Innovation in Cardiovascular Interventions

New DES, Scaffolds and other Devices

Have Angioplasty Results Improved

Alexandra Lansky, MD

Yale University School of Medicine

University College of London

3rd

Generation

2nd

Generation 1st

Generation

0.140 μm

(0.0055” )

Cypher®

Stent

0.091 μm

(0.0036”)

Endeavor®

Stent

TAXUS®

Liberté®

Stent

0.096 μm

(0.0038”)

TAXUS®

Express®

Stent

0.132 μm

(0.0052”)

ION™ /

TAXUS®

Element™

Stent

0.081 μm

(0.0032”)

4th

Generation

SYNERGY™ Stent

0.074 μm

(0.0029”)

DES Evolution to Thinner Strut Thickness

Stainless Steel Cobalt Alloys Platinum Chromium

Reported strut thicknesses are for 3.0mm diameter

PROMUS

Element™

Stent

0.081 μm

(0.0032”)

Xience V®

and

Xience

Prime®

Stents

0.081 μm

(0.0032”)

current benchmark for lowest strut thickness

Coating Thickness:

12.6 µm 19.6 µm 4.8 µm 7.8 µm

Drug-eluting Stents: 2nd Generation

Drug Polymer

Xie

nce V

VDF + HFP copolymer Everolimus Vision

O

O

O O HO

O

O

O O H O

O O

N O

H O

Stent

Pro

mu

s

Ele

men

t

VDF + HFP copolymer Everolimus Element (Ion)

O

O

O O HO

O

O

O O H O

O O

N O

H O

SPIRIT II, III, IV and COMPARE trials

Pooled database analysis (n=6,789)

MACE (Cardiac Death, MI, ID-TLR)

P<0.001

HR: 0.64 [0.54, 0.75] EES (n=4,247)

PES (n=2,542)

4247 4086 3942 3291

2542 2363 2269 1944

Number at risk

XIENCE

TAXUS

11.1%

Card

iac D

eath

, M

I,

Isc

he

mic

TL

R (

%)

0

15

Time in Months

0 3 6 9 12 15 18 21 24

3820

2193

7.3%

10

5

7.6%

4.4%

Kereiakes DJ et al. EuroIntervention 2011:7:74-83

SPIRIT II, III, IV and COMPARE trials

Pooled database analysis (n=6,789)

Stent thrombosis (ARC definite/probable)

4247 4177 4082 3479

2542 2463 2408 2110

Number at risk

XIENCE

TAXUS

2.3%

Ste

nt

thro

mb

osis

AR

C d

ef

or

pro

b (

%)

0

1

2

3

Time in Months

0 3 6 9 12 15 18 21 24

3998

2350

0.7%

p<0.001

HR: 0.30 [0.19, 0.47]

EES (n=4,247) PES (n=2,542)

Kereiakes DJ et al. EuroIntervention 2011:7:74-83

EXAMINATION Trial

0 1 2 3

Xience V

Vision

Acute Subacute Late

p = 0.01

1504 pts with STEMI undergoing PCI within 48 (85% primary PCI

within 12) were randomized to Xience V EES vs. Vision BMS

Stent thrombosis (Def/prob) within 1 year

2.6%

0.9%

Definite ST was reduced with Xience V from 1.9% to 0.5%, p=0.01

Sabate M et al. Lancet 2012

PLATINUM: Target Lesion Failure

Months Since Index Procedure

CoCr-EES

PtCr-EES

No. at risk

4-Year Follow-up (Primary Endpoint at 1 Year)

749 738 735 715 701 683 656 473

758 747 745 727 715 702 687 480

CoCr-EES (N=749)

PtCr-EES (N=758)

TL

F (

%) 8.5%

7.4%

Treatment Group PROMUS Element 0-4YPROMUS 0-4Y

Primary Endpoint

HR [95% CI] =

0.86 [0.60, 1.24]

P = 0.43

Kereiakes DJ et al. JACC 2014;63 (12):2905-4

Reso

lute

BioLinx Zotarolimus Driver

Drug Polymer Stent

Drug-eluting Stents: 2nd Generation

Hydrophilic

Hydrophobic

En

deav

or

Phosphorylcholine Zotarolimus Driver

Endeavor II Trial

Fajadet J et al. Circulation. 2006;114:798-806

1197 pts randomized to E-ZES vs. BMS

9 month

outcomes

E-ZES

(n=592)

