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Dual-therapy stent technology for patients with coronary artery diseaseA great catch?Kalkman, D.N.
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Citation for published version (APA):Kalkman, D. N. (2018). Dual-therapy stent technology for patients with coronary artery disease: A great catch?.
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Download date: 11 Dec 2020
Chapter 10Current evidence for the safety and efficacy of the bio-engineered dual-therapy COMBO stent
Kalkman DN, Chandrasekhar J, de Winter RJ, Mehran R
Minerva Cardioangiologica, 2018 Jan 29. [Epub ahead of print]. In press Feb 2018
15291-kalkman-layout.indd 179 18/04/2018 18:00
180 CHAPTER 10
ABSTRACT
The novel dual-therapy COMBO stent aims to promote vessel healing after percutaneous coronary intervention (PCI) in patients with coronary artery disease. The pro-healing technique consists of an anti-CD34+ antibody layer that attracts circulating endothelial progenitor cells (EPCs), which bind to the stent surface and allow rapid endothelialization by differentiation of the EPCs into normal endothelial cells. The COMBO stent combines this pro-healing technique with an abluminal drug elution of sirolimus. The promise of this dual-therapy stent is that it may safely allow a shortened duration of dual-antiplatelet therapy (DAPT) after stent placement. Moreover, with a mature endothelial layer, lower rates of in-stent restenosis may be expected. Clinical outcomes after COMBO stent implantation have been recently evaluated in both randomized trials and large, prospective, multicenter registries, showing low clinical event rates of in-stent restenosis and stent thrombosis. Randomized clinical trials (HARMONEE and RECOVERY) have demonstrated the non-inferiority of COMBO versus “first in class” second generation and newer generation drug-eluting stents. Safety and efficacy of 3 months of DAPT after COMBO stent placement in patients presenting with acute coronary syndrome has been evaluated in the large REDUCE randomized controlled trial, showing non-inferiority to standard duration of 12 months DAPT. In this review we provide an overview of the current pre-clinical and clinical evidence for the performance of the COMBO stent.
15291-kalkman-layout.indd 180 18/04/2018 18:00
181SAFET Y AND EFFICACY OF THE COMBO STENT
10
INTRODUCTION
New stent technologies have been developed to overcome the complications after second generation drug-eluting stent (DES) placement, mainly targeting lower in-stent restenosis and stent thrombosis (ST).1,2,3,4 Although significant advances have been made compared to bare metal stents (BMS), further reductions in event rates are desirable, primarily to reduce late target lesion revascularization and to facilitate shorter durations of dual-antiplatelet therapy (DAPT) after stent implantation. While the ideal duration of DAPT is debated, at least six months of DAPT after percutaneous coronary intervention (PCI) with DES is recommended by both the European Society of Cardiology and the American College of Cardiology/ American Heart Association (Table 1).5,6,7 However, DAPT cessation after PCI is not infrequently seen, either due to temporary interruption for elective procedures or disruption due to bleeding or non-compliance.8,9 Patients undergoing PCI may require elective surgery, or have a high bleeding risk profile, in whom a DES and shortest possible DAPT duration may offer optimal net benefit. Furthermore, ACS patients of a high bleeding risk predisposition may be at the greatest risk for future bleeding events on DAPT.
The COMBO stent (OrbusNeich Medical, Fort Lauderdale, Florida) is a novel coronary device with a dual-therapy stent (DTS) technology.10 This DTS technology consists of an abluminal sirolimus-eluting layer combined with a luminal bio-engineered layer, designed to promote vessel healing by stimulating rapid endothelialization and providing a layer of mature, normal endothelium on the inner surface of the stent.11 This novel stent might safely allow shortened duration of DAPT. In this review article we will discuss the design and mechanism of the COMBO stent, pre-clinical study data and the current updates to clinical trial evidence.
DESIGN OF THE COMBO STENT
The COMBO device is a 316L stainless-steel stent in a helical sinusoidal design with a strut thickness of 100µm. Sirolimus is delivered in an abluminal biodegradable polymer in a dosage of 5µg/mm. The circumferential layer consists of murine, monoclonal, anti-human CD34 antibody. This bio-engineered coating was first applied to the Genous Bio-engineered R stentTM stent (OrbusNeich Medical, Fort Lauderdale, Florida, USA).12,11 Circulating endothelial progenitor cells (EPCs), derived from the bone marrow, are captured by the immobilized antibodies on the luminal stent surface. Here the EPCs differentiate into mature, functional endothelium (Figure 1). The hypothesis of this novel technology is that not only is rapid endothelialization facilitated, but also by promoting healthy normal endothelium a lower rate of neo-atherosclerosis may be observed, resulting in a lower rate of stent thrombosis and in-stent restenosis.13
15291-kalkman-layout.indd 181 18/04/2018 18:00
182 CHAPTER 10
Tabl
e 1.
