James Hermiller, MD, FACC, FSCAI The St Vincent Medical Group The St Vincent Heart Center of Indiana Indianapolis, IN Drug-Eluting Stents 2013: Current

James Hermiller, MD, FACC, FSCAI The St Vincent Medical Group The St Vincent Heart Center of

Indiana Indianapolis, IN

James Hermiller, MD, FACC, FSCAI The St Vincent Medical Group The St Vincent Heart Center of

Indiana Indianapolis, IN

Drug-Eluting Stents 2013: Current Data and Future

Advances

Drug-Eluting Stents 2013: Current Data and Future

Advances

Hilton La Jolla Torrey Pines La Jolla, California - Oct 3rd, 2013

BL

2Y

Disclosures

• Consulting Fees/Honoraria

• Speaker Bureau

• Abbott, BSC, Medtronic and St Jude

• Medicines Company

Affiliation/Financial Relationship Company

OutlineOutline

• Introduction

• Current Data• Advances to Date

• Future Directions• Metallic DES Bioabsorbable Polymer• Metallic DES with No Polymer• Completetly Bioabsorbable DES

• Conclusions and Summary

• Introduction




Introduction: DES TalksIntroduction: DES Talks

First Generation DES P

ES

Polyolefin derivative Paclitaxel Express2

Drug Polymer Stent

SE

S

PEVA + PBMA blendSirolimus BX Velocity

1st Gen Drug-Eluting StentsThe good, the bad, and the ugly!

1st Gen Drug-Eluting StentsThe good, the bad, and the ugly!

7 years

40 mos

BMS DES

Incompleteapposition

Late stentthrombosis

Abn Vasomotion

*P<0.001 vs. control

Sirolimus Control

* *

Delayed Healing!

Angioscopy

BMS

DESLate loss = 0

Eos

Giant cells

IVUS

Inflammation

Second Generation DESZ

ES

BioLinx copolymerZotarolimus Integrity

Drug Polymer

EE

S

VDF + HFP copolymerEverolimus

Vision

OO

OO

OO OO HOHO

OO

OO

OOOOHHOO

OOOO

NNOO

HHOO

Stent

Omega

Stent EES - PROMUS

ZES - Resolute

EES - Xience Expedition

Underlying Stent PtCr – Element (Omega)

CoCr –Integrity

CoCr – Modified Vision

Strut Thickness 0.0032” 0.0036” 0.0032”

Strut Pattern

Lengths (mm)(Diameters 2.25 to 4.0 mm)

8,12,16,20,24,28, 32, and 38 mm(38 for >2.75 mm diameter)

9,12,15,18,22,26, 30, 34 and 38 mm(34 and 38 for >3.0 mm diameter)

8,12,15,18,23,28, 33, and 38 mm(33 and 38 mm for >2.5 mm diameter)

Current Stent Attributes

Stent EES – PROMUS ELEMENT

ZES - Resolute EES – Expedition

Max Expansion (mm)

2.25 to 2.752.5 & 2.75 to 3.53.0 & 3.5 to 4.254.0 to 5.25

2.25 – 2.75 to 3.25 3.0 – 4.0 to 4.75

2.25 & 2.5 to 3.25 2.75 &3.0 to 3.75 3.5 & 4.0 to 4.75

Sidebranch Cell Size (Max Expansion)

2.25 to 4.182.5 & 2.75 to 4.73.0 & 3.5 to 5.754.0 to 7.44

2.25 to 4.0 to 9.24 mm

6 Cresst -- 2.25 to 3.0 to 3.5mm9 Crest – 3.5 & 4.0 to 4.2 mm

Polymer Drug FluorinatedCopolymer - EES

Biolinx PolymerZES

FluorinatedCopolymer - EES

In Stent Late Loss <0.2mm <0.2 mm <0.2 mm

Current Stent Attributes

0

1

2

3

4

5

Cu

mu

lativ

e in

cid

en

ce (

%)

4135 3913 3793 3284 2604 1856 1041 514 208EES3784 3617 3569 3499 3404 3080 2521 2118 1734SES4214 3916 3797 3176 2905 2344 1880 1077 686PES

No. at risk

0 6 12 18 24 30 36 42 48Months after index PCI

Sirolimus Stent 2.9%

Everolimus Stent 1.4%

Paclitaxel Stent 4.4%

ARC Definite ST @ 4 Years

EES vs. SES Hazard Ratio* = 0.41, 95% CI 0.27–0.62, P<0.0001EES vs. PES Hazard Ratio* = 0.33, 95% CI 0.23-0.48, P <0.0001

Räber L, ESC 2011

Bern-Rotterdam Cohort Study

0

1

2

3

4

5

Cum

ulat

ive

inci

denc

e (%

)