BMS

(n=591) P

TVF (1 EP) 7.9% 15.1% 0.0001

- Death 1,2% 0.5% 0.34

- MI 2.7% 3.9% 0.26

- TLR 4.6% 11.8% 0.0001

- TVR 5.6% 12.5% <0.0001

Stent

thrombosis 0.5% 1.2% 0.22

In-segment binary restenosis

E-ZES: 13.2%

BMS: 35.0% P<0.0001

mm

Endeavor ZES

PROTECT Study Design

Largest RCT and first powered for ST

Cypher SES

6mo 4yr 3yr 30mo 18mo 24mo 12mo Clinical endpoints

5yr 30d

Real-world patients – N=8709 Single and multiple coronary artery lesions No limitations on number of lesions/vessels

1:1 Randomization

196 sites world wide in 5 continents

3-12 months of aspirin and clopidogrel

Primary endpoint: ARC definite or probable ST at 3 years

Powered for a 40% reduction with ZES

Camenzind E et al. Lancet 2012

Definite or probable stent thrombosis to 3 years

Patients at Risk

E-ZES 4357 4347 4222 4119

C-SES 4352 4344 4211 4100

PROTECT Primary Endpoint

Time After Initial Procedure (Years)

AR

C D

efi

nit

e / P

rob

ab

le S

T

0%

0 1 3

5%

2%

2

1%

Endeavor ZES (N = 4357)

Cypher SES (N = 4352)

1.42%

1.79%

3%

4%

Camenzind E et al. Lancet 2012

HR [95%CI =

0.81 [0.58-1.14]

P=0.22

Definite or probable stent thrombosis to 3 years

PROTECT Primary Endpoint

Camenzind E et al. Lancet 2012

Cypher SES (n = 4159) Endeavor ZES (n = 4181)

Late

(1 -12 months)

Early

(0-30 days)

Very late

(1-3 years)

P = 0.60

P = 0.02

P<0.001

P = 0.76 P = 0.21 P<0.0001

P = 0.03

Ra

te (

%)

Cypher SES (n = 4159) Endeavor ZES (n = 4181)

MI TVR Death TLR

PROTECT Secondary Endpoints - 3 years -

Camenzind E et al. Lancet 2012

Days after Initial Procedure

Cu

mu

lati

ve

In

cid

en

ce

of

Ev

en

ts

11.2% 10.7%

0%

0 180 360 540 720

20%

5%

15%

10%

EES (n=1,152)

R-ZES (n=1,140)

95% CI = 0.6% [-2.0%, 3.2%]

P = 0.73

RESOLUTE All-Comers: TLF (Cardiac Death, TV-MI or clinically-driven TLR)

Silber S et al. Lancet. 2011;377:1241-7

TWENTE (n=1,387)

Target Vessel Failure at 2-Year Follow-up

Tandjung K et al. J Am Coll Cardiol 2013;61:2406–16

0 60 120 180 240 300 360 420 480 540 600 660 720

TV

F (

%)

Follow-up (days)

0

5

10

15

20

25

30

Xience V (n=692)

Resolute (n=695)

P = 0.67

11.6%

10.9%

Stent Thrombosis Network Meta-analysis ARC Definite ST at 30 days

49 RCTs, 50,844 pts

Odds Ratio [95%] 30-day definite stent thrombosis*

CoCr-EES vs BMS

CoCr-EES vs PES

CoCr-EES vs SES

CoCr-EES vs End-ZES

CoCr-EES vs Res-ZES

PtCr-EES vs BMS

PtCr-EES vs PES

PtCr-EES vs End-ZES

PtCr-EES vs Res-ZES

SES vs BMS

0.21 (0.11-0.42)

0.27 (0.14-0.51)

0.40 (0.21-0.79)

0.22 (0.09-0.54)

0.07 (0.00-0.46)

0.06 (0.00-0.68)

0.07 (0.00-0.83)

0.06 (0.00-0.73)

0.02 (0.00-0.43)

0.54 (0.30-0.90)

