Five-Year Follow-up of Safety and Efficacy of the Resolute Zotarolimus-Eluting Stent: Insights from the RESOLUTE Global Clinical Trial Program in Approximately 8000 Patients Prof. Sigmund Silber, MD, PhD FESC, FACC, FAHA Cardiology Practice and Heart Center at the Isar, Munich, Germany on behalf of the RESOLUTE Global Clinical Program Investigators euro PCR 2015

Potential conflicts of interest Speaker's name: Sigmund Silber  Research Grant from Medtronic for the RESOLUTE All Comers Randomized Trial

Background Individual trials, while powered for composite endpoints of various parameters, are often underpowered to show real and truly evidence based differences for low-frequency but important adverse clinical events such as stent thrombosis. Objective of the current analysis is to assess the long-term safety and efficacy outcomes of the Resolute™ zotarolimus- eluting stent (R-ZES) in nearly 8000 patients enrolled in the RESOLUTE Global Clinical Trial Program. RESOLUTE Pooled – 5 Years

Methods This pooled analysis includes all trials within the RESOLUTE Global Clinical Program, including regulatory trials with 100% monitoring, all with high rates of follow-up. Patient level data of all 7618 Resolute patients were pooled, including data to the latest available follow-up of each trial. Kaplan Meier cumulative incidence out to 5 year follow-up was calculated. Strengths: All trials were prospectively performed and event definitions across studies were consistent. The independent clinical event adjudication was harmonized across all studies. Limitations: post-hoc analysis RESOLUTE Pooled – 5 Years

The RESOLUTE Global Clinical Program: 7618 Patients Included in this Pooled Analysis 1 Meredith IT, et al. EuroIntervention. 2010;5: Serruys PW, et al. N Engl J Med. 2010;363: Silber S, et al. Lancet. 2011;377: Neumann FJ, et al. EuroIntervention. 2012;7(10): Belardi JA, et al. J Interv Cardiol. 2013;26(5): Yeung AC, et al. JACC. 2011;57: Lee M, et al. Am J Cardiol. 2013;112(9): Xu B, et al. JACC Cardiovasc Interv. 2013;6(7): Qiao S, et al. Am J Cardiol. 2014;113(4): RESOLUTE 1 Non-RCT First-in-Human (R=139) 5 yr RESOLUTE AC 2,3 1:1 RCT vs. Xience V ™ EES (R=1140; X=1152) 5 yr 2.25 – 4.0 mm Non-RCT vs. Hx Control (R=1402) 5 yr RESOLUTE US – 3.5 mm Non-RCT (R=100) vs. Hx Control RESOLUTE Japan 5 yr 1:1 RCT vs. Taxus ™ PES (R=200; T=200) R-China RCT 8 3 yr Non-RCT Observational (R=2349) 3 yr RESOLUTE Int 4,5 R-China Registry 9 Non-RCT Observational (R=1800) 2 yr R-Japan SVS 2.25 Non-RCT vs. PG (R=65) 3 yr 38 mm sub-study Non-RCT vs. PG (R=114) 3 yr RESOLUTE US 7 Available follow-up RESOLUTE Asia 7 Non-RCT Observational (R=312) 2 yr

% N = 7618 Pts Age (yr) 63.0 ± 11.0 Male75.4 Diabetes mellitus30.4 IDDM6.7 Hypertension71.0 Hyperlipidemia62.3 Current smoker26.4 Family history29.1 Prior MI29.2 Prior PCI25.8 Prior CABG6.3 Cardiac Status: Stable angina33.0 Unstable angina38.1 All myocardial infarction25.9 Acute coronary syndrome52.4 Baseline Patient Characteristics RESOLUTE Pooled – 5 Years

% N = 7618 Pts, Lesions LAD53.2 LCx29.0 RCA34.4 Left Main1.8 Bypass graft1.1 B2/C lesion67.5 Reference Vessel Diameter (mm) 2.8 ± 0.5 Minimum Lumen Diameter (mm) 0.6 ± 0.5 Percent Diameter Stenosis 77.5 ± 16.2 Lesion length (mm) 18.2 ± 11.3 No. of lesions treated per patient 1.3 ± 0.6 No. of stents per patient 1.6 ± 1.0 Total stent length per patient (mm) ± Multi-vessel treament (%)20.5 Complex patient Complex patient definition: bifurcation, bypass grafts, ISR, AMI 2 vessels stented, renal insufficiency or failure (creatinine >140 µmol/L), lesion length >27 mm, >1 lesion per vessel, lesion with thrombus or total occlusion (preprocedure TIMI = 0). Lesion and Procedure Characteristics RESOLUTE Pooled – 5 Years

