YELLOW II Study: Reduction in Coronary Yellow Plaque, Lipids and Vascular Inflammation by Aggressive Lipid Lowering

• ClinicalTrials.gov Identifier: NCT01837823
• Recruitment Status: Completed
• First Posted: April 23, 2013
• Results First Posted: February 13, 2018
• Last Update Posted: February 13, 2018
• Sponsor: Icahn School of Medicine at Mount Sinai
• Collaborators: Texas Heart Institute (Wafic Said Molecular Cardiology Research Lab); AstraZeneca; InfraReDx (indirect)
• Information provided by (Responsible Party): Annapoorna Kini, Icahn School of Medicine at Mount Sinai

Study Description

Brief Summary:

Coronary artery disease (CAD) remains a leading cause of death in most countries. It is well known that the reduction of cholesterol levels by statin therapy is associated with significant decreases in plaque burden. REVERSAL, ASTEROID, and more recently the SATURN II trial showed that in patients with CAD, lipid lowering with atorvastatin or rosuvastatin respectively reduced progression of coronary atherosclerosis, even causing plaque regression of some lesions. CAD clinical events are related to plaque instability due to lipid content and activity within the atherosclerotic plaque. The investigators recently completed the YELLOW I study, and identified that intensive statin therapy (rosuvastatin 40mg) was associated with a reduction in the amount of lipid in obstructive coronary plaques, as measured by near-infrared spectroscopy (NIRS). The YELLOW II study is designed to expand and build upon these results, and to provide mechanistic insights into the potential benefits of intensive statin therapy on atherosclerotic plaques.

Condition or disease	Intervention/treatment	Phase
Obstructive Coronary Artery Disease; Coronary Artery Disease	Drug: rosuvastatin	Phase 2

Detailed Description:

YELLOW II is a single site study and will assess the regression of plaque lipid content and changes in plaque morphology from atherosclerotic lesions after high-dose statin therapy by utilizing NIRS, IVUS and optical coherency tomography (OCT) imaging modalities in the coronary arteries. We propose to image non-culprit coronary lesions using these modalities in patients with two or three diseased coronary vessels deemed to warrant intervention on clinical grounds. Thus, at the time of enrolment patients will undergo Percutaneous Coronary Intervention (PCI) of a non-study culprit lesion, and triple-modality imaging of the potential non-culprit ('YELLOW') lesion. If there is high baseline lipid content in the non-culprit YELLOW lesion (max 4mm LCBI > 150), patients will be formally entered into this study. Following this, all enrolled subjects will receive high-dose lipid lowering therapy (rosuvastatin 40mg daily). The non-culprit YELLOW lesion will undergo staged intervention 8-12 weeks following study enrolment and baseline imaging. At this time the YELLOW lesion will be reimaged to determine whether high-dose statin therapy caused a reduction in lipid content as assessed by NIRS, and other altered plaque morphology as assessed by OCT and IVUS. In addition, both at baseline and at the time of final non-culprit YELLOW lesion PCI, blood samples will be drawn during baseline and follow-up procedure to characterize reverse cholesterol transport by ability of patient HDL to accept cholesterol from cholesterol-laden (mouse J774) macrophage (cholesterol efflux) and the effect of patient HDL and apolipoprotein A1 on macrophage gene expression and migration.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 91 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: YELLOW II Study: Reduction in Coronary Yellow Plaque, Lipids and Vascular Inflammation by Aggressive Lipid Lowering
• Study Start Date: July 2013
• Actual Primary Completion Date: April 2015
• Actual Study Completion Date: April 2015

Arms and Interventions

Arm	Intervention/treatment
Experimental: rosuvastatin; All subjects will receive rosuvastatin 40mg/day	Drug: rosuvastatin; All subjects will receive rosuvastatin 40mg/day for 8-12 weeks; Other Name: Crestor

Outcome Measures

Primary Outcome Measures :

1. Correlation Between Plaque Morphology and HDL Functionality [ Time Frame: baseline and 8-12 weeks ]
   Correlation between the changes in plaque morphology composition by intravascular imaging with changes in HDL functionality. HDL functionality is measured by the Cholesterol Efflux Capacity (CEC). Plaque morphology is represented by the Fibrous Cap Thickness.
2. Correlation Between the Change in Fibrous Cap Thickness and Hs-CRP [ Time Frame: baseline and 8-12 weeks ]
   Correlation between the change in plaque morphology composition by intravascular imaging with inflammatory cell activity.

