Siegburg / Stanford

The Evolution of Drug-Eluting Stents

Biosensors International Cardiology Conference

August 3rd, 2005

Eberhard Grube MDFACC, FSCAI

Heart Center Siegburg, Siegburg, GermanyStanford University, School of Medicine, CA, USA

Siegburg / Stanford

56

7783

87

0

4741

19

Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4

pe

rce

nt

U.S. Penetration of DES

28% (2003)

75% (2004)

CypherCypher as of 4/03 and as of 4/03 and TaxusTaxus as of 3/04as of 3/04

2003 2004

Market penetration of DES 03/04

==Bare Metal Stents

Drug-Eluting Stents

==

Siegburg / Stanford

Suppression of intimal proliferationBare metal stent versus Drug Eluting Stent

Suppression of intimal proliferationBare metal stent versus Drug Eluting Stent

BMS DES

Siegburg / Stanford

How to Assess Efficacy

Intimal Hyperplasia

Angiographic Surrogate

Late Lumen Loss

Clinical Surrogate

Target Lesion Revascularization

Siegburg / Stanford

Overall 4.1 16.6 0.0001 124

Male 4.4 16.6 0.0001 122

Female 3.4 16.5 0.0007 130

Diabetes 6.9 22.3 0.0006 154

No Diabetes 3.2 14.3 0.0001 111

LAD 5.1 19.8 0.0001 147

Non-LAD 3.4 14.3 0.0001 109

Small Vessel (<2.75) 6.3 18.7 0.0001 125

Large Vessel 1.9 14.8 0.0001 128

Short Lesion 3.2 16.1 0.0001 129

Long Lesion (>13.5) 5.2 17.4 0.0001 122

Overlap 4.5 17.7 0.0003 131

No Overlap 3.9 16.1 0.0001 121

Hazards Ratio 95% CI 1.00.90.80.70.60.50.40.30.20.10 0.70.80.9

# events prevented per1,000 patients

Sirolimus Control P-value

Sirolimus better

SIRIUS ResultsTLR: Subset Summary

Siegburg / Stanford 1.01.0 1.51.5

RRRR TAXUSTAXUS ControlControl PP

All 0.27 3.0 11.3 <0.0001

Non-diabetic 0.24 2.4 9.8 <0.0001

Diabetic, oral meds 0.28 4.8 17.4 0.004

Diabetic, insulin 0.45 5.9 13.0 0.32

LAD 0.25 3.4 13.4 <0.0001

Non-LAD 0.29 2.8 9.7 0.0001

RVD ≤≤≤≤2.5 mm 0.22 3.4 15.4 <0.0001

RVD >2.5-3.0 mm 0.28 3.1 11.2 0.0004

RVD >3.0 mm 0.38 2.5 6.7 0.57

Lsn length <10 mm 0.35 3.3 9.3 0.01

Lsn length 10-20 mm 0.27 2.8 10.5 0.0001

Lsn length >20 mm 0.18 3.3 18.6 0.0009

TAXUS IV ResultsTLR: Subset Summary

00 0.50.5RR [95% CI]

Siegburg / Stanford

PaclitaxelSirolimusRavelSirius

The Winners

1. FIM (45)2. Sirolimus PK (19)

3. SECURE (252)

4. RAVEL (238)

5. SIRIUS (1058)

6. China (41)7. Taiwan (50)

8. Argentina (20)

9. BIF (86)

10. E-SIRIUS (353)

11. C-SIRIUS (100)12. ISR-Feas (41)

13. US ISR-Feas (8)

14. TROPICAL (160)

15. SISR (400)16. ISR-Barragan (23)

17. ARTS II (600)

18. FREEDOM (2600)

19. 2.25 mm (100)

20. 4.00 mm (100)21. ATLAS (100)

1. FIM (45)2. Sirolimus PK (19)

3. SECURE (252)

4. RAVEL (238)

5. SIRIUS (1058)

6. China (41)7. Taiwan (50)

8. Argentina (20)

9. BIF (86)

10. E-SIRIUS (353)

11. C-SIRIUS (100)12. ISR-Feas (41)

13. US ISR-Feas (8)

14. TROPICAL (160)

15. SISR (400)16. ISR-Barragan (23)

17. ARTS II (600)

18. FREEDOM (2600)

19. 2.25 mm (100)