Rec
omm
ende
d du
ratio
n of
P2Y
12 in
hibi
tors
and
asp
irin
(DA
PT) a
fter
DES
pla
cem
ent a
ccor
ding
to th
e Eu
rope
an S
ocie
ty o
f Car
diol
ogy
and
Am
eric
an C
olle
ge o
f Car
diol
ogy/
Am
eric
an H
eart
Ass
ocia
tion
guid
elin
es a
fter
per
cuta
neou
s co
rona
ry in
terv
entio
n.
Stab
le C
AD
DES
ACS
DES
No
HBR
HBR
No
HBR
HBR
ACC/
AH
A g
uide
lines
*
In p
atie
nts
trea
ted
with
DA
PT, a
dai
ly a
spiri
n do
se o
f 81
mg
(ran
ge, 7
5 m
g to
100
mg)
is re
com
men
ded
Clas
s I B
-NR
At l
east
6m
(clo
pido
grel
)Cl
ass
ID
isco
ntin
uatio
n af
ter 3
mo
may
be
reas
onab
le (c
lopi
dogr
el)
Clas
s IIb
At l
east
12m
(clo
pido
grel
, pr
asug
rel,
ticag
relo
r )Cl
ass
I
Dis
cont
inua
tion
afte
r 6m
may
be
reas
onab
le (c
lopi
dogr
el,
pras
ugre
l, tic
agre
lor)
Clas
s IIb
>6 m
may
be
reas
onab
leCl
ass
IIb>1
2m m
ay b
e re
ason
able
Clas
s IIb
ESC
guid
elin
es#
6m
DA
PTCl
ass
IA1m
DA
PTCl
ass
IIb C
3
m
DA
PTCl
ass
IIa B
12m
DA
PTCl
ass
IA6m
DA
PTCl
ass
IIA B
DA
PT >
6mCl
ass
IIb A
DA
PT >
12m
Clas
s IIb
A
*201
6 AC
C/A
HA
Gui
delin
e Fo
cuse
d U
pdat
e on
Dur
atio
n of
Dua
l Ant
ipla
tele
t The
rapy
in P
atie
nts W
ith C
oron
ary
Art
ery
Dis
ease
# 20
17 fo
cuse
d up
date
on
dual
ant
ipla
tele
t the
rapy
, ESC
clin
ical
pr
actic
e gu
idel
ines
SIH
D=
stab
le is
chem
ic h
eart
dis
ease
CA
D=
coro
nary
art
ery
dise
ase,
ACS
= A
cute
cor
onar
y sy
ndro
me,
DES
= dr
ug-e
lutin
g st
ent,
BMS=
bar
e m
etal
sten
t, D
CB=
drug
coa
ted
ballo
on, H
BR=
high
bl
eedi
ng ri
sk, D
APT
= du
al a
ntip
late
let t
hera
py
15291-kalkman-layout.indd 182 18/04/2018 18:00
183SAFET Y AND EFFICACY OF THE COMBO STENT
10
Figure 1. Origin of endothelial progenitor cells (EPCs) and the EPC-capturing stent technology.
With permission of OrbusNeich Medical Technologies Inc., FL, USA.
PRE-CLINICAL DATA
An overview of the preclinical work with the dual-therapy stent is given in Table 2.
Larsen et al performed pre-clinical experiments with the bio-engineered bare-metal GenousTM Bio-engineered RTM stent to evaluate the function of the bio-engineered layer. In 15 patients undergoing coronary angiography an extracorporeal femoral arteriovenous shunt was used, containing a (BMS) and the GenousTM stent. In this shunt model macroscopic thrombi were found on the BMS surface, but non with GenousTM. With scanning electron microscopy (SEM) the GenousTM stent showed better strut coverage (32.5% enhanced deposition on the struts was observed with GenousTM compared with BMS, p = 0.006). Quantitative polymerase chain reaction (qPCR) revealed increased expression of endothelial markers (KDR/VEGFR2 and E-selectin) with the GenousTM stent, and an increase in pro-thrombogenic markers (tissue factor pathway inhibitor and plasminogen activator inhibitor-1) in BMS.14 Additionally 20 rabbits were implanted with GenousTM and BMS in the aorta and iliac arteries for 7 days. SEM and qPCR showed a trend towards increased strut coverage and increased expression of endothelial markers for GenousTM compared with BMS.14
15291-kalkman-layout.indd 183 18/04/2018 18:00
184 CHAPTER 10
Tabl
e 2.