Favors Stent 1

10 1 0.1 0.01

Favors Stent 2

Palmerini T et al. Lancet 2012:On-line

Stent Thrombosis Network Meta-analysis ARC Definite ST at 1 year

49 RCTs, 50,844 pts

Odds Ratio

[95%] 1-year definite stent thrombosis*

CoCr-EES vs BMS

CoCr-EES vs PES

CoCr-EES vs SES

CoCr-EES vs Res-ZES

CoCr-EES vs End-ZES

SES vs BMS

End-ZES vs SES

0.23 (0.13-0.41)

0.28 (0.16-0.48)

0.41 (0.24-0.70)

0.14 (0.03-0.47)

0.21 (0.10-0.44)

0.57 (0.36-0.88)

1.92 (1.07-3.90)

Favors Stent 1 Favors Stent 2

10 1 0.1 0.01

Palmerini T et al. Lancet 2012:On-line

Number at risk

XIENCE V 669 646 616 601 582 571 565 548 537 529 521

TAXUS 332 310 288 274 269 262 255 248 243 231 223

Months

SPIRIT III: Target Lesion Failure @5 years T

LF

(%

)

1-year HR

0.56 [0.34, 0.90]

p=0.01

5-year HR

0.64 [0.46, 0.89]

p=0.008

9.2%

5.4%

Δ3.8%

19.0%

12.7%

Δ6.3%

TLF = cardiac death, target vessel MI, or ischemic-driven TLR

0%

5%

10%

15%

20%

25%

30%

0 6 12 18 24 30 36 42 48 54 60

TAXUS Express (n=332) XIENCE V (n=669)

Stone GW et al. JACC 2011

~1.8%/yr event rate after year 1

Number at risk

XIENCE V 2458 2390 2364 2323 2281 2238 2212 2187 2162 2132 2116 2095 2074

TAXUS 1229 1166 1138 1119 1095 1069 1060 1049 1029 1019 1008 994 979

Ta

rge

t le

sio

n f

ail

ure

(%

)

Months

XIENCE V (n=2,458)

TAXUS Express (n=1,229)

p=0.02

HR [95%CI] =

0.78 [0.63, 0.97]

6.7%

4.0%

p=0.001

HR [95%CI] =

0.61 [0.46, 0.81]

Δ 2.7%

0

5

10

15

20

25

0 3 6 9 12 15 18 21 24 27 30 33 36

11.7%

9.2%

Δ 2.5%

p=0.004

HR [95%CI] =

0.71 [0.56, 0.90]

TLF = cardiac death, target vessel MI, or ischemic-driven TLR

Stone GW et al. JACC 2011

~2.6%/yr event rate after year 1

SPIRIT IV: Target Lesion Failure @3 years

Etiology of metallic stent events beyond 1 yr

Very late thrombosis and restenosis

Possible causes

1.Uncovered stent struts (thrombosis)

2.Persistent stimulation of SMCs, from adherent fibrin and/or

loss of normal vessel curvature

3.Abnormal shear stress from protruding struts and/or loss

of cyclic strain relief (compliance mismatch)

4.Chronic inflammation due to late foreign body reactions

and polymer hypersensitivity

5.Positive remodeling with strut malapposition

6.Strut fracture

7.Neoatherosclerosis

6-mo Taxus

%NC 8%

%DC 2%

9-mo Taxus

%NC 28%

%DC 8%

22-mo Taxus

%NC 39%

%DC 20%

48-mo BMS

%NC 40%

%DC 25%

57-mo BMS

%NC 57%

%DC 15%

Neoatherosclerosis: Transformation of Neointimal

Hyperplasia to Necrotic Core in BMS and DES

Kang SJ et al. AJC 2010;106:1561-1565

TCFA Development in Neointimal Hyperplasia

Is More Common with DES than BMS, occurs earlier,

and can rupture causing stent thrombosis and occlusion

Nakazawa G et al. J Am Coll Cardiol 2011;57:1314–22

Three Approaches to Improve Late

DES Outcomes

1. Metallic DES with bioabsorbable polymers

2. Metallic DES, polymer-free

3. Bioresorbable scaffolds (BRS)

Stefanini GG et al. EHJ 2012;33:1214–22

Ste

nt

thro

mb

osis

(%

)

2

0

0

3

4

5

HR (95% CI) DP BP

ISAR-TEST 3 1/202 2/202

ISAR-TEST 4 9/1299 10/652

LEADERS 20/857 32/850

Overall 30/2358

0.47 (0.04, 5.04)

0.45 (0.18, 1.12)