20. 4.00 mm (100)21. ATLAS (100)

22. SICTO (25)23. SVG-Feas (150)

24. DIRECT (220)

25. DECODE US (100)

26. DECODE (100)

27. BRIDGE (1000)28. PORTO I & II (300)

29. SCORPIUS (190)

30. Cypher-SMART (256)

31. EVASTENT (2000)

32. TYPHOON (700)33. DESSERT (250)

34. SVELTE (101)

35. REDOX (60)

36. 3D (44)

37. SC US (tbd)38. SC EU (tbd)

39. SVS-Feas (45)

40. SIROCCO I (36)

41. SIROCCO II (57)42. GREAT (101)

22. SICTO (25)23. SVG-Feas (150)

24. DIRECT (220)

25. DECODE US (100)

26. DECODE (100)

27. BRIDGE (1000)28. PORTO I & II (300)

29. SCORPIUS (190)

30. Cypher-SMART (256)

31. EVASTENT (2000)

32. TYPHOON (700)33. DESSERT (250)

34. SVELTE (101)

35. REDOX (60)

36. 3D (44)

37. SC US (tbd)38. SC EU (tbd)

39. SVS-Feas (45)

40. SIROCCO I (36)

41. SIROCCO II (57)42. GREAT (101)

TAXUS

Siegburg / Stanford

5,7%3,5%

17,1%19,2%

TLR TVR

%

Sirolimus (n=1204) Control (n=870)

CYPHER Trials - Clinical Events

All Events (to 9 months)

P<0.0001P<0.0001

80% 70%

Siegburg / Stanford

TAXUS II + IV + VI Meta-analysis (n=2,289)

12 Month TLR and TVR

17.5%15.6%

7.6%4.9%

12

Mo

nth

Ev

en

ts (

%)

12

Mo

nth

Ev

en

ts (

%)

ControlControl TAXUSTAXUS

TVRTVRTLRTLR

RR=0.31 [0.24,0.42], P<0.0001 RR=0.44 [0.34,0.55], P<0.0001

N=1,148 N=1,141 N=1,148 N=1,141

Siegburg / Stanford

Control TAXUST

LR

(%

)

Insulin reqDiabeticsall patients

14.8

5.8

18.6

7.3

16.9

5.8

P<0.0001 P<0.0001 P<0.0001

TAXUS metaanalysis

TAXUS in diabetic patients

Siegburg / Stanford

II IIaIIa IIbIIb IIIIII

Recommendation DES

CypherCypher™™

RAVELRAVEL

SIRIUSSIRIUS

EE--SIRIUSSIRIUS

CC--SIRIUSSIRIUS

TAXUSTAXUS™™

TAXUSTAXUS--II

TAXUSTAXUS--IIII

TAXUSTAXUS--IVIV

TAXUSTAXUS--VIVI

De-Novo Läsionen

RVD 2.5 – 3.75 mm, ≤≤≤≤30 mm in length

DES - 2005Need for more Evidence ?

�� Long Long LesionsLesions

�� Small Small vesselsvessels

�� ISR ISR lesionslesions (esp. (esp. ultraultra--diffusediffuse andand s/p VBT)s/p VBT)

�� Bifurcations (esp. Bifurcations (esp. ostialostial sidebranchsidebranch))

�� LM LM diseasedisease (esp. distal bifurcation)(esp. distal bifurcation)

�� SVGsSVGs

�� CTOsCTOs

�� AMIAMI

�� MultivesselMultivessel DiseaseDisease

�� ……

Siegburg / Stanford

P<0.0001 P<0.0001

Binary restenosis in-stent

(%)

