Jeffrey J. Popma, MDKlaus A. Tiroch, MD

Brigham and Women’s HospitalHarvard Medical School

Boston, MA

CYPHER™ Stent Fracture:An Uncommon Complication

after “Ultra” Complex PCI

Within the past 12 months, I have had a financial Within the past 12 months, I have had a financial interest/arrangement or affiliation with the organization(s) listed interest/arrangement or affiliation with the organization(s) listed below.below.

Physician Name Company/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

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 Netherlands 4

Sianos G., et al., Catheterization and Cardiovascular Interventions 2004; 61:111–16.

The Netherlands 2

Wilczynska J., et al., International Journal of Cardiology 2006; Aug 11; E-pub ahead of print.

Poland 1

Min PK., et al., International Journal of Cardiology 2006; 106:404-06.

South Korea 1

Shite J., et al., EHJ 2006; 27:1389. Japan 1

Surmely, JF Circ J 2006; 70: 936 –938 Japan 1

Zaizen H., et al., International Journal of Cardiology 2006; Aug 22; E-pub ahead of print.

Japan 1

Definitions Used for Stent Fracture Classification Current Report Allie et al 1 Scheinert et al 2

Type 0 No strut fracture - -

Type I Single strut fracture or gap between struts greater than 2x normal

Single strut fracture only Minor – single strut facture

Type II Multiple strut fractures with V-form division of the stent

Multiple single stent fractures occurring at different sites

Moderate – facture >1 strut

Type III Complete 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 IV Complete 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

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 missing305 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 AnalysisDid We Miss Something Important?

Coronary Stents: CYPHER TAXUSPeripheral Stents:

Analysis population

125113 12101

CYPHER Angiograms Forwarded to Core Lab No Fracture By Available Paperwork No Stent Fracture Identified Bx Sonic

51 Cases291

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

Case 1: Diffuse LAD Disease

Case 1: Diffuse LAD Disease

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

Case 1: Diffuse LAD Disease

Final Angiographic Result

Case 1: Diffuse LAD Disease

3 Month Angiographic Follow-Up

Case 1: Diffuse LAD Disease

Stent Fracture with 3 mm of Stent Overlap

Type 4Stent Fractures

Case 1: Ostial RCA Stent Migration

2.5 mm x 13 mm Stent Overlap

Case 2: Ostial RCA Stent Migration

24 Month Follow-up Stent Fracture and Migration

Type 4Stent Fracture

Case 3: Late Aneursym Formation

2.5 mm x 23 mm CYPHER

Case 3: Late Aneursym Formation

3 Month Follow-up

Case 3: Late Aneursym Formation

4 Month Follow-up

Type 4Stent Fracture

Case 3: Late Aneursym Formation

BWH Angiographic AnalysisAdverse Event Reports (N=39)

13 mm4

(10.3%)4

(10.3%)

18 mm

23 mm

28 mm

33 mm

3(7.7%)

13(33.3%)

15 (38.4%)

Type 25 (12.9%)

Type 316

(41.0%)

Type 418

(46.1%)

Fracture Type Stent Length

Variable Stent fractureN = 28, (%)

SiriusN = 531, (%)

P Value

Location

LAD 12 (42.9) 234 (44.1) 0.94

LCx 4 (14.3) 134 (25.2) 0.27

RCA 12 (42.9) 160 (30.1) 0.23

Ostial Location 6 (21.4) 10 (1.9) <0.001

Lesion Length, mm 22.1±15.9 14.4±5.8 <0.001

0-9.9 mm 7 (25.0) 106 (20.0) 0.66

10-19.9 mm 9 (32.1) 342 (64.6) 0.001

20 or greater 12 (42.9) 82 (15.4) 0.002

Angulations ≥ 45 degrees 13 (46.4) 58 (10.9) < 0.001

Proximal Tortuousity 7 (25.0) 28 (5.3) 0.002

Calcification present 19 (67.9) 91 (17.1) <0.001

Total Occlusion 7 (25.0) 17 (3.2) <0.001

Stent Fracture: Baseline Angiographic FindingsStent Fracture: Baseline Angiographic Findings

Variable Stent fracture Sirius P Value

Baseline N = 28 N = 531

RVD, mm 2.66±0.50 2.79±0.45 0.14

MLD, mm 0. 56±0.39 0.97±0.40 <0.001

% Stenosis 77.8±15.3 65.1±12.6 <0.001

Final N = 28 N = 531

Within the Segment

Final MLD 2.06±0.48 2.38±0.42 <0.001

Final % Stenosis 24.6±11.1 16.1±9.7 <0.001

Within the Stent

Final MLD 2.33±0.49 2.67±0.40 <0.001

Final % Stenosis 14.8±8.9 5.4±8.2 <0.001

Stent Fracture: Baseline Angiographic FindingsStent Fracture: Baseline Angiographic Findings

