TCT-AP 2011

Will bioabsorbable stents transform PCI in the future?

Patrick W. Serruys, MD, PhDYoshinobu Onuma MDYoshinobu Onuma, MD

Thoraxcenter, Erasmus MC, Rotterdam, The Netherlands

12:20-12:30 April 27th, 2011, 10 min.Main Arena Level B2

POBA Bare-metal stent

Drug-eluting metallic stent

Vascular restoration

therapy

Post angioplasty Dissection and py

Acute Occlusion - + + +

A t ST + +

intraparietal hemorrhage

Acute ST na - + +

Subacute ST na - - +

Acute recoil - + + +

4 th l tConstrictive remodeling - + + +4 months laterDissection

Scaffolded by stentNeointimal hyperplasia - -- + +

Scaffolded by stent

Expansive remodeling + - - +

Late Luminal E l t + - - +Enlargement + +

Late ST na - - +

Overview of bioresorbable scaffolds in clinical arenaCompany Picture Polymer/Drug Features

Igaki-Tamai Zig-zag design deployed with a heated balloonPLLA

PLLA plus Tranilast

Biotronik Mg alloy Balloon

(2000)

Abbott

Biotronik Mg alloy Balloon expandable

design

cal

(2006)

Abbott(BVS) PLLA

with everolimus Balloon expandable

Clin

ic

(2006)

Tyrosine poly carbonate with Iodine

Design has ratchet links

for deployment

Reva Medical

for radio-opacity for deployment

(2008)

Salicylic acid blended i t l

(2008)BTI into polymer

(PLA or adipic acid) with sirolimus

Balloon expandable

Polylactide Degradation Mechanism

O

Hydrolysis via Random Chain Scission of Ester Bonds

HH OOR

O

R′OH2O+ R

OR′

OHHO+ OCH

CR,R′=, where

PLAPLA HH2OO

HydrolysisHydrolysisCH3 nP-D,L-LA

P-L L-LA

Molecular Weightchains

a

P L,L LALactic Acid

phou

s Tie c

ystal lam

ella

Mass Loss

Amorp

Cry

Mass Transport

Amorphous SemicrystallineKrebs Krebs CycleCycle COCO2 + H+ H2OO

Polylactide Degradation versus Radial Support

Bioabsorbable Drug Everolimus Eluting Stent (BVS)

Polylactide Degradation versus Radial SupportCrystal lamella

••••⊗ ⊗ ⊗ ⊗

Amorphous Tie chains

Tie chains

⊗• •••• •• •

•⊗⊗⊗

⊗ ⊗⊗ ⊗

•⊗

Support

Molecular

Mass Loss

⊗

⊗⊗

⊗

⊗

⊗Molecular

Weight

1 3 6 24 Mos12 18

44 pigs implanted with BVS fully bioresorbable scaffold (BVS)

2 Yorkshire landrace pigs were sacrificed after OCT immediately after procedure (4 BVS)OCT + HistologyAcute

•2 Yorkshire landrace pigs were sacrificed after OCT at  one month after procedure (4 BVS): OCT + Histology•7 Yucatan minipigs underwent histology only at one month (14 BVS) Histology*

1 month month (14 BVS): Histology*

7 Yucatan minipigs underwent histology only at 6 months (12 BVS): Histology*6 months

12 months 18 months

1 Yucatan minipig underwent Gel Permeate Chromatography (GPC, 3BVS)

2 Yucatan minipigs underwent GPC (6BVS)

•2 Yucatan minipigs underwent OCT and GPC (5 BVS): OCT+GPC •1 Yucatan minipig was sacrificed after OCT (2 BVS): OCT+ Histology•4 Yucatan minipig was sacrificed (7 BVS): Histology* 

24 months

•5 Yucatan minipigs were sacrificed  after OCT at 3 years (8 BVS): OCT + Histology•3 Yucatan minipigs underwent GPC (5 BVS)

36 months One pig died before 48 months

•5 Yucatan minipigs were sacrificed after OCT at 4 years (12 BVS): OCT + Histology•2 Yucatan minipigs underwent histology at 4 years (3 BVS)*48 months

g

OCT and Histology: 2 years after Procedure

2 years3 years

1.5 years1 yearsIn-vitro

E F G HG H

A, B: OCT: the “preserved box” appearance of strutsC, D: Locations of bioresorbed struts readily visible in histological sections stained with HEE: Alcian blue fills in the regions previously occupied by the struts (proteoglycan). F G: Neither collagen (red in Trichrome staining) nor smooth muscle (brown in smooth muscleF, G: Neither collagen (red in Trichrome staining) nor smooth muscle (brown in smooth muscle actin immunohistochemical staining) were detected in the strut footprint .H: A small rim of calcification in von Kossa staining, corresponding to the location of the PDLLA coating (black arrows, H).

