1. Follow-up Clinico e Trattamento Post- Rivascolarizzazione Percutanea Giuseppe Biondi Zoccai University of Turin, Turin, Italy gbiondizoccai@gmail.com Marrakesh, 24 April 2008 - 14.00-15.30 SIROLIMUS-ELUTING STENTS FOR THE TREATMENT OF SIROLIMUS-ELUTING STENTS FOR THE TREATMENT OF BARE-METAL IN-STENT RESTENOSIS

2. DISCLOSURE Consultant: Boston Scientific, Cordis, genae, Invatec, Mediolanum Cardio Research Lecture fees: Bristol Myers Squibb

3. BARE SOME BARE FACTS BARE METAL STENT (BMS) IN-STENT RESTENOSIS (ISR) DRUG-ELUTING STENT (DES)

4. LEARNING GOALS What is the scope of BMS ISR? What are the early and mid-term results of DES treatment for BMS ISR? What are the long-term results of DES treatment for BMS ISR?

5. LEARNING GOALS What is the scope of BMS ISR? What are the early and mid-term results of DES treatment for BMS ISR? What are the long-term results of DES treatment for BMS ISR? How can we further improve current results?

6. SCOPE OF THE PROBLEM ISR following BMS implantation remains a relatively common occurrence, especially given the recently renewed interest in BMS ISR rates are even higher in diabetics, small vessels, long lesions, saphenous vein grafts and bifurcations The most effective treatment of ISR has been investigated for many years, but until recently PTCA and brachytherapy were the only recommended strategies, yet with largely disappoiting results

7. Articulation or gap Margin Focal body Multifocal FOCAL Intra-stentProliferative Total occlusion DIFFUSE Mehran R et al. Circulation 1999;100:1872-78 PATTERNS OF RESTENOSIS VBTPTCA

8. PTCAELCARTBSTENT CUTTING BALLOON VBT DIABETES (%)273637282431 LESION LENGTH (MM) 13211991420 FINAL %DS2318 12219 TLR @ 1 YEAR (%) 132923251424 SCOPE OF THE PROBLEM WHC Registry, RESCUT trial, and Gamma One trial

9. PTCAELCARTBSTENT CUTTING BALLOON VBT DIABETES (%)273637282431 LESION LENGTH (MM) 13211991420 FINAL %DS2318 12219 TLR @ 1 YEAR (%) 13 29232514 24 DIFFUSE OR HIGH- RISK ISR SCOPE OF THE PROBLEM WHC Registry, RESCUT trial, and Gamma One trial FOCAL OR LOW- RISK ISR

10. BRACHYTHERAPY: A NUCLEAR BOMB? Edge effects / recurrent restenosis Stent thrombosis

11. LEARNING GOALS What is the scope of BMS ISR? What are the early and mid-term results of DES treatment for BMS ISR? What are the long-term results of DES treatment for BMS ISR? How can we further improve current results?

12. DES REVOLUTION – EARLY REGISTRY DATA ON ISR TREATED WITH DES

13. SELECTION OF REGISTRIES StudyJournalYearNFollow- up (m) Death (%) MACE (%) MI (%) TVR (%) TLR (%) ST (%) BAR (%) German Cypher Registry Clin Res Cardiol 200815337-13.8-12.3-0.7- Li et alChin Med J (Engl) 2006547------20.4 Airoldi et alAm J Cardiol2006161822.0 TRUEJ Am Coll Cardiol 200624491.67.01.6-4.9-- Ruchin et alHeart Lung Circ 20076012-12.0----- Bellandi et alItal Heart J Suppl 20055012-16.04.0-12.0-- Brambilla et alJ Cardiovasc Med 200710015-12.8----11.8 Anderson et alInt J Cardiovasc Intervent 200512117-13.2----6.6 ISR IICatheter Cardiovasc Interv 20052324-26.0--17.0-- Lee et alAm J Cardiol200712036-7.5--5.9-7.4

14. ISAR-DESIRE Kastrati et al, JAMA 2005

15. ISAR-DESIRE 12-month follow-up Kastrati et al, JAMA 2005 IN-STENT LATE LOSS 0.10 mm in SES vs 0.26 mm in PES P=0.004 IN-SEGMENT LATE LOSS 0.32 mm in SES vs 0.55 mm in PES P=0.02