0.62 (0.35, 1.08)

44/1704 0.56 (0.35, 0.90)

0.1

Favors BP HR

10

Favors DP

0.22 [0.08, 0.61]

P=0.004

0.02 [0.47, 1.38]

P=0.43

1 2 3 4

1

Ste

nt

thro

mb

osis

(%

)

Years

2

0

0

3

4

5

HR [95%CI] = 0.56 [0.35, 0.90]

P=0.015

1 2 3 4

1

Biodegradable polymer Durable polymer

Years

Test for heterogeneity P=0.84

Test for inconsistency 12=0%

Test for overall effect z2=2.43 (P=0.015)

Meta-analysis of Bioresorbable Polymer DES:

ISAR-TEST 3, ISAR-TEST 4, and LEADERS at 4 yrs

4,062 randomized pts assigned to bioresorbable polymer

eluting sirolimus or biolimus A (2,388) or Cypher (1,704)

Definite Stent Thrombosis

1.3%

2.8%

Abluminal Bioabsorbable Polymer

SYNERGY Stent (BSC)

Abluminal

bioabsorbable

polymer (PLGA)

3-4 um thick

Thin PtCr stent

(74 – 81 um)

PLGA bioabsorbable

polymer + everolimus on

abluminal side of stent

Coating weight on 16

mm stent ~200 µg (vs

~685 µg for Xience /

Promus)

Everolimus elutes

over ~3 months

(similar to Xience /

Promus)

PLG undetectable by

~4 months, leaving

behind a BMS

291 Pts Randomized to

Promus Element vs. Synergy vs Synergy ½ dose Primary Endpoints

Meredith I et al. JACC 2012;59:1362–70

P=0.19

Late Loss at 6 Months TLF at 30 Days

Late

lo

ss, m

m

0.0

0.5

0.6

PROMUS

Element

SYNERGY SYNERGY

½ Dose

P=0.56

0.4

0.3

0.2

0.1

0.15 0.10 0.13

P=0.49

Targ

et

lesio

n f

ailu

re, %

0.0

8.0

10.0

PROMUS

Element

SYNERGY

P=0.25

6.0

4.0

2.0

0

1.1

3.1

SYNERGY

½ Dose

EVOLVE II Study Design SYNERGY Stent Pivotal Trial

Randomized cohort (RCT)

SYNERGY

N=842

PROMUS Element

N=842

RCT Design

Multicenter noninferiority trial

Single-blind, 1:1 randomization

Primary Endpoint: TLF at 12 mo

Follow-up: 30d, 6m, 12m, 18m and annual 2-5 yrs

2,006 pts with native coronary lesions ≤34 mm in length, RVD ≥2.25 mm - ≤4.0, %DS ≥50%

Up to 3 lesions in 2 vessels

(excludes LM disease, CTO, ISR, STEMI)

SYNERGY

N=250-292

SYNERGY

N=20-30

Diabetes

Substudy

PK

Substudy

Up to 160 global sites

Enrollment Complete

Selectively micro-structured surface

holds drug in abluminal surface

structures

BioFreedom Stent (Biosensors) Hypothesis: Polymer-free drug

release via porous-eluting

stents may reduce late events

caused by polymer stent

coatings.

Potential advantages

• Avoid long term late adverse

effects that might be

attributable to the polymer

• Improved surface integrity

since there is no polymer to be

sheared or pealed away from

the stent struts

• Possible shorter need of dual

antiplatelet therapy

Biolimus A9 - lipophilic

DFS: Drug Filled Stent (Medtronic)

Drug elution controlled by diffusion physics

Elution Holes

Bioresorbable Vascular Scaffold

A new paradigm providing temporary vessel support and then allow the

physiology to recover and evolve naturally.

