1. Jeffrey J. Popma, MD Klaus A. Tiroch, MD Brigham and Women’s Hospital Harvard Medical School Boston, MA CYPHER™ Stent Fracture: An Uncommon Complication after “Ultra” Complex PCI

2. Within the past 12 months, I have had a financial interest/arrangement or affiliation with the organization(s) listed below. Physician NameCompany/Relationship Jeffrey J. Popma, MD Research Grants: Cordis, Boston Scientific, Medtronic, Abbott-Guidant, Biosensors, Radiant, eV3 Medical Advisory Board: Cordis, Boston Scientific, Medtronic Speaker’s Bureau: Sanofi, BMS, Boston Scientific, Pfizer Conflict of Interest Statement

3. Case Reports: CYPHER™ Stent Fractures Location# Pts Halkin A., Leon M., Heart 2004;90:e45. U.S.A.1 Takebayashi H., et al., Circulation. 2004;110:3430-34. U.S.A.2 Lemos P., et al., Circulation 2003; 108:257-260. The Netherlands4 Sianos G., et al., Catheterization and Cardiovascular Interventions 2004; 61:111–16. The Netherlands2 Wilczynska J., et al., International Journal of Cardiology 2006; Aug 11; E-pub ahead of print. Poland1 Min PK., et al., International Journal of Cardiology 2006; 106:404-06. South Korea1 Shite J., et al., EHJ 2006; 27:1389. Japan1 Surmely, JF Circ J 2006; 70: 936 –938 Japan1 Zaizen H., et al., International Journal of Cardiology 2006; Aug 22; E-pub ahead of print. Japan1

4. Definitions Used for Stent Fracture ClassificationCurrent ReportAllie et al 1 Scheinert et al 2 Type 0No strut fracture-- Type ISingle strut fracture or gap between struts greater than 2x normal Single strut fracture onlyMinor – single strut facture Type IIMultiple strut fractures with V-form division of the stent Multiple single stent fractures occurring at different sites Moderate – facture >1 strut Type IIIComplete transverse stent fracture without displacement of fractured fragments more than 1 mm during the cardiac cycle Multiple single stent fractures resulting in complete transverse linear fracture but without stent displacement Severe – complete separation of stent segments Type IVComplete transverse stent fracture with abundant movement and displacement of fractured fragments of more than 1 mm during the cardiac cycle Complete transverse linear type III fracture with stent displacement - 1 Allie et al Endovascular Today 2004; July/August: 22-34 2 Scheinert et al J Am Coll Cardiol 2005; 45:312-315

5. 349 Patients in the CYPHER arm with follow-up in SIRIUS -40 Patients with not available CINE films -2 patients neither of the follow-up CDs can be opened -2 patients all CD missing 305 patients analyzed with 497 follow-up angiograms 4 fractures identified (1.3%), -3x Fracture Type 1 (0.98%) -1x Fracture Type 2 (0.33%) All fractures occurred with multiple stents near the site of overlap, all vessels calcified including one chronic total occlusion. 1 ISR at that site with TLR (Type 1 Fracture – tissue growth) BWH SIRUS Angiographic Analysis Did We Miss Something Important?

6. Coronary Stents: CYPHER TAXUS Peripheral Stents: Analysis population 125 113 12 101 CYPHER Angiograms Forwarded to Core Lab No Fracture By Available Paperwork No Stent Fracture Identified Bx Sonic 51 Cases 2 9 1 226 Cases 39 Cases Baseline Angiogram Available 28 * 45 stent fractures in 39 patients Stent Fracture: Review of Adverse Event Reports MAUDE cases between August 2003-July 2006

