Evaluate Carotid Artery Plaque Composition by Magnetic Resonance Imaging in People Receiving Cholesterol Medication

Phase 4

Completed

• Conditions: Coronary Artery Disease; Carotid Artery Diseases; Atherosclerosis
• Interventions: Drug: Atorvastatin; Drug: Placebo Niacin; Drug: Niacin; Drug: Placebo Colesevelam; Drug: Colesevelam

• Registration Number: NCT00715273
• Lead Sponsor: University of Washington

Brief Summary

Atherosclerosis is a condition that occurs when fatty deposits build up along the inner walls of arteries. This study will examine the effectiveness of a combination of cholesterol-lowering medications at decreasing the fat content of atherosclerotic deposits in people who have coronary artery disease or carotid artery disease.

Detailed Description

Atherosclerosis is a condition in which deposits of fat, cholesterol, and other substances build up along the inner walls of arteries; these deposits are known as plaque. People with atherosclerosis are at risk of developing coronary artery disease, in which plaque build-up occurs in the arteries that supply blood to the heart, and carotid artery disease, in which plaque build-up occurs in the arteries that deliver blood through the neck to the brain. These conditions can lead to blood clots, heart attack, and stroke. Research has shown that people who have more fat content in atherosclerotic plaque may have a higher risk of experiencing a heart attack or stroke. Treatments for atherosclerosis include lifestyle changes, medicines, and medical procedures or surgery. There are several medications that can aid people in controlling their cholesterol levels, including atorvastatin, a medication that inhibits the production of cholesterol; niacin, a B-complex vitamin that can reduce cholesterol levels in combination with dietary changes; and colesevelam, a medication that inhibits fat absorption. Using magnetic resonance imaging (MRI), this study will evaluate whether these medications, alone or in combination, can decrease the fat content of atherosclerotic plaques within the carotid arteries of people with coronary artery disease and carotid artery disease.

This study will enroll people with coronary artery disease or carotid artery disease. Participants will be randomly assigned to one of the following 40-month treatment groups:

* Group 1 participants will receive atorvastatin, placebo niacin, and placebo colesevelam each day.

* Group 2 participants will receive atorvastatin, niacin, and placebo colesevelam each day.

* Group 3 participants will receive atorvastatin, niacin, and colesevelam each day.

At a baseline study visit, participants will undergo a blood collection and will receive dietary counseling that will focus on lowering cholesterol levels. They will also undergo an MRI scan of their carotid arteries. For the next 4 months, participants will attend monthly study visits for repeat blood collection and dietary counseling; for the subsequent 36 months, participants will attend study visits every other month. Repeat carotid artery MRI scans will occur at Months 12, 24, and 36. At three different times during the study, researchers will ask participants to record their food consumption for 3 consecutive days.

Study Timeline

• Study Start: 2001-05-01
• Study First Submitted: 2008-07-11
• Study First Submitted QC: 2008-07-11
• Study First Posted: 2008-07-15
• Primary Completion: 2018-12-12
• Study Completion: 2019-03-01
• Results First Submitted: 2021-12-08
• Status Verified: 2022-05
• Results First Submitted QC: 2022-05-16
• Last Update Submitted: 2022-05-16
• Results First Posted: 2022-06-07
• Last Update Posted: 2022-06-07

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 217

Inclusion Criteria

• Clinically established coronary artery disease or carotid artery disease with greater than 15% stenosis by ultrasound
• Family history of cardiovascular disease
• Apolipoprotein B level greater than or equal to 120 mg/dL (LDL level should be between 100 and 190 mg/dL without medication)
• Has been undergoing lipid therapy for no more than 12 months before study entry
• Medically stable
• Medically able to undergo MRI procedure

Exclusion Criteria

• Uses pacemaker or has metallic implants
• Has immediate plans for carotid endarterectomy
• History of alcohol or drug abuse
• Active liver disease or liver dysfunction, defined by elevations in alanine aminotransferase (ALT)/aspartate aminotransferase (AST) levels greater than 1.5 times the upper limit of normal
• Serum creatine kinase (CK) level greater than 3 times the upper limit of normal before study entry
• Serum creatinine level greater than 2.5 times the upper limit of normal
• Diabetes, with a fasting glucose level greater than 150 mg/dL or hemoglobin A1c (HbA1c) level greater than 8% before study entry
• Uncontrolled high blood pressure, defined as average resting systolic blood pressure greater than 200 mm Hg or average resting diastolic blood pressure greater than 95 mm Hg