0 6 12 18 24 30 36 42 48Months after index PCI

EES vs. SES HR* = 0.33, 95% CI 0.15 – 0.72, P=0.006EES vs. PES HR* = 0.24, 95% CI 0.13-0.47, P <0.0001

Very Late ST (1-4 yrs)

Sirolimus Stent 1.6%

Everolimus Stent 0.6%

Paclitaxel Stent 2.4%

*from Cox proportional hazards model

Bern-Rotterdam Cohort Study

Räber L, ESC 2011

SPIRIT II, III, IV and COMPARE trialsPooled database analysis (n=6,789)

Ischemic TLR

P<0.001HR: 0.60 [0.48, 0.75]

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

4247 4143 4004 33632542 2416 2328 2018

Number at risk

XIENCETAXUS

6.6%

Isch

emic

TL

R (

%)

0

10

Time in Months

0 3 6 9 12 15 18 21 24

38912260

4.1%5 4.7%

2.3%

∆=2.4%

∆=2.5%

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

SPIRIT II, III, IV and COMPARE trialsPooled database analysis (n=6,789)

Stent thrombosis (ARC definite/probable)

4247 4177 4082 34792542 2463 2408 2110

Number at risk

XIENCETAXUS

2.3%

Ste

nt

thro

mb

osi

sA

RC

def

or

pro

b (

%)

0

1

2

3

Time in Months

0 3 6 9 12 15 18 21 24

39982350

0.7%

p<0.001HR: 0.30 [0.19, 0.47]EES (n=4,247)

PES (n=2,542)

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

Time after Initial Procedure (Months)

Cu

mu

lati

ve In

cid

ence

of

Eve

nts

11.2%10.7%

0%

0 6 12 18 24

20%

5%

15%

10%

Log rank P = 0.73 Resolute ZES (N = 1140)

Xience V EES (N = 1152)

Silber S, et al. Lancet. 2011;377:1241-47.

RESOLUTE All ComersTarget Lesion Failure to 2 Years (Cardiac Death, TV-MI, CD-TLR)

TWENTE (n=1,387)Target Vessel Failure at 2-Year Follow-up

Von Birgelen C. TCT 2012

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

TV

F (

%)

30

Follow-up (days)

0

5

10

15

20

25

30

Xience V (n=692)

Resolute (n=695)

P = 0.67

11.6%

10.9%

TLF TLR Cardiac Death

MI TV MI Q-Wave MI

ST0

2

4

6

8

10

7.1

4.9

1.92.5

2.1

0.80.5

5.9

3.5

1.2

2.3

1.5

0.40.7

Presented by Ian T Meredith MBBS, PhD at ACC 2013

EES Pt-Cr vs EES Co-Cr3-Year Clinical Results

Incid

en

ce R

ate

(%

)

p = 0.81p = 0.21 p= 0.75 p = 0.40 p= 0.40

Xienca CoCr EES Promus PtCr EES

p = 0.27 p= 0.30

Longitudinal stent deformation: Angiographic patterns

• Longitudinal stent compression: Manifests itself as a dark band in the region of compression (also called stent “accordion”, “concertina”, “wrinkling”, etc.)

• Longitudinal stent elongation: Appears like a fracture in the stent (pseudo-fracture)

Longitudinal elongation with

pseudo-fracture

Longitudinal compression



Retrospective analysis of longitudinal stent deformation in the “real world”: Study

2,936 Promus Element stents implanted in 2,839 lesions in 1,295 pts at a single center over 22 months

LSD occurred in:

1.4% (n=20) of pts (95%CI 0.9%-2.2%)

0.7% of lesions (95%CI 0.4%-1.1%)

0.7% of Promus Element stents (95%CI 0.4%-1.1%)

Multivariable predictors of LSD:

# and length of stents, ostial and bifurcation lesions

30 Day MACE in pts with LSD = 5.0% (1 NQMI)

Leibundgut G et al. CCI 2012: doi: 10.1002/ccd.24472

Promus PREMIER Everolimus-Eluting Stent

Additional connectors on proximal end Provide increased axial strength

2 connectors throughout body

Customized Platinum Chromium (PtCr) Stent Architecture

Enhanced Stent Delivery System

Shorter tip to improve

flexibility

PTFE Coating on hypotube to reduce friction

Sarno et al, Eur Heart J 2012

SCAAR Registry (94,384 pts)Adjusted Risks of Adverse Events at 2 yrs

BMS BMS

“Old DES” “Old DES”

“New DES”“New DES”

