Carotid Plaque Characteristics by MRI in AIM-HIGH (Carotid MRI Substudy)

Carotid Plaque Characteristics by MRI in AIM-HIGH

Heart attacks and strokes caused by the unstable atherosclerotic plaques remain the leading cause of death in the United States. Unstable plaques often have more fat than stable plaques. This study will investigate if a treatment with LDL-lowering plus HDL-raising compared with LDL-lowering alone would more effectively reduce the plaque fat content assessed by magnetic resonance imaging (MRI), therefore, further reducing heart attacks and strokes.

Study Overview

• Status: Completed
• Conditions: Coronary Artery Disease; Atherosclerosis; Carotid Artery Diseases
• Intervention / Treatment: Drug: Simvastatin, simvastatin plus extended-release niacin

Detailed Description

Although studies have suggested that plaque morphology and composition are important determinants of plaque stability, our understanding on plaque tissue components is mainly from histological studies until recent development in MRI technique. A low level of HDL is associated with higher risk of cardiovascular events and increased amount of lipid content in the carotid plaques. Treatment with LDL-lowering plus HDL-raising compared with LDL-lowering alone more effectively protects against atherosclerosis progression. It is widely believed that HDL or its apolipoproteins mediate the removal of excess free cholesterol from peripheral cells and the cholesterol is delivered via either LDL or HDL to the liver for excretion into the bile. However, it has not been tested and approved in human atherosclerotic condition in vivo. The NIH/Abbott-funded multi-center AIM-HIGH trial is designed to compare the clinical efficacy of LDL-lowering alone with statin versus LDL-lowering plus HDL-raising with statin plus nicotinic acid combination therapy in patients with established vascular disease and high triglycerides and low HDL.

We propose to conduct a carotid MRI sub-study in 220 subjects enrolled in AIM-HIGH to investigate the important vascular biological mechanisms of HDL-raising therapy. Image collection will occur at 3 timepoints. The hypotheses and specific aims are:

• (1) To test the primary hypothesis that compared with LDL-lowering alone, intensive LDL-lowering plus HDL-raising therapy decreases the mean plaque lipid composition in carotid arteries assessed by MRI.
• (2) To test the hypothesis that compared with LDL-lowering alone, intensive LDL-lowering plus HDL-raising therapy decreases the plaque burden including volume and wall thickness.
• (3) To test the hypothesis that increased plaque lipid composition or vessel wall thickness by MRI is associated with increased risk of cardiovascular events.
• (4)To test a hypothesis that LDL-lowering plus HDL-raising, compared to LDL-lowering alone, will promote more rapid plaque lipid depletion. And determine the time-course of atherosclerotic plaque lipid depletion during lipid therapy.
• (5) To examine the association of clinical risk factors, lipids, lipoprotein heterogeneity, inflammatory markers and carotid plaque characteristics.

This MRI sub-study offers a unique opportunity to investigate the effectiveness of LDL-lowering plus HDL-raising therapy on human atherosclerotic plaque in vivo, to examine the association of plaque characteristics both lipid composition and volume assessed by MRI and cardiovascular outcome, and to gain novel insights in our understanding of atherosclerotic plaque pathology and the mechanisms of intensive lipid management in preventing cardiovascular events.

