Trial Outcomes & Findings for YELLOW II Study: Reduction in Coronary Yellow Plaque, Lipids and Vascular Inflammation by Aggressive Lipid Lowering (NCT NCT01837823)

NCT ID: NCT01837823

Last Updated: 2018-02-13

Results Overview

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.

• Recruitment status: COMPLETED
• Study phase: PHASE2
• Target enrollment: 91 participants
• Primary outcome timeframe: baseline and 8-12 weeks
• Results posted on: 2018-02-13

Participant Flow

Recruitment began in July 2013, with enrollment from August 2013 to February 2015, 91 patients with multivessel CAD, who underwent percutaneous coronary intervention (PCI) for a culprit lesion followed by OCT and NIRS/IVUS imaging of an obstructive NCL were enrolled.

Participant milestones

Measure	Rosuvastatin All subjects will receive rosuvastatin 40mg/day 8-12 weeks
Overall Study STARTED	91
Overall Study COMPLETED	85
Overall Study NOT COMPLETED	6

Reasons for withdrawal

Measure	Rosuvastatin All subjects will receive rosuvastatin 40mg/day 8-12 weeks
Overall Study Lost to Follow-up	6

Baseline Characteristics

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

Baseline characteristics by cohort

Measure	Rosuvastatin n=85 Participants All subjects will receive rosuvastatin 40mg/day 8-12 weeks
Age, Continuous	62.4 years STANDARD_DEVIATION 11.2 • n=5 Participants
Sex: Female, Male Female	58 Participants n=5 Participants
Sex: Female, Male Male	27 Participants n=5 Participants
Hypertension	76 Participants n=5 Participants
Hypercholesterolemia	75 Participants n=5 Participants
Diabetes mellitus	37 Participants n=5 Participants
Body mass index (BMI)	29.6 kg/m^2 STANDARD_DEVIATION 5.2 • n=5 Participants
Current smoking	12 Participants n=5 Participants
History of smoking	26 Participants n=5 Participants
Prior myocardial infarction (MI)	12 Participants n=5 Participants
Prior percutaneous coronary intervention (PCI)	24 Participants n=5 Participants
Statin use atorvastatin	29 Participants n=5 Participants
Statin use simvastatin	23 Participants n=5 Participants
Statin use rosuvastatin	12 Participants n=5 Participants
Statin use pravastatin	4 Participants n=5 Participants
Statin use fluvastatin	1 Participants n=5 Participants
Statin use none	16 Participants n=5 Participants
Location of coronary artery disease the left anterior descending artery (LAD)	36 Participants n=5 Participants
Location of coronary artery disease left circumflex artery (LCX)	23 Participants n=5 Participants
Location of coronary artery disease the right coronary artery (RCA)	26 Participants n=5 Participants

PRIMARY outcome

Timeframe: 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.

Outcome measures

Measure	Rosuvastatin n=85 Participants All subjects will receive rosuvastatin 40mg/day 8-12 weeks	8-12 Weeks After 8-12 weeks of rosuvastatin
Correlation Between Plaque Morphology and HDL Functionality	0.30 beta coefficient Interval 0.07 to 0.54	—

PRIMARY outcome

Timeframe: baseline and 8-12 weeks

Correlation between the change in plaque morphology composition by intravascular imaging with inflammatory cell activity.

Outcome measures

Measure	Rosuvastatin n=85 Participants All subjects will receive rosuvastatin 40mg/day 8-12 weeks	8-12 Weeks After 8-12 weeks of rosuvastatin
Correlation Between the Change in Fibrous Cap Thickness and Hs-CRP	-0.27 beta coefficient Interval -0.46 to -0.02	—

SECONDARY outcome

Timeframe: 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.

