The RESOLUTE Program today and tomorrow Sigmund Silber

The RESOLUTE Program: today and tomorrow Sigmund Silber, MD, Ph. D FESC, FACC, FAHA Professor of Medicine Heart Center at the Isar Munich, Germany

RESOLUTE Global Clinical Program Zotarolimus eluted from Bio. Linx™ durable polymer Enrollment Complete - In Follow Up RESOLUTE 1 Non-RCT First-in-Human (R=139) 5 yr 1: 1 RCT vs. Xience V™ EES (R=1140; X=1152) 3 yr RESOLUTE Int 4 Non-RCT Observational (R=2349) 3 yr RESOLUTE US 5 2. 25 – 4. 0 mm Non-RCT vs. Hx Control (R=1402) 2 yr 2. 5 – 3. 5 mm Non-RCT (R=100) vs. Hx Control 2 yr 38 mm sub-study Non-RCT vs. PG (R=114) 1 yr RESOLUTE AC 2, 3 RESOLUTE Japan RESOLUTE US R-Japan SVS 2. 25 Non-RCT vs. PG (R=65) < 1 yr R-China RCT 1: 1 RCT vs. Taxus™ PES (R=200; T=200) < 1 yr RESOLUTE Asia Non-RCT Observational (R=312) < 1 yr R-China Registry Non-RCT Observational (R=1800) < 1 yr Enrolling / Planning RI-US Registry 1 Meredith Post-approval study (R=230) enrolling IT, et al. Euro. Intervention. 2010; 5: 692 -7. 2 Serruys PW, et al. N Engl J Med. 2010; 363: 136 -46. 3 Silber S, et al. Lancet. 2011; 377: 1241 -47. 4 Neumann FJ, et al. Euro. Intervention. 2012; 7(10): 1181 -8. 5 Yeung AC, et al. JACC. 2011; 57: 1778 -83.

RESOLUTE All Comers Clinical Trial Design Co-PIs: Profs. Serruys, Silber, Windecker Open label, non-inferiority trial Any patient with symptomatic coronary artery disease eligible for DES implantation (no lesion/vessel limitations) 17 European sites 2300 patients randomized 1: 1 Subsets: QCA 460 pts (20%); OCT 50 pts (2%) 100% monitoring Resolute™ Stent n = 1150 Xience V™ Stent n = 1150 Clinical endpoints 30 d 6 mo 12 mo 13 mo 2 yr 3 yr 4 yr 5 yr Angio/OCT endpoints Primary Endpoint: • 12 -month target lesion failure (TLF), composite of cardiac death, target vessel MI & clinically driven TLR Secondary Endpoints: • Clinical: Patient composite of any death, any MI, & any repeat revascularisation • QCA (powered): 13 -month in-stent % diameter stenosis • QCA: % diameter stenosis, late loss, and binary restenosis Drug Therapy: ASA and clopidogrel/ticlopidine > 6 mo (per guidelines) Serruys PW, Silber, S. et al. , N Engl J Med. 2010; 363(2): 136 -46

RESOLUTE All Comers Patient Eligibility Inclusion Criteria Coronary artery disease • Stable angina • Silent ischemia • Acute coronary syndrome including UA, NSTEMI and STEMI Lesion characteristics • Number of lesions : no limitation • Number of vessels : no limitation • Lesion length : no limitation Written informed consent Exclusion Criteria Known intolerance to Aspirin, clopidogrel, heparin, cobalt alloy, everolimus, zotarolimus, contrast material, polymer coating Planned, elective surgery within 6 months of PCI Unless dual anti-platelet therapy could be maintained Pregnancy Participation in another trial Serruys PW, Silber, S. et al. , N Engl J Med. 2010; 363(2): 136 -46

RESOLUTE All Comers Baseline Characteristics Resolute™ ZES (N = 1140) Xience V™ EES (N = 1152) P value Age (yr) 64. 4 ± 10. 9 64. 2 ± 10. 8 0. 70 Men (%) 76. 7 77. 2 0. 80 Diabetes mellitus (%) 23. 5 23. 4 1. 00 IDDM 8. 4 7. 1 0. 28 ACS (%) 48. 3 47. 7 0. 80 AMI (within 12 hr) (%) 15. 4 17. 8 0. 13 AMI (within 72 hr) (%) 28. 9 28. 8 0. 96 Multivessel disease (%) 58. 4 59. 2 0. 73 Small vessel (RVD ≤ 2. 75 mm) 67. 8 67. 4 0. 88 Long lesion (length >18 mm) 18. 2 21. 2 0. 11 Bifurcation/trifurcation (%) 16. 9 17. 7 0. 62 Total occlusion (%) 16. 3 17. 2 0. 61 In-stent restenosis (%) 8. 1 8. 0 0. 94 Complex Patients 1 (%) 67. 0 65. 6 0. 51 1 Complex patient definition: bifurcation, bypass grafts, ISR, AMI <72 hr, LVEF <30%, unprotected LM, >2 vessels stented, renal insufficiency or failure (creatinine >140 µmol/L), lesion length >27 mm, >1 lesion per vessel, lesion with thrombus or TO (preprocedure TIMI = 0). Resolute Integrity DES is not specifically approved for the following patients subsets; bypass graft, LVEF<30%, unprotected LM and renal insufficiency or failure (creatinine>140µmol/L). Serruys PW, Silber, S. et al. , N Engl J Med. 2010; 363(2): 136 -46