7. Case 1: Diffuse LAD Disease

8. 2.5 mm x 23 mm; 2.5 mm x 33 mm; 3.0 x 18 mm CYPHER stents

9. Case 1: Diffuse LAD Disease Final Angiographic Result

10. Case 1: Diffuse LAD Disease 3 Month Angiographic Follow-Up

11. Case 1: Diffuse LAD Disease Stent Fracture with 3 mm of Stent Overlap Type 4 Stent Fractures

12. Case 1: Ostial RCA Stent Migration 2.5 mm x 13 mm Stent Overlap

13. Case 2: Ostial RCA Stent Migration 24 Month Follow-up Stent Fracture and Migration Type 4 Stent Fracture

14. Case 3: Late Aneursym Formation 2.5 mm x 23 mm CYPHER

15. Case 3: Late Aneursym Formation 3 Month Follow-up

16. Case 3: Late Aneursym Formation 4 Month Follow-up

17. Type 4 Stent Fracture Case 3: Late Aneursym Formation

18. BWH Angiographic Analysis Adverse Event Reports (N=39) 13 mm 4 (10.3%) 4 (10.3%) 18 mm 23 mm 28 mm 33 mm 3 (7.7%) 13 (33.3%) 15 (38.4%) Type 2 5 (12.9%) Type 3 16 (41.0%) Type 4 18 (46.1%) Fracture Type Stent Length

19. VariableStent fracture N = 28, (%) Sirius N = 531, (%) P Value Location LAD12 (42.9)234 (44.1)0.94 LCx4 (14.3)134 (25.2)0.27 RCA12 (42.9)160 (30.1)0.23 Ostial Location6 (21.4)10 (1.9)<0.001 Lesion Length, mm22.1±15.914.4±5.8<0.001 0-9.9 mm7 (25.0)106 (20.0)0.66 10-19.9 mm9 (32.1)342 (64.6)0.001 20 or greater12 (42.9)82 (15.4)0.002 Angulations ≥ 45 degrees13 (46.4)58 (10.9)< 0.001 Proximal Tortuousity7 (25.0)28 (5.3)0.002 Calcification present19 (67.9)91 (17.1)<0.001 Total Occlusion7 (25.0)17 (3.2)<0.001 Stent Fracture: Baseline Angiographic Findings

20. VariableStent fractureSiriusP Value BaselineN = 28N = 531 RVD, mm2.66±0.502.79±0.450.14 MLD, mm0. 56±0.390.97±0.40<0.001 % Stenosis77.8±15.365.1±12.6<0.001 FinalN = 28N = 531 Within the Segment Final MLD2.06±0.482.38±0.42<0.001 Final % Stenosis24.6±11.116.1±9.7<0.001 Within the Stent Final MLD2.33±0.492.67±0.40<0.001 Final % Stenosis14.8±8.95.4±8.2<0.001 Stent Fracture: Baseline Angiographic Findings

21. VariableStent fracture N = 28 (%) Sirius N = 531 (%) P Value Number of Stents1.5±0.71.4±0.70.46 Stent diameter2.79±0.392.91±0.500.21 Maximal Balloon2.97±0.553.3±0.5<0.001 Total overlapping-stent length35.1±16.521.5±6.7<0.001 Stent-to-lesion length ratio2.04±1.21.6±0.6<0.001 Mean angle Systole64.8±27.6NA Diastole32.5±23.1NA  Systole-Diastole 32.3±15.2NA Post-stenting20.4±16.6NA  Max Angle After Stent 44.5±21.3NA Dissection4 (14.3)7 (1.3)0.003 Perforation2 (7.1)0 (0.0)0.005 Stent Fracture: Baseline Angiographic Findings

22. VariableStent fractureSirius N = 38 (%)N = 350 (%)P Value RVD, mm2.72±0.482.79±0.420.33 Within the Segment Follow-up MLD1.41±0.692.15±0.61<0.001 Late Lumen Loss0.70±0.660.24±0.47<0.001 Restenosis Rate18 (47.4)31 (8.9)< 0.001 Follow-up % Stenosis48.6±23.023.6±16.4<0.001 Within the Stent Follow-up MLD1.52±0.822.50±0.58<0.001 Late Lumen Loss0.96±0.710.17±0.44<0.001 Follow-up % Stenosis44.1±28.510.4±16.5<0.001 Restenosis Rate18 (47.4)11 (3.2)<0.001 ISR Length, mm6.55±5.969.1±5.80.01 Total occlusions3 (7.9)2 (0.6)0.02 Aneurysm5 (13.2)2 (0.6)<0.001 Stent Fracture: Follow-up Findings

