Atherosclerosis, Carotid Artery Diseases, Coronary Artery Disease
Conditions
Keywords
Magnetic Resonance Imaging, Atherosclerotic Plaque, Lipid Lowering Therapy
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.
Interventions
DRUGAtorvastatin
10 to 80 mg of atorvastatin each day
DRUGNiacin
2000 mg of niacin each day
DRUGColesevelam
3.8 g of colesevelam each day
DRUGPlacebo Niacin
Placebo niacin each day
DRUGPlacebo Colesevelam
Placebo colesevelam each day
Sponsors
National Heart, Lung, and Blood Institute (NHLBI)
Pfizer
Abbott
Daiichi Sankyo
Upsher-Smith Laboratories
University of Washington
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
OTHER
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
21 Years to 70 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 1 - Single Therapy Group 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.
Atorvastatin: 10 to 80 mg of atorvastatin each day
Placebo Niacin: Placebo niacin each day
Placebo Colesevelam: Placebo colesevelam each day | 71 |
| 2 - Double Therapy Group Participants will receive atorvastatin, niacin, and placebo colesevelam. The treatment target for LDL-C will be ≤80 mg/dl for the double therapy group.
Atorvastatin: 10 to 80 mg of atorvastatin each day
Niacin: 2000 mg of niacin each day
Placebo Colesevelam: Placebo colesevelam each day | 73 |
| 3 - Triple Therapy Group Participants will receive atorvastatin, niacin, and colesevelam. The treatment target for LDL-C will be ≤60 mg/dl for the triple therapy group
Atorvastatin: 10 to 80 mg of atorvastatin each day
Niacin: 2000 mg of niacin each day
Colesevelam: 3.8 g of colesevelam each day | 73 |
| Total | 217 |
Baseline characteristics
| Characteristic | 3 - Triple Therapy Group | Total | 1 - Single Therapy Group | 2 - Double Therapy Group |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 13 Participants | 35 Participants | 11 Participants | 11 Participants |
| Age, Categorical Between 18 and 65 years | 60 Participants | 182 Participants | 60 Participants | 62 Participants |
| Current smoking, n (%) | 15 Participants | 45 Participants | 13 Participants | 17 Participants |
| Diabetes, n (%) | 9 Participants | 32 Participants | 10 Participants | 13 Participants |
| Established coronary artery disease, n (%) | 67 Participants | 189 Participants | 62 Participants | 60 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 10 Participants | 31 Participants | 9 Participants | 12 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 63 Participants | 186 Participants | 62 Participants | 61 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Family history of premature cardiovascular disease, n (%) | 36 Participants | 106 Participants | 34 Participants | 36 Participants |
| History of myocardial infarction, n (%) | 31 Participants | 82 Participants | 25 Participants | 26 Participants |
| Hypertension, n (%) | 44 Participants | 130 Participants | 42 Participants | 44 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 5 Participants | 11 Participants | 3 Participants | 3 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 5 Participants | 0 Participants | 3 Participants |
| Race (NIH/OMB) More than one race | 2 Participants | 6 Participants | 3 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 64 Participants | 194 Participants | 65 Participants | 65 Participants |
| Region of Enrollment United States | 73 participants | 217 participants | 71 participants | 73 participants |
| Sex: Female, Male Female | 30 Participants | 88 Participants | 28 Participants | 30 Participants |
| Sex: Female, Male Male | 43 Participants | 129 Participants | 43 Participants | 43 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 7 / 71 | 7 / 73 | 3 / 73 |
| other Total, other adverse events | 34 / 71 | 40 / 73 | 32 / 73 |
| serious Total, serious adverse events | 26 / 71 | 20 / 73 | 20 / 73 |
Outcome results
Primary
Annualized LRNC and Wall Volume Changes in Carotid Plaque Composition, as Assessed by MRI
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.