By chromatography, l i t t

2 years

polymeric struts were no longer detectable

HE staining

3 years

Strut voids were filled with young connective tissue

d l d3 years and coalesced with vessel wall.

Alcian Blue

Strut voids are minimally

Alcian Bluecollagen = yellow proteoglycans/muco

Alcian Blue

4 years

ydiscernible in histology, with localized low density of smooth

polysaccharides = blue/greenSMCs = red

density of smooth muscle cells at the presumed site of polymeric struts.Movat

Maturation of endothelial cell junctions

48 month BVS1 month BVS

Overlaying

1 month BVS

y gendothelial cells,dense continuous junctions

“weak” single junctionsingle junction

AP2932133 Rev. A 15Information contained herein for presentation at EuroPCR 2010 only.

Tests performed by and data on file at Abbott Vascular.

Background I: The first generation of everolimus-eluting bioresorbable scaffold (BVS1.0) showed signs of shrinkage at 6 months (dubbed “late recoil”) that contributed to the late luminal loss.recoil ) that contributed to the late luminal loss.

ABSORB

6 monthsABSORBBVS 1.0

∆ V l A +0 3%

Late Loss = 0.43mm

∆ Vessel Area = +0.3%∆ scaffold Area = -11.8%

% Scaffold Obstruction = 5.3%

∆ Lumen Area = -16.8%

Lancet 2008, Circulation 2010

Background I: The second generation (BVS1.1) has a modified platform design and a different manufacturing process of the polymerpolymer.

ABSORB ABSORB

6 months 6 monthsABSORBBVS 1.0

ABSORBBVS 1.1

∆ V l A +0 3%

Late Loss = 0.43mm

∆ Vessel Area = +2 4%

Late Loss = 0.19mm

∆ Vessel Area = +0.3%∆ scaffold Area = -11.8%

% Scaffold Obstruction = 5.3%

∆ Vessel Area = +2.4%

∆ Scaffold Area = -2.0%% Scaffold Obstruction = 1.2%

∆ Lumen Area = -16.8% ∆ Lumen Area = -3.1%

Lancet 2008, Circulation 2010

Cumulative frequency distribution curves of Late loss/gain: BVS 1.1 (Cohort B) vs. Xience V (Spirit I)

1001006 Months (SPIRIT I vs. B1) 12 Months (SPIRIT I vs. B2)

80

90

80

90 20112-011TLR

60

70

60

70

40

50

40

50

20

30

40

20

30

40

EES: 0.10±0.23 mm EES: 0.23 ± 0.29 mm

10

20

0

10

20

Cohort B: 0.19±0.18 mm

(N=22)EES: 0.23 ± 0.29 mm (N=22)

0

-0.5 0.5 1.5

0

-0.5 0.5 1.5(N=42)

Cumulative frequency distribution curves of Late loss/gain: BVS 1.1 (Cohort B) vs. Xience V (Spirit I)

1001006 Months (SPIRIT I vs. B1) 12 Months (SPIRIT I vs. B2)

80

90

80

90

60

70

60

70

40

50

40

50

20

30

40

20

30

40

EES: 0.10±0.23 mm EES: 0.23 ± 0.29 mm

10

20

0

10

20

Cohort B: 0.19±0.18 mm

(N=22)

Cohort B: 0.27 ± 0.32 mm (N=56)

EES: 0.23 ± 0.29 mm (N=22)

0

-0.5 0.5 1.5

0

-0.5 0.5 1.5(N=42)

Cumulative frequency distribution curves of Late loss/gain: BVS 1.1 (Cohort B) vs. Xience V (Spirit I)

100100103430 004

6 Months (SPIRIT I vs. B1) 12 Months (SPIRIT I vs. B2)

80

90

80

90

097969-007Myocardial bridge

103430-004TLR

60

70

60

70102589-011Myocardial BridgeTLR

Myocardial bridge

40

50

40

50

TLR

GAI

N

20

30

40

20

30

40

EES: 0.10±0.23 mm EES: 0.23 ± 0.29 mm

LATE

10

20

0

10

20

Cohort B: 0.19±0.18 mm

(N=22)

