Coronary Artery Disease
Conditions
Keywords
YELLO, Atorvastatin, Simvastatin, Rosuvastatin, lipid therapy, Statin therapy, Coronary artery disease, CHD
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.
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.
Interventions
DRUGstandard 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 \[less than 40mg\]
DRUGAggressive 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.
Sponsors
Annapoorna Kini
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Lipiscan - Lipid Core Burden Index (LCBI) | 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. |
| LCBI4mm Max | 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. |
| Change in LCBI4mm Max | 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. |
| Change in LCBI, Lesion | at baseline and at 6-8 weeks post intervention | Change in LCBI at 6-8 weeks after intervention as compared to baseline |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Major Adverse Cardiac Events (MACE) | 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. |
| Intravascular Ultrasound (IVUS) Parameters | 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. |
| Blood Chemistry - HsCRP | 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 |
| Fractional Flow Reserve (FFR) Value | 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. |
| Diameter Stenosis | 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. |
| Post PCI Cardiac Enzymes | at 6-8 weeks after intervention | Correlation of yellow plaque index with post procedure CK-MB, Troponin-I release. |
Countries
United States
Participant flow
Recruitment details
779 patients consecutive patients with chronic stable angina presenting for elective coronary angiography were screened from May 21, 2010 until Jan 10, 2012. 87 participants met criteria and were randomized.
Participants by arm
| Arm | Count |
|---|---|
| Standard of Care Lipid Therapy standard-care lipid-lowering therapy: Zocor or Lipitor
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 \[less than 40mg\] | 43 |
| Aggressive Lipid Therapy aggressive lipid therapy: Crestor
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. | 44 |
| Total | 87 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 3 | 2 |
Baseline characteristics
| Characteristic | Total | Standard of Care Lipid Therapy | Aggressive Lipid Therapy |
|---|---|---|---|
| ACE-I/ARB use no | 52 participants | 24 participants | 28 participants |
| ACE-I/ARB use yes | 35 participants | 19 participants | 16 participants |
| Age, Continuous | 63.6 years STANDARD_DEVIATION 9.5 | 62.9 years STANDARD_DEVIATION 9.8 | 64.4 years STANDARD_DEVIATION 9.29 |
| Beta-blocker use no | 24 participants | 13 participants | 11 participants |
| Beta-blocker use yes | 63 participants | 30 participants | 33 participants |
| Creatinine | 1.04 mg/dl STANDARD_DEVIATION 0.96 | 1.1 mg/dl STANDARD_DEVIATION 1.3 | 1.0 mg/dl STANDARD_DEVIATION 0.3 |
| Current tobacco use no | 74 participants | 39 participants | 35 participants |
| Current tobacco use yes | 13 participants | 4 participants | 9 participants |
| Diabetes mellitus no | 79 participants | 40 participants | 39 participants |
| Diabetes mellitus yes | 8 participants | 3 participants | 5 participants |
| Hypercholesterolemia no | 8 participants | 3 participants | 5 participants |
| Hypercholesterolemia yes | 79 participants | 40 participants | 39 participants |
| Hypertension no | 7 participants | 3 participants | 4 participants |
| Hypertension yes | 80 participants | 40 participants | 40 participants |
| LAD Coronary vessel no | 50 participants | 26 participants | 24 participants |
| LAD Coronary vessel yes | 37 participants | 17 participants | 20 participants |
| LCx coronary vessel no | 59 participants | 29 participants | 30 participants |
| LCx coronary vessel yes | 28 participants | 14 participants | 14 participants |
| Previous MI no | 71 participants | 35 participants | 36 participants |
| Previous MI yes | 16 participants | 8 participants | 8 participants |
| Previous PCI no | 51 participants | 23 participants | 28 participants |
| Previous PCI yes | 36 participants | 20 participants | 16 participants |
| Prior CVA/TIA no | 82 participants | 40 participants | 42 participants |
| Prior CVA/TIA yes | 5 participants | 3 participants | 2 participants |
| RCA coronary vessel no | 64 participants | 30 participants | 34 participants |
| RCA coronary vessel yes | 23 participants | 13 participants | 10 participants |
| Sex: Female, Male Female | 21 Participants | 12 Participants | 9 Participants |
| Sex: Female, Male Male | 66 Participants | 31 Participants | 35 Participants |
| Statin Use no | 15 participants | 8 participants | 7 participants |
| Statin Use yes | 72 participants | 35 participants | 37 participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 9 / 43 | 7 / 44 |
| serious Total, serious adverse events | 2 / 43 | 3 / 44 |
Outcome results
Primary
Change in LCBI4mm Max
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.
