Coronary Artery Disease, Obstructive Coronary Artery Disease
Conditions
Keywords
Coronary artery disease, Lipid, Regression, Plaque
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.
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.
Interventions
DRUGrosuvastatin
All subjects will receive rosuvastatin 40mg/day for 8-12 weeks
Sponsors
Texas Heart Institute (Wafic Said Molecular Cardiology Research Lab)
AstraZeneca
InfraReDx (indirect)
Icahn School of Medicine at Mount Sinai
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Correlation Between Plaque Morphology and HDL Functionality | 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. |
| Correlation Between the Change in Fibrous Cap Thickness and Hs-CRP | baseline and 8-12 weeks | Correlation between the change in plaque morphology composition by intravascular imaging with inflammatory cell activity. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Fibrous Cap Thickness (FCT) by OCT | baseline and at 8-12 weeks | ΔFibrous Cap Thickness measured by OCT at baseline and at 8-12 weeks |
| IVUS Imaging Measures | 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 %. |
| Inflammatory and Lipid Parameters | 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. |
| Lesion LCBI | 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 . |
| LCBI 4mm at Same Anatomical Site | 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. |
| MACE | 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. |
| Biomarker Release | within 24 hrs of PCI | Post procedure CK-MB, Troponin-I release at final YELLOW lesion PCI. |
| Correlation of Baseline Lipid Parameters With Baseline LCBI4mm Max | baseline | Correlation of baseline lipid parameters with baseline LCBI4mm max |
| Plaque Morphology as Related to Haptoglobin | baseline and at 8-12 weeks | To relate changes in plaque lipid content and morphology to the patient haptoglobin genotype. |
| Mechanism of Reverse Cholesterol Transport | 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. |
| Correlation of Changes in Plaque Morphology | 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. |
| Change in Atheroma Volume | baseline and at 8-12 weeks | Change in total atheroma volume (TAV) and lumen cross sectional area on OCT. |
| Maximal 4mm Lipid Core Burden Index (LCBI 4mm Max) | 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. |
Countries
United States
Participant flow
Recruitment details
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.
Participants by arm
| Arm | Count |
|---|---|
| Rosuvastatin All subjects will receive rosuvastatin 40mg/day 8-12 weeks | 85 |
| Total | 85 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Lost to Follow-up | 6 |
Baseline characteristics
| Characteristic | Rosuvastatin |
|---|---|
| Age, Continuous | 62.4 years STANDARD_DEVIATION 11.2 |
| Body mass index (BMI) | 29.6 kg/m^2 STANDARD_DEVIATION 5.2 |
| Current smoking | 12 Participants |
| Diabetes mellitus | 37 Participants |
| History of smoking | 26 Participants |
| Hypercholesterolemia | 75 Participants |
| Hypertension | 76 Participants |
| Location of coronary artery disease left circumflex artery (LCX) | 23 Participants |
| Location of coronary artery disease the left anterior descending artery (LAD) | 36 Participants |
| Location of coronary artery disease the right coronary artery (RCA) | 26 Participants |
| Prior myocardial infarction (MI) | 12 Participants |
| Prior percutaneous coronary intervention (PCI) | 24 Participants |
| Sex: Female, Male Female | 58 Participants |
| Sex: Female, Male Male | 27 Participants |
| Statin use atorvastatin | 29 Participants |
| Statin use fluvastatin | 1 Participants |
| Statin use none | 16 Participants |
| Statin use pravastatin | 4 Participants |
| Statin use rosuvastatin | 12 Participants |
| Statin use simvastatin | 23 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 30 / 85 |
| serious Total, serious adverse events | 3 / 85 |
Outcome results
Primary
Correlation Between Plaque Morphology and HDL Functionality
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.
Time frame: baseline and 8-12 weeks
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Rosuvastatin | Correlation Between Plaque Morphology and HDL Functionality | 0.30 beta coefficient |
Primary
Correlation Between the Change in Fibrous Cap Thickness and Hs-CRP
Correlation between the change in plaque morphology composition by intravascular imaging with inflammatory cell activity.