Pre
-clin
ical
rese
arch
pro
gram
with
EPC
cap
turin
g st
ent t
echn
olog
y st
ents
.
Stud
y Ph
ase
Mod
els
Sten
t typ
eSt
udy
dura
tion
Resu
lts
Lars
en e
t al
.Eu
r Hea
rt J
2012
1Ex
trac
orpo
real
AV
shun
t in
15
patie
nts
unde
rgoi
ng
CAG
BMS
and
GS
120
min
utes
Mac
rosc
opic
: sub
stan
tial p
rese
nce
of m
ural
thro
mbi
in th
e BM
S,
none
in G
SSE
M: I
ncre
ase
in s
tent
-str
ut c
ell c
over
age
in G
SqP
CR: e
xpre
ssio
n of
som
e en
doth
elia
l mar
kers
hig
her i
n G
S
2Ex
trac
orpo
real
AV
shun
t in
a b
aboo
nBM
S an
d G
S12
0 m
inut
esBM
S oc
clud
ed in
<65
min
, GS
pate
nt fo
r >2
hour
s
3Si
licon
tube
with
rot
atio
n of
hum
an m
onoc
ytes
and
hu
man
CD
34+
cells
BMS
and
GS
120
min
utes
Conf
ocal
mic
rosc
opy:
mor
e CD
34+
cells
to a
dher
e to
the
GS-
stru
t, no
diff
eren
ce in
mon
ocyt
e ad
here
nce
420
rabb
its, a
orta
and
ilia
c ar
terie
s
BMS
and
GS
7 da
ysSE
M: i
ncre
ased
str
ut c
over
age
in G
SqP
CR: i
ncre
ased
leve
ls o
f end
othe
lial m
arke
rs in
GS
Nak
azaw
a et
al.
JACC
Ca
rdio
vasc
In
terv
201
0
1 7
pigs
, 21
coro
nary
ar
terie
s9
sing
le (3
GS,
3 S
ES, 3
BM
S) a
nd 1
2 ov
erla
ppin
g st
ents
(4 G
S+G
S, 4
G
S+SE
S, 4
SES
+SES
)
14 d
ays
SEM
: Sin
gle
sten
ts: M
ore
stru
t cov
erag
e in
BM
S an
d G
S co
mpa
red
with
SES
. Ove
rlapp
ing
sten
ts: f
rom
hig
hest
to lo
wes
t co
vera
ge: G
S+G
S, G
S+SE
S, S
ES+S
ESM
icro
scop
y: s
light
ly in
crea
sed
expr
essi
on o
f CD
31/P
ECA
M-1
G
S+G
S an
d G
S+SE
S co
mpa
red
with
SES
+SES
213
pig
s, 22
cor
onar
y ar
terie
sG
S, S
ES a
nd S
ES-a
nti-
CD34
+ 3
and
14 d
ays
Conf
ocal
mic
rosc
opy:
mos
t exp
ress
ion
of C
D31
/PEC
AM
-1 o
n G
SSE
M: S
ES g
roup
has
the
leas
t end
othe
lial c
over
age,
GS
the
mos
t
Gra
nada
et
al.
Circ
Ca
rdio
vasc
In
terv
201
0
112
pig
s, 36
cor
onar
y ar
terie
sCO
MBO
abl
umin
al a
nd
COM
BO c
ircum
fere
ntia
l3,
14
and
28
days
Mic
rosc
opy:
sim
ilar n
eoin
timal
thic
knes
s se
en in
abl
umin
al a
nd
circ
umfe
rent
ial d
rug-
elut
ion.
SEM
: no
sign
ifica
nt d
iffer
ence
bet
wee
n ab
lum
inal
or
circ
umfe
rent
ial d
rug-
elut
ion.
221
pig
s, 96
cor
onar
y an
d m
amm
ary
vess
els
LD C
OM
BO, C
OM
BO,
Cyph
er6
hour
s an
d at
1,
3, 7
, 14,
28,
an
d 35
day
s
Intr
a-ar
teria
l siro
limus
con
cent
ratio
ns: R
apid
ly d
eclin
e LD
CO
MBO
aft
er 2
4h, s
imila
r see
n in
CO
MBO
and
Cyp
her
318
pig
s 50
cor
onar
y ve
ssel
sLD
CO
MBO
, CO
MBO
, Cy
pher
, Xie
nce,
GS
14 o
r 28
days
OC
T: h
ighe
st p
rotr
udin
g st
ruts
with
Cyp
her,
smal
lest
NIT
in
COM
BO, h
ighe
st N
IT I
Xien
ceM
icro
scop
y: c
onsi
stan
t with
OC
T fin
ding
s
AV:
arte
riove
nous
, BM
S: b
are
met
al s
tent
, CAG
, cor
onar
y ar
tery
byp
ass
graf
ting;
GS:
Gen
ous
sten
t. SE
M: s
cann
ing
elec
tron
mic
rosc
opy,
qPC
R: q
uant
itativ
e po
lym
eras
e ch
ain
reac
tion,
LD
CO
MBO
: 2.