Cohort B: 0.27 ± 0.32 mm (N=56)

EES: 0.23 ± 0.29 mm (N=22)

0

-0.5 0.5 1.5

0

-0.5 0.5 1.5(N=42)

KM estimate of MACE rate in patients treated with BVS (AbsorbCohort B, n=101) vs. patients treated

with a single 3x 18 mm metallic EES (Spirit I+II+III n=227)

BVS(B1+B2)XV(SPI SPII SPIII RCT)T

LR

)25.0%

BVS(B1+B2)XV(SPI SPII SPIII RCT)T

LR

)25.0%

with a single 3x 18 mm metallic EES (Spirit I+II+III, n=227)

393-day HR0.93 [0.38,2.24]

p=0.8678

XV(SPI+SPII+SPIII RCT)

MI,

ID-T

20.0% 393-day HR0.93 [0.38,2.24]

p=0.8678

XV(SPI+SPII+SPIII RCT)

MI,

ID-T

20.0%

De

ath

, M

10 0%

15.0%

De

ath

, M

10 0%

15.0%

6.9%

7.5%∆ 0.6%

CE

(C

-D

5.0%

10.0%

6.9%

7.5%∆ 0.6%

CE

(C

-D

5.0%

10.0%

MA

C

0.0%

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14

MA

C

0.0%

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14

XV Includes only patients with single 3.0 x 18mm stent

BVS Includes all patients

Time Post Index Procedure (Months)

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14

Time Post Index Procedure (Months)

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14

Patients at risk 0 days 37 days 194 days 284 days 365 days 393 daysy y y y y y

BVS(B1+B2) 101 99 96 96 95 94

XV(SPI+SPII+SPIII RCT) 227 224 219 211 209 208

What did we learn from ABSORB cohort A (2006-2011)?(2006 2011)?

QCA, IVUS, OCT, IVUS VH

Baseline 6 12 218 3 4 5Baseline 6 12 2YearsMonthsMonths

MSCT

18Months

3Years Years

5Years

Lancet, 2008

L t 2009Lancet, 2009

BL 2Y6M#4. Bioresorption and vessel wall integration are real phenomena. (Lancet 2009)

Resolved ISA Persistent ISA ISA

incomplete stent apposition

Non Discernibleapposition

L t i d ISA Resolved ISAApposedLate acquired ISA Resolved ISA

Non Discernible

#4. Bioresorption of jailed side branch are real phenomenon. (Okamura et al. EHJ 2010)phenomenon. (Okamura et al. EHJ 2010)

Endothelium-dependent vasomotion is restored (Lancet 2009)

3.5P=0.03

Scaffolded segment

3m P=0 3 P=0 4

1.81 1.86 1.93

3

ter,

mm P=0.3 P=0.4

9) Pre Ach

2.5

diam

etst

(n

=9

2

lum

en

Ach

tes

1.5

Mea

n A

1Pre-Ach

Ach

NitroPost Ach

Bioresorption and vessel wall integration are real phenomena. (Lancet 2009)

Pre-stenting Post-stenting 6-month 24-month

3.9mm2 7.1mm26.9mm2

10.1mm2

2‐Year IVUS Unpaired (BVS1 0)Late plaque reduction and lumen enlargement have been documented.

2 Year IVUS Unpaired (BVS1.0)

P t 6 h 2 % DiffPost-PCI

6-month F/U

2-year FU

% Diff (6M to 2Y)

p-value

n=25 n=25 n=18

Vessel (EEM) area 13 49* 13 79 12 68 3 91 0 08

( )(mm2)

13.49* 13.79 12.68 -3.91 0.08

Lumen area (mm2) 6 04 5 19 5 46 +10 85 0.03Lumen area (mm ) 6.04 5.19 5.46 +10.85

Minimal Lumen ( 2)

5.09 3.92 4.35 +17.24 0.005area (mm2)

