Compare Trial 2 year follow-up Peter Smits Maasstad Ziekenhuis Rotterdam The Netherlands

Disclosures I have received a speaking fee from Abbott Vascular Research Foundation of the Cardiology Department has received unrestricted research grants from: Abbott Vascular Boston Scientific Here are my disclosures, I have received ……. the research foundation of my cardiology department has received unrestricted research grants from Abbott Vascular and Boston Scientific.

Compare Trial The COMPARE trial is a physician initiated single center prospective randomized trial comparing the Taxus Liberté ™ versus Xience V™ stent in an all-comer / real world situation Zie dia

Compare Trial Purpose of the study To study the outcome of 2e generation drug eluting stents in a study design that reflects everyday clinical practice The study is patient oriented and uses only symptom driven clinical end-points Purpose of the COMPARE trial is to study …..

Study Outline The study outline was simple and straightforward. All eligible patients for PCI could be included. After guide-wire passage and pre-dilatation at the discretion of the operator, just before the stenting procedure, a operator blinded 1: 1 randomisation by a closed envelope method was performed. Patients were randomized towards a Taxus Liberte or a Xience V stent. Clinical events were adjudicated by an independent CEC and target vessel revascularizations were analysed by an independent core lab.

Study Outline Inclusion criteria All patients eligible for PCI Life expectancy of > 5 years Exclusion criteria No dual antiplatelet therapy for 12 months Cardiogenic shock at presentation Expected planned major surgery within 1 month Participation in another trial No informed consent Estimated life expectancy of > 5 years

Patient Diagram and Follow-up Randomized (N=1800) Taxus Liberté (N=903) XIENCE V (N=897) Lost to f/u = 2 Lost to f/u = 1 No study stent = 6 No study stent = 4 1-Year Follow-up (N=1797; 99.8%) Taxus Liberté (N=902) XIENCE V (N=895) Lost to f/u = 2 Lost to f/u = 0 Of the 1800 pts randomized, 903 were allocated to Taxus Liberte stents and 897 pts were allocated to Xience V stents. At 1 year follow up, only 3 patients were lost to follow up, and in the second year we lost another 2 patients for follw-up, so that at 2 year we have follow up data on 99.7 % of our patients. 2-Year Follow-up (N=1795; 99.7%) Taxus Liberté (N=900) XIENCE V (N=895) Clinical events were adjudicated by an independent CEC Target vessel revascularizations were analysed by an independent QCA core lab. 7

Endpoints Primary endpoint Secondary endpoints * All death, non fatal MI and Target Vessel Revascularization (TVR) at 12 months follow-up Secondary endpoints * Cardiac death, non fatal MI, ischemic driven TLR rate annually during 5 years follow-up All death, non fatal MI, TVR at 2 - 5 year follow-up Incidence of definite, probable or possible stent thrombosis annually during 5 years follow-up The primary endpoint was defined as the composite of: all death etc. The secondary endpoints: like the composite of cardiac death etc. and the primary endpoint and the stent thrombosis were originally defined at 1, 3 and 5 year follow-up, but these have been amended to an annual reporting during the 5 years follow up period. * amended from 1,3 and 5 years to annual time points during 5 year follow up

Baseline Characteristics Clinical presentation 1800 pts. Taxus 903 pts Xience 897 pts p Male 72 % 69 % 0.11 Previous AMI 17.6 % 15.2 % 0.37 Previous PCI 13.6 % 13.0% 0.57 Previous CABG 5.9 % 6.7 % 0.47 Previous CVA 6.4 % 4.2 % 0.07 Peripheral artery disease 3.5 % 5.7 % Diabetes 19 % 17.1 % 0.33 Smoking (active) 29 % 32.9 % 0.23 Hypercholesterolemia 49.9 % 53.2 % 0.24 Hypertension 49.5 % 46.5% 0.29 Family History 44.6 % 44.5 % 0.61 This slide represents the patient baseline characteristics. The cardiovascular antecedents and risk factors were similar in both patients groups.

Clinical Presentation 1800 pts. Taxus Xience Clinical presentation at the index procedure was similar between both groups. And in both groups approximately 60% of the patients presented with an acute coronary syndrome. ± 60% ACS p = ns

Baseline Characteristics 1800 patients / 2583 lesions Taxus Xience p Lesions 1294 1286 ns LM 1.6 % 0.46 LAD 37.4 % 39.9 % RCX 25.7 % 23.2 % RCA 33.3 % 32.9 % Grafts 1.9 % 2.1 % 0.55 Lesion per patient 1.46 1.45 0.92 Stent length per lesion 34.0 0.97 Stent per lesion 1.57 1.67 0.07 GP 2b3a blockers 32 % 0.64 B2 / C lesions 73 % 74% 0.20 This slide represents the baseline characteristics of 2583 lesions: 1294 lesions in the Taxus group and 1286 lesions in the Xience group. The lesions were equally distributed among the coronary arteries. On average 1.45 lesions per patient were treated, with an average stent length per lesion of 34 mm. A trend towards more stents per lesion in the Xience group possible reflects the situation that no 32 mm Xience stent is available compared to the 32 mm Taxus stent. Usage of GP2a3b blocers was the same in both groups.