5 μg
siro
limus
/mm
SES
-ant
i- CD
34+
sten
t, CO
MBO
: 2.5
μg
siro
limus
/mm
SES
-ant
i- CD
34+
sten
t, O
CT:
opt
ical
coh
eren
ce to
mog
raph
y, N
IT: n
eoin
timal
thic
knes
s.
15291-kalkman-layout.indd 184 18/04/2018 18:00
185SAFET Y AND EFFICACY OF THE COMBO STENT
10
Another pre-clinical study was conducted by Nakazawa et al to assess the differences in stent endothelialization between BMS, SES and GenousTM for single stenting and overlapping stents.13 They showed that the greatest percentage of endothelialization was found with single stent technique with GenousTM and BMS, compared to SES (99% vs. 55%, p=0.048). In overlapping stents endothelialization was significantly greater in GenousTM + GenousTM (95±6%) when compared with GenousTM + SES (79±5%) and SES +SES (36±14%). Moreover, they were the first to investigate endothelialization of the newly developed SES-anti-CD34. They compared the SES-anti-CD34 with single therapy SES, showing increased endothelialization for dual-therapy SES at 3 and 14 days after stenting (Figure 2).13
Further development of this novel stent technique was undertaken by Granada et al.10 They investigated abluminal versus circumferential sirolimus elution on the stent surface of the anti-CD34 coated COMBO stent. Abluminal elution of sirolimus showed better endothelialization on histology at 3, 14 and 28 days post stent-placement in a pig model. Proceeding with the abluminal drug-delivery COMBO stent the investigators tested two different drug dosages (low dose 2,5µg sirolimus/mm or 5µg sirolimus/mm) to assess neointimal formation and inflammation, compared to Cypher (Cordis, Miami, United States of America) and Xience V stents (Abbott Vascular, Santa Clara, California). Less neointimal formation and inflammation was observed on optical coherence tomography (OCT) and histological analysis with COMBO (normal and low dose) but maintaining an enhanced endothelialization. COMBO 5µg sirolimus/mm showed less neointimal thickness compared to COMBO 2.5µg sirolimus/mm (Figure 3).10
In conclusion, preclinical studies investigating the healing ability of the pro-healing COMBO stent showed promising results, while maintaining the antirestenotic effect of sirolimus-elution.
15291-kalkman-layout.indd 185 18/04/2018 18:00
186 CHAPTER 10
Figure 2. Endolthelialization of the pro-healing technology. A. Strut coverage above struts with scanning electron microscopy (SEM) after GenousTM stent (GS), single therapy SES (SES) and the bio-engineered SES (SES-anti-CD34). BCD31/PECAM expression C. SEM images.
Reprinted from JACC: Cardiovascular Interventions, Nakazawa et al, Anti-CD34 Antibodies Immobilized on the Surface of Sirolimus-Eluting Stents Enhance Stent Endothelialization, 68-75 Copyright (2010), with permission from Elsevier.
15291-kalkman-layout.indd 186 18/04/2018 18:00
187SAFET Y AND EFFICACY OF THE COMBO STENT
10
Figure 3. Histomorphometric images at 28 days after stent placement in A. Cypher, B. COMBO (5µg sirolimus/mm), C. COMBO low dose (LD-COMBO) (2.5µg sirolimus/mm) and D. Xience E. GenousTM.
Reprinted from Circ Cardiovasc Interv, Granada et al, Development of a novel prohealing stent designed to deliver sirolimus from a biodegradable abluminal matrix, 257-266, Copyright (2010), with permission from Wolters Kluwer Health.
CLINICAL EVIDENCE
Randomized clinical trialsAll the current randomized clinical trials are summarized in Table 3. The first-in-man Randomized study to Evaluate the safety and effectiveness of an abluMinal sirolimus coated bio-Engineered StEnt (REMEDEE) trial compared angiographic in-stent late lumen loss (LLL) at 9 months after stent placement in patients treated with COMBO or paclitaxel-eluting Taxus Liberté stent (PES) (Boston Scientific, Natick, Massachusetts). The COMBO stent was non-inferior to PES for LLL at 9 months follow-up (0.39±0.45 mm versus 0.44±0.56 mm, pnoninferiority= 0.0012). Secondary endpoints included adjudicated major adverse cardiac events (MACE), with low event rates in both stent-groups (8.9% in patients treated with COMBO and 10.2% in patients with PES, (p= 0.80). 15
15291-kalkman-layout.indd 187 18/04/2018 18:00
188 CHAPTER 10
Tabl
e 3.