Secondary Outcome Measures :

1. Maximal 4mm Lipid Core Burden Index (LCBI 4mm Max) [ Time Frame: baseline and at 8-12 weeks ]

   Maximum LCBI 4mm (ΔLCBI4mm max) of the non-culprit YELLOW lesion at baseline and 8-12 weeks thereafter.

   LCBI4mm max : 4-mm long segment with maximum lipid core burden index (LCBI), where the LCBI is calculated as the fraction of yellow pixels on a chemogram x 1000. Each pixel on the chemogram represents a probability of lipid presence in the given region; pixels are color-coded on a red-to-yellow color scale, with the low probability of lipid shown as red and the high probability of lipid shown as yellow.

2. Fibrous Cap Thickness (FCT) by OCT [ Time Frame: baseline and at 8-12 weeks ]
   ΔFibrous Cap Thickness measured by OCT at baseline and at 8-12 weeks
3. IVUS Imaging Measures [ Time Frame: Baseline and 8 weeks ]
   Correlation between ΔLCBI4mm max will be related to Δ values from baseline to 8-12 weeks thereafter in specific IVUS (ΔPlaque burden) imaging measures. Plaque burden is Plaque + Media divided by Total Plaque Area in %.
4. Inflammatory and Lipid Parameters [ Time Frame: baseline and at 8-12 weeks ]
   ΔLCBI4mm max will be related to Δ values from baseline to 8-12 weeks thereafter in inflammatory and lipid parameters responses to patient-derived samples.
5. Lesion LCBI [ Time Frame: at baseline and at 8-12 weeks ]
   As related to other outcomes, change in LCBI measured across the entire lesion (rather than ΔLCBI4mm max). The LCBI Score, computed as the fraction of valid pixels within the scanned region that exceeded a LCP probability of 0.6 multiplied by 1000, summarized the amount of LCP in the entire scanned region of the coronary vessel on a 0-to-1000 scale .
6. LCBI 4mm at Same Anatomical Site [ Time Frame: at baseline and at 8-12 weeks ]

   As related to other outcomes, change in LCBI 4mm measured at the identical anatomical site at both time points, as defined by the LCBI4mm max site at baseline (rather than ΔLCBI4mm max).

   LCBI4mm: 4-mm long segment with maximum lipid core burden index (LCBI), where the LCBI is calculated as the fraction of yellow pixels on a chemogram x 1000. Each pixel on the chemogram represents a probability of lipid presence in the given region; pixels are color-coded on a red-to-yellow color scale, with the low probability of lipid shown as red and the high probability of lipid shown as yellow.

7. Change in Atheroma Volume [ Time Frame: baseline and at 8-12 weeks ]
   Change in total atheroma volume (TAV) and lumen cross sectional area on OCT.
8. Biomarker Release [ Time Frame: within 24 hrs of PCI ]
   Post procedure CK-MB, Troponin-I release at final YELLOW lesion PCI.
9. Correlation of Baseline Lipid Parameters With Baseline LCBI4mm Max [ Time Frame: baseline ]
   Correlation of baseline lipid parameters with baseline LCBI4mm max
10. Plaque Morphology as Related to Haptoglobin [ Time Frame: baseline and at 8-12 weeks ]
    To relate changes in plaque lipid content and morphology to the patient haptoglobin genotype.
11. Mechanism of Reverse Cholesterol Transport [ Time Frame: baseline and at 8-12 weeks ]
    To assess the mechanism of reverse cholesterol transport that arises with high-dose statin therapy, as related to changes in plaque lipid content and morphology, and systemic vascular inflammation. Reverse cholesterol transport (RCT) is a pathway by which accumulated cholesterol is transported from the vessel wall to the liver for excretion, thus preventing atherosclerosis.
12. Correlation of Changes in Plaque Morphology [ Time Frame: baseline and at 8-12 weeks ]

    Correlation of changes in plaque morphology by OCT, IVUS and NIRS with the perturbations in peripheral blood mononuclear cell transcriptome using microarray analysis.

    data not collected for this measure.