Restenosis Definite STRestenosis Definite Stent Thrombosis

Old DES = SES, PES, ZES-Endeavor; New DES = EES, ZS-Resolute

Bangalore S et al. Circulation 2012:On-line

Network Meta-analysisEndpoints: Death, MI, ST, TVR early (<1 yr) and late

77 RCTs, 57,138 pts, 117,762 pt-yrs of FU

Evidencenetwork

1124

25

8

14

1

7 2

2

7

Paclitaxel-ElutingSirolimus-Eluting

BMS

Zotarolimus-ElutingEverolimus-Eluting

Zotarolimus-Eluting-Resolute

Bangalore S et al. Circulation 2012:On-line

Network Meta-analysis: 1-year TLR77 RCTs, 57,138 pts, 117,762 pt-yrs of FU

OR [95% CrI]

0.10

OR(95% Crl)

1.00 10.00

Control TreatmentFavorsControl

FavorsTreatment

BMS (Ref) SirolimusPaclitaxel

Zotarolimus-E Zotarolimus-R

Everolimus

0.20 (0.16, 0.25)0.39 (0.31, 0.49)

0.46 (0.32, 0.65)0.29 (0.15, 0.60)

0.21 (0.14, 0.29)

Sirolimus (Ref)Paclitaxel


Everolimus1.95 (1.60, 2.38)

2.30 (1.67, 3.22)1.47 (0.74, 3.04)

1.03 (0.75, 1.45)

Paclitaxel (Ref)


Everolimus1.18 (0.85, 1.64)0.76 (0.38, 1.53)

0.53 (0.38, 0.73)

Everolimus (Ref)Zotarolimus-E

Zotarolimus-R 2.23 (1.45, 3.47)1.43 (0.78, 2.71)

Zotarolimus-R 0.64 (0.30, 1.37)Zotarolimus-E (ref)

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=0.01Definite ST was reduced with Xience V from 1.9% to 0.5%, p=0.01Sabate M. ESC 2011

EES CoCr vs BMS: Lower Def. Stent ThrombosisEvidence from 5 RCT Network Meta-Analyses.

ARC Definite Stent Thrombosis:EES CoCr vs. BMS

Favors EES CoCr

Late ST Rates (30 Days - 1 Year)After DAPT Interruption

Su

bse

qu

ent

Lat

e S

T (

AR

C D

ef/P

rob

) (%

)

No Interruption Interruption After 30 Days*

13/3500 0/292

Interruption After 180 Days*

2/435

Interruption After 90 Days*

1/3782/1272 0/157 0/147 0/120

Overall

Standard Risk

Hermiller, JB, PCR 2010 – In Press JACC Int 2011

Timing of First DAPT Interruption and Stent Thrombosis Through 12 Months

EES Co-Cr Demonstrates 0% Stent Thrombosis Rate After DAPT Interruption from 3 to 12 Months1

1 in every 6 patients who receive stents may interrupt or discontinue DAPT within 12 months

post-PCI

60/8,996 11/700 18/8,996 0/919

-1%

0%

1%

2%

3%

4%

5%

6%

0.68%

1.64%

0.21%0.00%

Su

bse

qu

en

t S

ten

t T

hro

mb

osi

s A

RC

De

f/P

rob

(%

) Never Interrupted3

DAPT Interrupted

0-3 Months 3-12 Months

N=11,156

Combined XIENCE USA, SPIRIT V, XIENCE India. SPIRIT women

Palmerini, T. Stent Thrombosis and DAPT Interruption in XIENCE V Real-World Patients. PCR 2012

DES ProgressDES ProgressEvolution of Drug-Eluting Stents:

Better than Man’sEvolution of Drug-Eluting Stents:

Better than Man’s

TCFA Development in Neointimal Hyperplasia is More Common with DES than BMS, and can Rupture

Causing Stent Thrombosis and Occlusion

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

Late Incomplete Apposition in SIRTAX

p<0.001

Cook et al Eur Heart J 2012

Late ISA at 8 month IVUS was seen in 39/221 lesions (18%) treated with SES or PES, and was more common with SES

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

ailu

re (

%)

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]

SPIRIT IV: Target Lesion Failure @3 years

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

Stone GW et al. JACC 2011 (abstract)

~2.6%/yr event rate after year 1

OutlineOutline

• Introduction




• Introduction




Persistent LimitationsPersistent Limitations

• Uncovered stent struts with or without late malapposition (thrombosis)

• Chronic inflammation due to late foreign body reactions and polymer hypersensitivity

• Strut fracture

• Lack of vasomotion

• Neoatherosclerosis

Biolimus-A9 Eluting Stent

• Biolimus is a semi-synthetic sirolimus analogue with 10x higher lipophilicity and similar potency as sirolimus.

• Biolimus is immersed at a concentration of 15.6 g/mm into a biodegradable polymer, polylactic acid, and applied solely to the abluminal stent surface by a fully automated process.

• Biolimus is co-released with polylactic acid and completely desolves into carbon dioxide and water after a 6-9 months period.