RESOLUTE All Comers Procedure Characteristics Resolute™ ZES N = 1140 patients, 1661 lesions Xience V™ EES N = 1152 patients, 1705 lesions P value Lesions treated per patient 1. 46 ± 0. 73 1. 48 ± 0. 77 0. 46 Lesion length (mm) 11. 89 ± 7. 50 12. 15 ± 7. 86 0. 38 No. of stents per patient 1. 9 ± 1. 2 2. 0 ± 1. 3 0. 02 Stent length per patient (mm) 34 ± 24 37 ± 26 0. 02 Pre-stent balloon dilatation 69. 5% 70. 2% 0. 75 14. 85 ± 3. 14 15. 10 ± 3. 20 0. 01 Implantation of study stent only 98. 0% 96. 9% 0. 11 Lesion success 98. 9% 99. 1% 0. 62 Device success 97. 0% 96. 6% 0. 52 Procedure success 94. 6% 94. 2% 0. 78 Deployment pressure Serruys PW, Silber, S. et al. , N Engl J Med. 2010; 363(2): 136 -46

RESOLUTE All Comers Target Lesion Failure – Primary Endpoint Resolute™ ZES (N = 1140) Cumulative Incidence of Events 20% Xience V™ EES (N = 1152) Log rank P = 0. 92 15% 10% 8. 3% 8. 2% Primary endpoint Pnon-inferiority <0. 001 5% 0% 0 12 24 Time after Initial Procedure (months) 36

RESOLUTE All Comers Target Lesion Failure to 3 Years Resolute™ ZES (N = 1140) Cumulative Incidence of Events 20% Xience V™ EES (N = 1152) Log rank P = 0. 65 HR 1. 05 [0. 84, 1. 33] 15% 13. 1% 12. 4% 10% 5% 0% 0 12 24 Time after Initial Procedure (months) 36

RESOLUTE All Comers Components of Target Lesion Failure at 3 Years Resolute™ ZES (n = 1120) Xience V™ EES (n = 1130) P = 0. 77 0. 3% [-1. 5%, 2. 1%] P = 0. 86 0. 2% [-1. 7%, 2. 2%] Cardiac Death TV-MI TLR Events (%) P = 0. 43 0. 7% [-0. 9%, 2. 2%]

RESOLUTE All Comers Stent Thrombosis (Definite/Probable) to 3 Years Resolute™ ZES (N = 1140) Cumulative Incidence of ARC Definite/Probable ST 15% Xience V™ EES (N = 1152) Log rank P = 0. 10 10% 5% 2. 1% 1. 3% 0% 0 1 2 Time After Initial Procedure (Years) RESOLUTE All Comers was not specifically designed or powered for the analysis shown above. 3

RESOLUTE All Comers Very Late Stent Thrombosis (Definite/Probable) 1 -3 Years 3% Resolute™ ZES (N = 1140) Cumulative Incidence of ARC Definite/Probable ST Xience V™ EES (N = 1152) 2% Log rank P = 1. 00 1% 0. 56% 0. 55% 0% 1 2 Time After Initial Procedure (Years) 3 RZES 1140 1108 1081 CI% 0. 00 0. 27 0. 55 EES 1152 1107 1083 CI% 0. 00 0. 27 0. 56 Patients at Risk RESOLUTE All Comers was not specifically designed or powered for the analysis shown above.