Control TAXUS MR

40.4

7.3

23/57 4/55

7.0

50.0

17/34 3/43

40.5

8.1

17/42 3/37

P<0.0001

Small vessels<2.5mm

Long lesions≥26mm

Diabetics

82 % 86 % 80 %

Overlappingstents

25/55 3/62

45.5

4.8

89 %

P=0.0015

TAXUS VIRestenosis benefit independent of classic risk factors

Siegburg / Stanford Neumann et al., PCR 2004

SES vs. Historical Gamma VBT

n= 162 SES262 VBT

TROPICALTROPICAL

Clinical Outcome at 180 DaysClinical Outcome at 180 Days

Non- Hierarchical Event Rate (%)TROPICAL

GAMMA I/II

0

5

10

15

20

Death MI Clinicallydriven TLR

Stent thrombosis

MACE

P=0.490

P=0.004

P<0.001

P=0.080

P<0.001

3.7

0.6 1.82.5

0.6

18.8

2.0

25

9.4

14

3.9

30

Siegburg / Stanford

CYPHER in CYPHER in CTOCTO’’ss

RESEARCH RegistryRESEARCH Registry

Siegburg / Stanford

ISAR – DESIRECYPHER vs. TAXUS

Siegburg / Stanford

ISAR – DESIRECYPHER vs. TAXUS

Siegburg / Stanford

-- 3400 randomized patients undergoing primary PCI 3400 randomized patients undergoing primary PCI --

Hypothesis: Hypothesis: Use of the TAXUS Use of the TAXUS PTxPTx--

eluting eluting stentstent will safely reduce the 1will safely reduce the 1--year year

rate of ischemiarate of ischemia--driven TVRdriven TVR

Hypothesis: Use of bivalirudin + bailHypothesis: Use of bivalirudin + bail--out out

IIb/IIIa will rIIb/IIIa will reduce the composite rate of educe the composite rate of

death, death, reinfarctionreinfarction, TVR, disabling stroke , TVR, disabling stroke

and major bleeding at 30and major bleeding at 30--daysdays

HORIZONS AMI Study

Target vessel Target vessel stentingstenting

Bare metalBare metal

ExpressExpress™™ stentstentTAXUSTAXUS

stentstent

Randomize 1:3Randomize 1:3

AntiAnti--thromboticthrombotictherapytherapy

UFH + UFH +

IIb/IIIaIIb/IIIa

inhibitorinhibitor

BivalirudinBivalirudin++

bailbail--outout

IIb/IIIa IIb/IIIa

Randomize 1:1Randomize 1:1

PI: Gregg W. StonePI: Gregg W. Stone

MV-sirolimus stentingWith abciximab

Multivessel Sirolimus Stenting vs. CABG in Diabetics

Eligibility: DM patients with MV-CAD eligible for stent or surgeryExclude: Patients with acute MI and/or cardiogenic shock

CABGWith or without CPB

All concomitant Meds shown to be beneficial are encouraged, including: Plavix, ACE inhibitors, b-blockers, statins, etc.

1o Endpoint: 5-year mortality 5-year MACE2o Endpoint : MACE/stroke at 12 months

2300 pts Randomized 1:1

FREEDOM Trial

Siegburg / Stanford

SYNTAX StudieTAXUS vs. CABG

Left main disease 3-vessel disease

Primary endpoint – MACCE•All cause death •MI

•Cerebrovascular events•Repeat revascularization

TAXUS PCI CABG

OR

R

De novo disease acceptable for revascularization

N=4500

Need for Improvements?

Of course....

Siegburg / Stanford

Safety

Efficacy

Cost

Drug Eluting Stents

Siegburg / Stanford

Safety

Efficacy

Cost

DES - Animal StudiesWhat do the “bad things” look like…

• Excessive thrombus• Incomplete endothelialization

• Severe inflammatory response

• Persistent fibrin + inflammation

• Medial necrosis• Malapposition

Siegburg / Stanford

0.6

1.6

0.4

1.8

0.0

0.5

1.0

1.5

2.0

2.5

Intention-to-Treat Actually-Treated*

CYPHER® TAXUS™

0.6

1.6

0.4

1.8

0.0

0.5

1.0

1.5

2.0

2.5

Intention-to-Treat Actually-Treated*

CYPHER® TAXUS™

PP=0.0723=0.0723 PP=0.0196=0.0196

111144 121233

% of % of PatientsPatients

Stent Thrombosis (Acute + Subacute)

Per protocol analysis: CYPHERPer protocol analysis: CYPHER®® 0.4, TAXUS0.4, TAXUS™™ 1.7: 1.7: PP=0.033=0.033* 1 patient randomized to CYPHER* 1 patient randomized to CYPHER®® actually treated with a TAXUSactually treated with a TAXUS™™ stentstent