23. N In-Segment Follow-up % DS OcclusionAneurysmTLRNo ISR TLR Classification<50%≥ 50% Type I0000000 Type II5320121 Type III15690170 Type IV1812633114 Overall3820 (52.6%) 18 (47.4%) 3 (7.9%) 5 (13.2%) 20 (52.6%) 5 (13.2%) * One patient developed fracture with initial deployment

24. CYPHER stent fractures are an uncommon cause of complications late after stent placement (SIRIUS  no related complications) Compared with patients enrolled in the SIRIUS trial, patients with stent fractures have very diffuse and complex disease, including multiple stents, long lesions, total occlusions, and tortuosity Initial angiographic results are suboptimal compared with the SIRIUS trial, likely relating to vessel rigidity and diffuse disease TLR was performed in over 50% of cases – both with and without evidence of angiographic restenosis Newer designs may decrease the occurrence of stent fracture CYPHER™ Stent Fracture: Summary

25. Frequency of CYPHER stent fractures: Cordis World-wide Product Safety Database – 0.009% MAUDE – 113 cases reported (August 2003 - July 2006) Most reported by Cordis and not by health care practitioners Risk factors for Stent fracture – “Ultra-complex lesions”: RCA > LAD >> Circ Very diffuse and complex disease Long stented segments (long stents) Multiple overlapping stents Angulated vessel segments / tortuosity Mobile vessels (flexion, extension, torsion) Suboptimal initial angiographic results likely relating to vessel rigidity/calcification and diffuse disease Stent Fracture: Discussion

26. Restenosis and TLR rates depend on indication for follow-up angiography (routine or symptom-driven) –Reports clustered at sites who more routinely treat “ultra-complex” lesions and obtain routine angiographic f/u: –Visualization of CYPHER stent fractures more apparent than with other stent platforms due to its relative radio-opacity – “Ultracomplex lesions” - Routine angiographic f/u: –Binary angiographic restenosis 5-10%; TLR in half of these cases –TLR performed with and without angiographic restenosis “Ultracomplex lesions” with f/u only with symptoms : –Binary angiographic restenosis 40 - 70%; TLR in half of lesions with restenosis –TLR performed both with and without angiographic restenosis Stent Fracture: Discussion

27. Procedural Overexpansion Placement Post-dilation Length/overlap Material Elongation Yield strength Ultimate Tensile Strength Endurance Limit Grain size Processing Stent Fatigue is Multifactorial Stent Design Dimensions Anatomical Which vessel & where Compliance Angulation Dynamic motion # of cycles

28. Dynamic loading in a vessel results in the following deformations: –Pulsatile (current fatigue test & FEA) –Bend (static bend modeling in FEA) –Twist –Stretch Above are likely a function of species, vessel (RCA, LAD, LCX) and location (proximal, distal) Preclinical Testing: Dynamic Loading

29. Unusually high stent fracture rate in Korea relative to the rest of the world likely related to high proportion of routine angiographic f/u and frequent use of long stents Rates (ppm)KoreaJapanOUS USWorldwide Cypher1,650 258 210 4186 (0.009%) All BMS1990778 † Parts per million † Parts per million * Adjusted for returns (From launch to 8/31/2006) *All rates are in PPM CYPHER STENT FRACTURES: Complaint Databases (Cypher PPM † Levels)

30. CYPHER STENT FRACTURES: Fracture Rate by Stent Length

31. Study# of PatientsStent LengthFollow-upSTTLR/TVR RESEARCH9661.21 year04.2 ARTS II60747.61 year1.67.4 Colombo66801.1 years1.515.2 Park Long18444.49 months03.8 Park “FMJ”34771.917 months0.34.1 Park RCT25040.89 months0.52.5 Keriakes33732.31 year0.34.7 Long Lesions with SES: Summary No Fractures Reported in Large Series Degertekin M., et al., Am J Cardiol 2004;93:826–29; Serruys PW., et al., Eurointerv 2005; 2: 147-56;. Tsagalou E., et al., JACC 2005;45:1570-73; Kim YH., et al., CCI 2006; 67:181-87; Lee C., et al., AJC 2006;98:918-22; ACC 2006; Oral Presentation Kereiakes DJ., et al., JACC 2006;48(1):21-31..