Clin
ical
rese
arch
pro
gram
with
the
COM
BO s
tent
.
Rand
omiz
ed c
ontr
olle
d tr
ials
Stud
yTr
ial n
umbe
rN
=Pa
tien
tsCo
mpa
rato
rPr
imar
y en
dpoi
ntFo
llow
-up
peri
odPr
imar
y Re
sult
s
REM
EDEE
NCT
0096
7902
183
Firs
t in
man
Taxu
s Li
bert
éLL
L9
mon
ths
COM
BO n
on-in
ferio
r to
PES
REM
EDEE
-OCT
NCT
0140
5287
60AC
SXi
ence
VSt
rut c
over
age
60 d
ays
Hig
her p
erce
ntag
e of
un
cove
red
stru
ts in
CO
MBO
HA
RMO
NEE
NCT
0207
3565
572
Pred
omin
antly
stab
le C
AD
Xien
ce V
TVF
1-ye
arCO
MBO
non
-infe
rior t
o EE
S
RED
UCE
NCT
0211
8870
1496
ACS
3 m
onth
s ve
rsus
12
mon
ths
DA
PTCo
mpo
site
end
poin
t of a
ll-ca
use
deat
h, M
I, ST
, str
oke,
TVR
or
blee
ding
(BA
RC ty
pe II
, III
and
V)
1-ye
arSh
ort d
urat
ion
DA
PT
non-
infe
rior t
o st
anda
rd
dura
tion
DA
PT
RECO
VER
YN
CT02
5420
0743
2Pr
edom
inan
tly
unst
able
ang
ina
Nan
o po
lym
er
free
TLF
1-ye
arCO
MBO
non
-infe
rior t
o N
ano
poly
mer
free
SORT
OU
T X
NCT
0321
6733
3140
All-
com
ers
Ors
iroTL
F 1-
year
Curr
ently
enr
ollin
g pa
tient
s
Regi
stri
es
EGO
-CO
MBO
NCT
0175
6807
61A
ll-co
mer
s-
Stru
t cov
erag
e 2-
5 m
onth
sSt
rut c
over
age
COM
BO:
77.1
%, 9
2.5%
, 92.
7%, 9
4.9%
REM
EDEE
regi
stry
NCT
0187
4002
1000
All-
com
ers
-TL
F *
1-ye
arTL
F ra
te o
f 5.7
%
MA
SCO
TN
CT02
1834
5426
14A
ll-co
mer
s-
TLF
1-ye
arTL
F ra
te o
f 3.4
%
RCT:
rand
omiz
ed c
ontr
olle
d tr
ial,
LLL:
late
lum
en lo
ss, P
ES: p
aclit
axel
elu
ting
sten
t, A
CS: a
cute
cor
onar
y sy
ndro
me
, CA
D: c
oron
ary
arte
ry d
isea
se, T
VF: t
arge
t ves
sel f
ailu
re, E
ES: e
vero
limus
-el
utin
g st
ent,
BARC
: Ble
edin
g Ac
adem
ic R
esea
rch
Cons
ortiu
m, M
I: m
yoca
rdia
l inf
arct
ion,
ST:
ste
nt th
rom
bosi
s, TV
R: ta
rget
ves
sel f
ailu
re, a
com
posi
te o
f car
diac
dea
th, t
arge
t ves
sel M
I and
cl
inic
ally
indi
cate
d ta
rget
ves
sel r
evas
cula
rizat
ion,
DA
PT: d
ual-a
ntip
late
let t
hera
py, T
LF: t
arge
t les
ion
failu
re, a
com
posi
te o
f car
diac
dea
th, t
arge
t ves
sel M
I and
clin
ical
ly in
dica
ted
targ
et le
sion
re
vasc
ular
izat
ion.
* A
ll TL
R w
ere
incl
uded
.