• The stainless steel stent platform has a strut thickness of 120 m with a quadrature link design.

LEADERS 5-Year Results

Serruys P, et al. J Am Coll Cardiol Intv 2013;6:777–89

LEADERS: Definate Stent Thrombosis


LEADERS: Definate Stent Thrombosis


Landmark Analyses at 0-1 and 1-5 years

RR (95%CI); p value

0-1 yr: 0.99 (0.51-1.95); p= 0.98

1-5 yrs: (0.20-0.68); p=0.003

%

Drug-Eluting Technology Progression

Conformal Biostable Polymer Abluminal Bioabsorbable Polymer

Polymer + DrugPlatinum

ChromiumPlatinumChromium

Polymer + Drug

Current DES SYNERGY DES

Vessel Wall Polymer + Drug

BMS on luminal side

PLGA bioabsorbablepolymer + everolimus on abluminal side of stent

Coating weight on 16 mm stent ~200 µg (vs ~675 µg for Xience / Promus)

Everolimus elutes over ~3 months (similar to Xience / Promus)

PLG absorbs by ~4 months, leaving

behind a BMS

AbluminalThin strut

(0.0029”) PtCr stent

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 Scaffolds (BVS)

Igaki-Tamai PLLA

Magnesium (eluting paclitaxel)Biotronik Dreams

PLLA (w/PDLLA coat eluting everolimus)

Abbott Absorb

Reva ReSolveIodinated tyrosine-derivative (eluting

sirolimus)

Elixir DESolvePPLLA (eluting

myolimus)

What is the Minimum Duration of Radial Scaffolding?

After DES Placement, Scaffolding of the Vessel is Only a Transient Need

Serruys PW, et al., Circulation 1988; 77: 361.

n = 342 patients (n = 93 at 30-day F/U; n = 79 at 60-day F/U; n = 82 at 90-day F/U; n = 88 at 120-day F/U)

The lumen appears to stabilize approximately three months after PTCA.

p < 0.00001

p < 0.00001

Quantitative angiographic study in 342 consecutive patients at 1, 2, 3, and 4 months

Dudek D. ABSORB Cohort B 2-year data, ACC 2012.

Similar Rates of MACE Compared to Historical XIENCE Data

ABSORB Extend Clinical Results - MACE

Intent to Treat (ITT) Analysis; Interim Snapshot

Post-stenting 6-month 24-month

Complete strut apposition

Late acquired incomplete stent apposition with

tissue bridges between fractured struts

Corrugated endolumen

Smooth endoluminal lining

Struts largely disappeared although remnant just visible

(arrow)

Absorb Trial (BVS cohort A): OCT Results

Serruys PW et al. Lancet 2009;373:897-910.

6 m

on

ths

60

mon

ths

The Final Golden tube

Sealing and shielding of plaques as a result of scaffold implantation : can the scaffold cap the plaque? … and Late lumen enlargement

Presented by PW Serruys at TCT2012, accessed at www.tctmd.com

ABSORB Cohort BTemporal Lumen Dimensional Changes

ABSORBCohort B

Serial Analysis*

Lumen Area 6.53 mm2

6.36 mm2 6.85 mm2

n = 33 n = 33 n = 33

ScaffoldArea

1.7%

LumenArea

7,2%

Post-PCI 6 Months 2 Years

Very late lumen enlargement noted from 6 months to 2 years

*Serruys, PW., TCT 2011

ABSORB Vasomotor Function Testing

in

Vess

el D

iam

eter

(mm

)

Methergine

Acetylcholine

-1

-0.5

0

0.5

1

(n=15)

6 Months1

(n=6) (n=19)

12 Months2

(n=13) (n=9)

24 Months3

(n=7)

Vaso

dila

tion

Vaso

cons

tric

tion

ABSORB Cohort B1 ABSORB Cohort B2 ABSORB Cohort A

(pre

-dru

g in

fusi

on to

pos

t-dr

ug in

fusi

on)

1. Adapted from Serruys, PW. ACC 2011 2. Adapted from Serruys, PW. ACC 2011 3. Adapted from Serruys, PW, et al. Lancet 2009; 373: 897-910.

OutlineOutline

• Introduction




• Introduction




Conclusions: Current and future directions in stenting

• Current DES have appreciably improved safety and efficacy profiles in ACS and stable CAD compared to first generation devices

• By utilizing small amounts of a bioabsorbable polymer, polymer-free systems, or fully bioresorbable scaffolds, future generation DES will likely further reduce stent thrombosis and improve late outcomes

The Bar is High – For Advanced Devices

Thanks for your attention!Thanks for your attention!

Documents

James Hermiller, MD, FACC, FSCAI The St Vincent Medical Group The St Vincent Heart Center of Indiana Indianapolis, IN Drug-Eluting Stents 2013: Current