Clinical trial NCT00397657: Comparative Study of the Effect of Ezetimibe Versus Extended-Release Niacin on Atherosclerosis
Official title: ARBITER 6: ARterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol 6 - HDL and LDL Treatment Strategies in Atherosclerosis (HALTS)
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE4
Conditions: Atherosclerosis
Keywords: carotid intima media thickness
atherosclerosis
niacin
coronary heart disease
HDL-C
LDL-C
Lead sponsor: Walter Reed Army Medical Center
Sponsor class: FED
Collaborators: name: Abbott
First posted: 2006-11-09
Enrollment: 400
Sex: ALL
Minimum age (years): 30
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.


Eligibility criteria: 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

Primary outcomes:
measure: The primary endpoint is the change in carotid intima-media thickness between groups after 14 months
timeFrame: 14 months
Secondary outcomes:
measure: The change in lipid values and lipid subfractions
timeFrame: 14 months
measure: 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)
timeFrame: 14 months
measure: Drug discontinuation due to adverse effects
timeFrame: 14 months
measure: 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
timeFrame: 14 months
Other outcomes:
Locations:
city: Washington
country: United States
facility: Walter Reed Army Medical Center
state: District of Columbia
city: Takoma Park
country: United States
facility: Washington Adventist Hospital
state: Maryland
Study officials:
affiliation: Medstar Research Institute and Washington Hospital Center, Washington DC.
name: Allen J Taylor, MD
role: PRINCIPAL_INVESTIGATOR
References:
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citation: Taylor AJ, Lee HJ, Sullenberger LE. The effect of 24 months of combination statin and extended-release niacin on carotid intima-media thickness: ARBITER 3. Curr Med Res Opin. 2006 Nov;22(11):2243-50. doi: 10.1185/030079906x148508.
citation: Taylor AJ, Villines TC, Stanek EJ. Paradoxical progression of atherosclerosis related to low-density lipoprotein reduction and exposure to ezetimibe. Eur Heart J. 2012 Dec;33(23):2939-45. doi: 10.1093/eurheartj/ehs105. Epub 2012 May 7.
citation: Villines TC, Stanek EJ, Devine PJ, Turco M, Miller M, Weissman NJ, Griffen L, Taylor AJ. The ARBITER 6-HALTS Trial (Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol 6-HDL and LDL Treatment Strategies in Atherosclerosis): final results and the impact of medication adherence, dose, and treatment duration. J Am Coll Cardiol. 2010 Jun 15;55(24):2721-6. doi: 10.1016/j.jacc.2010.03.017.
citation: Taylor AJ, Villines TC, Stanek EJ, Devine PJ, Griffen L, Miller M, Weissman NJ, Turco M. Extended-release niacin or ezetimibe and carotid intima-media thickness. N Engl J Med. 2009 Nov 26;361(22):2113-22. doi: 10.1056/NEJMoa0907569. Epub 2009 Nov 15.