RESOLUTE Global Clinical Program Zotarolimus eluted from Bio. Linx™ durable polymer Enrollment Complete - In Follow Up RESOLUTE 1 Non-RCT First-in-Human (R=139) 5 yr 1: 1 RCT vs. Xience V™ EES (R=1140; X=1152) 3 yr RESOLUTE Int 4 Non-RCT Observational (R=2349) 3 yr RESOLUTE US 5 2. 25 – 4. 0 mm Non-RCT vs. Hx Control (R=1402) 2 yr 2. 5 – 3. 5 mm Non-RCT (R=100) vs. Hx Control 2 yr 38 mm sub-study Non-RCT vs. PG (R=114) 1 yr RESOLUTE AC 2, 3 RESOLUTE Japan RESOLUTE US R-Japan SVS 2. 25 Non-RCT vs. PG (R=65) < 1 yr R-China RCT 1: 1 RCT vs. Taxus™ PES (R=200; T=200) < 1 yr RESOLUTE Asia Non-RCT Observational (R=312) < 1 yr R-China Registry Non-RCT Observational (R=1800) < 1 yr Enrolling / Planning RI-US Registry 1 Meredith Post-approval study (R=230) enrolling IT, et al. Euro. Intervention. 2010; 5: 692 -7. 2 Serruys PW, et al. N Engl J Med. 2010; 363: 136 -46. 3 Silber S, et al. Lancet. 2011; 377: 1241 -47. 4 Neumann FJ, et al. Euro. Intervention. 2012; 7(10): 1181 -8. 5 Yeung AC, et al. JACC. 2011; 57: 1778 -83.

RESOLUTE Pooled Diabetic Analysis Diabetic vs. Non-Diabetic Patient Populations RESOLUTE 139 RESOLUTE AC 1140 RESOLUTE Int 2349 RESOLUTE US 1402 RESOLUTE Japan 100 5130 Resolute™ ZES population Total diabetic patient population N = 1535 “Standard risk” diabetic patient cohort pre-specified for FDA indication Matched cohort diabetic population N = 878 (less complex patients) Matched cohort is all enrolled diabetic subjects excluding subjects with bifurcation, saphenous vein graft (SVG), ISR, AMI (≤ 72 hours), left ventricular ejection fraction (LVEF) <30%, an unprotected left main lesion, ≥ 3 vessels, renal impairment (creatinine ≥ 140µmol/L), total lesion length per vessel >27 mm, ≥ 2 lesions per vessel, lesion with thrombus, or lesion with total occlusion. Silber S. et al, JACC Intv, 2013, (in press)

RESOLUTE Pooled Diabetic Analysis FDA Indication for Patients with Diabetes Mellitus Prespecified diabetes analysis designed with FDA for diabetes indication Performance goal prespecified based on meta-analysis: DIABETES, RAVEL DM, SIRIUS DM, TAXUS IV, SCORPIUS, ENDEAVOR Pooled DM. Standard risk patient population from Pooled RESOLUTE matched to performance goal patient population TVF at 12 Months (powered endpoint) P = 0. 001 Events (%) 14. 5 7. 8 Performance Goal TVF: target vessel failure (cardiac death, TV-MI, and clinically driven TVR) †RESOLUTE matched cohort diabetes pooled analysis (N = 878). Resolute™ DES† Silber S. et al, JACC Intv, 2013, (in press)

RESOLUTE Pooled Diabetic Analysis Baseline Characteristics: All Diabetic Patients, incl. Complex Standard Risk Diabetics N = 878 All Diabetics N = 1535 65. 2 ± 10. 2 65. 6 ± 10. 2 Male 66. 4 68. 1 Diabetes mellitus 100. 0 IDDM 28. 5 29. 6 Prior MI 24. 9 27. 6 Prior PCI 34. 6 34. 5 Stable angina 46. 2 39. 7 Unstable angina 28. 9 26. 8 Myocardial infarction 5. 4 18. 1 44. 8 46. 8 RVD (mm) 2. 7 ± 0. 5 Lesions per patient 1. 1 ± 0. 4 1. 3 ± 0. 6 22. 5 ± 11. 3 28. 5 ± 18. 8 0 42. 8 % Age (yr) Reason for Revascularization: LAD Stent length per patient Complex patients* * Complex patient definition: bifurcation, bypass grafts, ISR, AMI <72 hr, LVEF <30%, unprotected LM, >2 vessels stented, renal insufficiency or failure (creatinine >140 µmol/L), lesion length >27 mm, >1 lesion per vessel, lesion with thrombus or TO (preprocedure TIMI = 0). Silber S. et al, JACC Intv, 2013, (in press)

RESOLUTE Pooled Diabetic Analysis All Patients – Target Lesion Failure to 2 Years Non-Diabetics (N = 3595) All Diabetics (N = 1535) Cumulative Incidence of TLF 20% 15% 11. 2% 10% 7. 7% 5% 8. 4% 6. 1% 0% No. at risk Non-Diabetics 0 6 3595 1535 3540 1518 12 18 Time After Initial Procedure (months) 3399 1447 The RESOLUTE Pooled analysis was not specifically designed or powered for the analysis shown above. 3301 1386 24 3198 1345 Silber S. et al, JACC Intv, 2013, (in press)