Time frame: baseline and 8-12 weeks
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Rosuvastatin | Correlation Between the Change in Fibrous Cap Thickness and Hs-CRP | -0.27 beta coefficient |
Secondary
Biomarker Release
Post procedure CK-MB, Troponin-I release at final YELLOW lesion PCI.
Time frame: within 24 hrs of PCI
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Rosuvastatin | Biomarker Release | CK-MB | 30. ng/ml | Standard Deviation 3.5 |
| Rosuvastatin | Biomarker Release | Troponin-I | 0.35 ng/ml | Standard Deviation 1.22 |
Secondary
Change in Atheroma Volume
Change in total atheroma volume (TAV) and lumen cross sectional area on OCT.
Time frame: baseline and at 8-12 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Rosuvastatin | Change in Atheroma Volume | 182.3 mm^3 | Standard Deviation 94.5 |
| 8-12 Weeks | Change in Atheroma Volume | 182.7 mm^3 | Standard Deviation 95.5 |
Secondary
Correlation of Baseline Lipid Parameters With Baseline LCBI4mm Max
Correlation of baseline lipid parameters with baseline LCBI4mm max
Time frame: baseline
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Rosuvastatin | Correlation of Baseline Lipid Parameters With Baseline LCBI4mm Max | 0.07 Beta coefficient |
Secondary
Correlation of Changes in Plaque Morphology
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.
Time frame: baseline and at 8-12 weeks
Secondary
Fibrous Cap Thickness (FCT) by OCT
ΔFibrous Cap Thickness measured by OCT at baseline and at 8-12 weeks
Time frame: baseline and at 8-12 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Rosuvastatin | Fibrous Cap Thickness (FCT) by OCT | 100.9 μm | Standard Deviation 41.7 |
| 8-12 Weeks | Fibrous Cap Thickness (FCT) by OCT | 108.6 μm | Standard Deviation 39.6 |
p-value: 0.054Regression, Linear
Secondary
Inflammatory and Lipid Parameters
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.
Time frame: baseline and at 8-12 weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Rosuvastatin | Inflammatory and Lipid Parameters | LDL Cholesterol | 86.8 mg/dl | Standard Deviation 39.6 |
| Rosuvastatin | Inflammatory and Lipid Parameters | ApoB | 79.6 mg/dl | Standard Deviation 28 |
| Rosuvastatin | Inflammatory and Lipid Parameters | Total Cholesterol | 153.3 mg/dl | Standard Deviation 44.9 |
| Rosuvastatin | Inflammatory and Lipid Parameters | Apo-AI | 120.1 mg/dl | Standard Deviation 25.6 |
| Rosuvastatin | Inflammatory and Lipid Parameters | Triglyceride | 128.6 mg/dl | Standard Deviation 111.8 |
| Rosuvastatin | Inflammatory and Lipid Parameters | hs-CRP | 35.0 mg/dl | Standard Deviation 55 |
| Rosuvastatin | Inflammatory and Lipid Parameters | HDL Cholesterol | 41.2 mg/dl | Standard Deviation 12.7 |
| 8-12 Weeks | Inflammatory and Lipid Parameters | hs-CRP | 27.0 mg/dl | Standard Deviation 42 |
| 8-12 Weeks | Inflammatory and Lipid Parameters | HDL Cholesterol | 42.2 mg/dl | Standard Deviation 13.1 |
| 8-12 Weeks | Inflammatory and Lipid Parameters | Total Cholesterol | 115.0 mg/dl | Standard Deviation 29.9 |
| 8-12 Weeks | Inflammatory and Lipid Parameters | LDL Cholesterol | 50.6 mg/dl | Standard Deviation 25 |
| 8-12 Weeks | Inflammatory and Lipid Parameters | Triglyceride | 107.8 mg/dl | Standard Deviation 66.7 |
| 8-12 Weeks | Inflammatory and Lipid Parameters | ApoB | 57.4 mg/dl | Standard Deviation 17.5 |
| 8-12 Weeks | Inflammatory and Lipid Parameters | Apo-AI | 126.9 mg/dl | Standard Deviation 23.3 |
Secondary
IVUS Imaging Measures
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 %.
