The IBIS-4 trial was supported by the Swiss National Science Foundation

1. Effect of high-intensity statin therapy on atherosclerosisin non-infarct related coronary arteries: a serial intravascular ultrasonography study IBIS-4 (Integrated Biomarkers and Imaging Study) Lorenz Räber, Masanori Taniwaki, Serge Zaugg Henning Kelbaek, Marco Roffi, Lene Holmvang Stephane Noble, Giovanni Pedrazzini, Aris Moschovitis Thomas F. Lüscher, Christian M. Matter, Patrick W. Serruys Peter Jüni, Hector M. Garcia Garcia, Stephan Windecker Bern University Hospital, Switzerland

2. Speaker’s name: Lorenz Räber, MD  I have the following potential conflicts of interest to report:  Research contracts  Consulting  Employment in industry  Stockholder of a healthcare company  Owner of a healthcare company  Other(s):  I do not have any potential conflict of interest X The IBIS-4 trial was supportedbytheSwiss National Science Foundation and an unrestrictedgrantbyVolcano Europe, Belgiumand Biosensors S.A., Switzerland.

3. Background I • Statinspotentlyreducecardiovascularadverseeventsandare • particularlyeffective in patientswithacutecoronarysyndromes. • Intravascularultrasoundstudieshaveshownthat high • intensitystatintherapyresults in atheromaregression in patients • withstable, non-obstructive CAD. • STEMI patientsare at high riskforrecurrentatherothromboticevents • relatedto multi-focaldiseasewith a high prevalenceof vulnerable • plaquestypicallyextendingbeyondtheculpritlesionsite.

4. Hypothesis I Coronary atherosclerosis regression can be achieved by high-intensity rosuvastatin therapy (40 mg daily) in the proximal segments of non-infarct related arteries (non-IRA) of STEMI patients within 13 months.

5. Background II • Plaque phenotype is relevant in the pathogenesis of future • cardiovascular events. Therefore, it is of interest to study • changes in plaque compositionin response to high-intensity • statin therapy. • Radiofrequency-IVUS has been validated for the characterization • of plaque composition including necrotic core based on ex-vivo • histological analyses.

6. Hypothesis II High-intensity rosuvastatin therapy results in a reduction of RF-IVUS defined necrotic core and a decrease in the frequency of RF-IVUS defined thin cap fibroatheromas (TCFA).

7. Study Design 1161 Acute STEMI Patients 1:1 Randomization Biomatrix vs. BMS (COMFORTABLE AMI) 11 international sites Inclusion 9/2009 - 1/2011 TIMI >2 Hemodynamicstability Age <90 yrs Nostenosis >50% in non-IRA Anatomicallysuitable 103 Acute STEMI Patients IVUS RF-IVUS OCT Rosuvastatin 20 mg over 2 Weeks Rosuvastatin 40mg over 13 Mo 5 Sites (N=103) Bern (60) Copenhagen (21) Geneva (13) Lugano (6) Zurich (3) 1° Endpoint @ 1 Year Räber et al. JAMA 2012 2year follow-up 1° Endpoint@ 13mo Change in % Atheroma Volume Change in % Necrotic Core IVUS RF-IVUS OCT 5 year follow-up

8. Study Design Non-IRA IRA (not reported) Baseline Proximal part (>40 mm) 2 major non-IRA vessels 1 IRA vessel (stent) Matched BL - FUP 13 MonthsF/U

9. Methods and Definitions

10. RF-IVUS LesionClassification Lesion = 40% plaqueburden > 3 consecutiveframes Confluentnecroticcore > 10% NO YES >15% Fibrofatty 30° NC abuttinglumen in 3 cons. frames NO YES NO YES Path. Int. Thick. Fibrous ThCFA TCFA >10% confluentcalcium Fibrocacific

11. IBIS-4 Trial: Flow of Patients 103 patients 206 major coronary vessels 34 vessels with unsuccessful imaging Successful imaging @ baseline 101 patients 172 vessels (IVUS and RV-IVUS) 12 patients refused FUP (12%) 11 vessels with unsuccessful imaging Successful serial imaging @ 13 months 82 patients (80%) 146 vessels (IVUS and RF-IVUS)

12. Clinical Characteristics

13. Medication @ Follow-up

14. Lipid Levels @ 30 days and 13 months Δ -1.4 mmol/L p<0.0001 Δ -0.1 mmol/L p<0.0001 1.2 mmol/L 3.3 mmol/L 1.1 mmol/L 1.9 mmol/L

15. Study Segments: Non-Infarct Related Arteries Vessel type and Length LAD 26% RCX 39 % RCA 35 % Vessellength per patient @ BL 64.4 ± 27.2 mm Vessellength per patient @ FUP 64.5 ± 26.9 mm

16. Primary (and Secondary) IVUS Endpoint Measures 1° EP PercentAtheroma Volume 43.95 ± 9.66 mm2 -0.9% (-1.56 to -0.25) P=0.007 43.02 ± 9.82 mm2

17. Proportion of Patients With Plaque Regression Regression In one non-IRA Baseline % In both non-IRA 67.5% Plaque burden 57.8% 13 months

18. Stratified Analysis According to Lipid Levels Change in PAV

19. Primary RF-IVUS Endpoint Change PercentNecroticCore Baseline 13 MonthsF/U 21.02 ± 7.04 % 21.14 ± 7.43 % Δ-0.05 % (-1.05 to 0.96), p=0.93 Exploratory EP: Absolute Change Necrotic Core 0.84 ± 0.68 mm² 0.92 ± 0.73 mm² Δ-0.08 mm² (-0.13 to –0.03), p=0.002

20. RF-IVUS Lesion Phenotype Analysis 82 seriallyassessedpatientswith 146 analysedvessels 70% 75% 15% 13% 158 lesions 165 lesions 6% 5% 5% 6% 4% Other: fibrocalcific, fibrotic 1 lesion was not present at BL but at FUP

21. Limitations • No formal sample sizecalculationasthis was a pre-specifiedsubstudyof a RCTcomparing BMS with DES in STEMI patients. • - Exploratoryanalysisusingconfidenceintervalsshows 80% power • todetect a PAV reductionof 0.94%. • Serial imagingstudywithoutcontrolgroup. • - Absence of high-intensitystatintherapy was consideredclinicallyunacceptable. • Onlyselected STEMI patientsunderwentserialimaging. • - Multi-vesselimaging in thesettingof STEMI istechnically • demandingandcanonlybeperformed in stabilized STEMI • patients. • Imaging was obtained at 13 months, whichmightaffecttheabilitytodetectlong-term changes in plaquecompositionandphenotype.

22. Conclusions • The proximal segmentsof non-IRA of STEMI patientsfeature a high athero- • scleroticplaqueburdenwiththemajorityoflesionscharacterizedas • RV-IVUS definedthin-capfibroatheromas. • High-intensitystatintherapythroughout13 monthsisassociatedwith a • significantreductionofcoronaryatherosclerosis. • High-intensitystatintherapydid not changetheproportionofRF-IVUS definednecroticcoreandplaquephenotypes.