Newer Generation Drug-Eluting Stents: What is the...

Newer Generation Drug-Eluting Stents: What is the Promise?

Stephan Windecker

Department of Cardiology

Swiss Cardiovascular Center and Clinical Trials Unit Bern

Bern University Hospital, Switzerland

SES vs BMS: HR=0.30 (0.24-0.37), p<0.0001PES vs BMS: HR=0.42 (0.33-0.53), p<0.0001SES vs PES: HR=0.70 (0.56-0.84), p<0.0021

Drug-Eluting Stent SafetyNetwork Meta-Analysis: DES vs BMS

Stettler C et al. Lancet 2007;370:937-48

Mortality Repeat Revasc

18,023 Patients 18,023 Patients

Drug-Eluting Stent Safety in Large VesselsBASKET-PROVE: DES vs BMS

Kaiser C et al. N Engl J Med 2010

Death or MI Repeat Revasc

2,314 Patients 2,314 Patients

Very Late StentThrombosis

Bavry A et al. Lancet 2008

Newer Generation Drug-Eluting Stents:What is the Promise?

Durable Polymer DES

Biodegradable Polymer DES

Polymer-free DES

Comparison of Everolimus-Elutingand Paclitaxel-Eluting Stents

Meta-Analysis of SPIRIT II, III, IV and COMPARE

Favors EES Favors PES

6,789 Patients

Year 1

Year 2

Year 3

Overall

1.5.25.2.15.1 2 4 6

0.49 (0.38-0.64)

0.83 (0.32-2.18)

0.44 (0.14-1.39)

0.51 (0.40-0.65)

Year 1

Year 2

Year 3

Overall

1.5.25.2.15.1 2 4 6

0.65 (0.50-0.84)

0.56 (0.10-3.09)

0.54 (0.11-2.56)

0.63 (0.49-0.81)


TLR Cardiac Death or MI

Clinical Outcomes Up to 3 Years

Jüni, Windecker

Long-term Propensity-Score MatchedComparison of Everolimus-Eluting and

Sirolimus-Eluting Stents (LESSON-I)Räber L et al. J Am Coll Cardiol 2011, in press

Myocardial Infarction

1,342 Matched Pairs 1,342 Matched Pairs

Death, MI or TVR

Everolimus-Eluting vs Zotarolimus-ElutingEndeavor Resolute Stent

Serruys PW et al. N Engl J Med 2010

Cardiac Death or MI

@ 1 YearTarget Lesion Revasc

@ 1 Year

Comparison of Everolimus-Elutingand Paclitaxel-Eluting Stents

Meta-Analysis of SPIRIT II, III, IV and COMPARE

ARC Definite or Probable ST up to 3 Years

Jüni, Windecker

Year 1Year 2

Year 3

Overall

1.5.25.2.15.1 2 4 6

6,789 Patients

0.37 (0.16-0.85)

0.96 (0.27-3.42)

0.76 (0.02-26.7)

0.49 (0.24-0.99)


Long-term Propensity-Score MatchedComparison of Everolimus-Eluting and

Sirolimus-Eluting Stents (LESSON-I)Räber L et al. J Am Coll Cardiol 2011, in press

Everolimus Stent 0.5%

Sirolimus Stent 1.6%

P=0.01

Everolimus Stent 2.5%

Sirolimus Stent 4.0%

P=0.04

Definite ST Definite or Probable ST

1,342 Matched Pairs 1,342 Matched Pairs

2,0 2,0

3,3

1,2

0,3 0,3 0,4

0

1

2

3

4

CYPHER SIRTAX

CYPHER LEADERS

TAXUS SYNTAX

ENDEAVOR RESOLUTE

RAC

XIENCE RAC

XIENCE SPIRIT IV

XIENCE COMPARE

Stent Thrombosis in Perspective

%

Definite Stent Thrombosis in All Comer Trials @ 12 Months

Early Generation DES Newer Generation DES

• Newer generation durable polymer DES are

associated with a lower rate of MI compared with early

generation DES

• The risk of very late ST appears lower with newer

generation durable polymer DES but requires

confirmation in larger and more complex patient

cohorts

• Newer generation DES combine improved efficacy

with improved safety profile and constitute a new

standard of care in patients undergoing PCI

• Limus analogues are the drug of choice for current

DES applications

Durable Polymer Newer Generation DES

Biodegradable Polymer Based DES Platforms

0%

20%

40%

60%

80%

100%

0 3 28 90%

Myo

lim

us

Re

lea

se

dNumber of Days

Sirolimus – ISAR TESTBiolimus A9 – BioMatrix

Nobori, Axxess, XTENTSirolimus – NEVO

Sirolimus – Genous

Bioengineered R StentEverolimus - BSC Myolimus – ELIXIR

ISAR TEST 4 – Randomized Trial of 3 Limus-ElutingStent Platforms With Different Polymer Coatings