BioResorbable Scaffolds

Scaffold Compromise is thicker struts (>130 μm )

150-220 μm

130 μm

157 μm

150 μm

Late Lumen Enlargement

Potentials of Fully Bioresorbable Coronary Scaffolds

Ormiston J et al. Circ Cardiovasc Interv 2012;5:620-32

Long-term Mechanical Differences between

Scaffolds and Metallic Stent Metallic Stent Scaffold

• Restoration of vascular physiology

• Restoration of cellular response

• Restoration of vasomotion and positive

remodeling

• “Caging” inhibits natural vessel

movement and remodeling

Baseline

1 year At 1 year, the

vessel is no longer

mechanically

constrained

At 6 months scaffold

begins to resorb

Cu

mu

lati

ve f

req

uen

cy d

istr

ibu

tio

n (

mm

)

Late loss (mm)

Late Loss with Absorb Cohort B vs. Xience V

6 month (SPIRIT II): 0.17 ± 0.32 mm (N=97)

24 month (SPIRIT II): 0.33 ± 0.37 mm (N=97)

6 month (Cohort B): 0.19 ± 0.18 mm (N=42)

24 month (Cohort B): 0.27 ± 0.20 mm (N=38)

Claessen BE et al. Circ CV Int. 2009;2:339-47

Serruys PW. ESC 2012

ABSORB II 1-Year Patient Flowchart

Intent To Treat N=501

Absorb BVS

N=335

N=334

N=331

N=329

(98.2%)

Xience N=166

N=166

N=165

N=164

(98.8%)

1 subject consent withdrawn

3 subjects consent withdrawn

2 subjects consent withdrawn

1 subject died

Baseline

30-day

180-day

1-year

1 subject consent withdrawn

Cumulative incidence in percentage Absorb 335 pts

Xience 166 pts

p value

Target Lesion Failure 4.8 % 3.0 % 0.35

Cardiac death 0 % 0 % 1.00

Target vessel MI 4.2 % 1.2 % 0.07

Clinically indicated TLR 1.2 % 1.8 % 0.69

All TLR 1.2 % 1.8 % 0.69

MACE 7.3 % 9.1 %

All death 0 % 0.6 %

All MI 4.5 % 1.2 %

All revascularization 3.6 % 7.3 %

ABSORB II: Clinical Outcomes

Cumulative incidence in percentage Absorb 335 pts

Xience 166 pts

p value

Definite scaffold/stent thrombosis

Acute (0-1 day) 0.3 (1pt) 0.0 NS

Sub-acute (2–30 days) 0.3 (1pt) 0.0 NS

Late (31–365 days) 0.0 0.0 NS

Probable scaffold/stent thrombosis

Acute (0-1 day) 0.0 0.0 NS

Sub-acute (2–30 days) 0.0 0.0 NS

Late (31–365 days) 0.3 (1pt) 0.0 NS

ABSORB II: Definite scaffold/stent thrombosis

GHOST Registry Centers

Ferrarotto Hospital,

Catania

C. Tamburino (PI)

D. Capodanno (co-PI)

P. Capranzano

S. G. Di Dio Hospital, Agrigento

G. Caramanno

S. Geraci

San Raffaele Hospital and

Emocolumbus Clinic, Milan

A. Colombo

A. Lateeb

Klinikum Großhadern,

Munich

J. Mehilli

Medizinische Klinik, Mainz

T. Gori

ElisabethKrankenhaus, Essen

C. Naber

S. Pyxaras

Uniwersytet Medyczny, Poznan

M. Lesiak

A. Araszkiewicz

Royal Brompton Hospital,

London

C. Di Mario

A. Mattesini

University of Giessen, Giessen

H. Nef

*Compared to ABSORB II eligibility (Diletti et al. Am Heart J. 2012;164:654-63)

Clin

ical

An

gio

gra

ph

ic

GHOST: All Comers

CV Death All Death TV MI Any MI ID TLR ID TVR

Ghost: 6-Month Outcomes*

TLF** TVF ST

defin/prob

GHOST: Scaffold Thrombosis

1.5%

• There were 20 cases of angiographically confirmed ST and three of probable ST.

• 70% occurred in the first month after PCI, at a median of 5 days, suggesting the need for scrupulous lesion selection

and PCI techniques when using BVS

• Intravascular imaging was performed in only 9 of 23 patients who experienced ST

• 20 of 23 patients were on DAPT at the time of ST

• ST rates were numerically higher when more experience was accumulated and more complex patients were treated

Conclusions: Current and future

directions in stenting

• Current DES have improved safety and efficacy profiles

in ACS and stable CAD compared to first generation

devices

• By limiting polymer, polymer-free systems, or fully

bioresorbable scaffolds, will likely further reduce stent

thrombosis and improve late outcomes

• If BRS reduce very late events from 1-5 years and/or

stabilize or regress plaque, this will be transformative