Chronic renal failure 3 % COMPARE TRIAL AMI 25 % Calcification 34 % Multistenting 62 % Ostial 19 % Thrombus 24 % CTO 4 % NSTEMI 23 % Multivessel 27 % Saphenous graft 2 % Bifurcation 10 % Diabetes 18 % Chronic renal failure 3 % Left main 2 % Direct stenting 34 % “REAL WORLD” Therefore, we can say that the COMPARE trial truly reflects a real world situation with:………

Summary 12 months endpoints Taxus Xience Primary endpoint : All death, MI and TVR Cardiac death, MI and Ischemia driven TLR P = 0.023 P = 0.005 Def. & Prob. stent thrombosis Myocardial infarction This is a summary of the 12 months endpoints that were published in the Lancet paper january this year. The primary endpoint, the lesion specific composite endpoint , thombosis and myocardialo infarction rate all were significant lower in the Xience V stent group P = 0.002 P = 0.007 Kedhi et al. Lancet 2010; vol 375: 201-9

Summary 12 months endpoints All death Taxus Xience Cardiac death P = 0.58 P = 0.81 TVR TLR P = 0.0001 P = 0.0002 Kedhi et al. Lancet 2010; vol 375: 201-9

SPIRIT IV TRIAL COMPARE TRIAL 12 months result Overall Overall Everolimus better Paclitaxel better Everolimus better Paclitaxel better Overall Overall < 65 yr > 65 yr No diabetes Diabetes Male Female Female Male Diabetes No diabetes No ACS ACS Hypertension No hypertension Single vessel Multivessel Hypercholesterol No hyperchol. Restenosis De Novo BMI < 30 BMI > 30 Stable angina No stable ang. No Acute MI Acute MI In the subgroup analysis at 12 months a trend was observed towards better outcome with the Xience V stent in almost all subgroups, apart from the diabetic population. The same was observed in the 12 months results of the Spirit IV trial. 1 lesions 2 or more lesions No proximal LAD Proximal LAD No complex Complex lesions Lesion < 20 mm Lesion ≥ 20 mm RVD < 2.75 RVD > 2.75 RVD ≥ 2.75 mm RVD < 2.75 mm Lesion < 13.3 Lesion > 13.3 0.1 Bail-out No Bail-out 0.1 1.0 10.0 0.1 1.0 10.0

Dual anti platelet therapy ns ns ns P = 0.02 Now I come to the 2 year follow-up data. According daily clinical practice DAPT was stopped in vast majority of patients after 1 year, and at 2 year Taxus stent group 15.2% and in the Xience group 11.4 % were on DAPT, which was significant different. * 15.2 % 11.4 %

Primary Endpoint Result @ 2 yr MACE (all death, non-fatal MI and TVR) 13.7 % Taxus Xience Δ 4.7 % 9.1 % Δ 2.9 % 9.0 % 6.2 % P = 0.0016 (log-rank test) RR = 0.66 (0.50-0.86) This is the result of the primary end-point at 2 year: the composite of all death, non fatal MI and TVR. At 12 months follow up, the significant difference of 2.9% in MACE increased to 4.7 % at 2 years follow-up. At two year follow-up, the MACE rate is 13.7 % in Taxus versus 9.0% in Xience group, which is highly statistic significant different according the log rank test, with a rate ratio of 0.66 and 95% Confidence Interval of 0.50 to 0.86 This absolute difference of 4.7% results in a 33 % relative risk reduction. # Patients at Risk Taxus 903 864 852 840 833 822 818 808 800 798 785 781 777 Xience 897 871 866 859 852 844 840 836 832 830 822 818 815

Secondary Endpoint Result @ 2 yr MACE (cardiac death, non-fatal MI and TLR) Taxus Xience 11.4 % 8.2 % Δ 4.0 % Δ 3.3 % 7.4 % 4.9 % This is the result of the first secondary endpoint: the composite of cardiac death, non-fatal MI and ischemic driven target lesion revascularization. Again, the difference in event rate between both stent groups gradually increased over time with an significant difference of 3.3% at 1 year, which increased to 4.0 % at 2 year, with a 11.4% MACE rate in the Taxus group compared to 7.4 % in the Xience group, which is highly significant different with a p value of 0.0038 and rate ratio of 0.65 with confidence interval below 1.0. P = 0.0038 (log-rank test) RR = 0.65 (0.48-0.88) # Patients At Risk: Taxus 903 865 854 844 837 826 822 812 806 804 795 792 788 Xience 897 873 870 863 856 848 845 841 837 835 827 823 820