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The prospective multicenter Study of Vascular Healing With the Combo Stent Versus the Everolimus Eluting Stent in ACS Patients by Means of OCT (REMEDEE-OCT study) randomized 60 patients with ACS to treatment with COMBO or everolimus-eluting Xience V stent (EES) (Abbott Vascular).16 The primary endpoint was the median percentage of uncovered stent struts per stent, measured by (OCT) at 60 days after stent implantation. A higher percentage of uncovered struts were observed in COMBO (14.7% versus 7.7% in EES, p=0.04), even after accounting for clustering (13.6% versus 6.9%, p=0.09). This is a remarkable and somewhat disappointing finding. The authors correctly note that stent strut coverage may not necessarily reflect strut endothelialization. A thin layer of endothelial cells of less than 40 μm may not be visible with OCT.16,17,18,19 Neointimal thickness at 60days was lower with COMBO compared with EES (30.17 versus 50.26µm, p==0.02). MACE in the REMEDEE-OCT, defined as the composite of cardiac death, myocardial infarction (Q-wave or non-Q-wave), emergent coronary artery bypass surgery, or clinically justified target lesion revascularization by repeat PCI or coronary artery bypass graft surgery at hospital discharge was assessed as secondary outcome. No significant differences in MACE between COMBO and EES were observed at 30, 60, 180, 360 and 540 days post-procedure and no ST was observed in both arms.16
Another OCT study, the EGO-COMBO study (OCT Evaluation of Healing of Combo Stent), is a prospective single-center OCT study evaluating healing profile from 2 months post COMBO implant to two years follow-up. Sixty-one patients underwent longitudinal OCT analyses at baseline PCI and at the time of early (2-5 months), 9 month and 24 month follow-up. At 3 months follow-up 92.5% of struts were covered. A recent publication suggested a cut-off value of 90% covered struts on OCT as safe for discontinuation of DAPT, when three additional criteria were met: no frame with a ratio of uncovered to total stent struts of >30%, incomplete stent apposition (defined as a separation between strut and vessel wall with a distance greater than the thickness of the strut) area ≤2 mm2 and last intraluminal defect (defined as an irregularly shaped structure, free from the vessel wall or attached to the vessel wall or the stent) area <300 µm2.20 Unfortunately, these numbers were not provided in EGO-COMBO, so no statement can be given on safe cessation of DAPT based on OCT findings. However, another interesting finding was observed. Neointimal regression was seen from 9 months to 24 months of follow-up (median neointimal volume decreased from 17.8% to 15.7%). This finding should be further evaluated in other OCT studies comparing COMBO with other new-generation DES with sequential OCT measurements.21
The primary results of the RECOVERY (Safety and Efficacy of the Combo Bio-engineered Sirolimus-eluting Stent Versus the Nano Polymer-free Sirolimus-eluting Stent in the Treatment of Patients With de Novo Stenotic Lesions) , HARMONEE (Japan-USA Harmonized Assessment by Randomized, Multi-Center Study of OrbusNEich's Combo
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StEnt) and REDUCE (Randomized Evaluation of short-term DUal anti platelet therapy in patients with acute coronary syndrome treated with the COMBO dual-therapy stent) trials were presented at the Transcatheter Therapeutics Congress 2017 in Denver, Colorado. RECOVERY showed non-inferiority of COMBO stent to the polymer-free sirolimus-eluting Nano stent (Lepu Medical Technology, Beijing, China) with regards to angiographic in-segment late-loss at 9 months (COMBO 0.29±0.04mm versus Nano 0.31±0.03mm, pnoninferiority=0.0001). No definite and probable ST with both COMBO and Nano stents were observed throughout one year follow up.
The HARMONEE trial conducted in the United States and Japan is the first randomized controlled trial comparing COMBO with the best-in-class everolimus-eluting Xience stent (EES) (Xience V, Xience Prime, Xience Xpedition, Xience Alpine stents; Abbott Vascular). The trial was designed to assess 3 endpoints/hypotheses (see Figure 4): 1) non-inferiority of COMBO for 1-year clinical efficacy and safety compared with second-generation EES, 2) superiority of COMBO compared with EES for LLL at 12 months follow-up assessed with OCT and 3) a superior intimal tissue coverage of stent struts on OCT with COMBO at 12 months, compared to EES. A total of 572 patients were enrolled with mean age 68 years, 26% females, approximately 35% of patients had diabetes mellitus. In this head-to-head comparison event rates were lower than expected in both arms (assumed event rate of 9.0%), with a target vessel failure rate of 7.0% in COMBO and 4.2% in EES. The non-inferiority boundary was met (pnoninferiority=0.02), although the study was clearly underpowered. TLF event rates were numerically higher in patients treated with COMBO, driven by a higher ischemia-driven target-vessel revascularization. The ‘spike’ of target vessel revascularization (TVR) at 1 year, more prominent in the COMBO-arm, is thought to be related to the protocol mandated re-catheterization, despite the use of fractional flow reserve (FFR). The secondary objectives revealed the following findings: LLL (0.293 versus 0.219) and binary in-stent restenosis (1.3% versus 2.6%) were similar between COMBO stent and EES and superior healthy tissue strut coverage (homogenous tissue quality) was observed with COMBO (81.2%) versus EES (68.8%).