Byrne RA al. Eur Heart J 2009

16,4 17.2

0

5

10

15

20

1

Biodegradable Polymer (N=1299)

Durable Polymer (N=1304)

Cardiac Death,

MI or TLR

Cardiac Death

or MI% %

TLR

P=0.51

7,1 7.2

0

5

10

15

20

1



11 11.7

0

5

10

15

20

1



P=0.89 P=0.56

%

Clinical Outcomes Through 2 Years (Byrne RA et al. CTU @ ESC 2010)

Definite/Probable Stent Thrombosis

Months after randomization

0

1

2

3

4

5

0 2 4 6 8 10 12 14 16 18 20 22 24

RR 0.67 [95% CI, 0.34-1.13], P=0.24

Biodegradable Polymer DES 1.1%

Permanent Polymer DES 1.7%

%

Byrne RA et al. CTU @ ESC 2010

MACE = Cardiac Death, MI, or Clinically-Indicated TVR

* P values for superiority

%

Number at risk

BES 857 851 761 743 729 712 668

SES 850 846 749 732 713 686 639

Months

13.0%

15.4%

2-year HR0.84 [0.65 to 1.08]

P = 0.18*

Δ 2.4%12.1%

10.7%

1-year HR0.88 [0.66 to 1.17]

P = 0.37*

Δ 1.4%

0

5

10

15

20

0 6 12 18 24

BES

SES

3630

15.7%

19.0%

Δ 3.3%

3-year HR0.82 [0.65 to 1.03]

P = 0.09*

LEADERS – MACEBiolimus-Eluting vs Sirolimus-Eluting Stent

Serruys P. TCT 2010

3,1

2,1

1,3

2,7

0,3

4,4

2,5 2,6

3,4

0,9

0

1

2

3

4

5

Death Cardiac death Myocardial infarction

TLR Definite ST

Biolimus-Eluting Stent Sirolimus-Eluting Stent

LEADERS – Landmark Analysis from 1 to 3 YearsBiolimus-Eluting vs Sirolimus-Eluting Stent

P=0.15 P=0.59 P=0.07 P=0.41 P=0.11

%

3,5

50,5

0

10

20

30

40

50

60

Biolimus Stent Sirolimus Stent

-45.5

(-76.9 to –14.3)

P<0.01

LEADERS - OCT SubstudyBarlis P et al. Eur Heart J 2010

Lesions With At Least

5% Uncovered Struts

(%)

29 Lesions 35 LesionsBioMatrix

N=29

CYPHER

N=35

0,13

0,05

0,36

0,2

0

0,1

0,2

0,3

0,4

0,5

In-Stent In-Segment

NEVO TAXUS

P<0.001

P<0.001

mm

NEVO RES-I: Sirolimus Release FromBiodegradable Polymer Reservoirs

6,1

2,5

3,6

10,8

5,45,9

0

4

8

12

MACE Death/MI TLR

NEVO TAXUS

%

Angiographic Outcome Clinical Outcome

P=0.14

P=ns P=ns

Primary Endpoint: 12M Composite Clinical Endpoint of Cardiac Death, TV-related MI and Clinically Driven TLR

All-Comers~2500 patients @ 32 sites

30day 6M 1Yr 3Yr 5Yr18M

2:1 randomization

Off-label~ 1000 pts

Near on-label~ 667 pts (40%)

Off-label~ 500 pts

Near on-label~ 333 pts (40%)

13M

Angiographic sub

Clinical/ MACE

NEVO II Study Overview

NEVO™ Sirolimus-eluting Stent

(n~1667)

Xience VEverolimus-eluting Stent

(n~833)

Sub-study: NEVO near on-label: 150 Angio/75 IVUS Xience V near on-label: 75 Angio/38

IVUS

• Safety and efficacy of biodegradable polymer based

limus releasing DES is at least as good as first

generation durable polymer based DES

• A large scale randomized trial is required to address

whether biodegradable polymer based DES are

superior to permanent polymer based DES in terms of

safety and very late ST

• The majority of novel and upcoming newer generation

DES are based on biodegradable polymer platforms

owing to the appealing concept of leaving no polymer

behind

Biodegradable Polymer DES

Polymer-Free DES PlatformsAbizaid A al. Circ Cardiovasc Interv 2010

YUKON

Various DrugsBioFreedom

Biolimus A9

Optima

Tacrolimus

VESTAsync

Sirolimus

Amazon Pax

Paclitaxel

Sirolimus Release From Durable Polymer, Biodegradable Polymer and Polymer-Free Surfaces

Mehilli J et al. Eur Heart J 2008 (ISAR TEST 3)