Plaque area (mm2) 7.44* 8.60 7.22 -12.74 <0.001

*n=24 P-values per Wilcoxon’s signed rank test% Diff based on paired values

+Compensatory Expansive Remodeling of EEM

+PIT FAIT

Metallic stent is the cageLate acquired BL1Y5Y

tion

qmalapposition

-

Red

uct

Struts

Metallic Struts

Lumen Reduction

Lum

en Metallic Struts

Lumen Reduction by Intrastent Growth

of tissueL

-ll l l dll d l d d

-Metallic Stent – A classical treatment Paradigm

for Atherosclerotic PlaqueMetallic Stent – A caged lumen doomed to get reduced, or a cage doomed to get malapposed

+Compensatory Expansive Remodeling of EEM

+PIT FAITLumen Enlargement

by Plaque Regression

BL6M2Y

tion

Regression

-

Red

uct

Struts

Scaffolding

Lum

en Scaffolding

L

Lumen Enlargement By Bioresorbable

b bl ff ld d

-By Bioresorbable

Scaffolding

Bioresorbable Scaffold – A new treatment Paradigm for Atherosclerotic Plaque-

#8 No acute/Subacute/Late stent thrombosis up to 4 years

4 Year Clinical Results – Intent to Treat

Hierarchical 6 Months 12 Months 3 Years 4 Years

4 Year Clinical Results Intent to Treat

Hierarchical30 Patients 29 Patients* 29 Patients* 29 Patients*

Ischemia Driven MACE, %(n) 3.3% (1)* 3.4% (1)* 3.4% (1)* 3.4% (1)*Cardiac Death, % 0.0% 0.0% 0.0% 0.0%Cardiac Death, % 0.0% 0.0% 0.0% 0.0%MI, %(n)

Q-Wave MI 0.0% 0.0% 0.0% 0.0%Non Q-Wave MI 3.3% (1)** 3.4% (1)** 3.4% (1)** 3.4% (1)**

Ischemia Driven TLR , %

by PCI 0 0% 0 0% 0 0% 0 0%by PCI 0.0% 0.0% 0.0% 0.0%by CABG 0.0% 0.0% 0.0% 0.0%

No new MACE events between 6 months and 4 yearsNo new MACE events between 6 months and 4 yearsNo stent thrombosis up to 4 years (All patients off clopidogrel)

*One patient withdrew consent after 6 months but the vital status of the patients and absence of cardiac event is known through

Ormiston et al. 2008, Serruys et al. 2009, Onuma et al. 2010

the referring physician. **This patient also underwent a TLR, not qualified as ID-TLR (DS = 42%) followed by post-procedural troponin qualified as non-Q MI and died from his Hodgkin’s disease at 888 days post-procedure.

Case 1 (5YR FU)Non-invasive imaging for early and late follow-up is now feasible.

Case 1 (5YR FU)

Prospective mode 128-DSCTDi t li (HR 53)Diastolic exposure (HR 53)100 Kv tube voltageEffective dose 2.5 mSv

BVS proximal RCA

Case 1 (5YR FU)Case 1 (5YR FU)

C D Ethe safety of this technology remains up to 10 years.

E

BD

B

C

BA

A

Arrow indicates a metallic marker

The Promise of biodegradable scaffolding as a vessel restoration device1. Bioresorbable drug-eluting vascular scaffold treatment consists of implanting a transient

scaffold made of the most common human molecule (lactic-acid). This scaffold is more flexible

than Xience and is highly conformable to the vessel.

2 A t il i bl t th t lli t t A t l iti d j il d id b h2. Acute recoil is comparable to the metallic stents. Acute malapposition and jailed side branch

fully disappeared within two years.

3. BVS does not hinder shear stress from inducing late luminal enlargement and compensatory3. BVS does not hinder shear stress from inducing late luminal enlargement and compensatory

expansive remodeling.

4. Residual drug or struts are inconceivable after 2-4 years follow-up.proximal5. Reduction of vessel wall thickness has been documented and the phenomenon has to be

confirmed.

proximal

6. Allergic reaction on dissolved lactic-acid, CO2 and water are unknown.

7. Strut fractures is no longer a sign of fatigue, but of the unavoidable “programmed fate“ of the

struts before their complete bioresorption.

8. Vasomotion in the scaffold area is attended by normal endothelial-dependent vasomotion

distal to the device No thrombosis at 4 years follow up in absence of clopidogreldistal to the device. No thrombosis at 4 years follow-up in absence of clopidogrel.

9. The lumen of the vessel have been followed-up by MSCT up to 10 years (Igaki-Tamai case).distal