Bernard Chevalier, Jean Fajadet on behalf of the CRISTAL investigators

1. CRISTAL: A Prospective Randomized Trial of Sirolimus-Eluting Stents Compared to Balloon Angioplasty for Restenosis of Drug-Eluting Coronary Stents Bernard Chevalier, Jean Fajadet on behalf of the CRISTAL investigators TCT 2010, Late Breaking Trials and First Report Investigations; September 25, 2010

2. My potential conflict of interest: • I received a modest research grant for the conduct of this trial from Cordis France.

3. Background • Restenosis occurring within a drug-eluting stent (DES) is a rare event. • Optimal treatment strategies have not been identified and options range from simple repeat balloon angioplasty to the placement of another DES • CRISTAL is the first prospective randomized clinical trial comparing balloon angioplasty and Cypher Select™ in this setting

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

5. Hypothesis 1 Cypher Select™ stent placement has a lower in-stent late loss than balloon angioplasty for treatment of a restenosed Cypher™ as well as for the treatment of a restenosed Taxus™ stent. n = 80 Group 1: Cypher Select Restenosis in a Cypher stent 2:1 Randomization Repeat PTCA n = 120 n = 40 n = 80 Group 2: Cypher Select Restenosis in a Taxus stent 2:1 Randomization Repeat PTCA n = 120 n = 40

6. Hypothesis 2 The in-stent late lumen loss for a restenosedCypher™ stent treated with a Cypher™ Select stent is equivalent to the late lumen loss of a restenosedTaxus™ stent treated with a Cypher Select™ stent n = 80 Group 1: Cypher Select Restenosis in a Cypher stent 2:1 Randomization Repeat PTCA n = 120 n = 40 n = 80 Group 2: Cypher Select Restenosis in a Taxus stent 2:1 Randomization Repeat PTCA n = 120 n = 40

7. Sample Size Determinations • Hypothesis 1 (superiority): • Assumptions: • LL Cypher : 0.30±0.60mm • LL re-PTCA : 0.80±0.70mm • Alpha (two sided) : 0.025 • Power : 80% • Sample size : 34 pts./group • Hypothesis 2 (non-inferiority): • Non-inferiority margin : 0.25mm • LL standard deviation : 0.50mm • Alpha (two sided) : 0.025 • Power : 80% • Sample size : 64 pts./group • Assumed lost-to-follow-up : 20% (in each group) • Sample size for hypothesis 1: 40 pts. • Sample size for hypothesis 2: 80 pts.

8. Follow-Up and Endpoints • Clinical follow-up : 30 days, 1 year • Angiographic follow-up : 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

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

10. Quantitative Coronary Analysis Treatment with Cypher™ Treatment with PTCA* alone Stent #1 Stent #1 Pre Post F/U 5mm 5mm 5mm 5mm Stent #2 5mm 5mm 5mm 5mm 5mm 5mm 5mm 5mm Analysis segment Analysis segment *PTCA LL confounded by recoil

11. Study Sites and Enrolment • 281 patients were enrolled at 34 active sites between 3/2006 and 3/2009. • Enrollment stopped at 88% due to slower than expected recruitment. • Participating investigators: Dr. Moulichon, Perpignan 32 Dr. Teiger, Creteil 25 Dr. Brunel, Nantes 24 Dr. Metzger, Paris 19 Dr. Pansieri, Avignon 13 Dr. Carrie, Toulouse 16 Dr. Fajadet, Toulouse 13 Dr. Machecourt, Grenoble 11 Dr. Darremont, Bordeaux 11 Dr. Boschat, Brest 11 Dr. Funck, Pontoise 10 Dr. Lefevre, Massy 9 Dr. Elhadad, Lagny-sur-Marne 8 Dr. Berland, Rouen 7 Dr. Ledermann, Nimes 6 Dr. Dambrin, Le Chesnay 6 Dr. Leroy, Lille 6 Dr. Dibie, Paris 6 Dr. Druelles, Rennes 5 Dr. Bouchayer, Caluire-et-Cuire 5 Dr. Chevalier, Paris 4 Dr. Maupas, Nimes 4 Dr. Chassaing, Tours 4 Dr. Bedossa, Rennes 3 Dr. Garot, Quincy-sous-Senart 3 Dr. Lablanche, Lille 2 Dr. Champagnac, Villeurbanne 2 Dr. Maillard, Aix-en-Provence 2 Dr. Richard, Caen 1 Dr. Sainsous, Avignon 1 Dr. Jacquemin, Mulhouse 1 Dr. Khalife, Metz1

12. Hypothesis 3 (Amendment 22.12.2009) Estimated = 80 Group 1: Cypher Select Restenosis in a Cypher stent 2:1 Randomization Repeat PTCA Estimated = 120 Estimated = 40 Estimated = 80 Group 2: Cypher Select Achieved: 75 Restenosis in a Taxus stent 2:1 Randomization Repeat PTCA Estimated = 120 Estimated = 40 Hypothesis 3: Cypher Select™ stent placement has a lower LL than balloon angioplasty for treatment of a restenosed Cypher™ or Taxus™ stent (pooled analysis). Achieved: 33 Achieved: 61 n = 136 Pooled analysis: Cypher Select Restenosis Cypher / Taxus pooled 2:1 Randomization Achieved: 28 Repeat PTCA n = 197 n = 61

13. Baseline Clinical Characteristicsper Initial Stent Treatment

14. Baseline Lesion Characteristicsper Initial Stent Treatment

15. Baseline Clinical Characteristics per Pooled Study Cohort

16. Baseline Lesion Characteristics per Pooled Study Cohort

17. Angiographic Endpoints – “ITT” per Pooled Study Cohort All parameters are “in-stent” Numbers between brackets indicate the number of lesions analyzed per variable

18. Clinical Endpoints per Pooled Study Cohort ITT population

19. Angiographic Endpoints Patients Treated With Cypher According To Initial stent Type All parameters are “in-stent” Numbers between brackets indicate the number of lesions analyzed per variable

20. Summary • As recruitment was slower than expected prospective pooling of both initial DES types was necessary to maintain power for the final analysis. • 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 treatment. • The performance of Cypher seems superior in BMS restenosis than in DES restenosis with the limitation of differences in baseline characteristics.

21. Conclusion For DES restenosis in Cypher™ or Taxus™ stents, repeat treatment with Cypher™ is associated with a betterangiographicoutcome at 1 year than repeat PTCA.

22. Thank You !

23. Angiographic Endpoints – “As Treated” All parameters are “in-stent”

24. In-Stent Late Loss – “ITT” Hypothesis 2: Hypothesis 1: