does aggressive statin therapy reduce coronary atherosclerotic plaque lipid content? results from:...
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Does Aggressive Statin Therapy Reduce Coronary Atherosclerotic Plaque Lipid Content?
Results From: Reduction in YELlow Plaque by Aggressive Lipid LOWering Therapy (YELLOW) Trial
Annapoorna S Kini, PR Moreno, J Kovacic, A Limaye, ZA Ali, J Sweeny, U Baber, R Mehran, G Dangas, SK Sharma
Cardiac Catheterization LaboratoryMount Sinai Heart
Mount Sinai Hospital, NY, NY
Annapoorna S. Kini – Institutional research support for the COLOR registry from InfraReDx
Disclosures
Principal Investigator: Annapoorna S. Kini, MD
Co-PI: Pedro R. Moreno, MD
DSMB: Chair- Donald Smith, MD, Mount Sinai School of Medicine (MSSM)
Imaging Core Laboratory: Akiko Maehara, MD, Cardiovascular Research Foundation
Data Coordination/Analysis: Usman Baber, MD, Roxana Mehran, MD, MSSM
Sponsor: Mount Sinai School of Medicine
Study Organization
Background
• Multiple large RCT have shown beneficial effects of statin therapy in both primary and secondary prevention.1
• Several studies using gray-scale IVUS have demonstrated modest atherosclerotic plaque regression in non-obstructive coronary atheroma using statin therapy.2
• Whether statins modulate coronary atherosclerotic plaque composition or coronary flow physiology in obstructive lesions, and the timing for these effects remains unclear.
1. 4S, WOSCOPS, CARE, LIPID2. REVERSAL, ASTEROID, PROSPECT, CAMELOT, STRADIVARIUS, SATURN
High-Dose statin therapy will reduce lipid core content in severely obstructive coronary lesions in the short term (6-8
weeks), as evaluated by Near-infrared Spectroscopy .
Hypothesis
Primary outcomeChange in coronary lipid core burden index (LCBI) after short-term high-dose statin therapy, as determined by Near-infrared Spectroscopy (NIRS).
Near Infrared Spectroscopy - Validation
Gardner et al. JACC Imaging 2008;1(5):638-48.
Chemogram
Chemogram Interpretation
Histology Interpretation
Histology
NIRS provides lipid contents based on the spectra processed by principal component analysis, and shown as lipid core burden index;
LCBI (range 1~1000) for each region of interest.
• Prospective, single-center, single blinded randomized trial in patients with multivessel, hemodynamically significant coronary lesions who were eligible for staged PCI at Mount Sinai Medical Center were screened.
• Following PCI of the target lesion, remaining non-target, angiographically significant lesions were evaluated for hemodynamic significance with FFR. If FFR ≤0.8 the patient was enrolled in the study.
• Baseline intracoronary imaging of the non-target lesion• Gray-scale IVUS• NIRS
• Randomization - Standard of Care (Standard) versus Intensive statin therapy with Rosuvastatin 40mg daily (Aggressive).
Methods
Total number of patients screened: N = 779
Generally/Clinically Excluded: N = 108• Hypersensitivity N = 28)• Renal Insufficiency (N = 28)• Currently prescribed Crestor 40mg therapy (N = 19)• Participating in another investigational drug/device study (N = 5) • Unable to sign or withdrew informed consent (N= 28)
Angiographically Excluded: N = 487•Normal coronaries, non-obstructive or 1 vessel CAD (N = 417)•ISR, CTO, vein graft or highly calcified lesions (N = 62)•Left main disease (N = 8)
Other Exclusions: N= 97•FFR > 0.80 (N = 17)•PMD refused (N = 41)•Surgical or medical therapy (N = 36)•Technical issues (N = 3)
Number of Subjects Randomized: N = 87
Methods
Two/Three Vessel CAD
(n= 87)
After stenting the target vesselThe non-target lesion underwent FFR
FFR≤0.8 IVUS, NIRS
Randomized Standard Aggressive n = 43 n = 44 Continue statin the patient was taking Rosuvastatin 40 mg daily Dual antiplatelet therapy for 1 year Dual antiplatelet therapy for 1 year
Follow up Cath (6-8 weeks)FFR, IVUS and NIRS repeated.
If FFR ≤0.8, lesion stented and imaging repeated.If FFR > 0.8 the patient was treated medically.
