brs: present and future - solaci3)presentand... · report vlst; psp defined extended study through...

BRS: Present and Future

Stephen G. Ellis, MD

Professor of Medicine

Senior Academic Officer

Director, Invasive/Interventional Cardiology

Cleveland Clinic Lerner College of Medicine

Is It Time to Give Up on the Dream?

• Significant Consulting Fees

• Significant Consulting Fees

• Significant Consulting Fees

• Direct Research Support

• Direct Research Support

• Boston Scientific

• Abbott Vascular

• Medtronic

• Abbott Vascular

• Boston Scientific

Affiliation/Financial Relationship Company

Disclosure Statement of Financial Interest

Within the past 12 months, I or my spouse/partner have had a financial

interest/arrangement or affiliation with the organization(s) listed below.

Co-Principal Investigator, ABSORB III and IV

Best LTFU after DES: SORT Out II

SGE; 0317-4, 3

Galløe et al., JACC 2017;69:616-24

SORT OUT II- TLR

SGE; 0517-1, 3 Galløe, J. et al., J Am Coll Cardiol. 2017;69(6):616-24

Still Room for Improvement.. Vascular

Response to Current PERMANENT

Polymers

SGE; 0717-7, 3 Images courtesy of Renu Virmani, MD

Focal

inflammation

Chronic

inflammation Neoatherosclerosis

Late Stent

Thombosis

CoCr EES

Focal

inflammation with

eosinophils

(4 months)

CoNi ZES

Chronic

inflammation

with giant cells

secondary to

polymer

delamination

(3 months)

CoCr EES

Foamy macrophage

accumulation

(neoatherosclerosis)

CoCr EES

EES implanted

within PES

6 months

antemortem

MeRes (Meril Life Sciences)

Stanza (480 Biomedical)

Xinsorb (Huaan

Biotechnology)

Amaranth (Amaranth Medical)

ART18Z (ART 2nd generation)

ART (Arterial

Remodeling Technology)

IDEAL (BTI 2nd generation)

BTI (Xenogenics Corp.)

DESolve (Elixir Medical)

Absorb BVS (BVS 1.1)

BVS 1.0 (Abbott Vascular)

REVA (REVA Medical)

ReZolve (REVA 2nd

generation)

AMS 4.0 (Dreams 2nd generation)

AMS 3.0 (Dreams 1st generation)

AMS 1.0 (Biotronik)

Igaki-Tamai (Kyoto Medical)

BRS (Micropost)

Everolimus/PDLLA (1:1) matrix coating

• 7 µm

• Conformal coating

• Controlled drug release similar to Xience CoCr-EES

PLLA Backbone

• Semi-crystalline

• Circumferential sinusoidal rings connected by linear links

• Strut thickness 150 µm

• Platinum markers in each end ring

Fully

Bioresorbable

Absorb BVS

Early BVS Thrombogenicity

• Ex vivo AV shunt in pigs (carotid artery-JV)

• 3 stents deployed in a series in a silicone tube

• Order of devices was varied in different shunts

• Stents exposed to flowing blood for ~60 minutes

• Staining for platelets (CD61) was performed

Absorbable Polymer DES vs. BVS

Koskinas et al. JACC 2012;59:1337-49 SGE; 0814-7, 7

\\\\

Any early excess risk will be offset

by long term benefit

The BVS Value Proposition

Absorb Beyond 2 Years: Cohort B. vs Xience 5-Year FU (3.0 x 18 mm)

Days 0 37 194 284 393 573 758 1123 1488 1853

Absorb 101 99 96 96 94 92 91 88 86 85

Xience 227 224 219 211 204 202 191 182 174 169

Serruys PW. TCT 2015 SGE; 0317-3, 13

ABSORB II: In-segment Late Lumen Loss at 3 Years

3 Years Excluding Def. ST

BVS 0.29 ± 0.54mm (238) 0.24 ± 0.43mm (232)

CoCr-EES 0.16 ± 0.40 mm

(119)

0.16 ± 0.40 mm (119)

P-value (t-test) 0.007 0.06

Definite Late ST on Day 139

Definite VLST (Day 494-810)

SGE; 0617-3, 3

ABSORB II: Late Lumen Loss at

13M, 2Y and 3Y LLL increase from 2Y to 3Y was marginal in both group Associated with low rates of

incremental ID-TLR between 2-3 years (1.6% in both arms)