First Stent Thrombosis @ 2 yr (Definite / Probable according to ARC) Taxus Xience 3.9 % Δ 3.0 % 2.6 % P < 0.0001 (log-rank test) RR = 0.23 (0.11-0.49) Definite & probable stent thrombosis rate according to the ARC definitions which was already highly significant different between both groups, with a 2.6% in the Taxus group versus 0.7% in the Xience group at 12 months, increased to an absolute difference of 3.0 % at 2 years follow-up. Of interest is the low stent thrombosis rate of less then 1% in the Xience group in this all-comer polulation and with only 11% of the patients on DAPT. Δ 1.9 % 0.9 % 0.7 %

Early, Late and Very Late stent Thrombosis (Definite / Probable according to ARC) Early ST 92 % pts on DAPT Late ST 70 % pts on DAPT Very Late ST 13 % pts on DAPT p = 0.002 RR 0.13 (0.04-0.58) p = 0.13 RR 0.38 (0.10-1.42) p = 0.013 RR 0.23 (0.07-0.81) Taxus Xience This landmark presentation represents the differences in stent thrombosis rate during the early, late and very late phase. There is a significant difference in the early phase, a trend in the late phase and a significant difference in the very late phase with only 13% on average on DAPT, all in favour of the Xience V stent. 1.7 % 1.5 % 0.9 % 0.2 % 0.3 % 0.3 % 15 30 30 60 120 180 240 300 360 360 420 480 540 600 660 720 Days

First Definite Stent Thrombosis @ 2 yr (Definite according to ARC) Taxus Xience P < 0.0001 (log-rank test) RR = 0.21 (0.08-0.55) 2.7 % Annual increase 0.7% 2.0 % This slide represents the definite stent thrombosis rate of both stent groups at 2 years follow-up. At one year there was a significant difference which again gradually increases at 2 years follow up. If one disregards the early stent thrombosis rate, the data suggests that with Taxus Liberte one has annual definite stent thrombosis rate of 0.7%, whereas this is only 0.2% for the Xience V, though the number of events are low and the study was not powered for detecting this difference. Δ 2.1 % Δ 1.7 % Annual increase 0.2% 0.3 % 0.6 %

Endpoint Analysis @ 2 yr First Non Fatal MI Taxus Xience P = 0.0009 (log-rank test) RR = 0.52 (0.35-0.77) 7.6 % 5.4 % Δ 3.7 % When looking at the individual components of the composite endpoints, the non fatal MI curves showed a similar outcome to the primary endpoint and stent thrombosis curves. With a significant higher rate of non fatal MI in the Taxus group compared to the Xience group at 12 months follow-up. Δ 2.6 % 3.9 % 2.8 %

Endpoint Analysis @ 2 yr All Death & Cardiac Death Taxus Xience P = 0.67 All Death All death and cardiac death rates, however, were similar in both groups Cardiac Death P = 0.49

Endpoint Analysis @ 2yr Ischemic driven TVR & TLR Taxus Xience P < 0.0001 RR = 0.40 (0.25–0.61) 7.7 % TVR 3.1 % Taxus Xience But TVR and ischemic driven target lesion revascularization rates were highly significantly higher in the Taxus stent group compared to the Xience V stent group. Again with an early difference, which gradually increased over time. P = 0.0005 RR = 0.44 (0.27-0.71) TLR 5.9 % 2.6 %

Subgroup analysis @ 2 yr RR ( 95% CI ) Everolimus better Paclitaxel p value for interaction 0.1 1.0 10.0

Conclusions In this all-comer trial, reflecting a real world patient population, the major secondary endpoints at 2 years showed : superiority of Xience V versus Taxus Liberté (p = 0.0016) MI, TVR, TLR and Stent thrombosis consistently resulted in significant better outcomes for Xience V compared to Taxus Liberté Between 1 and 2 years, when the vast majority of patients were no longer taking DAPT, a significant 77% reduction in very late definite or probable stent thrombosis in favour of Xience V was observed While there was a significant reduction in primary and secondary endpoints in the general patient population with Xience V, no such difference was observed in diabetic patients at 1 and 2 year FU

COMPARE TRIAL DSMB Investigators Eric Boersma (chairman) Elvin Kedhi Eugene McFadden Carlos van Mieghem Kaiyum Sheikjoesoef Peter Smits (PI) Jochem Wassing CEC & Core Lab & Statistics Cardialysis, Rotterdam DSMB Eric Boersma (chairman) Patrick Serruys Benno Rensing CEC Martijn Akkerhuis Jean-Paul Herrman Peter Radke Evelyne Regar Jeroen Vos Pascal Vranckx (chairman) First I would like to thank my co-investigators, the independent DSMB and Clinical Event Committee members and the contract research organisation Cardialysis and last but not least the 1800 patients that were instrumental for completing this study.