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 Laboratory Mount 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, LIPID 2.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 outcome Change 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): 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 vessel The 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 Lab Data analysis for primary outcome analyzed by MSH independent Core Lab *Optimal medical therapy for all patients

Baseline Characteristics Standard (n = 43) Aggressive (n = 44) P Age62.9 ± ± Female (%) Current tobacco use (%) Hypertension (%) Hypercholesterolemia Family history Insulin-dependent Diabetes Prior CVA/TIA Previous MI Previous PCI Statin use, % Total cholesterol (mg/dl)144.4 ± ± Triglycerides123.2 ± ± HDL-C (mg/dl)37.0 ± ± LDL-C (mg/dl)82.8 ± ± Creatinine (mg/dl)1.1 ± ± C-reactive protein2.7 ± ±

Baseline Angiography/IVUS VariableStandard (n = 43)Aggressive (n = 44)P Angiography Diameter stenosis, %79.9 ± ± Number of stents1.1 ± FFR, mean0.73 ± ± IVUS Volumetric Lumen CSA (mm 2 ) 2.4 ± ± Luminal Stenosis (%) 75.7 ± ± EEM CSA (mm 2 ) 10.6 ± ± Plaque + media CSA (mm 2 ) 8.2 ± ± Plaque burden, % 75.7 ± ± Total atheroma volume (normalized) ± ± Percent atheroma volume 62.5 ± ± EEM CSA (mm 3 /mm) 11.4 ± ± Lumen CSA (mm 3 /mm) 4.2 ± ± Plaque + Media CSA (mm 3 /mm) 7.1 ± ± Lesion Length (mm) 25.3 ± ± EEM Volume (mm 3 ) ± ± Lumen Volume (mm 3 ) ± ±

Variable Standard (n = 43) Aggressive (n = 44) P LCBI (lesion) ± ± LCBI (10 mm max segment) ± ± LCBI (4 mm max segment) ± ± Block Chemogram Yellow, % Tan, % Orange, % Red, % Baseline NIRS Parameters

Variable Standard (n = 43) Aggressive (n = 44) P Percent atheroma volume 0.26% 0.24%0.98 TAV (normalized) -2.4% Plaque burden, % -1.8% 0.06%0.15 Plaque + Media CSA (mm 3 /mm) -0.8% 1.5%0.41 Diameter stenosis 5.3% -1.0%0.12 FFR increase to > % 9%0.47 Any FFR increase, % Variable Standard (n = 43) Aggressive (n = 44) P Total cholesterol, mg/dl (Δ) 149 ± 23 (5.2 ± 5.4)123 ± 27 (-20 ± 4.8) LDL-C, mg/dl (Δ) 82 ± 5 (-0.2 ± 4.7)60 ± 5 (-19 ± 4) 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 ± ± Percent Change in IVUS/angiographic parameters Absolute Change in Lipid Parameters

Paired Analysis – Lesion LCBI Baseline Follow-up LCBI StandardAggressive P = 0.47P = Absolute LCBI Reduction

Paired Analysis – 10mm LCBI StandardAggressive P < P = 0.57 Baseline Follow-up LCBI 118 Absolute LCBI Reduction

Paired Analysis – 4mm LCBI StandardAggressive LCBI P < P = 0.90 Baseline Follow-up 154 Absolute LCBI Reduction

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 5.6mm 2 Plaque Area 5.5mm 2 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

END

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

EventStandardAggressiveP Death, %0.0 NA Myocardial infarction, % Periprocedural, % Spontaneous, % Unplanned Revascularization, % Major Bleeding, % Periprocedural complications, % Myalgias, % 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 Δ LCBI P = 0.04P = 0.09P = 0.05 Standard Aggressive

Adjusted associations between aggressive treatment and LCBI reduction UnivariateAge/Sex adjustedMultivariable adjusted* βp-valueβ β Lesion LCBI LCBI (10 mm max)-109.2< LCBI (4 mm max) Adjustment for change in LDL-C, HDL-C, CRP