Variable Stent fractureN = 28 (%)

SiriusN = 531 (%)

P Value

Number of Stents 1.5±0.7 1.4±0.7 0.46

Stent diameter 2.79±0.39 2.91±0.50 0.21

Maximal Balloon 2.97±0.55 3.3±0.5 <0.001

Total overlapping-stent length 35.1±16.5 21.5±6.7 <0.001

Stent-to-lesion length ratio 2.04±1.2 1.6±0.6 <0.001

Mean angle

Systole 64.8±27.6 NA NA

Diastole 32.5±23.1 NA NA

Systole-Diastole 32.3±15.2 NA NA

Post-stenting 20.4±16.6 NA NA

Max Angle After Stent 44.5±21.3 NA NA

Dissection 4 (14.3) 7 (1.3) 0.003

Perforation 2 (7.1) 0 (0.0) 0.005

Stent Fracture: Baseline Angiographic FindingsStent Fracture: Baseline Angiographic Findings

Variable Stent fracture Sirius

N = 38 (%) N = 350 (%) P Value

RVD, mm 2.72±0.48 2.79±0.42 0.33

Within the Segment

Follow-up MLD 1.41±0.69 2.15±0.61 <0.001

Late Lumen Loss 0.70±0.66 0.24±0.47 <0.001

Restenosis Rate 18 (47.4) 31 (8.9) < 0.001

Follow-up % Stenosis 48.6±23.0 23.6±16.4 <0.001

Within the Stent

Follow-up MLD 1.52±0.82 2.50±0.58 <0.001

Late Lumen Loss 0.96±0.71 0.17±0.44 <0.001

Follow-up % Stenosis 44.1±28.5 10.4±16.5 <0.001

Restenosis Rate 18 (47.4) 11 (3.2) <0.001

ISR Length, mm 6.55±5.96 9.1±5.8 0.01

Total occlusions 3 (7.9) 2 (0.6) 0.02

Aneurysm 5 (13.2) 2 (0.6) <0.001

Stent Fracture: Follow-up FindingsStent Fracture: Follow-up Findings

Stent Fracture: Follow-up FindingsStent Fracture: Follow-up Findings

N

In-Segment Follow-up

% DS

Occlusion Aneurysm TLR No ISR TLR

Classification <50% ≥ 50%

Type I 0 0 0 0 0 0 0

Type II 5 3 2 0 1 2 1

Type III 15 6 9 0 1 7 0

Type IV 18 12 6 3 3 11 4

Overall 38 20(52.6%)

18 (47.4%)

3(7.9%)

5 (13.2%)

20 (52.6%)

5(13.2%)

* One patient developed fracture with initial deployment

• 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

CYPHERCYPHER™™ Stent Fracture: Summary Stent Fracture: Summary

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: DiscussionStent Fracture: Discussion

• 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: DiscussionStent Fracture: Discussion

ProceduralOverexpansion

PlacementPost-dilation

Length/overlap

MaterialElongation

Yield strength Ultimate Tensile Strength

Endurance LimitGrain size

Processing

Stent Fatigue is Multifactorial

StentDesign

Dimensions

AnatomicalWhich vessel & where

Compliance Angulation

Dynamic motion# of cycles

• 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

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) Korea Japan OUS US Worldwide

Cypher 1,650 258 210 41 86 (0.009%)

All BMS 199 0 7 7 8

†† Parts per millionParts per million* Adjusted for returns (From launch to 8/31/2006) *All rates are in PPM

CYPHER STENT FRACTURES:Complaint Databases (Cypher PPM† Levels)

Korea vs. Rest of World (ROW) Comparison -Fracture Rate by Stent Length

0102030405060708090

8mm 13mm 18mm 23mm 28mm 33mmStent Length

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CYPHER STENT FRACTURES:CYPHER STENT FRACTURES:Fracture Rate by Stent LengthFracture Rate by Stent Length

Study # of Patients Stent Length Follow-up ST TLR/TVR

RESEARCH 96 61.2 1 year 0 4.2

ARTS II 607 47.6 1 year 1.6 7.4

Colombo 66 80 1.1 years 1.5 15.2

Park Long 184 44.4 9 months 0 3.8

Park “FMJ” 347 71.9 17 months 0.3 4.1

Park RCT 250 40.8 9 months 0.5 2.5

Keriakes 337 32.3 1 year 0.3 4.7

Long Lesions with SES: SummaryNo 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. .