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DOI: 10.1161/CIRCULATIONAHA.113.001811
Drug-Eluting Balloon in peripherAl inTErvention for Below the Knee
Angioplasty Evaluation (DEBATE-BTK): A Randomized Trial in Diabetic
Patients with Critical Limb Ischemia
Running title: Liistro et al.; Drug-eluting balloon in BTK angioplasty
Downloaded from http://circ.ahajournals.org/ by guest on September 29, 2016
Francesco Liistro, MD1; Italo Porto, MD PhD1; Paolo Angioli, MD1; Simone Grotti, MD1,2;
Lucia Ricci, MD3; Kenneth Ducci, MD1; Giovanni Falsini, MD1; Giorgio Vent
Ventoruzzo,
nttorruz
uzzo
zo
o, MD1;
Filippo Turini, MD1; Guido Bellandi, MD1; Leonardo Bolognese, MD1
1
Cardiovascular
Ca
ardiovascul
ular
ar aand
nd
dN
Neurological
euro
eu
rolo
ro
lo
ogi
gica
caal De
Dept
Dept;
ptt; 3Di
Diabetes
D
ab es
abete
es Unit,
Unnit,
nit, San
San
n Donato
Don
o at
ato
to Hospital,
Hosppittal
Ho
al,, Arezzo;
Arez
Ar
e zo
ez
zo; 2De
Dept
ptt of
Ca
Cardiovascular
ard
rdiova
vascuular Diseases,
va
Disseaase
ses, U
University
nivversiity of Siena,
Siena,
a, L
Lee Sc
Scotte
cottte H
Hospital,
osppittal,
tal,, Siena,
Sie
iena,, Italy;
Ittal
alyy;
Addr
Ad
Address
dres
esss for
for Correspondence:
C rr
Co
rres
espo
pond
nden
ence
ce::
Francesco Liistro, MD
Cardiovascular and Neurological Diseases Department
San Donato Hospital
via Pietro Nenni 20
52100, Arezzo Italy
Tel: +39 0575 255617
Fax: +39 0575 255617
E-mail: [email protected]
Journal Subject Codes: Treatment:[123] Restenosis, Hypertension:[17] Peripheral vascular
disease
1
DOI: 10.1161/CIRCULATIONAHA.113.001811
Abstract:
Background—One-year restenosis rate after balloon angioplasty of long lesions in below-theknee (BTK) arteries may be as high as 70%. Our aim was to investigate the efficacy of a
paclitaxel drug-eluting balloon (DEB) vs. conventional percutaneous transluminal angioplasty
(PTA) for the reduction of restenosis in diabetic patients with critical limb ischemia (CLI)
undergoing endovascular intervention of BTK arteries.
Methods and Results—The Drug Eluting Balloon in peripherAl inTErvention (DEBATE)-BTK
is a randomized, open label, single-center study comparing DEB vs. PTA. Inclusion criteria
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were: diabetes, critical limb ischemia (Rutherford •4), significant stenosis or occlusion > 40mm
of at least one BTK vessel with distal run-off, and life expectancy > 1 year. Binary in-segment
estenosis at 1-year angiographic or ultrasonographic follow-up was the primary endpoint.
end
ndpo
poin
po
int.
t.
restenosis
Clinically-driven target lesion revascularization (TLR), major amputation and target
taarg
rget
et vessel
ves
esse
sell
se
occlusion were the secondary endpoints. One hundred and thirty two patients with 158
nfrrap
apop
opli
op
lite
li
teal
te
al ath
th
her
eroosclerotic lesions were enrolle
leed.
d. Mean length of th
he tr
treated segments was
infrapopliteal
atherosclerotic
enrolled.
the
12
29±
±83
83mm iin
n th
thee DE
DEB
B vs
s. 13
131±
1±79
79mm
79
mm iin
n th
thee PT
PTA
A ggroup
rouup (p
(p=0.7
.77). B
inar
in
arry re
est
sten
enos
en
o is
os
is,, as
asse
sess
se
sssed bby
y
129±83mm
vs.
131±79mm
(p=0.7).
Binary
restenosis,
assessed
ang
an
ngiography in >90%
>90% off patients,
pattie
iennts, occurred
occ
ccuurr
urred in
in 20/74
74 (27%)
(27
27%)
27
%) lesions
leesions
ns inn the
thhe
he DEB
DEB group
grooup vs.
vs. 55/74
55/
5/74
74
angiography
74%
4%)) lesions
lesi
le
sion
onss in the
on
thhe
he PTA
PTA
A group
gro
oup (p<0.001);
(p<
p<0.
0 00
001)
1);; TLR
1)
TL
LR in
in 12(18%)
12(
2(18
2(
18%
18
%) vs.
vs. 29(43%)
29(
9(43
4 %)) (p=0.002);
43
(p=
p=0.
0 00
0.
02)
2);; and
and target
tarrgeet
ta
et
(74%)
vess
ve
ssel
ss
el oocclusion
cclu
cc
lusi
lu
sion
si
on iin
n 12 ((17%)
17%)
17
%) vvs.
s. 441
1 (5
(55%
5%)) (p
5%
(p<0
<0.001
001
01)). O
nlyy 1 ma
nl
majo
jorr am
jo
ampu
puta
pu
tati
ta
tion
ti
on ooccurred,
ccur
cc
urre
ur
redd, iin
re
n th
thee
vessel
(55%)
(p<0.001).
Only
major
amputation
PTA gr
grou
oupp (p
(p=0
=0 9)
PTA
group
(p=0.9).