Definition of Composite Endpoints Device Oriented Composite Endpoint Target Lesion Failure (TLF) Cardiac Death Target Vessel Myocardial Infarction (TV-MI) Target Lesion Revascularization (clinically indicated, TLR) Patient Oriented Composite Endpoint (POCE) All Deaths All Myocardial Infarctions All Revascularizations Cutlip DE, et al. Circulation. 2007; 115: RESOLUTE Pooled – 5 Years

Individual Components of the Device-Oriented Endpoint Time After Initial Procedure (years) 3 Cumulative Incidence (%) Cardiac Death %1.0%1.9%2.8%4.0%5.0% RESOLUTE Pooled – 5 Years Cardiac Death

Individual Components of the Device-Oriented Endpoint Time After Initial Procedure (years) 3 Cumulative Incidence (%) Cardiac Death %1.0%1.9%2.8%4.0%5.0% TV-MI %2.8%3.2%3.6%3.9%4.4% RESOLUTE Pooled – 5 Years Cardiac Death Target Vessel MI (TV-MI) 4.4

Individual Components of the Device-Oriented Endpoint Time After Initial Procedure (years) 3 Cumulative Incidence (%) Cardiac Death %1.0%1.9%2.8%4.0%5.0% TV-MI %2.8%3.2%3.6%3.9%4.4% TLR %2.6%4.0%4.5%5.1%6.3% RESOLUTE Pooled – 5 Years Cardiac Death Target Vessel MI (TV-MI) 4.4 Target Lesion Revascularization (TLR) 6.3

Device Oriented = Target Lesion Failure (TLF) Time After Initial Procedure (years) 3 Cumulative Incidence (%) TLF %5.7%8.1% 9.5%11.4%13.4% RESOLUTE Pooled – 5 Years Device-Oriented Endpoint (TLF): Cardiac Death, TV-MI, TLR

Device- vs. Patient-Oriented Endpoint Time After Initial Procedure (years) 3 Cumulative Incidence (%) TLF POCE RESOLUTE Pooled – 5 Years Device-Oriented Endpoint (TLF): Cardiac Death, TV-MI, TLR Patient-Oriented Endpoint (POCE): All Deaths, All MI, All Revascularizations Note for reference: POCE in RESOLUTE All-Comers was not statistically significant between Resolute ZES and Xience V EES.

DAPT Usage - overall Patients Receiving DAPT (%) Time After Initial Procedure (months) 31.9% R-Pooled (N=7618) RESOLUTE Pooled – 5 Years

DAPT Usage - Individual Trials Patients Receiving DAPT (%) Time After Initial Procedure (months) R-US (N=1402) R-All Comers (N=1140) R-International (N=2349) 11.0% (Europe + Israel) 46.6% (US) RESOLUTE FIM (N=139) R-Japan (N=100) R-Japan SVS (N=65) 62.5% (Japan) R-38mm (N=223) R-Asia Dual vessel (N=202) R-China RCT (N=200) R-China Registry (N=1800) 20.1% (China) 39.4% (ANZ) R-Pooled (N=7618) 34.6% (Intern.) 66.1% (Japan) 65.6% (Asia + US) 51.0% (China) 65.8% (Asia) 31.9% RESOLUTE Pooled – 5 Years

Definite Stent Thrombosis (ARC) Time After Initial Procedure (years) 1 3 Cumulative Incidence of ARC Definite ST (%) 0.46 No. at risk % CI RESOLUTE Pooled – 5 Years

Definite/Probable Stent Thrombosis Time After Initial Procedure (years) 1 3 Cumulative Incidence of ARC Definite/Probable ST (%) No. at risk % CI RESOLUTE Pooled – 5 Years

Very Late Stent Thrombosis (Definite / Probable) Time After Initial Procedure (years) 1 Cumulative Incidence of ARC Very Late Definite/Probable ST (%) No. at risk % CI RESOLUTE Pooled – 5 Years

Conclusions The current analysis of 7618 patients is the largest and longest dataset to date of Resolute patients evaluated. While the complexity of patients varied by study, approximately half of all patients had one or more complex patient characteristics. Significant differences were observed in DAPT duration between trials and geographies, reflective of different clinical practices around the world. The event rates were stable through long-term follow-up. In particular, the rate of very late ST (>1 yr, definite/probable) is low at 0.5% out to 5 years. Long-term follow-up of current generation DES remains critically important to evaluate if there is any increased risk over time of low frequency events. In this pooled analysis, we did not observe any concerns of long term safety associated with the Resolute stent. Over 5 years, more than half of the adverse events were not device (= stent) related, indicating that we still need better general treatment options for patients with coronary artery disease - even after stenting the culprit lesion(s). RESOLUTE Pooled – 5 Years