• Study Type: Observational
• Enrollment (Actual): 230

Contacts and Locations

Study Locations

• Canada
  • Alberta
    • Calgary, Alberta, Canada, T2E-7C5
      • Heart Health Institute
    • Calgary, Alberta, Canada, T2N-2T9
      • University of Calgary
  • British Columbia
    • Vancouver, British Columbia, Canada, V5Z-1M9
      • Vancouver General Hospital
  • Ontario
    • London, Ontario, Canada, N6A-5A5
      • University of Western Ontario
• United States
  • Arizona
    • Phoenix, Arizona, United States, 85032
      • Cardiovascular Consultants
  • California
    • Long Beach, California, United States, 90822
      • Long Beach VA Medical Center
    • Los Angeles, California, United States, 90033
      • University of Southern California
  • Maryland
    • Baltimore, Maryland, United States, 21201
      • University of Maryland
    • Baltimore, Maryland, United States, 21205
      • Johns Hopkins University
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Duke University
    • Winston-Salem, North Carolina, United States, 27157
      • Wake Forest University
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Philadelphia VA Medical Center
  • Texas
    • Houston, Texas, United States, 77030
      • Baylor College of Medicine
    • Houston, Texas, United States, 77030
      • Methodist Hospital
    • Houston, Texas, United States, 77030
      • Kelsey Research Foundation
  • Washington
    • Seattle, Washington, United States, 98104
      • Harborview Medical Center
    • Seattle, Washington, United States, 98105
      • University of Washington
    • Seattle, Washington, United States, 98108
      • Puget Sound VA Medical Center, Seattle Campus

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 45 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Probability Sample

Study Population

Participants in the main AIM-HIGH study (NCT00120289)

Description

Inclusion Criteria:

• Eligible for main AIM-HIGH study (NCT00120289)
• Medically able to undergo MRI procedure
• Willing to provide informed consent for participation in this substudy

Exclusion Criteria:

• Uses pacemaker or has metallic implants
• History of bilateral carotid endarterectomy
• Glomerular filtration rate less than 60 mL/min/1.73 m^2

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Simvastatin; Participants in the main AIM-HIGH study who are receiving simvastatin.	Drug: Simvastatin, simvastatin plus extended-release niacin; Participants will be enrolled in this substudy only if they are candidates for the main AIM-HIGH study (NCT00120289). Participants will be randomly assigned to simvastatin or simvastatin plus niacin as a part of the main AIM-HIGH protocol, and adjustments in simvastatin and/or niacin doses will be made as per the protocol for the main AIM-HIGH study.; Other Names: Zocor; Niaspan; simvastatin; niacin
Simvastatin and Extended-Release Niacin; Participants in the main AIM-HIGH study who are receiving simvastatin and extended-release niacin.	Drug: Simvastatin, simvastatin plus extended-release niacin; Participants will be enrolled in this substudy only if they are candidates for the main AIM-HIGH study (NCT00120289). Participants will be randomly assigned to simvastatin or simvastatin plus niacin as a part of the main AIM-HIGH protocol, and adjustments in simvastatin and/or niacin doses will be made as per the protocol for the main AIM-HIGH study.; Other Names: Zocor; Niaspan; simvastatin; niacin

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mean plaque lipid composition in carotid arteries assessed by MR	To test the primary hypothesis that compared with LDL-lowering alone, intensive LDL-lowering plus HDL-raising therapy decreases the mean plaque lipid composition in carotid arteries assessed by MRI.	Through 24Months post AIM-HIGH Randomization

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Additional plaque characteristics as assessed by MRI	To test the additional hypotheses regarding plaque burden, plaque lipid depletion time course, association with cardiovascular event risk and lipid characteristics.	Through 24Months post AIM-HIGH Randomization

Collaborators and Investigators

• Sponsor: University of Washington
• Collaborators: National Heart, Lung, and Blood Institute (NHLBI)