13. MACE [ Time Frame: at 30 days ]
    Major Adverse Cardiac Events (MACE) defined as a combined clinical endpoint of death, MI (Q wave or non Q-wave with CK-MB >3 times above the upper normal limit (48 U/L), urgent revascularization or stroke at 30 days.
14. MACE [ Time Frame: at 1 year ]
    Major Adverse Cardiac Events (MACE) defined as a combined clinical endpoint of death, MI (Q wave or non Q-wave with CK-MB >3 times above the upper normal limit (48 U/L), urgent revascularization or stroke at 1 year.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Patients >18 years of age and willing to participate.
• Fluency in either English or Spanish.
• Stable patients who will undergo cardiac catheterization and PCI (intent to stent).
• Patient is willing to go on high-dose cholesterol lowering medication for the duration of the study
• Signed written Informed Consent.
• Women of childbearing potential must agree to be on an acceptable method of birth control/contraceptive such as barrier method (condoms/diaphragm); hormonal contraceptives (birth control pills, implants (Norplant) or injections (Depo-Provera)); Intrauterine Device.
• Proposed non-culprit YELLOW study lesion with max 4mm LCBI ≥ 150.

Exclusion Criteria:

• Patients who have acute myocardial infarction (ST-segment elevation presentation, new Q waves or non-ST segment elevation with CK-MB > 5 times above the upper normal (31.5 ng/ml) within 72 hours).
• Patients who are in cardiogenic shock.
• Patients requiring coronary artery bypass graft surgery.
• Patients with platelet count < 100,000 cell/mm3.
• Patients who have co-morbidity which reduces life expectancy to one year.
• Patients who are currently participating in another investigational drug/device study.
• Patients with liver disease.
• Patient with creatinine > 2.0 mg/dL.
• Pregnant women and women of childbearing potential who intend to have children during the duration of the trial.
• Patients having undergone heart transplantation, or those that may undergo heart transplantation during the study period.
• Active autoimmune disease.
• Nursing mothers

Contacts and Locations

Locations

United States, New York

Icahn School of Medicine at Mount Sinai

New York, New York, United States, 10029

Sponsors and Collaborators

Icahn School of Medicine at Mount Sinai

Texas Heart Institute (Wafic Said Molecular Cardiology Research Lab)

AstraZeneca

InfraReDx (indirect)

Investigators

• Principal Investigator: Annapoorna Kini, MD; Icahn School of Medicine at Mount Sinai
• Principal Investigator: Jason Kovacic, MD, PhD; Icahn School of Medicine at Mount Sinai

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Kini AS, Vengrenyuk Y, Shameer K, Maehara A, Purushothaman M, Yoshimura T, Matsumura M, Aquino M, Haider N, Johnson KW, Readhead B, Kidd BA, Feig JE, Krishnan P, Sweeny J, Milind M, Moreno P, Mehran R, Kovacic JC, Baber U, Dudley JT, Narula J, Sharma S. Intracoronary Imaging, Cholesterol Efflux, and Transcriptomes After Intensive Statin Treatment: The YELLOW II Study. J Am Coll Cardiol. 2017 Feb 14;69(6):628-640. doi: 10.1016/j.jacc.2016.10.029. Epub 2016 Oct 29.

• Responsible Party: Annapoorna Kini, Professor of Medicine, Icahn School of Medicine at Mount Sinai
• ClinicalTrials.gov Identifier: NCT01837823
• Other Study ID Numbers: GCO 12-1507; HS#: 12-00741
• First Posted: April 23, 2013
• Results First Posted: February 13, 2018
• Last Update Posted: February 13, 2018
• Last Verified: January 2018

Keywords provided by Annapoorna Kini, Icahn School of Medicine at Mount Sinai:

Coronary artery disease; Lipid; Regression; Plaque

Additional relevant MeSH terms:

Coronary Artery Disease; Myocardial Ischemia; Coronary Disease; Inflammation; Pathologic Processes; Heart Diseases; Cardiovascular Diseases; Arteriosclerosis; Arterial Occlusive Diseases; Vascular Diseases; Rosuvastatin Calcium; Anticholesteremic Agents; Hypolipidemic Agents; Antimetabolites; Molecular Mechanisms of Pharmacological Action; Lipid Regulating Agents; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Enzyme Inhibitors