16. 488 patients (40 sites) Beta-source VBT TAXUS-SR stent A Prospective, Randomized Trial Evaluating the Slow-Release Formulation TAXUS™ Paclitaxel-Eluting Coronary Stent in the Treatment of In-Stent Restenosis Primary endpoints: TVF at 9 months Angiographic: all patients at 9 months IVUS: 250 patients at 9 months Inclusion: Lesion length < 46 mm RVD > 2.5 mm and < 3.75 mm Randomized TAXUS V - ISR Stone et al, JAMA 2006

17. TAXUS V – ISR 9-month follow-up Stone et al, JAMA 2006

18. Primary endpoints:TVF @ 9 months Angiographic: all patients @ 6 months IVUS: 5-7 center substudy @ 6 months Inclusion: Lesion length < 45 mm RVD > 2.75 mm and < 3.5 mm A Multicenter, Randomized Study of the Sirolimus-Eluting Bx Velocity ® Balloon Expandable Stent vs. Intravascular Brachytherapy in the Treatment of Patients with In-Stent Restnotic Coronary Artery Lesions SISR 400 patients (30 sites) Beta or gamma VBT Sirolimus- eluting Bx Randomized Holmes et al, JAMA 2006

19. SISR 9-month follow-up Holmes et al, JAMA 2006

20. RIBS II Aflsono et al, JACC 2006

21. RIBS II Alfonso et al, JACC 2006

22. ISR META-ANALYSIS – TARGET LESION REVASCULARIZATION Dibra et al, JACC 2007

23. ISR META-ANALYSIS – DEATH OR MYOCARDIAL INFARCTION Dibra et al, JACC 2007

24. ISR META-ANALYSIS – STENT THROMBOSIS Dibra et al, JACC 2007

25. LEARNING GOALS What is the scope of BMS ISR? What are the early and mid-term results of DES treatment for BMS ISR? What are the long-term results of DES treatment for BMS ISR? How can we further improve current results?

26. StudyJournalYearNFollow- up (m) Death (%) MACE (%) MI (%) TVR (%) TLR (%) ST (%) BAR (%) German Cypher Registry Clin Res Cardiol 200815337-13.8-12.3-0.7- Li et alChin Med J (Engl) 2006547------20.4 Airoldi et alAm J Cardiol2006161822.0 TRUEJ Am Coll Cardiol 200624491.67.01.6-4.9-- Ruchin et alHeart Lung Circ 20076012-12.0----- Bellandi et alItal Heart J Suppl 20055012-16.04.0-12.0-- Brambilla et alJ Cardiovasc Med 200710015-12.8----11.8 Anderson et alInt J Cardiovasc Intervent 200512117-13.2----6.6 ISR IICatheter Cardiovasc Interv 20052324-26.0--17.0-- Lee et alAm J Cardiol200712036-7.5--5.9-7.4 SELECTION OF REGISTRIES

27. StudyJournalYearNFollow- up (m) Death (%) MACE (%) MI (%) TVR (%) TLR (%) ST (%) BAR (%) German Cypher Registry Clin Res Cardiol 200815337-13.8-12.3-0.7- Li et alChin Med J (Engl) 2006547------20.4 Airoldi et alAm J Cardiol2006161822.0 TRUEJ Am Coll Cardiol 200624491.67.01.6-4.9-- Ruchin et alHeart Lung Circ 20076012-12.0----- Bellandi et alItal Heart J Suppl 20055012-16.04.0-12.0-- Brambilla et alJ Cardiovasc Med 200710015-12.8----11.8 Anderson et alInt J Cardiovasc Intervent 200512117-13.2----6.6 ISR IICatheter Cardiovasc Interv 20052324-26.0--17.0-- Lee et alAm J Cardiol200712036-7.5--5.9-7.4 SELECTION OF REGISTRIES

28. StudyJournalYearNFollow- up (m) Death (%) MACE (%) MI (%) TVR (%) TLR (%) ST (%) BAR (%) German Cypher Registry Clin Res Cardiol 200815337-13.8-12.3-0.7- Li et alChin Med J (Engl) 2006547------20.4 Airoldi et alAm J Cardiol2006161822.0 TRUEJ Am Coll Cardiol 200624491.67.01.6-4.9-- Ruchin et alHeart Lung Circ 20076012-12.0----- Bellandi et alItal Heart J Suppl 20055012-16.04.0-12.0-- Brambilla et alJ Cardiovasc Med 200710015-12.8----11.8 Anderson et alInt J Cardiovasc Intervent 200512117-13.2----6.6 ISR IICatheter Cardiovasc Interv 20052324-26.0--17.0-- Lee et alAm J Cardiol200712036-7.5--5.9-7.4 SELECTION OF REGISTRIES