The REDUCE trial is an investigator-initiated, prospective multicenter trial that randomized patients with ACS to a DAPT duration of 3 months (short DAPT) or standard 12 months after COMBO stent placement.22 This non-inferiority study included 1496 patients, of mean age 61years and approximately 20% women, to investigate the composite primary endpoint of ischemic (cardiac death, MI, stroke, ST or TVR) and bleeding endpoints (BARC II, III and V). The non-inferiority margin was met, with an observed 8.2% event rate in the 3 months DAPT-arm and 8.4% event rate in the 12 months DAPT-arm, pnoninferiority<0.001. However, numerically higher rates of cardiac
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death, MI and ST were observed in patients with short DAPT. Bleeding rates were not significantly different in patients with 3 months compared with 12 months DAPT (2.5% versus 3.0%, p=0.54).
Cohort A (N=30)Serial 6M & 12M OCT
12M QCA, FFRCOMBO N=15, EES N=15
Inclusion/Exclusion Criteria and ConsentN= 572*
Randomized 1:1 COMBO versus EES
Cohort B (N=110)12M QCA, OCT and FFR
HAMA base, 30D and 12MCOMBO N=55, EES N=55
Early and Late OCTObservational
N= 30
Cohort C (N=432)12M Angio/FFR only
COMBO N=216, EES N=216
Intimal Tissue CoverageSuperiority
N= 140
HAMAObservational
N= 110
Primary endpointIschemia & FFR driven TVF
N= 572*
* Includes an assumed 5% 1 year lost to follow-upbase = at baseline, D = days, M = months
Figure 4. The study design of the HARMONEE trial.
Adaptation of the HARMONEE Flowchart Figure from Am Heart J., 187, Kong et al., Rationale and design of the Japan-USA harmonized assessment by randomized, multicenter study of OrbusNEich's combo StEnt (Japan-USA HARMONEE): Assessment of a novel DES platform for percutaneous coronary revascularization in patients with ischemic coronary disease and non–ST-elevation acute coronary syndrome, 112-121, Copyright Elsevier (2017).
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REGISTRY DATA
The Multicenter, Prospective, Clinical Outcomes after Deployment of the Abluminal Sirolimus Coated Bio-Engineered Stent (Combo Bio-Engineered Sirolimus Eluting Stent) Post Market Registry (REMEDEE registry) is a prospective, investigator-initiated, multicenter, European all-comers registry that enrolled 1000 patients between June 2013 and March 2014. This registry was the first to evaluate clinical outcomes after PCI with COMBO stent in all-comers patients. Clinical follow up to 5 years is ongoing. The primary endpoint of the REMEDEE Registry was (TLF) at one year follow-up, a composite of cardiac death, target-vessel myocardial infarction (TV-MI) and any (TLR). All events were adjudicated by an independent clinical event committee (CEC). One year TLF occurred in 5.7% of patients, with a 1.7% rate of cardiac death, 0.7% TV-MI and 4.4% TLR.23 Definite or probable ST was observed in 0.6% of patients. When these clinical results are compared with outcomes of other DES all-comers trials, they are amongst the lowest rates, driven by low TV-MI and cardiac death rates.24,25,26,27,23 TLF at two year follow-up remained low (8.4%) with a TLR rate of 5.9%.28 Subgroup analyses have been performed on one year clinical outcomes in patients with diabetes mellitus (DM) and patients presenting with ACS. In the ACS sub-analysis, there was a statistical trend towards higher TLF, in patients presenting with ACS compared to patients treated in an elective setting (7.1% versus 4.4%, p=0.07). 29 In the pre-specified DM sub-analysis, patients with insulin-treated DM (ITDM) had a significantly higher TLF rate compared with patients without DM (non-DM) or with non-ITDM: 4.4% in non-DM, 6.8% in nITDM and 20.3% in ITDM (p<0.001).30 In an exploratory analysis of patients from the REMEDEE registry treated with shorter duration of DAPT than recommended in the guidelines (duration of DAPT < 6 months, n=78) no safety issues were observed, with no ST in patients with early DAPT discontinuation.31
Propensity score matched analysis has been performed of REMEDEE registry patients treated with COMBO and patients from the DUTCH PEERS trial, treated with Resolute Integrity zotarolimus eluting stents (Medtronic, Dublin, Ireland) and Promus Element EES (Boston Scientific, Marlborough, USA), showing similar event rates at two year follow-up in all-comers patients (7.9% in COMBO vs 6.4% in PROMUS Element/Resolute Integrity, p=0.26).32 Longer follow up of the REMEDEE patients up to five years will be collected to assess the incidence of late target lesion revascularization in order to assess the potential clinical effects of intimal hyperplasia regression that was seen in previous studies.