Time frame: at baseline and at 6-8 weeks after intervention
Population: Data were not available in 17 patients because of loss to follow-up (n = 5), incorrect image formatting that could not be recovered at the time of core laboratory analysis (n = 5), NIRS console/catheter malfunction at the time of index PCI (n = 3), and loss of disc integrity or corruption before core laboratory analysis (n = 4).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Standard of Care Lipid Therapy | Change in LCBI4mm Max | 2.4 ratio |
| Aggressive Lipid Therapy | Change in LCBI4mm Max | -149.1 ratio |
p-value: 0.01ANCOVA
Primary
Change in LCBI, Lesion
Change in LCBI at 6-8 weeks after intervention as compared to baseline
Time frame: at baseline and at 6-8 weeks post intervention
Population: Data were not available in 17 patients because of loss to follow-up (n = 5), incorrect image formatting that could not be recovered at the time of core laboratory analysis (n = 5), NIRS console/catheter malfunction at the time of index PCI (n = 3), and loss of disc integrity or corruption before core laboratory analysis (n = 4).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Standard of Care Lipid Therapy | Change in LCBI, Lesion | 8.0 ratio |
| Aggressive Lipid Therapy | Change in LCBI, Lesion | -22.5 ratio |
p-value: 0.02ANCOVA
Primary
LCBI4mm Max
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.
Time frame: at baseline and at 6-8 weeks after intervention
Population: Data were not available in 17 patients because of loss to follow-up (n = 5), incorrect image formatting that could not be recovered at the time of core laboratory analysis (n = 5), NIRS console/catheter malfunction at the time of index PCI (n = 3), and loss of disc integrity or corruption before core laboratory analysis (n = 4).
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Standard of Care Lipid Therapy | LCBI4mm Max | Baseline LCBI4mm max | 356.7 ratio |
| Standard of Care Lipid Therapy | LCBI4mm Max | Follow-up LCBI4mm max | 385.7 ratio |
| Aggressive Lipid Therapy | LCBI4mm Max | Baseline LCBI4mm max | 490.6 ratio |
| Aggressive Lipid Therapy | LCBI4mm Max | Follow-up LCBI4mm max | 336.1 ratio |
Primary
Lipiscan - Lipid Core Burden Index (LCBI)
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.
Time frame: at baseline and at 6-8 weeks after intervention
Population: Data were not available in 17 patients because of loss to follow-up (n = 5), incorrect image formatting that could not be recovered at the time of core laboratory analysis (n = 5), NIRS console/catheter malfunction at the time of index PCI (n = 3), and loss of disc integrity or corruption before core laboratory analysis (n = 4).
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Standard of Care Lipid Therapy | Lipiscan - Lipid Core Burden Index (LCBI) | Baseline LCBI, lesion | 95.4 ratio |
| Standard of Care Lipid Therapy | Lipiscan - Lipid Core Burden Index (LCBI) | Follow-up LCBI, lesion | 99.9 ratio |
| Aggressive Lipid Therapy | Lipiscan - Lipid Core Burden Index (LCBI) | Baseline LCBI, lesion | 132.4 ratio |
| Aggressive Lipid Therapy | Lipiscan - Lipid Core Burden Index (LCBI) | Follow-up LCBI, lesion | 99.8 ratio |
Secondary
Blood Chemistry - HsCRP
Correlation of yellow plaque index with changes in levels of blood HsCRP as compared from baseline to 6-8 weeks after intervention
Time frame: at baseline and at 6-8 weeks after intervention
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Standard of Care Lipid Therapy | Blood Chemistry - HsCRP | Baseline | 1.7 mg/l |
| Standard of Care Lipid Therapy | Blood Chemistry - HsCRP | Follow-Up | 1.9 mg/l |
| Aggressive Lipid Therapy | Blood Chemistry - HsCRP | Baseline | 1.7 mg/l |
| Aggressive Lipid Therapy | Blood Chemistry - HsCRP | Follow-Up | 1.2 mg/l |
Secondary
Diameter Stenosis
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.