Publications and helpful links

General Publications

• Hippe DS, Phan BAP, Sun J, Isquith DA, O'Brien KD, Crouse JR, Anderson T, Huston J, Marcovina SM, Hatsukami TS, Yuan C, Zhao XQ. Lp(a) (Lipoprotein(a)) Levels Predict Progression of Carotid Atherosclerosis in Subjects With Atherosclerotic Cardiovascular Disease on Intensive Lipid Therapy: An Analysis of the AIM-HIGH (Atherothrombosis Intervention in Metabolic Syndrome With Low HDL/High Triglycerides: Impact on Global Health Outcomes) Carotid Magnetic Resonance Imaging Substudy-Brief Report. Arterioscler Thromb Vasc Biol. 2018 Mar;38(3):673-678. doi: 10.1161/ATVBAHA.117.310368. Epub 2018 Jan 4.
• Sun J, Zhao XQ, Balu N, Hippe DS, Hatsukami TS, Isquith DA, Yamada K, Neradilek MB, Canton G, Xue Y, Fleg JL, Desvigne-Nickens P, Klimas MT, Padley RJ, Vassileva MT, Wyman BT, Yuan C. Carotid magnetic resonance imaging for monitoring atherosclerotic plaque progression: a multicenter reproducibility study. Int J Cardiovasc Imaging. 2015 Jan;31(1):95-103. doi: 10.1007/s10554-014-0532-7. Epub 2014 Sep 13.
• Chen H, Sun J, Kerwin WS, Balu N, Neradilek MB, Hippe DS, Isquith D, Xue Y, Yamada K, Peck S, Yuan C, O'Brien KD, Zhao XQ. Scan-rescan reproducibility of quantitative assessment of inflammatory carotid atherosclerotic plaque using dynamic contrast-enhanced 3T CMR in a multi-center study. J Cardiovasc Magn Reson. 2014 Aug 1;16(1):51. doi: 10.1186/s12968-014-0051-7.
• Zhao XQ, Hatsukami TS, Hippe DS, Sun J, Balu N, Isquith DA, Crouse JR 3rd, Anderson T, Huston J 3rd, Polissar N, O'Brien K, Yuan C; AIM-HIGH Carotid MRI Sub-study Investigators. Clinical factors associated with high-risk carotid plaque features as assessed by magnetic resonance imaging in patients with established vascular disease (from the AIM-HIGH Study). Am J Cardiol. 2014 Nov 1;114(9):1412-9. doi: 10.1016/j.amjcard.2014.08.001. Epub 2014 Aug 13.
• Zhao XQ, Sun J, Hippe DS, Isquith DA, Canton G, Yamada K, Balu N, Crouse JR 3rd, Anderson TJ, Huston J 3rd, O'Brien KD, Hatsukami TS, Yuan C; AIM-HIGH Carotid MRI Substudy Investigators. Magnetic Resonance Imaging of Intraplaque Hemorrhage and Plaque Lipid Content With Continued Lipid-Lowering Therapy: Results of a Magnetic Resonance Imaging Substudy in AIM-HIGH. Circ Cardiovasc Imaging. 2022 Nov;15(11):e014229. doi: 10.1161/CIRCIMAGING.122.014229. Epub 2022 Nov 15.
• O'Brien KD, Hippe DS, Chen H, Neradilek MB, Probstfield JL, Peck S, Isquith DA, Canton G, Yuan C, Polissar NL, Zhao XQ, Kerwin WS. Longer duration of statin therapy is associated with decreased carotid plaque vascularity by magnetic resonance imaging. Atherosclerosis. 2016 Feb;245:74-81. doi: 10.1016/j.atherosclerosis.2015.11.032. Epub 2015 Dec 1.

Study record dates

Study Major Dates

• Study Start: March 1, 2008
• Primary Completion (Actual): April 1, 2013
• Study Completion (Actual): February 1, 2015

Study Registration Dates

• First Submitted: August 5, 2010
• First Submitted That Met QC Criteria: August 6, 2010
• First Posted (Estimate): August 10, 2010

Study Record Updates

• Last Update Posted (Actual): February 9, 2018
• Last Update Submitted That Met QC Criteria: February 7, 2018
• Last Verified: February 1, 2018

More Information

Terms related to this study

• Keywords: Magnetic Resonance Imaging; Atherosclerotic Plaque; Lipid Lowering Therapy
• Additional Relevant MeSH Terms: Myocardial Ischemia; Heart Diseases; Cardiovascular Diseases; Vascular Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Arteriosclerosis; Arterial Occlusive Diseases; Coronary Disease; Coronary Artery Disease; Carotid Artery Diseases; Atherosclerosis; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Vasodilator Agents; Enzyme Inhibitors; Antimetabolites; Micronutrients; Anticholesteremic Agents; Hypolipidemic Agents; Lipid Regulating Agents; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Vitamins; Vitamin B Complex; Nicotinic Acids; Simvastatin; Niacinamide; Niacin
• Other Study ID Numbers: 627; R01HL088214 (U.S. NIH Grant/Contract)