Outcome measures

Measure	Rosuvastatin n=85 Participants All subjects will receive rosuvastatin 40mg/day 8-12 weeks	8-12 Weeks n=85 Participants After 8-12 weeks of rosuvastatin
Maximal 4mm Lipid Core Burden Index (LCBI 4mm Max)	416.6 LCBI4mm max Standard Deviation 172.9	400.2 LCBI4mm max Standard Deviation 180.4

SECONDARY outcome

Timeframe: baseline and at 8-12 weeks

ΔFibrous Cap Thickness measured by OCT at baseline and at 8-12 weeks

Outcome measures

Measure	Rosuvastatin n=85 Participants All subjects will receive rosuvastatin 40mg/day 8-12 weeks	8-12 Weeks n=85 Participants After 8-12 weeks of rosuvastatin
Fibrous Cap Thickness (FCT) by OCT	100.9 μm Standard Deviation 41.7	108.6 μm Standard Deviation 39.6

SECONDARY outcome

Timeframe: 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 %.

Outcome measures

Measure	Rosuvastatin n=85 Participants All subjects will receive rosuvastatin 40mg/day 8-12 weeks	8-12 Weeks n=85 Participants After 8-12 weeks of rosuvastatin
IVUS Imaging Measures Reference Site	38.75 percent of plaque burden Standard Deviation 10.54	38.93 percent of plaque burden Standard Deviation 10.57
IVUS Imaging Measures Minimum Lumen Area Site	75.93 percent of plaque burden Standard Deviation 7.07	75.79 percent of plaque burden Standard Deviation 7.96

SECONDARY outcome

Timeframe: 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.

Outcome measures

Measure	Rosuvastatin n=85 Participants All subjects will receive rosuvastatin 40mg/day 8-12 weeks	8-12 Weeks n=85 Participants After 8-12 weeks of rosuvastatin
Inflammatory and Lipid Parameters HDL Cholesterol	41.2 mg/dl Standard Deviation 12.7	42.2 mg/dl Standard Deviation 13.1
Inflammatory and Lipid Parameters Triglyceride	128.6 mg/dl Standard Deviation 111.8	107.8 mg/dl Standard Deviation 66.7
Inflammatory and Lipid Parameters Total Cholesterol	153.3 mg/dl Standard Deviation 44.9	115.0 mg/dl Standard Deviation 29.9
Inflammatory and Lipid Parameters LDL Cholesterol	86.8 mg/dl Standard Deviation 39.6	50.6 mg/dl Standard Deviation 25.0
Inflammatory and Lipid Parameters ApoB	79.6 mg/dl Standard Deviation 28.0	57.4 mg/dl Standard Deviation 17.5
Inflammatory and Lipid Parameters Apo-AI	120.1 mg/dl Standard Deviation 25.6	126.9 mg/dl Standard Deviation 23.3
Inflammatory and Lipid Parameters hs-CRP	35.0 mg/dl Standard Deviation 55.0	27.0 mg/dl Standard Deviation 42.0

SECONDARY outcome

Timeframe: 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 .

Outcome measures

Measure	Rosuvastatin n=85 Participants All subjects will receive rosuvastatin 40mg/day 8-12 weeks	8-12 Weeks n=85 Participants After 8-12 weeks of rosuvastatin
Lesion LCBI	142.84 LCBI4mm max Interval 88.74 to 215.8	141.93 LCBI4mm max Interval 96.92 to 239.21

SECONDARY outcome

Timeframe: 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.

Outcome measures

Measure	Rosuvastatin n=85 Participants All subjects will receive rosuvastatin 40mg/day 8-12 weeks	8-12 Weeks n=85 Participants After 8-12 weeks of rosuvastatin
LCBI 4mm at Same Anatomical Site	416.6 LCBI4mm max Standard Deviation 172.9	383.2 LCBI4mm max Standard Deviation 188.2

SECONDARY outcome

Timeframe: baseline and at 8-12 weeks

Change in total atheroma volume (TAV) and lumen cross sectional area on OCT.

Outcome measures

Measure	Rosuvastatin n=85 Participants All subjects will receive rosuvastatin 40mg/day 8-12 weeks	8-12 Weeks n=85 Participants After 8-12 weeks of rosuvastatin
Change in Atheroma Volume	182.3 mm^3 Standard Deviation 94.5	182.7 mm^3 Standard Deviation 95.5

SECONDARY outcome

Timeframe: within 24 hrs of PCI

Post procedure CK-MB, Troponin-I release at final YELLOW lesion PCI.