Data include definite ST cases > 31 days (6 in BVS, 0 in CoCr-EES)

* 2 year analysis is from subgroup of 125 pts

In-Segment LLL

P=0.74

P=0.03 P=0.07

260 129 77 40 238 119

In-Device LLL

P=0.35

P=0.04 P=0.003

260 129 77 40 238 119

SGE; 0617-3, 4

SGE; 0116-7, 6

Randomized

N=2008

ITT

N=1322

ABSORB III

ITT

N=1313*

ITT

N=677 99.2%

Completed

98.7%

Completed

n= -10 Lost to follow-up/

withdrew consent*

ITT

N=686

1-year ITT

Analysis

Absorb Xience

As-Treated

N=1245

As-Treated

N=726

n= -55 Crossed over to Xience

n= -10 Mixed use of devices

n= -3 Non-study device used

n= -1 No device implanted

n= +1 Crossed over to Absorb

* One of the six withdrawals had an event and therefore was included in the 1-year follow-up

1-year As-Treated

Analysis

Lost to follow-up/ n= -

9

withdrew consent

Crossed over to Absorb n= -1

Non-study device used n= -3

No device implanted n= -2

Crossed over to Xience n= +55

No. at Risk:

Absorb

TL

F (

%)

Xience

Months Post Index Procedure

20%

100%

80%

60%

40%

0%

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

1322

686

1254

661

1230

651

1218

643

1196

634

13

Absorb BVS (n=1322) Xience CoCr-EES (n=686)

Diff [95% CI] =

1.7% [-0.5% to 3.9%]

Pnon-inferiority=0.007

20%

15%

10%

5%

0%

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

7.7%

6.0%

12

Target Lesion Failure

12,9%

4,6%

6,7%

0,9%

8,3%

1,5%

5,5%

0,6%

0%

5%

10%

15%

20%

TLF ST TLF ST

Absorb Xience

RVD <2.25 mm (median 2.09 mm)

1-Y

ea

r E

ve

nts

(%

)

Median based on pooled Absorb and Xience

RVD ≥2.25 mm (median 2.74 mm)

Outcomes by QCA RVD 2.25 mm

# Events: 31 11 11 2 71 30 9 3

# Risk: 241 133 238 133 1067 542 1058 540

TLF: Pint diff = 0.31

ST: Pint diff = 0.12

Risk Estimates of Device Thrombosis

SGE; 0617-8, 1

Montone., et al, Circulation 2017;135:2145-2154

Late BVS Thrombosis/Dismantelling

SGE; 0515-3, 1 © Karanasos 2014. Published by Oxford University Press on behalf of the

European Society of Cardiology

Baseline BVS Implantation

Very Late BVS Thrombosis After 2 Years

LEARNING CURVE A BVS-specific implantation strategy can improve outcomes

P PREPARE THE LESION S SIZE APPROPRIATELY P POST-DILATE

Adapted from Gori, T., EuroPCR 2015 and Puricel S et al. JACC 2016;67:921–31

P

S

P (N=292)

(N=369)

3.3%

1.0%

Log rank p=0.02

0

100 200 300 400 0

Days

Early Experience

BVS-specific Protocol

1

2

3

4

5 Scaffold thrombosis (%) Propensity-matched groups

• Pooled ABSORB data at 2 years: ABSORB EXTEND,

ABSORB II, ABSORB Japan, ABSORB China, and

ABSORB III

• Definition of Full PSP (must satisfy all the criteria

below)

Pre-dilatation (performed in 99.9% of Absorb patients)

Sizing (vessel): 2.25mm ≤ QCA RVD ≤ 3.5mm

Post-dilatation:

• Pressure ≥ 18 atm

• Balloon diameter: Scaffold diameter > 1:1 and Balloon diameter

≤ Scaffold diameter + 0.5mm

PSP Analysis

PSP Analysis

Pooled ABSORB Trials Absorb Arm1

Implantation Technique

Absorb

(N=2858)

Pre-dilatation 99.9%

2.25 mm ≤ QCA RVD ≤ 3.5 MM 79.3%

High pressure Post-dilatation2 12.8%

Full PSP3 10.4%

1. Based on patient population treated with Absorb BVS in ABSORB II, ABSORB III, ABSORB

China, ABSORB Japan and ABSORB EXTEND

2. Defined as post-dilatation balloon pressure ≥18 atm, post-dilatation balloon diameter > nominal

scaffold diameter and post-dilatation balloon diameter ≤nominal scaffold diameter+0.5mm

