1. Approach to the Patient with DES Restenosis Roxana Mehran, MD, FACC Professor of Medicine (Cardiology) and Health Evidence Policy Director of Interventional Cardiovascular Research and Clinical Trials The Icahn School of Medicine at Mount Sinai, New York, NY Chief Scientific Officer Cardiovascular Research Foundation, New York, NY

2. Roxana Mehran, MD  Institutional Grant/Research Support :  Bristol-Myers Squibb/ Sanofi  Lilly/ Daichii Sankyo  The Medicines Company  Consulting Fees/Honoraria  Abbott Vascular  Astra Zeneca  Merck  Regado Biosciences  Janssen (J+J)

3. Distal left main, PLCX, Ramus bifurcation 3 DES with crush technique Pre Post

4. A Few Months Later

5. Mechanisms of DES Restenosis Biological factors Drug resistance Hypersensitivity Mechanical factors Non uniform stent strut distribution Stent fractures Polymer peeling Non uniform drug deposition Technical factors Incomplete stent expansion Stent gaps or “misses” (uncovered lesion segments) Barotrauma to unstented segments

6. Giant cells CYPHER in LCX @ 4 months Hypersensitivity Reactions Nebecker JR. et al. JACC 2006; 47: 175-181 Eosinophils Fibrin Taxus in LAD @ 130 days Rash, hives, dyspnea, persistence after stopping Plavix, eosinophilia, elevated IgE, skin biopsy consistent with drug reaction when no drugs administered, Gallium scan consistent with inflammation at the stent site or LV draining lymph nodes, and eosinophils attacking the stent at autopsy.

7. Stent Follow-upPost a b c a’a’a’a’ b’b’b’b’ c’c’c’c’ Restenosis DES fractures Aoki J. et al. CCI 2007;69: 380-6

8. Incidence of SES fracture and restenosis rate Incidence of SES fracture Restenosis rate at the fracture site % % Lee MS, et al. TCT 2006 Aoki J, et al. CCI 2006 In press Kadota et al. JASS 2006;47:203A Yang TH, et al. TCT 2006 530 Pts 256 Pts 431 Pts 596 Pts

9. Stent underexpansion Technical factors

10. Stent underexpansion Technical factors Minimum Stent Area (MSA, mm 2 ) 0 10 20 30 40 50 60 70 80 90 3.5 4.0 4.55.5 6.0 6.5 7.0 7.5 8.0 8.5 Cypher 5.0 Minimum stent area (mm 2 ) 100 Taxus 5.5 Post-Procedure MSA and Binary Restenosis (sensitivity and specificity curves) Sonoda S. et al. J Am Coll Cardiol 2004;43:1959-63 Weissman N. TCT 2006

11. Gap Incomplete stent coverage Technical factors Stent edge restenosis is frequently associated with local trauma outside the stent. In-stent restenosis occurs as a localized lesion, commonly associated with a discontinuity in stent coverage. Lemos A. et al. Circulation 2003; 108: 257-60

12. Pattern I (Focal) Type IA: Articulation / Gap Pattern I (Focal) Type IB: Margin Pattern I (Focal) Type IC: Focal Body Pattern I (Focal) Type ID: Multifocal In-Stent Restenosis Patterns Pattern II (Diffuse): Intra-stent Pattern III (Diffuse): Proliferative Pattern IV (Diffuse): Total Occlusion Classification proposed by Mehran et al. Circulation 1999;100:1872-1878 Classification proposed by Mehran et al. Circulation 1999;100:1872-1878

13. Patterns of in-stent restenosis predict outcomes in the BMS era 282 lesions reviewed; restenosis patterns classified by angiography and confirmed by IVUS % Frequency TLR @ 1 Year Mehran et al. Circulation 1999;100:1872-1878

14. Non focal (N = 71) Repeat DES 69%, POBA 31% Focal (N = 132) Repeat DES 57.1%, POBA 42.9% Focal (N = 132) Repeat DES 57.1%, POBA 42.9% P=0.69P=0.12 P=0.04 P=0.25 P=0.11 Cosgrave J. et al. JACC 2006;47: 2399-404 Do patterns of in-stent restenosis predict outcomes in the DES era? Clinical outcomes @ median 13.7 months

15. DES Restenosis Mechanisms Mechanisms Predictors Predictors Morphological patterns Morphological patterns Treatment Options Treatment Options

16. Conventional therapies vs SES for DES Failures Kim YH. et al. Am J Cardiol 2006;98:1451-4 % In-stent restenosis mm In-stent late loss N=33 P=0.006 P=0.021 35 4 0 10 20 30 40 50 Conventional SES 0.76 0.27 0 0.25 0.5 0.75 1 Conventional N=25 Cutting balloon 11 VBT 14 N=33 6-month angiographic outcomes N=25 Cutting balloon 11 VBT 14

17. Event rate at 23±10 months FU Tagliareni, EuroIntervention, 2010 213 pts with DES ISR 213 pts with DES ISR  94 tx with repeat DES  119 tx with BA alone Same DES vs PTCA for DES Failures

18. 2.02.0 10.0 0.0 4.0 2.0 8.0 0.0 0.0 5.0 10.0 15.0 DeathQ-MITLRLate thrombosis % IRT (N = 61) DES (N = 50) Radiation (IRT) vs DES for DES Failures RESCUE trial Torguson R. et al. Am J Cardiol 2006;98:1340-4 p = 0.59 p = 1.0 Clinical outcomes @ 8 months

19. 137 Patients with DES ISR (177 lesions) 137 Patients with DES ISR (177 lesions) 68% of patients had a focal pattern of restenosis 68% of patients had a focal pattern of restenosis Solinas et al, Am J Cardiol, 2008 Same DES vs other DES for DES Failures Does the switch therapy work?

