezetimibe coadministered with pravastatin, lovastatin, or simvastatin. In the extensions, the initial dose of each drug administered was 10 mg/d, with the option to up-titrate the statins if low-density lipoprotein cholesterol (LDL-C) goals were not met.

Pooled analyses of effects on C-reactive protein and low density lipoprotein cholesterol in placebo-controlled trials of ezetimibe monotherapy or ezetimibe added to baseline statin therapy.

Inflammation is associated with coronary artery disease (CAD), and statins reduce the inflammatory marker C-reactive protein (CRP). The effects of ezetimibe, alone or in combination with statins, on CRP and low-density lipoprotein (LDL) cholesterol were examined in 2 pooled analyses of randomized, placebo-controlled trials of ezetimibe 10 mg/day in patients with hypercholesterolemia: 6 12-week trials as monotherapy (n = 1,372) and 7 6- to 8-week trials as add-on to baseline statin therapy (n = 3,899). Mean percentage changes from baseline in CRP and LDL cholesterol were examined using analysis of variance in patients with CRP < or =10 mg/L.

Rationale and design of IMPROVE-IT (IMProved Reduction of Outcomes: Vytorin Efficacy International Trial): comparison of ezetimbe/simvastatin versus simvastatin monotherapy on cardiovascular outcomes in patients with acute coronary syndromes.

Background: Reduction in low-density lipoprotein cholesterol (LDL-C) improves clinical outcomes in patients with chronic coronary artery disease and acute coronary syndromes (ACSs). The combination of ezetimibe/simvastatin produces greater reductions in LDL-C compared to simvastatin monotherapy. The IMProved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT) is a multicenter, randomized, double-blind, active-control trial designed to test the hypothesis that the addition of ezetimibe to statin therapy, using ezetimibe/simvastatin, will translate into increased clinical benefit on cardiovascular outcomes relative to simvastatin monotherapy in patients with ACS.

Efficacy and safety of coadministration of ezetimibe and simvastatin in adolescents with heterozygous familial hypercholesterolemia.

Objectives: The study evaluated the efficacy and safety of long-term coadministration of ezetimibe and simvastatin in adolescents with heterozygous familial hypercholesterolemia (HeFH).

Background: Aggressive intervention to achieve lipid goals for adolescents with HeFH is recommended to reduce risk of premature cardiovascular disease.

Methods: In a multicenter, randomized, double-blind, placebo-controlled study, 248 male and female subjects ages >or=10 and View Article and Find Full Text PDF

Long-term safety and tolerability of ezetimibe coadministered with simvastatin in hypercholesterolemic patients: a randomized, 12-month double-blind extension study.

Objectives: To assess the long-term safety and tolerability and to further evaluate the effect of ezetimibe plus simvastatin on LDL-C, HDL-C, and triglyceride levels in subjects with primary hypercholesterolemia.

Methods: This was a 12-month, double-blind, placebo-controlled extension study that enrolled patients with primary hypercholesterolemia who had successfully completed the 12-week, double-blind, placebo-controlled trial of ezetimibe coadministered with simvastatin. The initial dose administered to patients in the extension was ezetimibe 10 mg coadministered with simvastatin 10 mg with the option to up-titrate statin dosage if LDL-C goals were not met.

Simvastatin with or without ezetimibe in familial hypercholesterolemia.

Background: Ezetimibe, a cholesterol-absorption inhibitor, reduces levels of low-density lipoprotein (LDL) cholesterol when added to statin treatment. However, the effect of ezetimibe on the progression of atherosclerosis remains unknown.

Methods: We conducted a double-blind, randomized, 24-month trial comparing the effects of daily therapy with 80 mg of simvastatin either with placebo or with 10 mg of ezetimibe in 720 patients with familial hypercholesterolemia.

Efficacy and safety of ezetimibe/simvastatin versus simvastatin monotherapy in hypercholesterolemic patients with metabolic syndrome.

Background: The combination of ezetimibe and simvastatin (EZE/SIMVA) inhibits intestinal absorption and hepatic synthesis of cholesterol, providing significantly greater LDL-C-lowering compared to either drug alone. We examined the efficacy and safety of EZE/SIMVAin hypercholesterolemic patients with metabolic syndrome (MetS).

Methods: We evaluated pooled data from three similarly designed, randomized, doubleblinded, placebo-controlled studies in patients with primary hypercholesterolemia.

Effects of ezetimibe, simvastatin, atorvastatin, and ezetimibe-statin therapies on non-cholesterol sterols in patients with primary hypercholesterolemia.