0,23

0,17

0,47

0

0,2

0,4

0,6

Durable Polymer

Biodegrad Polymer

Polymer free

In-Stent Late Loss Binary Restenosis Clinical TLR

p=0.94*

mm

P<0.001*

* Pnon-inferiority vs durable polymer

10,8

9

16,9

0

5

10

15

20

Durable Polymer

Biodegrad Polymer

Polymer free

%

7,9

5,9

12,9

0

5

10

15

20

Durable Polymer

Biodegrad Polymer

Polymer free

%

N=202 N=202 N=201 N=202 N=202 N=201 N=202 N=202 N=201

12,1

17,2 17,2

0

5

10

15

20

25

Durable Polymer Sirolimus (N=1036)

Polymer Free

Sirolimus (N=565)

Durable Polymer

Paclitaxel (N=740)

P=0.003

Durability of Antirestenotic Efficacy of DESByrne RA et al. JACC Cardiovasc Interv 2009;2:291-9

Restenosis

@ 6-8 Months

17,3 16,6

21,8

0

5

10

15

20

25

Durable Polymer Sirolimus (N=1036)

Polymer Free

Sirolimus (N=565)

Durable Polymer

Paclitaxel (N=740)

P=0.02

Restenosis

@ 2 Years

% %

12 11

19,318,6

13,9

20,9

0

10

20

30

SES Dual DES ZES

6-8 months 2 years

N=335 N=333

%

6.6%

N=339

2.9% 1.6%

Two Year Angiographic and Clinical Outcome of Polymer-Free Dual Release DES Versus Durable

Polymer Based Sirolimus and Zotarolimus StentsByrne R et al. J Am Coll Cardiol 2010 (ISAR TEST 2 Investigators)

Death or MI Angiographic Restenosis

Months

51

78

96

0

20

40

60

80

100

BMS BioFreedom SES

% %

0,280,31

0,86

0

0,2

0,4

0,6

0,8

1

BMS BioFreedom SES

2,92,6

8,7

0

2

4

6

8

10

BMS BioFreedom SES

Struts With Fibrin Inflammation Score Struts With Giant Cells

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

0 5 10 15 20 25 30 35 40 45 50

Cum

ula

tive

Rele

ase (

%)

Time (Hrs)

Biolimus A9 Elution from Stents

(MEDIUM: PBS pH 7.4/Tween, 37°C)

Bi

Pol

Biolimus A9

Polymer-Free Biolimus-A9 Coated StentTada N et al. Circ Cardiovasc Interv 2010;3:174-83

Tada et al.,

Circ Cardiovasc Interv

2010;3;174-183

Pre-Clinical Study - EfficacyBES vs. SES &

BMSSD LD SES BMS

28 Days

180 Days

n 28 days 180 days

Standard dose Bio-freedom 24 23

Low dose Bio-freedom 26 27

Sirolimus-eluting stents 30 39

Bare metal stents 24 24

0.08

0.12

0.06

0.12 0.130.11

0.37

0.18

0.15

0.09

0

0.1

0.2

0.3

0.4

In-Stent In-Segment Proximal Edge Distal Edge

BioFreedom SD BioFreedom LD Taxus LiberteL

ate

Lo

ss

mm

(m

ed

ian

)

P= 0.002

P< 0.0001

In-segment

P= 0.09

P = 0.32

P = 0.35

P = 0.09

P = 0.89

P = 0.99

P = 0.77

P = 0.19

P = 0.37

P = 0.71

Polymer-Free BioFreedom Stent – 4 Month Results

12 Month Angiographic FUIn-Segment Binary Restenosis: 2nd Cohort

6.7

14.3

9.7

0

2

4

6

8

10

12

14

BFD SD BFD LD Taxus

P = 0.6683

P = 0.5670

(%)

N = 30 N = 31N = 35

BioFreedom - Clinical Outcomes @ 12 Months

BioFreedom

Standard

Dose

N=60

BioFreedom

Low Dose

N=62

Taxus Liberté

N =50

P-valueBFM SD vs.

Taxus

P-valueBFM LD vs

Taxus

MACE 3 (5%) 7 (11.6%) 0 (0.0%) N/A 0.09

Death 1 (1.8%) 0 (0.0%) 0 (0.0%) N/A N/A

MI* 1 (1.8%) 1 (1.6%) 0 (0.0%) N/A 0.34

Q Wave MI 0 (0.0%) 0 (0.0%) 0 (0.0%) N/A N/A

Non-Q Wave MI* 1 (1.8%) 1 (1.6%) 0 (0.0%) N/A 0.34

Emergent Bypass 0 (0.0%) 0 (0.0%) 0 (0.0%) N/A N/A

TLR** 1 (1.8%) 6 (10%) 3 (5%) N/A 0.17

Stent Thrombosis 0 (0.0%) 0 (0.0%) 0 (0.0%)

