DECLARATION OF CONFLICT OF INTEREST

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1 DECLARATION OF CONFLICT OF INTEREST In the last five years, I received research grants or speaker fees or I am/was consultant for: Abbott Vascular, Asahi, Astra Zeneca, AVI, Boston Scientific, Biotronik, Cook, Cordis, Daichi-Sankyo, Eli-Lilly, Iroko, Medtronic, Terumo. I am currently minor shareholder & general mamager of CERC

2 CHALLENGE OF INSTENT RESTENOSIS: THE STENTING APPROACH B. Chevalier, ICPS Massy / GCS Creil, France

3 DES is the gold standard for BMS restenosis Dibra et al. J Am Coll Cardiol 2007 TLR: 1% vs 11.5%

4 But DES restenosis is a different animal

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6 Kastrati JACC Interv 2011

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8 Timing 5 years

9 Mechanisms DES implantation Underdeployment Geographical miss Non-apposition Biological effect of antiproliferative therapy SMC not affected (Ca, strut, malapposition) Coating injury Potency of the DES Resistance to antiproliferative drug (genetics) Late injury Stent fracture Late hypersensitivity

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11 Mechanisms DES implantation Underdeployment Geographical miss Non-apposition Biological effect of antiproliferative therapy SMC not affected (Ca, strut, malapposition) Coating injury Potency of the DES Resistance to antiproliferative drug (genetics) Late injury Stent fracture Late hypersensitivity

12 It is unlikely to use only one technique High Pressure/Non compliant balloon Drug eluting balloon Drug eluting stent CABG

13 DES «sandwich» TLR is twice for DES in DES restenosis vs BMS restenosis.

14 CRISTAL Study Design Group 1: Restenosis in a Cypher stent n = 120 2:1 Randomization n = 80 Cypher Select Repeat PTCA n = 40 Group 2: Restenosis in a Taxus stent n = 120 2:1 Randomization n = 80 Cypher Select Repeat PTCA n = 40 Group 3*: Restenosis in a bare metal stent n = 80 Cypher Select n = 80 *No randomization to PTCA, as already investigated in ISAR-DESIRE with poor outcome.

15 Follow-Up and Endpoints Clinical follow-up Angiographic follow-up : 30 days, 1 year : 9-12 months Primary endpoint : In-stent late lumen loss by QCA Secondary endpoints angiographic : MLD pre, MLD post, Acute gain, MLD at f/u, net gain (acute gain late loss) clinical : Death (cardiac, non-cardiac), MI (Q, non-q), TLR, TVR (clinically driven), Stent thrombosis (per-protocol: similar to ARC definite ), Procedural success rates

16 Study Organization and Set Up Coordinating Investigators: Bernard Chevalier, Jean Fajadet Study sites Angiographic corelab Study coordination Independent CEC Medical monitor Project management Sponsor : 37 hospitals in France : Bio-Imaging Technologies, Leiden, NL : Clinquest Europe BV, Leiden, NL : Clinquest Europe BV, Leiden, NL : Hans-Peter Stoll, MD, Cordis : Isabelle Ploton, AAI France Christophe de Vleeschouwer, Cordis Kristel Wittebols, Cordis : Cordis Clinical Research, Waterloo, Belgium

17 Baseline Clinical Characteristics per Pooled Study Cohort Cypher Cypher/Taxus Pooled (n=136 patients) (n=141 Lesions) PTCA Cypher/Taxus Pooled (n=61 patients) (n=61 Lesions) Age(years) 68 ± ± Male Gender(%) Diabetes(%) Hypertension(%) Hyperlipidemia(%) Smoking(%) CAD(%) PVD(%) Previous MI(%) Previous PCI(%) CABG p

18 Baseline Lesion Characteristics per Pooled Study Cohort Cypher PTCA p Cypher/Taxus Pooled (n=136 patients) (n=141 Lesions) Cypher/Taxus Pooled (n=61 patients) (n=61 Lesions) RVD (mm) 2.6 ± ± Lesion Length (mm) 14.6 ± ± Calcified Lesions (%) 2.13 (3/141) 1.64 (1/61) Ostial Lesions (%) 12.8 (18/141) 11.5(7/61) Bifurcations (%) 9.9 (14/141) 11.5(7/61)

