Peter Smits Maasstad Ziekenhuis Rotterdam The Netherlands Compare Trial Peter Smits Maasstad Ziekenhuis Rotterdam The Netherlands

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.

Disclosures No personal disclosures Research Foundation of the Cardiology Department has received unrestricted research grants from: Abbott Vascular Boston Scientific I have no personal disclosures, but 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

Randomized Controlled Trials Pitfalls AMI Calcification Multistenting Ostial Thrombus Long lesions CTO Unstable angina Multivessel Saphenous graft Bifurcation Diabetes Chronic renal failure Left main Diffuse disease “REAL WORLD” The large randomized controlled trials have their pitfalls. It’s always debated whether the RCT reflect daily practice. In the RCT often many subsets of patients and/or lesions are excluded; like left main, bifurcation, grafts, CTO, thrombotic, ostial or severe calcified lesions, , but also patients with acute MI, multivessel disease, or chronic renal failure.

Compare Trial Purpose of the study To study the outcome of 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 …..

Taxus Liberté Paclitaxel TransluteTM Liberté™ Xience V Everolimus The Taxus Liberte consists of a thin strut stainless steel stent, coated with Translute - a hydro-carbon elastomer- from which paclitaxel elutes. The Xience V stent consists of a thin strut cobalt chromium stent , coated with a Fluoropolymer: perfluor elastomer- from which everolimus gradually elutes Everolimus Fluoropolymer VisionTM

Strut and Polymer Thickness CYPHER® TAXUS® Liberté ENDEAVOR XIENCE V Strut Thickness: 140 mm Polymer Thickness: 13.7 mm Strut Thickness: 97 mm Polymer Thickness: 17.8 mm Strut Thickness: 91 mm Polymer Thickness: 4.8 mm Strut Thickness: 81 mm Polymer Thickness: 7.8 mm If we compare the commercially available DES stents, we can see that the Xience V stent has a thinner stent strut and a thinner polymer compared to the Taxus Liberte. 3.0 mm diameter stents, 500x magnification Data on file at Abbott Vascular.

Rapid Re-endothelialization 14-Day Rabbit Iliac Study XIENCE V CYPHER® TAXUS® ENDEAVOR Pre-clinical data from a rabbit model, indicates that the everolimus eluting Xience V stent has a more rapid and pronounced re-endothelialization compared to the other commercially available DES, like the Taxus Liberte stent. Joner M et al. JACC 2008:52:333-342

Study Outline Clinical events were adjudicated by an independent CEC 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. With an expected MACE of 9 versus 14 %, we calculated that with a power of 85%, we needed at least 1800 patients. All patients were monitored during the 1 year follow-up period, only 3 patients out of 1800 patents (0.16%) were lost for follow-up. Clinical events were adjudicated by an independent CEC and target vessel revascularizations were analysed by an independent core lab. Clinical events were adjudicated by an independent CEC Target vessel revascularizations were analysed by an independent QCA core lab. All patients were monitored for 12 months; only 3 pts (0.16%) were lost for FU.

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

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 at 12 months follow-up. all death, non fatal MI, TVR at 3 and 5 years follow-up incidence of definite, probable or possible stent thrombosis at 12 months, 3 and 5 years

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 at the index procedure of 903 patients randomized to Taxus and 897 patients randomized to Xience V. 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: 37-39 % stable angina, 2-3 % silent ischemia, 12 % unstable angina, 22-24 % non-stemi and 23-26% stemi; indicating that in both groups 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 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.

Lesion Characteristics 1800 patients / 2583 lesions Taxus Xience Lesion characteristics according the ACC/AHA classification showed also a equal distribution between both randomised study groups. With 5-6% type A lesions, ….. Indicating that in both stent groups almost three quarter of the lesions were classified to B2, type C lesions. 73 % B2 / C 74 % B2 / C p = 0.20

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:………

Primary Endpoint Result MACE (all death, non-fatal MI and TVR) Taxus Xience P = 0.023 (log-rank test) RR = 0.69 (0.50-0.95) 9.1 % Δ 2.9 % Δ 1.1% 6.2 % This is the result of the primary end-point: the combination of all death, non fatal MI and TVR. At 12 months follow up, a significant higher incidence of MACE occurred in the Taxus stent group compared to the Xience stent group. The MACE rate is 9.1% in Taxus versus 6.2% in Xience, which is significant different according the log rank test, with a rate ratio of 0.69 and 95% Confidence Interval of 0.50-0.95. Of interest is the early difference in events between both groups of 1.1% at 30 days, which gradually increased over time to 2.9% at 12 months follow-up . # Patients at Risk Taxus 903 868 865 860 853 849 842 838 833 825 823 822 819 Xience 897 872 870 867 865 864 858 854 851 849 844 842 840

Secondary Endpoint Result MACE (cardiac death, non-fatal MI and TLR) Taxus Xience P = 0.005 (log-rank test) RR = 0.60 (0.42-0.86) 8.2 % Δ 3.3 % Δ 1.2 % This is the result of the secondary endpoint of the combination of cardiac death, non-fatal MI and ischemic driven target lesion revascularization. Again, a significant difference between both groups at 12 months follow-up, with a 8.2% MACE rate in the Taxus group compared to 4.9 % in the Xience group, which is highly significant different with a p value of 0.005 and rate ratio of 0.6 with confidence interval below 1.0. The same early difference in event rate occurred between both stent groups, which gradually increased over time. 4.9 % # Patients At Risk: Taxus 903 869 866 861 854 849 844 841 835 828 826 825 822 Xience 897 873 872 869 869 867 862 857 855 853 848 847 845

Secondary Endpoint Result Stent Thrombosis (Definite & probable according to ARC) Taxus Xience P = 0.002 (log-rank test) RR = 0.26 (0.11-0.64) 2.6 % Definite & probable stent thrombosis rate according to the ARC definitions was also highly significant different between both groups, with a 2.6% in the Taxus group versus 0.7% in the Xience group. This is mainly due to a difference in early stent thrombosis, as shown ……(next dia) 0.7 %

Secondary Endpoint Result Early and Late Stent Thrombosis (definite & probable according ARC) Early ST Late ST Taxus Xience Taxus Xience P = 0.002 P = 0.39 as shown in this landmark presentation of early and late stent thrombosis. In late stent thrombosis no difference was noted.

Endpoint Analysis Non Fatal MI Taxus Xience P = 0.007 (log-rank test) RR = 0.52 (0.33-0.84) 5.4 % 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. 2.8 %

Endpoint Analysis All Death & Cardiac Death Taxus Xience P = 0.58 All Death All death and cardiac death rates, however, were similar in both groups Cardiac Death P = 0.81

Endpoint Analysis TVR & Ischemic driven TLR Taxus Xience 6.0 % TVR P = 0.0001 2.4 % 4.8 % 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. TLR P = 0.0002 1.7 %

Conclusions In an all-comer population, reflecting real world, implantation of the Everolimus eluting Xience V stent significantly reduced major adverse cardiac events compared to the Paclitaxel eluting Taxus Liberté stent Superiority of the Everolimus eluting Xience V stent was reached mainly due to less early stent thrombosis and less target lesion revascularization In an all-comer population, reflecting real world, implantation of the Everolimus eluting Xience V stent significantly reduced major adverse cardiac events compared to the Paclitaxel eluting Taxus Liberté stent in our prospective randomized COMPARE trial. Superiority of the Everolimus eluting Xience V stent was reached mainly due to less early stent thrombosis and less target lesion revascularization