Background: Levels of cholesterol are regulated by its synthesis, absorption, and elimination. Plasma levels of phytosterols (e.g.

Zetia: inhibition of Niemann-Pick C1 Like 1 (NPC1L1) to reduce intestinal cholesterol absorption and treat hyperlipidemia.

Zetia (ezetimibe) is a selective cholesterol absorption inhibitor, which potently inhibits the absorption of biliary and dietary cholesterol from the small intestine without affecting the absorption of fat-soluble vitamins, triglycerides or bile acids. Ezetimibe reduces the small intestinal enterocyte uptake and absorption of cholesterol by binding to Niemann-Pick C1 Like 1 (NPC1L1), which keeps cholesterol in the intestinal lumen for excretion. Ezetimibe undergoes glucuronidation to a single metabolite and localizes at the intestinal wall, where it binds with higher affinity for NPC1L1 than ezetimibe to prevent cholesterol absorption.

Comparison of effects of ezetimibe/simvastatin versus simvastatin versus atorvastatin in reducing C-reactive protein and low-density lipoprotein cholesterol levels.

The lowering effects of ezetimibe/simvastatin combination therapy on low-density lipoprotein (LDL) cholesterol and high-sensitivity C-reactive protein (CRP) were compared with those of simvastatin or atorvastatin monotherapy in a large cohort of patients with primary hypercholesterolemia. To compare ezetimibe/simvastatin with simvastatin, data were combined from 3 identical, prospective 12-week trials in which patients were randomized to receive placebo; ezetimibe 10 mg; ezetimibe 10 mg added to simvastatin 10, 20, 40, or 80 mg; or simvastatin 10, 20, 40, or 80 mg. To compare ezetimibe/simvastatin with atorvastatin, data were analyzed from a phase III double-blind, active-controlled study in which patients were randomized equally to receive ezetimibe/simvastatin 10/10, 10/20, 10/40, or 10/80 mg or atorvastatin 10, 20, 40, or 80 mg for 6 weeks.

Comparison of the lipid-modifying efficacy and safety profiles of ezetimibe coadministered with simvastatin in older versus younger patients with primary hypercholesterolemia: a post Hoc analysis of subpopulations from three pooled clinical trials.

Background: Despite the need for effective and well-tolerated lipid-lowering therapies for primary hypercholesterolemia in older patients, there is a relative paucity of published data on such treatments in this population.

Objective: We conducted a post hoc analysis to examine the lipid-modifying efficacy and safety profile of simvastatin (SIMVA) monotherapy, and the coadministration of ezetimibe (EZE) and SIMVA (EZE/SIMVA) in older (ie, aged>or=65 years) versus younger (ie, aged<65 years) patients with primary hypercholesterolemia.

Methods: We analyzed pooled data from 3 previously published, similarly designed, randomized, double-blind, placebo-controlled studies in patients with primary hypercholesterolemia.

Efficacy and safety of coadministration of ezetimibe and simvastatin in African-American patients with primary hypercholesterolemia.

The purpose of this study was to examine the efficacy and safety of ezetimibe (EZE) coadministered with simvastatin (SIMVA) in a large cohort of African Americans with primary hypercholesterolemia. In a multicenter, randomized, double-blind study, patients were considered eligible for enrollment if after a washout/placebo run-in period, low-density-lipoprotein (LDL) cholesterol level was > or = 145 and < or = 250 mg/dl and triglyceride level was < or = 350 mg/dl. Eligible patients were randomized to SIMVA 20 mg coadministered with either EZE 10 mg (n = 124) or placebo (n = 123) for 12 weeks.

Consistency of lipid-altering effects of ezetimibe/simvastatin across gender, race, age, baseline low density lipoprotein cholesterol levels, and coronary heart disease status: results of a pooled retrospective analysis.

Background: The combination tablet containing ezetimibe and simvastatin (EZE/SIMVA), inhibits both the intestinal absorption and endogenous production of cholesterol, providing significantly greater low-density lipoprotein cholesterol (LDL-C) lowering than EZE or SIMVA alone. The purpose of this pooled analysis was to evaluate the consistency of efficacy (i.e.

Comparison of ezetimibe plus simvastatin versus simvastatin monotherapy on atherosclerosis progression in familial hypercholesterolemia. Design and rationale of the Ezetimibe and Simvastatin in Hypercholesterolemia Enhances Atherosclerosis Regression (ENHANCE) trial.