The Multinational Abluminal Sirolimus Coated BiO-Engineered StenT –The MASCOT Post-Marketing Registry (MASCOT) is the largest prospective, multicenter, international registry that enrolled 2614 patients across 60 sites in less than two years, between June
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2014 to March 2016.33 The primary endpoint was one-year TLF, a composite of cardiac death, TV-MI or clinically-driven TLR. The primary results have been presented at the Transcatheter Therapeutics Congress 2017 in Denver, Colorado. The primary endpoint was observed in 3.4% (n=88) of patients, with a definite or probable ST rate of 0.9% at one-year follow-up. The MASCOT registry also collected systematic data on adherence to DAPT during follow up and adjudicated DAPT according to the mode of cessation as physician recommended discontinuation, temporary interruption for <14 days or non-recommended disruption due to bleeding or non-compliance as per the PARIS registry definitions9 Any DAPT cessation was observed in 24.8% patients at 12 months follow-up (including 21.7% discontinuation, 2.2% disruption and 0.9% interruptions).33 Interestingly however, 6 month rate of any DAPT cessations were low, suggesting that physicians across these global sites tended to continue DAPT up to 12 months in these patients. The MASCOT registry also adjudicated bleeding endpoints. Major bleeding (Bleeding Academic Research consortium types 3 or 5) was noted in 1.8% (n=46) patients.
EXPERT SUMMARY
The large global research program investigating preclinical and clinical outcomes of the COMBO stent has given much insight into the performance of the bio-engineered COMBO stent.34 Its safety profile has been assessed in both randomized trials and all comer registries, showing low ST rates and acceptably low rates of in-stent restenosis.23,33,16,35 RCT’s have demonstrated the non-inferiority of COMBO with Nano SES and Xience EES.36,37
Indeed, the clinical results in patients treated with COMBO stent are excellent, even beyond one year follow-up. Moreover, no special implantation technique is required for COMBO. For instance the pre-dilatation, sizing, and post-dilatation (PSP) technique needed for bioresorbable scaffolds, and issues with stent dislodgements and longitudinal foreshortening seen with some metallic stents have not been observed to be of concern with COMBO.
Nevertheless, despite the anticipated benefits of the COMBO stent allowing shorter DAPT duration, only limited data are available. Short duration of DAPT after the bare metal EPC capturing GenousTM stent has been reported and showed no differences between short DAPT (<15 days) and long DAPT. 38,39,40 The results of the REDUCE trial22 suggest that 3 months of DAPT in ACS-patients treated with COMBO stent may be feasible, however additional studies are warranted.
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Future directionsFurther prospective clinical data after PCI with the DTS-COMBO is emerging. The highly anticipated SORT OUT X trial is currently recruiting patients. This is an investigator-initiated, randomized clinical trial comparing the sirolimus-eluting DTS COMBO stent with the sirolimus-eluting biodegradable polymer Orsiro stent (Biotronik, Berlin, Germany). This trial will allow evaluation of the added value of the bio-engineered pro-healing technique from the COMBO stent compared to the new generation Orsiro stent. Clinicaltrials.gov identifier: NCT03216733. Furthermore, long-term follow-up from the REMEDEE registry will provide up to 5 year clinical outcomes.
Despite this, a gap exists for relevant clinical research on the safety of DAPT discontinuation in COMBO treated patients. Randomized controlled trials in patients with an indication for short duration of DAPT are needed with this platform. Certainly, a randomized comparison between COMBO and stents that are designed to safely shorten DAPT, such as the polymer- and carrier free BioFreedom stent (Biosensors International, Switzerland), powered for relevant clinical endpoints, would be extremely useful in assessing the safety and efficacy of these stent platforms in patients that might benefit the most from such technologies.
CONCLUSION
The bio-engineered COMBO stent has shown low clinical events rates and a remarkable safety profile with a low incidence of target lesion failure and stent thrombosis. Although limited trial data support the feasibility of short DAPT with this stent, additional, prospective clinical data are needed to confirm the safety of short DAPT after COMBO stent placement. Future trials should focus on patients with greater predisposition for DAPT disruption such as patients at high bleeding risk who may stand to gain maximum benefit from this technology.
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35. Haude M, Lee SWL, Worthley SG, et al. The REMEDEE trial: A randomized comparison of a combination sirolimus-eluting endothelial progenitor cell capture stent with a paclitaxel-eluting stent. JACC Cardiovasc Interv. 2013;6(4):334-343. doi:10.1016/j.jcin.2012.10.018.
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