REALITY

Siegburg / Stanford

2229 patients after successful DES implantation 2229 patients after successful DES implantation

PESPES

1167 pts1167 pts

2223 stents 2223 stents

SATSAT

4 (0.4%)4 (0.4%)SATSAT

10 (0.9%)10 (0.9%)

LSTLST

5 (0.5%)5 (0.5%)

LSTLST

10 (0.9%)10 (0.9%)

Total SESTotal SES

9 (0.9%) 9 (0.9%) Total PESTotal PES

20 (1.7%)20 (1.7%)

9.3 9.3 ±±±±±±±± 5.6 months 5.6 months

Total DES 29/2229 Total DES 29/2229 (1.3%)(1.3%)

P=0.5P=0.5

P=0.3P=0.3

P=0.09P=0.09

10.2 10.2 ±±±±±±±± 4.44.4 mm 7.9 7.9 ±±±±±±±± 3.63.6 mm

Stent Thrombosis after DES

SESSES

1062 pts 1062 pts

2272 stents 2272 stents

Siegburg / Stanford

Acute stent thrombosis: Up to 30 days

Range in each program

4.0 0 4.02.0 2.0

Observed

Range

Observed

Range

Stent Thrombosis (%)

SIRIUSMILESTONE

II

Limus Paclitaxel

TAXUS IV

SIRTAX

ENDEAVOR

IITAXUS V

REALITY REALITY

ARRIVEE-SIRIUS

C-SIRIUS

SIRTAX

RESEARCH

/TSEARCH

WISDOM

MILAN DES

TAXUS II SR

TAXUS VI

2.0 0.2 0.2 1.6

Siegburg / Stanford

Single TLR in TAXUS-SR at Day 522

•• Mid RCAMid RCA

•• RVD:4 mmRVD:4 mm

•• LL: 4 mmLL: 4 mm

•• % DS: 75%% DS: 75%

Baseline61 y.o. male with prior MI and hypercholesterolemia61 y.o. male with prior MI and hypercholesterolemia

•• PrePre--dilationdilation

•• 1 SS: 3.5 x 15mm1 SS: 3.5 x 15mm

•• No complicationsNo complications

•• 6mo FU 6mo FU

•• AsymptomaticAsymptomatic

•• No restenosisNo restenosis

Post

•• Non QNon Q--wave MIwave MI

•• Thrombectomy, PTCAThrombectomy, PTCA

•• On ASA, off On ASA, off

clopidogrelclopidogrel

Stent Thrombosis

Day 522

2 year

•• AsymptomaticAsymptomatic

Day 738

Siegburg / Stanford

Stent thrombosis

Siegburg / Stanford

0,3 0,3

0,3

0,2

0,3 0,5

0 0,5 1 1,5

Control

(n=613)

TAXUS

(n=625)

Stent thrombosis, %

In-hospital Discharge - 30 days

31 days - 1 year* 1-2 years

P=0.77

1.1%(n=7)

0.8%(n=5)

* All within 1-6 months

TAXUS IV TAXUS IV

Stent ThrombosisStent Thrombosis

Siegburg / Stanford

Safety

Efficacy

Cost

Siegburg / Stanford

Restenosis of ABT-578-eluting stent (OCT)

ENDEAVOR-II 8 mths follow-up

Stent overlap area

4.8 mm2

2.1 mm2

1.0 mm21.4 mm2

3.5 mm2

6.1 mm2 5.5 mm2

6.5 mm2

53.8%

25.5%16.4%

43.8%

LA / SA

Lumen A

Stent A

Siegburg / Stanford

TAXUS V9-Month Angiography2.25 mm Stent Subgroup (n=203)

44,749,4

24,731,2

InIn--stentstent InIn--SegmentSegmentInIn--stentstent InIn--SegmentSegment

Late LossLate Loss Binary RestenosisBinary Restenosis

Control (n=85)Control (n=85) TAXUS (n=93)TAXUS (n=93)