3. Defined as patients with pre-dilatation, QCA RVD ≥2.25mm-≤3.5mm, and high pressure post-

dilatation defined above in 2

12,1

2,6

8,9

1,9

9,0

1,9

7,6

1,5

6,7

0,9

5,5

0,7

0

2

4

6

8

10

12

14

16

18

20

TLF ST (Def/Prob) TLF ST (Def/Prob) TLF ST (Def/Prob)

1. Based on patient population treated with Absorb BVS in ABSORB II, ABSORB III, ABSORB China, ABSORB Japan and ABSORB EXTEND

2. Defined as post-dilatation balloon pressure ≥18 atm, post-dilatation balloon diameter > nominal scaffold diameter and

post-dilatation balloon diameter ≤nominal scaffold diameter+0.5mm

3. Defined as patients with pre-dilatation, QCA RVD ≥2.25mm-≤3.5mm, and high pressure post-dilatation defined above in 2.

QCA RVD ≥ 2.25 mm

to ≤ 3.5 mm

High Pressure

Post-dilatation2

Even

ts (

%)

fro

m 1

to

2 Y

ears

Impact of Implantation Technique on Clinical Outcomes

from 0 to 2 Years – Pooled Trials Absorb Arm1

P=0.0006 P=0.047

Full PSP3

No (N=590) Yes (N=2261) No (N=2493) Yes (N=365) No (N=2559) Yes (N=298)

Literature and Industry Review for:

High quality RCT or registries with ≥ 200 BVS

patients, clinical follow up ≥12 months, clinical

and QCA data potentially available

105 cases;

210 controls

ABSORB II, China and Japan

report VLST; PSP defined

Extended study through

3 year follow up as possible

177 cases (55 VLST); 354 controls

through 24-48 months

N = 18

N = 14 studies

Statistical Analysis

Plan Developed

• 10 cases: covariate

• Covariates prioritized

• 2:1 control cases

• 12 month ST primary

endpoint (30 day ST and

1-12 months ST identified

as secondary endpoints)

• Dedicated CRF with

definitions

Separate 12-48 month

study of VLST using same

criteria

Addition of PSP as

covariate

4 Declined

SGE; 0317-1, 3

Multicenter BVS Consortium

0-12 Month Scaffold Thrombosis Risk: RVD

N = 46 N = 49 N = 25 N = 24

RVD (mm) by Quintiles

N = 49 N = 49 N = 49

SGE; 0317-1, 16

p for trend = 0.09

Lowest 2 Deciles

0-12 Month Scaffold Thrombosis Risk: Intravascular Imaging and Scaffold Length

N = 47

p = 0.43

N = 268

p =

0.079

N = 23 N = 133 N = 81 N = 71

Scaffold Length (mm)

p for trend = 0.071

SGE; 0317-1, 15

0-12 Month Scaffold Thrombosis Risk:

Post-dilatation

N = 38 N = 83 N = 137 N = 178 N = 61

p=.07 vs not

p=0.38

SGE; 0317-1, 13

0-12 Month Scaffold Thrombosis Risk:

In-segment % Stenosis and MLD

SGE; 0317-1, 12

By Quintiles

% In-Segment Stenosis

N=255

In-Segment MLD

N=255

Correlates of MLD

RVD p<0.001

% stenosis p<0.001

Lesion length

p=0.054

p for trend = 0.038

p = 0.017

p = 0.005

0-12 Month Scaffold Thrombosis Risk:

DAPT at Time of ST

N = 239

p=0.007

N = 32

SGE; 0317-1, 14

Independent Correlates of

0-12 Month Scaffold Thrombosis

Odds Ratio p

Model 1

Off DAPT 3.47 0.006

No Post Dilatation ≥1.1 2.29 0.022

RVD <2.40 2.12 0.036

Model p=0.002 McFadden’s Rho-sq=0.052 c-statistic-=0.64

Model 2

MLD<1.85 mm 3.07 0.004

Off DAPT 2.49 0.053

Model p=0.003 McFadden’s Rho-sq=0.051 c-statistic-=0.63

SGE; 0317-1, 20

Independent Correlates of

12-48 Month Scaffold Thrombosis

Univ OR Univ p Multi OR Multi p

Scaffold:RVD <1.18 7.5 0.002 4.7 0.029

RVD > 2.72 mm 3.4 0.001 2.2 0.086

SGE; 0317-1, 20

No apparent effect of post-dilatation parameters, DAPT

• The Absorb scaffold’s ultimate role will depend

on whether or not it meets long term

expectations

• For now, it seems reasonable for use in

patients with stable CAD, 2.4<RVD<3.0, with

meticulous attention to implant technique

• Use of 2nd Gen DAPT is not unreasonable for at

least 30 days, especially in patients at higher

risk of scaffold thrombosis

Summary and Overall Conclusions

Blinded, Pooled, Interim ABSORB IV

Outcomes: Comparison to ABSORB III

ABSORB III: 2008 pts randomized 2:1 BVS:EES (1322:686)

ABSORB IV: 3000 pts being randomized 1:1 BVS:EES

1. Assuming the observed event rates for each arm in ABSORB III, but adjusted for the 1:1 randomization ratio in

ABSORB IV. The actual observed pooled ST rates in ABSORB III were 1.0% at 30 days and 1.3% at 1 year.

2. Based on February 15, 2017 data cut (N=2397 with 30-day FU and N=1415 with 1-year FU).

3. ABSORB IV includes ~25% non A-III like subjects (troponin+ ACS, 3 lesions treated, and planned staged

procedures).

ABSORB III

Pooled

(N=2008)1

ABSORB IV

Pooled

(N=2546)2,3

QCA RVD < 2.25 mm 19% 4%

Post-dilatation (BVS) 66% 84%

Pooled Stent/Scaffold Thrombosis

30 days 0.9% 0.4%

1 year 1.1% 0.5%

Bioresorbable Scaffolds: Getting Thinner

SGE; 0316-9, 23 Meredith IT, CRT 2016

REVA ReZolve

ART18Z

Abbott Absorb BVS 1.1

Amaranth ELIXIR DESolve

Biotronik DREAMS21

REVA Fantom2

Amaranth Fortitude3

ELIXIR DESolve Cx

Boston Scientific

FAST

PolyCarb PDLLA PLLA PLLA PLLA Mg, PLA PolyCarb PLLA PLLA PLLA

SES None EES SES NES SES SES SES NES EES

228

170 157 150 150 150 125 120 120

≤99 120

0

100

200

300

Stru

t Th

ickn

ess

(µm

)

1st Generation BRS 2nd Generation BRS

Scaf

fold

D

rug

Novel Attributes of Other BRS

SGE; 0717-7, 3

Elixir DESolve

PLLA

(eluting novolimus)

Amaranth Magnitude

Ultra-high MW

amorphous PLLA

(eluting sirolimus)

Reva Fantom

lodinated

desaminotyrosine

polycarbonate

(eluting sirolimus)

Biotronik Magmaris

Magnesium

(eluting sirolimus)

• Self-correcting property

• Over-expansion w/o fracture

• More rapid bioresoption

• Lumen growth after 6 mo

• Elongation at break properties >10x above

"typical" PLLA ploymers

• Wide expansion range

• <100 um version

• 125 um

• Radiopacity similar to DES

• Able to rapidly deploy

• Over-expansion w/o fracture

• Greater tensile strength and ductility

\\\\

Any early excess risk will be offset

by long term benefit

The BRS Value Proposition

\\\\

Any early excess risk will be offset

by long term benefit

The BRS Value Proposition

Seems Reasonable, but

\\\\

Any early excess risk will be offset

by long term benefit

The BRS Value Proposition

Lots of Ongoing Work- Yet

Remains Unproven

• Excellent procedural technique will lessen but not

eliminate the difference between BRS and

contemporary DES 1 year outcomes

• Thinner struts and faster resorption will not eliminate

the problem of dismantling- only shift it’s timing (the

vessel wall still be need to heal around the scaffold to

prevent it from collapsing into the lumen)

• Incomplete adoption of OCT will hamper good BRS

outcomes

• BRS placement will delay but not eliminate clinical

events related to neoatherosclerosis

BRS Predictions

Conclusions

Many Promising Designs

No Firm Proof of Long Term Benefit

Conclusions

Many Promising Designs

No Firm Proof of Long Term Benefit

But the Dream is Far From Dead