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
1 - single therapy group	Placebo Niacin	Participants will receive atorvastatin, placebo niacin, and placebo colesevelam. The treatment target for LDL-C will be ≤80 mg/dl for the single therapy group.
1 - single therapy group	Placebo Colesevelam	Participants will receive atorvastatin, placebo niacin, and placebo colesevelam. The treatment target for LDL-C will be ≤80 mg/dl for the single therapy group.
2 - double therapy group	Placebo Colesevelam	Participants will receive atorvastatin, niacin, and placebo colesevelam. The treatment target for LDL-C will be ≤80 mg/dl for the double therapy group.
3 - triple therapy group	Niacin	Participants will receive atorvastatin, niacin, and colesevelam. The treatment target for LDL-C will be ≤60 mg/dl for the triple therapy group
3 - triple therapy group	Colesevelam	Participants will receive atorvastatin, niacin, and colesevelam. The treatment target for LDL-C will be ≤60 mg/dl for the triple therapy group
1 - single therapy group	Atorvastatin	Participants will receive atorvastatin, placebo niacin, and placebo colesevelam. The treatment target for LDL-C will be ≤80 mg/dl for the single therapy group.
2 - double therapy group	Atorvastatin	Participants will receive atorvastatin, niacin, and placebo colesevelam. The treatment target for LDL-C will be ≤80 mg/dl for the double therapy group.
2 - double therapy group	Niacin	Participants will receive atorvastatin, niacin, and placebo colesevelam. The treatment target for LDL-C will be ≤80 mg/dl for the double therapy group.
3 - triple therapy group	Atorvastatin	Participants will receive atorvastatin, niacin, and colesevelam. The treatment target for LDL-C will be ≤60 mg/dl for the triple therapy group

Primary Outcome Measures

Name	Time	Method
Annualized LRNC Volume Change in Carotid Plaque Composition, as Assessed by MRI	Measured at Years 1, 2, and 3	The primary endpoint of this study is carotid plaque lipid composition identified by MRI. The determination of plaque lipid content for each carotid artery will be performed using the automated interactive system. These measurements will be performed from the MRI scans at four time points blinded to time sequence of MRI examinations, patient treatment, lipid levels and clinical course.; Volume Measurements: Contours were placed around the lumen, outer-wall boundaries, and plaque features of carotid artery. (Arterial wall area) = (outer-wall area) - (lumen area). Volume calculated as: area x 2 mm (slice thickness). Tissue volume/wall volume x (100%) is presented as percentage. Annualized change presented mm\^3/year (for volume) and as percentage change/year.
Annualized LRNC and Wall Volume Changes in Carotid Plaque Composition, as Assessed by MRI	Measured at Years 1, 2, and 3	The primary endpoint of this study is carotid plaque lipid composition identified by MRI. The determination of plaque lipid content for each carotid artery will be performed using the automated interactive system. These measurements will be performed from the MRI scans at four time points blinded to time sequence of MRI examinations, patient treatment, lipid levels and clinical course.; Volume Measurements: Contours were placed around the lumen, outer-wall boundaries, and plaque features of carotid artery. (Arterial wall area) = (outer-wall area) - (lumen area). Volume calculated as: area x 2 mm (slice thickness). Tissue volume/wall volume x (100%) is presented as percentage. Annualized change presented mm\^3/year (for volume) and as percentage change/year.

Secondary Outcome Measures

Name	Time	Method
Composite of Cardiovascular Endpoints: Number of Participants With Cardiovascular Disease Death, Non-fatal Heart Attack, Stroke, and Worsening Ischemia Requiring Medical Interventions	Measured at Years 3, 4, and 5	Any cardiovascular events such as death from any cause, nonfatal myocardial infarction, stroke, and revascularization procedures (PCI or CABG) due to unstable ischemia will be recorded and verified.

Trial Locations

Locations (4)

University of Washington Coronary Atherosclerosis Research Lab; 🇺🇸 Seattle, Washington, United States

St. Luke's Idaho Cardiology; 🇺🇸 Boise, Idaho, United States

Yakima Heart Center; 🇺🇸 Yakima, Washington, United States

University of Southern California; 🇺🇸 Los Angeles, California, United States