Outcome measures

Measure	Rosuvastatin n=85 Participants All subjects will receive rosuvastatin 40mg/day 8-12 weeks	8-12 Weeks After 8-12 weeks of rosuvastatin
Biomarker Release CK-MB	30. ng/ml Standard Deviation 3.5	—
Biomarker Release Troponin-I	0.35 ng/ml Standard Deviation 1.22	—

SECONDARY outcome

Timeframe: baseline

Correlation of baseline lipid parameters with baseline LCBI4mm max

Outcome measures

Measure	Rosuvastatin n=85 Participants All subjects will receive rosuvastatin 40mg/day 8-12 weeks	8-12 Weeks After 8-12 weeks of rosuvastatin
Correlation of Baseline Lipid Parameters With Baseline LCBI4mm Max	0.07 Beta coefficient Interval -0.64 to 1.27	—

SECONDARY outcome

Timeframe: baseline and at 8-12 weeks

Population: Only those participants with these genotypes were analyzed

To relate changes in plaque lipid content and morphology to the patient haptoglobin genotype.

Outcome measures

Measure	Rosuvastatin n=31 Participants All subjects will receive rosuvastatin 40mg/day 8-12 weeks	8-12 Weeks n=54 Participants After 8-12 weeks of rosuvastatin
Plaque Morphology as Related to Haptoglobin Baseline	440.3 LCBI4mm max Standard Deviation 171.8	403.0 LCBI4mm max Standard Deviation 173.7
Plaque Morphology as Related to Haptoglobin at 8-12 weeks	411.0 LCBI4mm max Standard Deviation 201.5	393.9 LCBI4mm max Standard Deviation 168.8

SECONDARY outcome

Timeframe: 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.

Outcome measures

Measure	Rosuvastatin n=85 Participants All subjects will receive rosuvastatin 40mg/day 8-12 weeks	8-12 Weeks n=85 Participants After 8-12 weeks of rosuvastatin
Mechanism of Reverse Cholesterol Transport	0.81 percentage of cholesterol Standard Deviation 0.14	0.84 percentage of cholesterol Standard Deviation 0.14

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: 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.

Outcome measures

Measure	Rosuvastatin n=85 Participants All subjects will receive rosuvastatin 40mg/day 8-12 weeks	8-12 Weeks After 8-12 weeks of rosuvastatin
MACE Myocardial infarction	1 Participants	—
MACE Revascularization	2 Participants	—
MACE Stroke	0 Participants	—

SECONDARY outcome

Timeframe: 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.

Outcome measures

Measure	Rosuvastatin n=85 Participants All subjects will receive rosuvastatin 40mg/day 8-12 weeks	8-12 Weeks After 8-12 weeks of rosuvastatin
MACE	33 Participants	—

Adverse Events

Rosuvastatin

Serious events: 3 serious events

Other events: 30 other events

Deaths: 0 deaths

Serious adverse events

Measure	Rosuvastatin n=85 participants at risk All subjects will receive rosuvastatin 40mg/day 8-12 weeks
Cardiac disorders Myocardial infarction	3.5% 3/85 • Number of events 3

Other adverse events

Measure	Rosuvastatin n=85 participants at risk All subjects will receive rosuvastatin 40mg/day 8-12 weeks
Vascular disorders Urgent revascularization	15.3% 13/85 • Number of events 13
Surgical and medical procedures Periprocedural complication	2.4% 2/85 • Number of events 2
Cardiac disorders Hospitalization for chest pain	17.6% 15/85 • Number of events 15

Additional Information

Dr. Annapoorna Kini

Mount Sinai Hospital and Icahn School of Medicine at Mount Sinai

Phone: 212-241-4181

Email: annapoorna.kini@mountsinai.org

Results disclosure agreements

• Principal investigator is a sponsor employee
• Publication restrictions are in place