Imaging data analyzed by CRF Core LabData analysis for primary outcome analyzed by MSH independent Core Lab
*Optimal medical therapy for all patients
Baseline CharacteristicsStandard(n = 43)
Aggressive (n = 44)
P
Age 62.9 ± 9.8 64.4 ± 9.29 0.46
Female (%) 27.9 20.5 0.42
Current tobacco use (%) 9.5 20.5 0.52
Hypertension (%) 95.3 90.9 0.41
Hypercholesterolemia 93.0 88.6 0.48
Family history 41.9 45.5 0.74
Insulin-dependent Diabetes
7.0 11.4 0.48
Prior CVA/TIA 7.0 4.5 0.62
Previous MI 18.6 18.2 0.96
Previous PCI 46.5 36.4 0.34
Statin use, % 81 83 0.81
Total cholesterol (mg/dl) 144.4 ± 30.8 143.8 ± 26.4 0.93
Triglycerides 123.2 ± 61.7 107.0 ± 66.2 0.25
HDL-C (mg/dl) 37.0 ± 10.4 41.6 ± 10.5 0.04
LDL-C (mg/dl) 82.8 ± 26.9 79.1 ± 25.3 0.51
Creatinine (mg/dl) 1.1 ± 1.3 1.0 ± 0.3 0.38
C-reactive protein 2.7 ± 3.0 4.7 ± 10.9 0.24
Baseline Angiography/IVUS
Variable Standard (n = 43) Aggressive (n = 44) P
Angiography
Diameter stenosis, % 79.9 ± 8.3 79.6 ± 7.8 0.89
Number of stents 1.1 ± 0.4 1.1 ± 0.4 0.60
FFR, mean 0.73 ± 0.1 0.72 ± 0.08 0.83
IVUS
Volumetric Lumen CSA (mm2) 2.4 ± 2.1 2.5 ± 2.2 0.77 Luminal Stenosis (%) 75.7 ± 7.2 76.0 ± 6.0 0.86 EEM CSA (mm2) 10.6 ± 3.8 10.8 ± 4.3 0.86 Plaque + media CSA (mm2) 8.2 ± 3.5 8.4 ± 3.7 0.89 Plaque burden, % 75.7 ± 7.2 75.9 ± 6.0 0.86 Total atheroma volume (normalized) 197.3 ± 61.7 195.8 ± 63.3 0.93 Percent atheroma volume 62.5 ± 6.1 61.5 ± 5.0 0.46 EEM CSA (mm3/mm) 11.4 ± 3.2 11.4 ± 3.1 0.96 Lumen CSA (mm3/mm) 4.2 ± 1.3 4.3 ± 1.0 0.75
Plaque + Media CSA (mm3/mm) 7.1 ± 2.2 7.1 ± 2.3 0.92
Lesion Length (mm) 25.3 ± 11.5 33.26 ± 14.6 0.02
EEM Volume (mm3) 290.5 ± 152.0 371.3 ± 166.1 0.05
Lumen Volume (mm3) 110.3 ± 64.4 143.3 ± 66.1 0.05
VariableStandard
(n = 43)
Aggressive
(n = 44)P
LCBI (lesion) 130.3 ± 139.6 167.9 ± 118 0.21
LCBI (10 mm max segment) 245.9 ± 216.8 350.1± 66.1 0.05
LCBI (4 mm max segment) 362.6 ± 268.9 510.9 ± 193.5 0.01
Block Chemogram Yellow, % 15.8 22.9 0.11
Tan, % 8.8 12.0 0.16
Orange, % 9.5 10.7 0.52
Red, % 65.9 54.3 0.05
Baseline NIRS Parameters
VariableStandard (n = 43)
Aggressive (n = 44) P
Percent atheroma volume 0.26% 0.24% 0.98
TAV (normalized) -2.4% -0.2 0.41
Plaque burden, % -1.8% 0.06% 0.15
Plaque + Media CSA (mm3/mm) -0.8% 1.5% 0.41
Diameter stenosis 5.3% -1.0% 0.12
FFR increase to >0.80 4.6% 9% 0.47
Any FFR increase, % 34.9 40.9 0.62
VariableStandard
(n = 43)
Aggressive
(n = 44)P
Total cholesterol, mg/dl (Δ) 149 ± 23 (5.2 ± 5.4) 123 ± 27 (-20 ± 4.8) 0.001
LDL-C, mg/dl (Δ) 82 ± 5 (-0.2 ± 4.7) 60 ± 5 (-19 ± 4) 0.003
HDL-C, mg/dl (Δ) 36 ± 11 (1.5 ± 0.9) 41 ± 9.2 (0.6 ± 1.2) 0.58
Triglycerides, mg/dl (Δ) 161 ± 19 (17 ± 14) 145 ± 20 (1.9 ± 7.8) 0.34
C-reactive protein, mg/dl (Δ) 3.5 ± 2.9 -1.2 ± 0.9 0.11
Percent Change in IVUS/angiographic parameters
Absolute Change in Lipid Parameters
Paired Analysis – Lesion LCBI
Baseline
Follow-up
LC
BI
400
200
0
Standard Aggressive
P = 0.47 P = 0.0008
33
Absolute LCBIReduction
Paired Analysis – 10mm LCBI
400
200
0
Standard Aggressive
800
600
P < 0.0001P = 0.57Baseline
Follow-up
LC
BI
118
Absolute LCBIReduction
Paired Analysis – 4mm LCBI
400
200
0
Standard Aggressive
800
600
1000
LC
BI
P < 0.0001P = 0.90 Baseline
Follow-up
154
Absolute LCBIReduction
Baseline
Lesion LCBI: 259
Follow-up
Max10mm LCBI: 511
Max4mm LCBI: 802
Lesion LCBI: 177
Max10mm LCBI: 289
Max4mm LCBI: 474
Case Example
Plaque Area 5.6mm2
Plaque Area 5.5mm2 FFR: 0.78
FFR: 0.74
• Single-center, small sample size and lack of long-term follow-up limits evaluation for clinical events
• Despite randomization and comparable baseline characteristics, there was higher baseline maximum LCBI in the 4 and 10mm analysis in the aggressive treatment group that may be a reflection of random play of chance in a small sample size.
