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