29. LONG-TERM EFFICACY - YES Lee et al, CCI 2008

30. LONG-TERM EFFICACY - YES Lee et al, CCI 2008 TLR MACE

31. LONG-TERM EFFICACY – NO? Sheiban et al, JCM 2008

32. LONG-TERM EFFICACY – NO? Sheiban et al, JCM 2008 Design: prospective multicenter (Turin, Milan) study of patients with in-stent restenosis treated with sirolimus-eluting stents Primary endpoint: freedom from major adverse cardiovascular events Follow-up: ≥24 months, with 6-month angiography planned for all patients N=271 – Average follow-up 28.3 months

33. LONG-TERM EFFICACY – NO? Sheiban et al, JCM 2008

34. LONG-TERM EFFICACY – NO? Sheiban et al, JCM 2008

35. LEARNING GOALS What is the scope of BMS ISR? What are the early and mid-term results of DES treatment for BMS ISR? What are the long-term results of DES treatment for BMS ISR? How can we further improve current results?

36. POSSIBLE MECHANISMS OF RECURRENT FAILURE Asymmetric strut distribution Drug failure or resistance Incomplete re-endothelialization Polymer disruption Polymer (or drug) hypersensitivity Peri-stent vessel wall injury Stent fracture Stent under-expansion

37. GEOGRAPHY MATTERS

38. IMPACT OF IVUS EJVES 2007

39. IMPACT OF IVUS

40. 3,535 patients (5,046 lesions) treated with DES Roy et al, AJC 2007

41. DRUG-ELUTING BALLOON: THE PEPCAD-2 ISR STUDY Unverdorben. ACC 2008 End points Paclitaxel-coated balloon Taxus stent p Intention-to-treat analysis n=66n=65 Late lumen loss (mm)0.200.450.02 Binary in-segment restenosis (%)7200.06 TLR (%)6.315.40.10 MACE (%)7.816.90.20 Per-protocol analysis n=66n=60 Late lumen loss (mm)0.190.470.03 Binary in-segment restenosis (%)3.420.40.007 TLR (%)3.116.70.02 MACE (%)4.718.30.02

42. ANY ROLE FOR ORAL ANTI- RESTENOTIC DRUG THERAPY? Review:Cilostazol in patients treated with drug-eluting stents Comparison:Cilostazol versus control in patients treated with drug-eluting stents Outcome:Binary angiographic restenosis Study Cilostazol Control Peto OR or sub-category n/N 95% CI DECLARE-Long 14/250 23/250 0.59 [0.30, 1.16] CIDES 9/113 20/124 0.47 [0.22, 1.02] DECLARE-DIABETES 13/200 26/200 0.48 [0.25, 0.93] Total (95% CI)563 574 0.51 [0.34, 0.77] Total events: 36 (Cilostazol), 69 (Control) Test for heterogeneity: P = 0.87, I² = 0% Test for overall effect: P = 0.001 0.1 0.2 0.5 1 2 5 10 Favours cilostazol Favours control Biondi-Zoccai et al, AHJ 2008

43. IN CASE OF RECURRENT FAILURE? GISE-CROSS Costa, AHJ 2007

44. TAKE HOME MESSAGES

45. Currently available studies (including RCTs) indicate that DES provide favorable results for the treatment of ISR at both short and mid- term Long-term data are preliminary, with some studies suggesting the presence of a late catch-up phenomenon long after DES implantation, especially in higher risk patients (eg diabetics or post-VBT) These issues will have to be addressed by long-term follow-up of RCTs

46. TAKE HOME MESSAGES In the meanwhile, technique remains paramount: a) sizing appropriately the stent, b) avoiding inter-stent gaps, c) aiming for full lesion coverage, d) high pressure dilation IVUS proves essential to identify the mechanism of restenosis and ensure adequate stenting Additional treatments, eg drug-eluting balloons or oral anti-restenotic therapy, could be envisioned in the future

47. For further slides on these topics please feel free to visit the metcardio.org website: http://www.metcardio.org/slides.html http://www.metcardio.org/slides.html