Reduction in YEllow Plaque by Aggressive Lipid LOWering Therapy (YELLOW)

• ClinicalTrials.gov Identifier: NCT01567826
• Recruitment Status: Completed
• First Posted: March 30, 2012
• Results First Posted: February 27, 2017
• Last Update Posted: May 19, 2017
• Sponsor: Annapoorna Kini
• Information provided by (Responsible Party): Annapoorna Kini, Icahn School of Medicine at Mount Sinai

Study Description

Brief Summary:

The study will assess the regression of yellow plaque content of the lipid pool after aggressive lipid therapy by utilizing NIR spectroscopy. Statin therapy using Rosuvastatin 10-40 mg will be compared to the statin therapy of either Atorvastatin or Simvastatin. This is a single site study. A total of 100 subjects will randomized, of which 40 will receive intensive lipid therapy (Rosuvastatin 40mg) and 40 will receive standard care lipid lowering therapy.

Condition or disease	Intervention/treatment	Phase
Coronary Artery Disease	Drug: standard of care lipid therapy; Drug: Aggressive lipid therapy	Phase 4

Detailed Description:

Coronary artery disease (CHD) remains to be a leading cause of death in most countries (1) (2). It is well known that reducing cholesterol level by statin therapy is associated with significant reduction in plaque burden. REVERSAL (3) and ASTEROID (4) trials showed that in patients with coronary artery disease lipid-lowering with atorvastatin or rosuvastatin respectively reduced progression of coronary atherosclerosis and even cause repression of some lesions. CHD clinical events are related to plaque instability due to lipid content within the atherosclerotic plaque. High dose atorvastatin has shown to reduce the plaque lipid contents on serial IVUS analysis at 12 months. Therefore reduction in lipid content and thereby the plaque burden by lipid lowering therapy may stabilize the plaque and reduce cardiovascular events. High sensitivity C-reactive Protein (HsCRP) is an inflammatory biomarker that independently predicts future vascular events. In JUPITER (5) trial rosuvastatin (Crestor) significantly reduced the incidence of major cardiovascular events in apparently healthy people with elevated HsCRP. IVUS was utilized to demonstrate change in coronary artery vessel wall morphology over a relatively short period of time, but provided no data on the lipid content in the vessel wall. The application of NIR spectroscopy to identify lipid deposition within coronary arteries has been validated in ex vivo studies. Infrared spectra are collected as follows: Light of discrete wavelengths from a laser is directed onto the tissue sample via glass fibers. Light scattered from the samples is collected in fibers and launched into a spectrometer. The plot of signal intensity as a function of wavelength was used to develop chemometric models to discriminate lipid-cores from non-atherosclerotic tissue, and from atherosclerotic tissue that is predominantly fibrotic and from blood elements.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 87 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Single (Investigator)
• Primary Purpose: Treatment
• Official Title: Reduction in YEllow Plaque by Aggressive Lipid LOWering Therapy. (YELLOW Trial)
• Study Start Date: May 2010
• Actual Primary Completion Date: February 2012
• Actual Study Completion Date: February 2012

Arms and Interventions

Arm	Intervention/treatment
Active Comparator: standard of care lipid therapy; standard-care lipid-lowering therapy: Zocor or Lipitor	Drug: standard of care lipid therapy; Patients will be randomized in a 1:1 fashion to receive either A) Rosuvastatin (Crestor) 40mg daily, or B) standard-care lipid-lowering therapy. Zocor, Lipitor [any dose] and Crestor [less than 40mg]; Other Names: Zocor; Lipitor; (Zocor, Lipitor, Crestor)
Experimental: aggressive lipid therapy; aggressive lipid therapy: Crestor	Drug: Aggressive lipid therapy; Patients will be randomized in a 1:1 fashion to receive either A) Rosuvastatin (Crestor) 40mg daily, or B) standard-care lipid-lowering therapy.; Other Names: Rosuvastatin; Crestor

Outcome Measures

Primary Outcome Measures :

1. Lipiscan - Lipid Core Burden Index (LCBI) [ Time Frame: at baseline and at 6-8 weeks after intervention ]
   The regression of yellow plaque content from the atherosclerotic lipid pool after statin therapy by utilizing NIR spectroscopy as compared from baseline to 6-8 weeks after intervention. Spectroscopic information obtained from raw spectra was transformed into a probability of lipid core that was mapped to a red-to-yellow color scale, with the low probability of lipid shown as red and the high probability of lipid shown as yellow. Analyses were performed offline using the Matlab-based software, as previously published. Yellow pixels within the analyzed segment were divided by all viable pixels to generate the lipid-core burden index (LCBI). The maximal value of LCBI for each nonculprit obstructive lesion was recorded and used for comparison.
2. LCBI4mm Max [ Time Frame: at baseline and at 6-8 weeks after intervention ]
   LCBI4mm max = change in lipid-core burden index at the 4-mm maximal segment. Spectroscopic information obtained from raw spectra was transformed into a probability of lipid core that was mapped to a red-to-yellow color scale, with the low probability of lipid shown as red and the high probability of lipid shown as yellow. Yellow pixels within the analyzed segment were divided by all viable pixels to generate the lipid-core burden index (LCBI). The maximal value of LCBI for each nonculprit obstructive lesion was recorded and used for comparison.
3. Change in LCBI4mm Max [ Time Frame: at baseline and at 6-8 weeks after intervention ]
   Change in LCBI4mm max at 6-8 weeks after intervention as compared to baseline. LCBI4mm max = change in lipid-core burden index at the 4-mm maximal segment.
4. Change in LCBI, Lesion [ Time Frame: at baseline and at 6-8 weeks post intervention ]
   Change in LCBI at 6-8 weeks after intervention as compared to baseline

