Comparative Study of the Effect of Ezetimibe Versus Extended-Release Niacin on Atherosclerosis

Study Overview
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Brief Summary
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Recent evidence on the use of statin therapy indicates the potential for ultra-low levels of low-density lipoprotein (LDL-C) to provide greater protection from recurrent coronary heart disease (CHD) events. Thus, in August 2005, the guidelines for the treatment of lipid disorders (NCEP ATPIII) were revised to indicate that an LDL-C treatment goal of 70 mg/dL (revised from 100 mg/dL) was optional for patients with known CHD. In these same guidelines, low levels of high-density lipoprotein (HDL-C) are also suggested but not specifically proscribed as a target of therapy. Recently the ARBITER 2 trial has provided the first evidence of the potential of raising HDL-C with extended release niacin when added to statin monotherapy. However, whether this approach would be superior to a strategy in which lower concentrations of LDL-C are targeted is unknown. The purpose of ARBITER 6 - HALTS is to compare HDL and LDL-focused strategies of lipid treatments for their effects of atherosclerosis. This study is a prospective, randomized, open-label, blinded endpoint trial comparing treatment strategies of either HDL-raising therapies or LDL reduction for dyslipidemia on carotid atherosclerosis. Subjects with known atherosclerotic coronary or vascular disease or otherwise at high cardiovascular risk through the presence of a coronary risk equivalent who are currently being treated with a statin will be eligible. Subjects will be randomly assigned in an allocation-concealed fashion to open label treatment with either Ezetimibe 10 mg/d for additional LDL-lowering OR Extended-release niacin (1 gm/d, titrated to max tolerable dose up to 2 gm/d) for HDL improvement. The effects of these 2 different strategies of intensified lipid management on atherosclerosis will be assessed by the change in the carotid intima-media thickness, a validated surrogate endpoint. The data will help guide clinicians on the potential benefits of these lipid treatment strategies.

Official Title
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ARBITER 6: ARterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol 6 - HDL and LDL Treatment Strategies in Atherosclerosis (HALTS)

Conditions
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Atherosclerosis

Intervention / Treatment
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* Drug: extended release niacin
* Drug: ezetimibe


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male and female subjects, ≥ 30 years old with either known atherosclerotic coronary or vascular disease OR coronary risk equivalents defined as either: diabetes mellitus, multiple coronary risk factors with a Framingham Risk Score > 2% per year, or an elevated coronary calcium score (> 400 for men, > 200 for women) Currently being treated with a statin (Simvastatin 20 mg/d or its equivalent) as monotherapy for treatment of hyperlipidemia Recent lipids (within the past 3 months without interval change in the statin regimen) showing both: LDL-C < 100 mg/dL and HDL-C < 50 mg/dL (men) or < 55 mg/dL (women) Exclusion Criteria: Current use of or known intolerance to niacin or ezetimibe Known history of liver disease (cirrhosis, chronic hepatitis) or abnormal liver associated enzymes, > 3x the upper laboratory reference value Enrollment in another drug or device research protocol Females who are pregnant, expect to get pregnant during the course of the study, or are breastfeeding

Ages Eligible for Study
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Minimum Age: 30 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Extended release niacin<br> | Drug: extended release niacin<br>* Extended release niacin will be started at 1000mg and titrated to 2000mg once a day<br>Drug: ezetimibe<br>* Ezetimibe 10mg once daily<br>|
| Active Comparator: Ezetimibe<br> | Drug: ezetimibe<br>* Ezetimibe 10mg once daily<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The primary endpoint is the change in carotid intima-media thickness between groups after 14 months |  | 14 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The change in lipid values and lipid subfractions |  | 14 months | 
| A composite endpoint consisting of all major adverse cardiovascular events (coronary heart disease death, myocardial infarction, myocardial revascularization, admission to the hospital for an acute coronary syndrome) |  | 14 months | 
| Drug discontinuation due to adverse effects |  | 14 months | 
| Quality of life measured with the EQ-5D questionnaire- a generic questionnaire for describing and valuing subjects' health-related quality of life that has been studied in cardiovascular subjects |  | 14 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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niacin, carotid intima media thickness, atherosclerosis, coronary heart disease, HDL-C, LDL-C