Time frame: Baseline and 6-8 weeks post intervention
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Standard of Care Lipid Therapy | Diameter Stenosis | Baseline | 79.9 percentage of lesions |
| Standard of Care Lipid Therapy | Diameter Stenosis | Follow-up | 83 percentage of lesions |
| Aggressive Lipid Therapy | Diameter Stenosis | Baseline | 79.6 percentage of lesions |
| Aggressive Lipid Therapy | Diameter Stenosis | Follow-up | 79.4 percentage of lesions |
Secondary
Fractional Flow Reserve (FFR) Value
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.
Time frame: at baseline and at 6-8 weeks after intervention
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Standard of Care Lipid Therapy | Fractional Flow Reserve (FFR) Value | Baseline | 0.73 ratio | Standard Deviation 0.1 |
| Standard of Care Lipid Therapy | Fractional Flow Reserve (FFR) Value | Follow-up | 0.73 ratio | Standard Deviation 0.1 |
| Aggressive Lipid Therapy | Fractional Flow Reserve (FFR) Value | Baseline | 0.73 ratio | Standard Deviation 0.1 |
| Aggressive Lipid Therapy | Fractional Flow Reserve (FFR) Value | Follow-up | 0.75 ratio | Standard Deviation 0.01 |
Secondary
Intravascular Ultrasound (IVUS) Parameters
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.
Time frame: at baseline and at 6-8 weeks after intervention
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Standard of Care Lipid Therapy | Intravascular Ultrasound (IVUS) Parameters | Baseline Total atheroma volume | 193.7 mm^2 | Standard Deviation 61.7 |
| Standard of Care Lipid Therapy | Intravascular Ultrasound (IVUS) Parameters | 6-8 weeks Total atheroma volume | 199.6 mm^2 | Standard Deviation 63.9 |
| Standard of Care Lipid Therapy | Intravascular Ultrasound (IVUS) Parameters | Baseline Lumen CSA | 2.4 mm^2 | Standard Deviation 0.6 |
| Standard of Care Lipid Therapy | Intravascular Ultrasound (IVUS) Parameters | 6-8 weeks Lumen CSA | 2.4 mm^2 | Standard Deviation 0.7 |
| Aggressive Lipid Therapy | Intravascular Ultrasound (IVUS) Parameters | 6-8 weeks Lumen CSA | 2.5 mm^2 | Standard Deviation 0.7 |
| Aggressive Lipid Therapy | Intravascular Ultrasound (IVUS) Parameters | Baseline Total atheroma volume | 195.8 mm^2 | Standard Deviation 63.3 |
| Aggressive Lipid Therapy | Intravascular Ultrasound (IVUS) Parameters | Baseline Lumen CSA | 2.5 mm^2 | Standard Deviation 0.8 |
| Aggressive Lipid Therapy | Intravascular Ultrasound (IVUS) Parameters | 6-8 weeks Total atheroma volume | 209.6 mm^2 | Standard Deviation 74.1 |
Secondary
Major Adverse Cardiac Events (MACE)
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.
Time frame: at 6-8 weeks after intervention
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Standard of Care Lipid Therapy | Major Adverse Cardiac Events (MACE) | 2 participants |
| Aggressive Lipid Therapy | Major Adverse Cardiac Events (MACE) | 3 participants |
Secondary
Post PCI Cardiac Enzymes
Correlation of yellow plaque index with post procedure CK-MB, Troponin-I release.
Time frame: at 6-8 weeks after intervention
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Standard of Care Lipid Therapy | Post PCI Cardiac Enzymes | CK-MB | 5.1 ng/mL | Standard Deviation 9 |
| Standard of Care Lipid Therapy | Post PCI Cardiac Enzymes | Troponin-I | 0.4 ng/mL | Standard Deviation 1 |
| Aggressive Lipid Therapy | Post PCI Cardiac Enzymes | CK-MB | 3.7 ng/mL | Standard Deviation 0.3 |
| Aggressive Lipid Therapy | Post PCI Cardiac Enzymes | Troponin-I | 0.3 ng/mL | Standard Deviation 5.1 |