Secondary Outcome Measures :

1. Intravascular Ultrasound (IVUS) Parameters [ Time Frame: at baseline and at 6-8 weeks after intervention ]

   Change in atheroma volume and lumen CSA on IVUS as related to change in yellow plaque index as compared from baseline to 6-8 weeks after intervention.

   Data not analyzed. Data not available.

2. Fractional Flow Reserve (FFR) Value [ Time Frame: at baseline and at 6-8 weeks after intervention ]
   Change in FFR as related to change in yellow plaque index as compared from baseline to 6-8 weeks after intervention. Fractional flow reserve (FFR), defined as the ratio of maximum flow in the presence of a stenosis to normal maximum flow, is a lesion-specific index of stenosis severity that can be calculated by simultaneous measurement of mean arterial, distal coronary, and central venous pressure.
3. Diameter Stenosis [ Time Frame: Baseline and 6-8 weeks post intervention ]
   Percentage stenosis of vessel diameter in the analysis segment of nontarget lesions as measured by angiography that remained >70%, after successful PCI of the target lesion.
4. Post PCI Cardiac Enzymes [ Time Frame: at 6-8 weeks after intervention ]
   Correlation of yellow plaque index with post procedure CK-MB, Troponin-I release.
5. Major Adverse Cardiac Events (MACE) [ Time Frame: at 6-8 weeks after intervention ]
   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 and 1 year. Details reported in adverse events section.
6. Blood Chemistry - HsCRP [ Time Frame: at baseline and at 6-8 weeks after intervention ]
   Correlation of yellow plaque index with changes in levels of blood HsCRP as compared from baseline to 6-8 weeks after intervention

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:

• Patient > 18 years of age and willing to participate
• Stable patients who will undergo cardiac catheterization and PCI (intent to stent)
• Patient is willing to go on a cholesterol lowering medication for the duration of the study and willing to change statin therapy to the randomized statin therapy regardless of previous statin therapy and dose (e.g. Atorvastatin 80 mg) Patients that are screened for this study and are receiving another Statin such as Pravachol will be required to be willing to change their therapy to Rosuvastatin as per is randomization. If patients are receiving another statin, such as pravachol, or any other agent, and are at appropriate Lipid levels, they will be permitted to continue this therapy (if randomized to the standard therapy arm). There are a virtually unlimited number of possible scenarios for potential combination of all Lipid lowering agents at the time of enrollment that patients may be taking.
• 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; or abstinence (no sexual activity).
• Fluency in English and/or Spanish

Exclusion Criteria:

• Patients who have acute myocardial infarction (Q wave or non-Q wave with CK-MB > 5 times above the upper normal (31.5 ng/ml) within 72 hours)
• Patients who are in cardiogenic shock
• Patients with left main disease or restenotic lesions
• Patients with elevated CK-MB (> 6.5 ng/ml) or Tnl (> 0.5ng/L) at baseline
• 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 known hypersensitivity to HMG CO-A reductase therapy (statins)
• 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

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

Annapoorna Kini

Investigators

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

More Information

Publications of Results:

Kini AS, Baber U, Kovacic JC, Limaye A, Ali ZA, Sweeny J, Maehara A, Mehran R, Dangas G, Mintz GS, Fuster V, Narula J, Sharma SK, Moreno PR. Changes in plaque lipid content after short-term intensive versus standard statin therapy: the YELLOW trial (reduction in yellow plaque by aggressive lipid-lowering therapy). J Am Coll Cardiol. 2013 Jul 2;62(1):21-9. doi: 10.1016/j.jacc.2013.03.058. Epub 2013 May 1.

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

Dohi T, Maehara A, Moreno PR, Baber U, Kovacic JC, Limaye AM, Ali ZA, Sweeny JM, Mehran R, Dangas GD, Xu K, Sharma SK, Mintz GS, Kini AS. The relationship among extent of lipid-rich plaque, lesion characteristics, and plaque progression/regression in patients with coronary artery disease: a serial near-infrared spectroscopy and intravascular ultrasound study. Eur Heart J Cardiovasc Imaging. 2015 Jan;16(1):81-7. doi: 10.1093/ehjci/jeu169. Epub 2014 Sep 4.

• Responsible Party: Annapoorna Kini, Associate Professor, Icahn School of Medicine at Mount Sinai
• ClinicalTrials.gov Identifier: NCT01567826
• Other Study ID Numbers: GCO 09-1294; IF1292822
• First Posted: March 30, 2012
• Results First Posted: February 27, 2017
• Last Update Posted: May 19, 2017
• Last Verified: April 2017

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

YELLO; Atorvastatin; Simvastatin; Rosuvastatin; lipid therapy; Statin therapy; Coronary artery disease; CHD

Additional relevant MeSH terms:

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