RESOLUTE Pooled Diabetic Analysis Baseline Characteristics: ITDM = Insulin Treated Diabetes Mellitus Non-Diabetics N = 3595 63. 1 ± 11. 2 Non-ITDM N = 1080 65. 8 ± 10. 2* ITDM N = 455 65. 2 ± 10. 1 77. 8 0 71. 9* 100. 0* 59. 3** 100. 0 0 0 100. 0** Hypertension 67. 8 84. 6* 90. 3** Hyperlipidemia 67. 7 80. 0* 81. 8 Current smoker Family history 26. 0 19. 7* 14. 7** 38. 1 34. 0* 37. 6 Prior MI Prior PCI 25. 9 26. 7 29. 8 29. 3 32. 7* 38. 9** Prior CABG 7. 4 11. 2* 11. 2 % Age (yr) Male Diabetes mellitus IDDM Clinical status: * Stable angina 38. 0 40. 2 38. 5 Unstable angina 25. 5 26. 2 28. 1 Myocardial infarction 24. 3 17. 8 18. 9 *p-value <0. 05 Non-IDDM vs. Non-Diabetics ** p-value <0. 05 IDDM vs Non-IDDM The RESOLUTE Pooled analysis was not specifically designed or powered for the analysis shown above. Silber S. et al, JACC Intv, 2013, (in press)

RESOLUTE Pooled Diabetic Analysis All Patients – Target Lesion Revascularization to 2 Years Non-Diabetics (N = 3595) Diabetics Non-ITDM (N = 1080) Diabetics ITDM (N = 455) Cumulative Incidence of TLR 20% 15% 10% 4. 7% 4. 3% 5% 3. 0% 0% No. at risk Non-Diabetics Non-IDDM 9. 0% 6. 3% 0 6 3595 1080 455 3589 1078 454 12 18 Time After Initial Procedure (months) 3479 1046 428 3385 1007 409 24 3285 985 389 Error bars indicate a point-wise two-sided 95% confidence interval (± 1. 96*SE). Standard Error based on the Greenwood Formula. Silber S. et al, JACC Intv, 2013, (in press)

RESOLUTE Pooled Diabetic Analysis All Patients – Cardiac Death/TVMI to 2 Years Non-Diabetics (N = 3595) Diabetics Non-ITDM (N = 1080) Diabetics ITDM (N = 455) Cumulative Incidence of Cardiac Death/TVMI 20% 15% 10% 9. 6% 6. 6% 5. 2% 4. 9% 5% 3. 8% 3. 5% 0% No. at risk Non-Diabetics Non-IDDM 0 6 3595 1080 455 3543 1075 445 12 18 Time After Initial Procedure (months) 3442 1041 423 3387 1017 416 24 3306 1005 400 Error bars indicate a point-wise two-sided 95% confidence interval (± 1. 96*SE). Standard Error based on the Greenwood Formula. Silber S. et al, JACC Intv, 2013, (in press)

RESOLUTE Pooled Diabetic Analysis All Patients – ARC Def/Prob Stent Thrombosis to 2 Years Non-Diabetics (N = 3595) Diabetics Non-ITDM (N = 1080) Diabetics ITDM (N = 455) Cumulative Incidence of ARC Def/Prob ST 10% 8% 6% 4% 1. 6 % 0. 8 % 0. 7 % 2% 1. 8 % 0. 9 % 0. 8 % 0% No. at risk Non-Diabetics Non-IDDM 0 6 3595 1080 455 3590 1078 454 12 18 Time After Initial Procedure (months) 3522 1054 437 3471 1032 431 24 3396 1020 417 Error bars indicate a point-wise two-sided 95% confidence interval (± 1. 96*SE). Standard Error based on the Greenwood Formula. Silber S. et al, JACC Intv, 2013, (in press)

RESOLUTE Global Clinical Program Zotarolimus eluted from Bio. Linx™ durable polymer Take Home Messages: • In an all-comer patient population, the Resolute ZES and Xience V EES remained clinically equivalent through 3 years (TLF 13. 1% vs. 12. 4, P = 0. 65). • The incidence of very late stent thrombosis rate is low and similar between Resolute ZES and Xience V EES (definite ST 0. 3% vs. 0. 5%, P = 0. 48). • In patients with diabetes, the Resolute ZES is safe and effective. Patients with diabetes not taking insulin had similar clinical outcomes as patients without diabetes. • But for patients with diabetes who are taking insulin, continued attention is needed and bypass surgery should be considered as an alternative.