Time frame: Baseline and 8 weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Rosuvastatin | IVUS Imaging Measures | Reference Site | 38.75 percent of plaque burden | Standard Deviation 10.54 |
| Rosuvastatin | IVUS Imaging Measures | Minimum Lumen Area Site | 75.93 percent of plaque burden | Standard Deviation 7.07 |
| 8-12 Weeks | IVUS Imaging Measures | Reference Site | 38.93 percent of plaque burden | Standard Deviation 10.57 |
| 8-12 Weeks | IVUS Imaging Measures | Minimum Lumen Area Site | 75.79 percent of plaque burden | Standard Deviation 7.96 |
Comparison: for minimum lumen area sitep-value: 0.5Pearson correlation coefficient
Secondary
LCBI 4mm at Same Anatomical Site
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.
Time frame: at baseline and at 8-12 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Rosuvastatin | LCBI 4mm at Same Anatomical Site | 416.6 LCBI4mm max | Standard Deviation 172.9 |
| 8-12 Weeks | LCBI 4mm at Same Anatomical Site | 383.2 LCBI4mm max | Standard Deviation 188.2 |
Secondary
Lesion LCBI
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 .
Time frame: at baseline and at 8-12 weeks
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Rosuvastatin | Lesion LCBI | 142.84 LCBI4mm max |
| 8-12 Weeks | Lesion LCBI | 141.93 LCBI4mm max |
Secondary
MACE
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.
Time frame: at 1 year
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Rosuvastatin | MACE | 33 Participants |
Secondary
MACE
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.
Time frame: at 30 days
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Rosuvastatin | MACE | Myocardial infarction | 1 Participants |
| Rosuvastatin | MACE | Revascularization | 2 Participants |
| Rosuvastatin | MACE | Stroke | 0 Participants |
Secondary
Maximal 4mm Lipid Core Burden Index (LCBI 4mm Max)
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.
Time frame: baseline and at 8-12 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Rosuvastatin | Maximal 4mm Lipid Core Burden Index (LCBI 4mm Max) | 416.6 LCBI4mm max | Standard Deviation 172.9 |
| 8-12 Weeks | Maximal 4mm Lipid Core Burden Index (LCBI 4mm Max) | 400.2 LCBI4mm max | Standard Deviation 180.4 |
Secondary
Mechanism of Reverse Cholesterol Transport
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.
Time frame: baseline and at 8-12 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Rosuvastatin | Mechanism of Reverse Cholesterol Transport | 0.81 percentage of cholesterol | Standard Deviation 0.14 |
| 8-12 Weeks | Mechanism of Reverse Cholesterol Transport | 0.84 percentage of cholesterol | Standard Deviation 0.14 |
Secondary
Plaque Morphology as Related to Haptoglobin
To relate changes in plaque lipid content and morphology to the patient haptoglobin genotype.
Time frame: baseline and at 8-12 weeks
Population: Only those participants with these genotypes were analyzed
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Rosuvastatin | Plaque Morphology as Related to Haptoglobin | Baseline | 440.3 LCBI4mm max | Standard Deviation 171.8 |
| Rosuvastatin | Plaque Morphology as Related to Haptoglobin | at 8-12 weeks | 411.0 LCBI4mm max | Standard Deviation 201.5 |
| 8-12 Weeks | Plaque Morphology as Related to Haptoglobin | Baseline | 403.0 LCBI4mm max | Standard Deviation 173.7 |
| 8-12 Weeks | Plaque Morphology as Related to Haptoglobin | at 8-12 weeks | 393.9 LCBI4mm max | Standard Deviation 168.8 |