Limitations
Conclusions
• Aggressive lipid therapy results in significant reductions in the lipid content of coronary atherosclerotic plaque detected by NIRS in a short time frame (6-8 weeks)
Conclusions
• Aggressive lipid therapy results in significant reductions in the lipid content of coronary atherosclerotic plaque detected by NIRS in a short time frame (6-8 weeks)
• Concordant changes in conventional parameters (i.e: coronary flow physiology [FFR] or gray-scale IVUS) were not observed.
Conclusions
• Aggressive lipid therapy results in significant reductions in the lipid content of coronary atherosclerotic plaque detected by NIRS in a short time frame (6-8 weeks)
• Concordant changes in conventional parameters (i.e: coronary flow physiology [FFR] or gray-scale IVUS) were not observed.
• These findings suggest that aggressive statin therapy modulates lipid composition of significant coronary atherosclerotic plaque, properties that may contribute to plaque stabilization and/or regression.
Conclusions
• Aggressive lipid therapy results in significant reductions in the lipid content of coronary atherosclerotic plaque detected by NIRS in a short time frame (6-8 weeks)
• Concordant changes in conventional parameters (i.e: coronary flow physiology [FFR] or gray-scale IVUS) were not observed.
• These findings suggest that aggressive statin therapy modulates lipid composition of significant coronary atherosclerotic plaque, properties that may contribute to plaque stabilization and/or regression.
• A large randomized trial (YELLOW II) based on the present concept with long-term follow-up is forthcoming.
• Co-Investigators:– Samin Sharma
– Pedro Moreno
– Jason Kovacic
• Mount Sinai Cath Lab:– Atul Limaye
– Joseph Sweeney
– George Dangas
– Ziad Ali
• Statistical Analysis:– Usman Baber
• Trial Coordinators:– Kristen Falciglia
– Asif Adam
• Imaging Core Lab (CRF):
– Akiko Maehara
• Data Coordinating Center:– Roxana Mehran
Acknowledgments
ENDEND
Randomized to Rosuvastatin 40mg
N= 44
Randomized to SOC: N= 43
• Baseline imaging: N = 43• Follow-up imaging: N = 39• Follow-up imaging not done: N = 4
• Lost to FU: 3• PMD refused: 1
• Baseline imaging: N = 44• Follow-up imaging: N = 42• Follow-up imaging not done: N = 2
• Lost to FU: 2
• Paired IVUS: N= 32/43• Paired LIPISCAN: N= 34/43
• Paired IVUS: N= 38/44• Paired LIPISCAN: N= 38/44
Total number of patients enrolled: N= 87
Event Standard Aggressive P
Death, % 0.0 0.0 NA
Myocardial infarction, %
20.9 15.9 0.59
Periprocedural, % 18.6 15.9
Spontaneous, % 2.3 0.0
Unplanned Revascularization, %
4.7 0.0 0.24
Major Bleeding, % 4.7 0.0 0.24
Periprocedural complications, %
2.3 6.8 0.61
Myalgias, % 0.0 4.5 0.24
Adverse Events
Chemogram
Landmark
Wire Detection
Block Chemogram
Near Infrared Spectroscopy (NIRS)
NIRS provides lipid contents based on the spectra processed by algorithm and
shown as lipid core burden index; LCBI (range 1~1000) for each region of interest.
Proximal
Percent Change in LCBI
Lesion LCBI mLCBI/10mm mLCBI/4mm
P = 0.04 P = 0.09 P = 0.05
Standard
Aggressive
Adjusted associations between aggressive treatment and LCBI reduction
Univariate Age/Sex adjusted Multivariable adjusted*
β p-value β p-value β p-value
Lesion LCBI -48.9 0.012 -47.0 0.016 -45.1 0.07
LCBI (10 mm max) -109.2 <0.001 -107.9 0.001 -116.9 0.002
LCBI (4 mm max) -133.0 0.001 -133.6 0.001 -150.2 0.003
Adjustment for change in LDL-C, HDL-C, CRP