20. Garg S. et al. CCI. 2007;70: 9-14 Same DES vs other DES vs. other treatment for DES Failures Does the switch therapy work? Clinical outcomes @ 1 year % 2.7 7.7 30.8 35 7.5 0 26.8 32.6 0 10 20 30 40 DeathQ-MITVRMACE Same DES Different DES N=43 N=40 P=0.62 P=0.24 P=0.70 P=0.81

21. Cosgrave J. et al. AHJ.2007;153: 354-9 Same DES vs other DES for DES Failures Does the switch therapy work? % In-stent restenosis @ mean 25.7 months N=107N=94N=107N=94 P=1.0 % P=1.0 TLR

22. Events at 25.6±16.5 months n=59 PCI (58% DES); n=7 CAB; n=4 med tx DES ISR in Unprotected Left Main was relatively benign, only 2 patients (2.9%) presented with an acute MI. DES ISR in Unprotected Left Main was relatively benign, only 2 patients (2.9%) presented with an acute MI. Treatment results are comparable to non-Unprotected Left Main lesions Treatment results are comparable to non-Unprotected Left Main lesions Groups are too small to allow a comparison between the treatment strategies Groups are too small to allow a comparison between the treatment strategies Sheiban, JACC, 2009 DES ISR in Left Main (N=70)

23. ISAR DESIRE-2 Pts w/ SES-ISR (n=225 per group) P = 0.75 mm P = 0.71 Byrne, TCT, 2009 No differences between same or different DES treatment strategies

24. Paclitaxel-Eluting Balloon in SES-ISR RCT 50 Pts SES ISR 50 Pts SES ISR 25 PEB 25 BA RCT 50 Pts SES ISR 50 Pts SES ISR 25 PEB 25 BA Late Loss Habara S. J Am Coll Cardiol Intv 2011;4:149 –54 TLRTLR Restenosis Rate

27. Late (delayed) restenosis in patients receiving SES 7 months 20.4 months 7 months 18.9 months Wessely R. et al. Ann Int. 2005;143: 392-3

28. 100 120 140 160 180 200 0246810 0246810 024681002468100246810 Neointimal volume (mm 3 ) Plaque volume behind stent (mm 3 ) 1 year 2 years 4 years Post procedure 4 months Neointima keeps growing over 4 years after SES implantation Aoki J, et al. JACC 2005;46:1670-1676 FIM 23 patients without events

29. Change in % net volume obstruction from 6 months to 2 years Control N = 77 Control TAXUS SR N = 43 TAXUS SR N = 43 TAXUS MR N = 41 TAXUS MR N = 41 Compaction of neointima in Control but not in TAXUS -2.43 ± 12.54 3.43 ± 8.87 4.98 ± 10.42 p =0.0064 p =0.0007 Change in % Net Volume Obstruction baseline 6 months 2 years Aoki J et al. Circulation. 2005;112:3876-83

30. Costa MA. et al. AHJ.2007;153: 447-9 Current therapeutic options according to potential mechanisms of DES restenosis Type of restenosisPotential mechanismsTreatment options Focal in-stentUnderexpansionBA FractureDES Local vessel biologyDES, BA, DCB Heterogeneous drug distribution DES, BA, DCB Focal at stent edgeGeographic missDES Plaque progressionDES Diffuse in-stentVessel biology / Drug resistanceDifferent DES, ?IRT, CABG Proliferative Vessel biology / Drug resistance Different DES, CABG

31. SummarySummary Though much less frequent than BMS ISR, DES ISR poses its own challenges and requires better understanding of the underlying mechanism (Intravascular imaging). Though much less frequent than BMS ISR, DES ISR poses its own challenges and requires better understanding of the underlying mechanism (Intravascular imaging). The morphologic patterns of DES restenosis are different from BMS, favoring a more focal and easily treated pattern with expected improved clinical outcomes. The morphologic patterns of DES restenosis are different from BMS, favoring a more focal and easily treated pattern with expected improved clinical outcomes. The treatment of DES restenosis is based on appreciation of underlying mechanisms and can vary from simple POBA, to DES when appropriate, to CABG in the most extreme cases. The treatment of DES restenosis is based on appreciation of underlying mechanisms and can vary from simple POBA, to DES when appropriate, to CABG in the most extreme cases. Late DES restenosis remains an infrequent clinical event, despite the differing healing patterns relative to BMS. Late DES restenosis remains an infrequent clinical event, despite the differing healing patterns relative to BMS. DES Restenosis