19 Angiographic Endpoints ITT per Pooled Study Cohort (mm) Cypher Cypher/Taxus Pooled (n=136 patients) (n=141 Lesions) PTCA Cypher/Taxus Pooled (n=61 patients) (n=61 Lesions) p Pre-procedural MLD 1.09 ± 0.50(93) 1.18 ± 0.58(48) 0.40 Post-procedural MLD 2.51 ± 0.46(130) 2.12 ± 0.39(54) < Acute Gain 1.39 ± 0.52(92) 0.90 ± 0.57(46) < Follow-up MLD 2.14 ± 0.62(104) 1.71 ± 0.55(44) < Late Lumen Loss 0.37 ± 0.57(104) 0.41± 0.63(42) 0.73 Net Gain 1.07 ± 0.69(74) 0.49 ± 0.67(35) < Inlesion % DS <0.05 All parameters are in-stent Numbers between brackets indicate the number of lesions analyzed per variable

20 Clinical Endpoints per Pooled Study Cohort Cypher Cypher/Taxus Pooled (n=136 patients) (n=141 Lesions) PTCA Cypher/Taxus Pooled (n=61 patients) (n=61 Lesions) p Cardiac Death 0.7%(1/136) 1.6%(1/61) 0.52 Non-cardiac Death 2.2%(3/136) 1.6%(1/61) Q-Wave MI 0.7%(1/136) 0.0%(0/61) Non Q-Wave MI 2.2%(3/136) 1.6%(1/61) TLR (Clinically Driven) 5.9%(8/136) 13.1%(8/61) TVR (Clinically Driven) 2.2%(3/136) 0.0%(0/61) 0.55 Stent Thrombosis 0.7%(1/136) 0.0%(0/61) ITT population

21 Angiographic Endpoints Patients Treated With Cypher According To Initial stent Type Initial Stent Cypher (n=108 Patients) (n=109 Lesions) Initial Stent Taxus (n=89 Patients) (n=93 Lesions) Initial Stent BMS (n=84 Patients) (n=85 Lesions) p Pre-procedural MLD 1.07 ± 0.53(73) 1.17 ± 0.52(68) 1.04± 0.41(63) 0.27 Post-procedural MLD 2.42 ± 0.52(97) 2.36 ± 0.42(87) 2.51± 0.40(72) 0.12 Acute Gain Follow-up MLD Late Lumen Loss 1.31 ± 0.61(72) 1.13 ± 0.54(66) 1.47± 0.46(59) ± 0.68(75) 2.00 ± 0.58(73) 2.27± 0.58(65) ± 0.58(74) 0.35 ± 0.59(72) 0.28± 0.54(60) 0.40 Net Gain 0.97± 0.80(53) 0.80± 0.66(56) 1.24± 0.53(53) All parameters are in-stent Numbers between brackets indicate the number of lesions analyzed per variable

22 Lessons from CRISTAL trial There was no difference between Cypher treatment and PTCA in the primary endpoint LL, but significant differences in follow-up MLD, acute gain and net gain, favor the Cypher stent treated group. It is likely that post-balloon recoil acted as a confounding factor in the primary endpoint analysis. A trend towards reduced TLR was noted in the Cypher group The angiographic results of Cypher treatment were favorable irrespective of initial stent implantation. The performance of Cypher seems superior in BMS restenosis than in DES restenosis with the limitation of differences in baseline characteristics.

23 In the real world

24 [mm] DEB vs DES in BMS restenosis? 1,2 Taxus SeQuent Please 25% Taxus SeQuent Please 1,0 20% p=0.1 20,3% p=0.04 0,8 16,9% 0,6 p=0.01 p= % 0,4 0,45 0,38 10% 7,0% 7,0% 0,2 0,19 0,17 5% 0,0 late loss in-stent late loss in-segment 0% restenosis in-stent restenosis in-segment Circulation 2009 Circulation 2009; 119:

25 DES vs DEB in DES restenosis? Limitations Absence of randomised studies No class effect (no head to head comparison)

26 DEB in DES restenosis: 8 m. TLR Stella EuroPCR 2011

27 Conclusions 1. Cypher in DES restenosis is associated with the best angiographic outcome whatever the initial type of DES 2. Some DEB have some efficacy in BMS restenosis but needs validation against DES in DES restenosis, using a different endpoint than LL 3. The different nature of DES restenosis precludes exptrapolation of DEB efficacy from BMS restenosis DEB data.

28 Future directions A substitute to Cypher? DEB validation? New DEBs? Fully biobabsorbable DES? No double metallic layer