Time frame: Measured at Years 1, 2, and 3
Population: Analysis group was limited from total study population due to the need for detectable lipid-rich necrotic core (LRNC) measurement at study baseline.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| 1 - Single Therapy Group | Annualized LRNC and Wall Volume Changes in Carotid Plaque Composition, as Assessed by MRI | LRNC change | -1.6 percentage change/year | Standard Error 1.1 |
| 1 - Single Therapy Group | Annualized LRNC and Wall Volume Changes in Carotid Plaque Composition, as Assessed by MRI | Wall Volume change | -0.6 percentage change/year | Standard Error 0.5 |
| 2 - Double Therapy Group | Annualized LRNC and Wall Volume Changes in Carotid Plaque Composition, as Assessed by MRI | LRNC change | -3.6 percentage change/year | Standard Error 0.8 |
| 2 - Double Therapy Group | Annualized LRNC and Wall Volume Changes in Carotid Plaque Composition, as Assessed by MRI | Wall Volume change | -1.4 percentage change/year | Standard Error 0.4 |
| 3 - Triple Therapy Group | Annualized LRNC and Wall Volume Changes in Carotid Plaque Composition, as Assessed by MRI | LRNC change | -2.8 percentage change/year | Standard Error 0.7 |
| 3 - Triple Therapy Group | Annualized LRNC and Wall Volume Changes in Carotid Plaque Composition, as Assessed by MRI | Wall Volume change | -1.2 percentage change/year | Standard Error 0.5 |
Primary
Annualized LRNC Volume Change in Carotid Plaque Composition, as Assessed by MRI
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.
Time frame: Measured at Years 1, 2, and 3
Population: Analysis group was limited from total study population due to the need for detectable lipid-rich necrotic core (LRNC) measurement at study baseline.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 1 - Single Therapy Group | Annualized LRNC Volume Change in Carotid Plaque Composition, as Assessed by MRI | -4.6 mm^3/year | Standard Error 5 |
| 2 - Double Therapy Group | Annualized LRNC Volume Change in Carotid Plaque Composition, as Assessed by MRI | -15.1 mm^3/year | Standard Error 3.2 |
| 3 - Triple Therapy Group | Annualized LRNC Volume Change in Carotid Plaque Composition, as Assessed by MRI | -9.4 mm^3/year | Standard Error 3 |
Secondary
Composite of Cardiovascular Endpoints: Number of Participants With Cardiovascular Disease Death, Non-fatal Heart Attack, Stroke, and Worsening Ischemia Requiring Medical Interventions
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.
Time frame: Measured at Years 3, 4, and 5
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| 1 - Single Therapy Group | Composite of Cardiovascular Endpoints: Number of Participants With Cardiovascular Disease Death, Non-fatal Heart Attack, Stroke, and Worsening Ischemia Requiring Medical Interventions | Composite Measured at Year 4 (cumulative) | 7 Participants |
| 1 - Single Therapy Group | Composite of Cardiovascular Endpoints: Number of Participants With Cardiovascular Disease Death, Non-fatal Heart Attack, Stroke, and Worsening Ischemia Requiring Medical Interventions | Composite Measured at Year 3 | 6 Participants |
| 1 - Single Therapy Group | Composite of Cardiovascular Endpoints: Number of Participants With Cardiovascular Disease Death, Non-fatal Heart Attack, Stroke, and Worsening Ischemia Requiring Medical Interventions | Composite Measured at Year 5 (cumulative) | 9 Participants |
| 2 - Double Therapy Group | Composite of Cardiovascular Endpoints: Number of Participants With Cardiovascular Disease Death, Non-fatal Heart Attack, Stroke, and Worsening Ischemia Requiring Medical Interventions | Composite Measured at Year 4 (cumulative) | 11 Participants |
| 2 - Double Therapy Group | Composite of Cardiovascular Endpoints: Number of Participants With Cardiovascular Disease Death, Non-fatal Heart Attack, Stroke, and Worsening Ischemia Requiring Medical Interventions | Composite Measured at Year 3 | 6 Participants |
| 2 - Double Therapy Group | Composite of Cardiovascular Endpoints: Number of Participants With Cardiovascular Disease Death, Non-fatal Heart Attack, Stroke, and Worsening Ischemia Requiring Medical Interventions | Composite Measured at Year 5 (cumulative) | 11 Participants |
| 3 - Triple Therapy Group | Composite of Cardiovascular Endpoints: Number of Participants With Cardiovascular Disease Death, Non-fatal Heart Attack, Stroke, and Worsening Ischemia Requiring Medical Interventions | Composite Measured at Year 3 | 7 Participants |
| 3 - Triple Therapy Group | Composite of Cardiovascular Endpoints: Number of Participants With Cardiovascular Disease Death, Non-fatal Heart Attack, Stroke, and Worsening Ischemia Requiring Medical Interventions | Composite Measured at Year 5 (cumulative) | 9 Participants |
| 3 - Triple Therapy Group | Composite of Cardiovascular Endpoints: Number of Participants With Cardiovascular Disease Death, Non-fatal Heart Attack, Stroke, and Worsening Ischemia Requiring Medical Interventions | Composite Measured at Year 4 (cumulative) | 9 Participants |