• Newer generation durable polymer DES provide

improved safety and efficacy compared with early

generation DES

• The majority of future generation DES are based on

biodegradable polymer drug release providing similar

safety and efficacy as durable polymer DES

– Appealing concept requiring confirmation in adequate trials

• Polymer-free based DES may even further decrease

polymer related adverse events, but potentially at the

cost of reduced efficacy

Future of Newer Generation DES

Drug-Coated Balloon Catheters

Mechanism of action

Immunofluorescence micrographs after staining with a monoclonal anti-tubulin AB

antibody

A lipophilic drug applied on a carrier is passively transferred to the intima of the

coronary artery by balloon expansion. Variable tissue retention rates determine

local inhibition of neointimal hyperplasia.

Control animal seven days after BD showing heterogeneous staining within the neointima

Histologic section seven days after local paclitaxel delivery showing an intensely stained “fluorescence band” at the luminal cell lining

Herdeg et al. J Am Coll Cardiol 2000)

Dru

gC

arr

ier

Pla

tfo

rms

Paclitaxel is lipophilic, has a high absorption rate (10-15%),

and is transferred quickly to the endoluminal surface-other drugs (i.e limus) also being tested

Governs total drug load,

coating durability and

uniformity, vessel uptake

and downstream drug dose-i.e. Iopromide

Paccocath (Bayer Schering)

SeQuent Please (B. Braun)

Dior (Eurocor)

Moxy (Lutonix, Inc.)NO Additive Carrier E Carrier F Carrier G Carrier H

Pe

ak

Pa

cli

tax

el L

eve

l in

Ta

rge

t T

iss

ue S

eg

me

nt

Different Carriers, Same Dose of Paclitaxel

No Carrier

Sub-

therapeutic

Drug-Coated Balloon CathetersGray WA et al. Circulation 2010;121:2672-80

Drug-Coated Balloons for Instent-Restenosis

0,11

0,8

0

0,2

0,4

0,6

0,8

1

DCB POBA

Paccocath ISR I&II

In-segment late loss

p=0.001

n=108

0,17

0,38

0

0,2

0,4

0,6

0,8

1

DCB POBA

PEPCAD II

PES

n=131

p=0.03


0,16

0

0,2

0,4

0,6

0,8

1

PERVIDEO I

DCB

n=41


6%

51%

0%

10%

20%

30%

40%

50%

60%

DCB POBA

Binary restenosis

p=0.001

7,0%

20,3%

0%

10%

20%

30%

40%

50%

60%

DCB POBA

p=0.06

PES

Binary restenosis

12,8%

0%

10%

20%

30%

40%

50%

60%

DCB

Binary restenosis

Scheller B et al. Clin Res Cardiol 2008 Unverdorben et al. Circulation 2009 Mauri L, TCT 2010

3,0%

0,0%

6,3%5%

2%

15%

0%

10%

20%

30%

40%

Death MI TLR

DCB POBAPES

4%2%

4%6%

9%

37%

0%

10%

20%

30%

40%

Death MI TLR

DCB POBA

Paccocath ISR I&II PEPCAD II

Clinical follow-up at 12 months

N=108 N=131

p=ns p=nsp=ns

p=0.001

p=ns

p=ns

Drug-Coated Balloons for Instent-Restenosis

Drug-Coated Balloons for Native,De-Novo Coronary Artery Disease

0.20 0.11

0

0,2

0,4

0,6

0,8

1

DEB+BMS DES

PEPCAD III

P=0.06

n=114 n=637 n=60

14%

5%

0

10

20

30

40

50

DEB+BMS DES

p<0.001

32%

10%

0

10

20

30

40

50

DEB DES

p=0.043

In-s

eg

men

tla

telo

ss

Bin

ary

Reste

no

sis

PICCOLETO - SVD

SirolimusPaclitaxel

Sirolimus0.16

0.62

0

0,2

0,4

0,6

0,8

1

DEB DEB+BMS

PEPCAD I - SVD

p<0.0001

6%

45%

0

10

20

30

40

50

DEB DEB+BMS

p<0.0001

1

4,7

10,5

0,3 0,3

4,7

0

5

10

15

20

Death MI TLR

DEB+BMS DES

(Sirolimus)

4 4

32

4

0

10

0

10

20

30

40

Death MI TLR

DEB DES

PEPCAD III PICCOLETO - SVD

Clinical follow-up

Hamm et al.

AHA 2009

Cortese et al.

Heart 2010

n=637 n=60

p=nsp=ns p=ns p=ns

p=ns

at 9 monthsat 9 months

(Paclitaxel)

Drug-Coated Balloons for Native,De-Novo Coronary Artery Disease

p=0.01

Newer Generation Drug-Eluting Stents: What is the...

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