0.900.90±±±±±±±±0.630.63

0.490.49±±±±±±±±0.610.61

0.610.61±±±±±±±±0.590.59

0.360.36±±±±±±±±0.530.53

p<0.0001 p=0.01p=0.004 p=0.007

8585 9393 8585 9393 38/8538/85 23/9323/93 42/8542/85 29/9329/93

Siegburg / Stanford

Various Approaches to Improve Drug Eluting Stents

Better Better Stent designStent design

Better Better

Pharmacologic Pharmacologic

agentagent

Better Better Drug carrier Drug carrier

vehiclevehicle

Drug-

Eluting

Stent

DrugDrug--

Eluting Eluting

StentStent

Siegburg / Stanford

BioMatrix™ Stent Components(Biosensors International Group)

S-Stent™ (stainless steel)• Quadrature-link design; increased flexibility

• Excellent scaffolding

• Reduced turbulence and wall injury

PLA Polymer• Uniform thickness; bioresorbable

• Simultaneously releases drug and polymer

• Controlled biodegradability

• High drug-carrying capacity

• Minimizes polymer weight to minimize

inflammation; polymer absorbed into tissue

Stent

Biolimus A9™ (rapamycin derivative)• Powerful immunosuppressant, anti-inflammatory

• Prevents smooth muscle cell proliferation

• More lipophilic; faster cellular absorption

Siegburg / Stanford

STEALTH I: Clinical Follow-up

6-Month Follow-up:

95% (n=114)

12-Month Follow-up:

99.2% (n=119)

120 Patients

Control BMS S-Stentn = 40

BioMatrixn = 80

Siegburg / Stanford

STEALTH I: Hierarchical MACE at 6 and12 Months

Cumulative

1.3%0.0%0.0%0.0%TLR-CABG

1.3%0.0%1.3%0.0%TLR-PTCA

12 Months*6 Months

RESULTS

2.5%

0.0%

2.5%

5.0%

S-Stent

1.3%1.3%2.5%Non-Q Wave MI

6.3%3.8%2.5%MACE

1.3%0.0%0.0%Death**

1.3%1.3%0.0%Q Wave MI

BioMatrixBioMatrixS-Stent

*Not adjudicated

**Death events were noncardiac: 1 traffic accident (S-Stent); 1 acute leukemia (BioMatrix)

Siegburg / Stanford

Biolimus-eluting stent

STEALTH-1 12 mths follow-up

Siegburg / Stanford

STEALTH I: Late Loss—Edge Results

In-segment

0.140,00

0,20

0,40

0,60

0,80

Late Loss

Proximal In-Stent Distal In-

Segment

Control BMSBiolimus A9

P=0.004P=0.73P=0.23 P<0.001

50%

65%20%

69%

0.170.10

0.08

0.74

0.26 0.10

0.400.14

Siegburg / Stanford

Comparison of Neointimal Volume

32,0

16,712,8 12,2

7,9 7,23,1 2,9 2,6 1,5 1,1 1,00,0

5,010,015,020,025,030,035,0

%

BMS

ASPE

CT L

owAS

PECT

Hig

hTA

XUS

IVTA

XUS

IITA

XUS

ISI

RIUS

FUTU

RE 1

STEA

LTH

ISV

ELTE

FUTU

RE II

RAVE

L

Taxol family Limus family

No PolymerNo Polymer

PolymerPolymer

PolymerPolymer

Courtesy Shimada, Honda, Hassan, Fitzgerald

Siegburg / Stanford

DES are highly efficient in prevention of restenosis; this DES are highly efficient in prevention of restenosis; this

has been demonstrated by the largest body of has been demonstrated by the largest body of

evidence ever collected in the history of device evidence ever collected in the history of device

evaluation evaluation

More data are coming up soon, which will expand the More data are coming up soon, which will expand the

official recommendations for DES use; however there official recommendations for DES use; however there

is still need for further investigations in specific is still need for further investigations in specific

subgroups (SVG, etc)subgroups (SVG, etc)

DES are safe, but continuing surveillance is recommended to monitor the unknown long-term effects of this young technology

New DES will improve both safety and efficacy of this revolutionary treatment concept

Conclusions

Siegburg / Stanford

Siegburg / Stanford

Thank youThank you

Siegburg / Stanford

Stent thrombosis in BMS

Siegburg / Stanford

Stent thrombosis in BMS