Does Aggressive Statin Therapy Reduce Coronary Atherosclerotic Plaque Lipid Content?

1. Does Aggressive Statin Therapy Reduce Coronary Atherosclerotic Plaque Lipid Content? Results From: Reduction in YELlow Plaque by Aggressive Lipid LOWeringTherapy(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

2. Disclosures Annapoorna S. Kini – Institutional research support for the COLOR registry from InfraReDx

3. Study Organization 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

4. 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. • 4S, WOSCOPS, CARE, LIPID • REVERSAL, ASTEROID, PROSPECT, CAMELOT, STRADIVARIUS, SATURN

5. Hypothesis 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 . Primary outcome Change in coronary lipid core burden index (LCBI) after short-term high-dose statin therapy, as determined by Near-infrared Spectroscopy (NIRS).

6. Near Infrared Spectroscopy - Validation Chemogram 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. Chemogram Interpretation Histology Interpretation Histology Gardner et al. JACC Imaging 2008;1(5):638-48.

7. Methods • 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).

8. 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

9. Two/Three Vessel CAD (n= 87) After stenting the target vessel The non-target lesion underwent FFR FFR≤0.8 IVUS, NIRS Randomized StandardAggressive 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

10. Baseline Characteristics

11. Baseline Angiography/IVUS

12. Baseline NIRS Parameters

13. Percent Change in IVUS/angiographic parameters Absolute Change in Lipid Parameters

14. Paired Analysis – Lesion LCBI P = 0.47 P = 0.0008 Baseline 400 Follow-up LCBI Absolute LCBI Reduction 200 33 0 Standard Aggressive

15. Paired Analysis – 10mm LCBI P = 0.57 P < 0.0001 800 Baseline Follow-up 600 Absolute LCBI Reduction LCBI 400 118 200 0 Standard Aggressive

16. Paired Analysis – 4mm LCBI 1000 P = 0.90 P < 0.0001 Baseline Follow-up 800 Absolute LCBI Reduction 600 LCBI 154 400 200 0 Standard Aggressive

17. Case Example Lesion LCBI: 259 Max10mm LCBI: 511 Baseline Max4mm LCBI: 802 Plaque Area 5.6mm2 FFR: 0.74 Lesion LCBI: 177 Follow-up Max10mm LCBI: 289 Max4mm LCBI: 474 Plaque Area 5.5mm2 FFR: 0.78

18. Limitations • 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.

19. 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)

20. 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.

21. 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.

22. 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.

23. Acknowledgments • 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

24. END

25. Total number of patients enrolled: N= 87 Randomized to SOC: N= 43 Randomized to Rosuvastatin 40mg N= 44 • 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

26. Adverse Events

27. 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 Chemogram Block Chemogram Wire Detection Landmark

28. Percent Change in LCBI P = 0.04 P = 0.09 P = 0.05 Δ LCBI Standard Aggressive Lesion LCBI mLCBI/10mm mLCBI/4mm

29. Adjusted associations between aggressive treatment and LCBI reduction