Post on 07-Aug-2020
transcript
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