Background: Lipid lowering through statin therapy significantly reduces the risk of cardiovascular events. The ENHANCE study is an international 2-year, randomized, double-blind, controlled trial designed to test the hypothesis that treatment of hypercholesterolemia by use of 2 complementary agents, ezetimibe (a specific cholesterol absorption inhibitor) and simvastatin (a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor), will result in larger beneficial effects on carotid artery intima-media thickness (CA IMT) than simvastatin monotherapy.

Methods: The study will recruit 725 men and women with heterozygous familial hypercholesterolemia.

Projected coronary heart disease risk benefit with ezetimibe.

Low density lipoprotein (LDL) cholesterol and total cholesterol (TC) are the primary clinical parameters of interest for any cholesterol intervention. Clinicians are interested in how the reduction of these lipid parameters as well as increases in high density lipoprotein (HDL) relate to changes in coronary heart disease (CHD) risk. The objective of this analysis was to estimate the additional CHD risk reduction that could potentially be provided by co-administration of ezetimibe with statin therapy.

Effects of ezetimibe coadministered with simvastatin on C-reactive protein in a large cohort of hypercholesterolemic patients.

Objective: This study assessed the effect of coadministration of ezetimibe and simvastatin on high sensitivity C-reactive protein (hs-CRP) in a large subject cohort (N=1089).

Methods: Data were combined from two nearly identical prospective trials. After dietary stabilization, washout period, and placebo lead-in period, patients with baseline low-density lipoprotein cholesterol (LDL-C) > or =3.

Cost-effectiveness of ezetimibe coadministration in statin-treated patients not at cholesterol goal: application to Germany, Spain and Norway.

Background: Despite the growing use of statins, many hypercholesterolaemic patients fail to reach their lipid goal and remain at elevated risk of coronary heart disease (CHD). Alternative treatment strategies, such as ezetimibe coadministration and statin titration, can help patients achieve greater lipid control, and thereby lower their CHD risk. But is it cost effective to more aggressively lower cholesterol levels across a broad range of current statin users?

Methods: Using a decision-analytic model based on epidemiological and clinical trials data, we project the lifetime benefit and cost of alternative lipid-lowering treatment strategies for CHD and non-CHD diabetic patients in Germany, Spain and Norway.

Consistency in efficacy and safety of ezetimibe coadministered with statins for treatment of hypercholesterolemia in women and men.

Background: Women are often not treated as aggressively as men to control levels of low-density lipoprotein cholesterol (LDL-C), despite evidence that women and men realize comparable cardiovascular benefit from lipid-lowering therapy. Statins are the most effective drugs currently available for treating hypercholesterolemia. Despite the impressive cholesterol-lowering capacity of statins, however, many patients on statin therapy fail to reach established target levels of LDL-C.

Efficacy and safety of coadministration of ezetimibe and statins in elderly patients with primary hypercholesterolaemia.

Objective: To compare the efficacy and safety of statin (HMG-CoA reductase inhibitor) monotherapy versus ezetimibe 10mg plus statin in older and younger adults with primary hypercholesterolaemia.

Patients And Methods: Four multicentre, randomised, double-blind, placebo-controlled, balanced parallel-group trials were pooled for analysis. After washout and placebo run-in period, men and women >/=18 years of age (n = 1861) with primary hypercholesterolaemia (plasma low-density lipoprotein-cholesterol [LDL-C] level from >/=3.

Achieving lipoprotein goals in patients at high risk with severe hypercholesterolemia: efficacy and safety of ezetimibe co-administered with atorvastatin.

Background: Despite the efficacy of statins in lowering low-density lipoprotein cholesterol (LDL-C) levels, many patients who are at high risk for heart disease with hypercholesterolemia require additional LDL-C level reduction. The cholesterol absorption inhibitor, ezetimibe, has been shown to provide significant incremental reductions in LDL-C levels when co-administered with statins. This study was performed to compare the efficacy and safety of ezetimibe (10 mg) plus response-based atorvastatin titration versus response-based atorvastatin titration alone in the attainment of LDL-C goals in subjects who are at high risk for coronary heart disease (CHD) and are not at their LDL-C goal on the starting dose of atorvastatin.

Pharmacodynamic and pharmacokinetic interaction between fenofibrate and ezetimibe.

Objective: The cholesterol absorption inhibitor, ezetimibe, significantly decreases low-density lipoprotein-cholesterol (LDL-C) levels in patients with primary hypercholesterolemia. The pharmacodynamic, pharmacokinetic, and safety profiles of ezetimibe and fenofibrate were evaluated alone and after co-administration in 32 subjects with primary hypercholesterolemia.

Research Design And Methods: This was a randomized, evaluator (single)-blind, placebo-controlled, parallel-group study.