Conclusions—DEB, as compared to PTA, strikingly reduce 1-year restenosis, target lesion
revascularization, and target vessel occlusion in the treatment of BTK lesions in diabetic patients
with CLI.
Clinical Trial Registration Information—http://ClinicalTrials.gov; Identifier: NCT01558505.
Key words: percutaneous procedure, peripheral artery disease, restenosis, drug-eluting balloon
2
DOI: 10.1161/CIRCULATIONAHA.113.001811
Introduction
Critical limb ischemia (CLI), characterized by ischemic rest pain and/or tissue loss, represents
the most advanced state of peripheral artery disease, burdened by high morbidity and
mortality1,2. CLI generally occurs in diabetics with extensive atherosclerotic disease of belowthe-knee (BTK) vessels1.
The optimal strategy for treating CLI patients, however, has not been clearly defined yet:
the outcome of medical therapy is unsatisfactory3, and early, aggressive percutaneous
Downloaded from http://circ.ahajournals.org/ by guest on September 29, 2016
revascularization with the aim to obtain direct flow to the foot is increasingly considered as firstline strategy 4,5. Indeed, although vessel patency alone cannot match patient-centered clinical
endpoints6, and any endovascular program has to be integrated in a network-based
network-base
seed system
s stem
sy
stem
m ooff ca
ccare
re
involving
nvolving different professional figures7,8, an increased cutaneous oxygen pressure due to
ucccesssf
sful
ul rrevascularization
ev
vasscu
cula
larization promotes infection cclearance
leaarance and ulc
le
cer
e gr
gran
anuulation at a crucial timean
successful
ulcer
granulation
poin
point
nt 9 .
Thee ef
Th
eefficacy
ffi
ficcacy
cy ooff conv
cconventional
onven
e ti
en
tion
onal
on
al ppercutaneous
e cu
er
cuta
taneeou
ta
o s ttransluminal
r nslu
ra
lum
lu
mina
nall angi
na
aangioplasty
ngi
giop
opplaast
styy (P
(PTA
(PTA)
TA)) uusing
TA
sin
in
ng
conventionall bballoons,
a lo
al
oon
ons,
s, hhowever,
ow
wev
everr, is
i llimited
imit
im
ited
it
ed bby
y th
thee hi
hhigh
g 112-month
gh
2 mo
2mont
nthh restenosis
nt
reest
s en
enos
osis
os
iss and
and ttarget
arge
ar
gett lesion
ge
revascularization (TLR) rates10. Loss of vessel patency affects the healing process resulting in no
healing, decrease-increase behavior of the lesion or appearance of new foot lesions11. While
drug-eluting stents (DES) may offer a therapeutic alternative to PTA in the BTK district12,13,
widespread use in CLI patients is limited by the complex pattern of BTK atherosclerosis,
characterized by long, calcific stenoses/occlusions.
Local delivery of paclitaxel via drug eluting balloons (DEB) has recently shown
promising results in the treatment of femoropopliteal disease14, and, in the BTK district, a
reduction of 3-month binary restenosis has been observed in comparison with historical controls
3
DOI: 10.1161/CIRCULATIONAHA.113.001811
treated with standard PTA 15. Historical data, however, may not represent an adequate
comparator due to changes in technology and clinical practice over time16, and the efficacy of
DEB in diabetic patients with CLI has not been validated in a randomized fashion.
We designed a prospective, randomized trial designed to compare the performance of a
novel DEB (Amphirion In.Pact, Medtronic, Santa Rosa, CA) with conventional PTA in diabetics
with de-novo, long atherosclerotic lesions of the BTK district, using 1-year binary restenosis rate
as primary endpoint.
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Methods
Study design
The Drug Eluting Balloon in peripherAl inTErvention for Below The Knee angioplasty
ev
val
alua
uati
ua
tion
ti
onn (DEBATE-BTK)
(DE
D BA
BATE
T -BTK) is a single-center, pa
para
allel-group, pr
ros
o peect
ctiv
ive,
iv
e randomized, openevaluation
parallel-group,
prospective,
abeel involvin
ng th
tthee bl
lin
i de
dedd ev
eva
aluaati
alua
t on
on off endd ppoints
oin
ntss (PR
PROB
PR
OB
BE)
E) ttrial
rial17 evaluating
evalu
valuat
atin
at
ingg the
in
th
he efficacy
effi
ef
f caacy of
fi
of a
label
involving
blinded
evaluation
(PROBE)
0.
0.014”
.01
014”
4” guidewire-compatible
gui
uide
dewi
de
wire
ree-ccom
mpaati
tibl
blee DEB
DEB (Amphirion
(Amp
(Amp
mphi
hirrion
hi
on In.Pact,
In
n.P
Pacct, Medtronic)
Medtr
edtr
tron
onnicc) vs.
vs. standard
stan
stan
nda
dard
r P
rd
PTA
TA
TA
(Amphirion
Amphirion Deep,
Dee
eep,
p, Medtronic)
Med
e tr
t onnicc) inn reducing
redu
d ci
cing
ng 12-month
122 mo
mont
nthh restenosis
nt
rest
re
sten
st
enos
en
o is rate
os
rat
a e in
n diabetic
dia
iabe
beti
be
t c patients
pati
pa
tien
ti
ents
en
t with CLII
undergoing endovascular BTK revascularization. It was approved by the local ethics committee
and was carried out in accordance with the Helsinki declaration. All patients provided written
informed consent. The study was registered with ClinicalTrials.gov (unique identifier
NCT01558505).
The study was performed without any industry financial support.
Study Patients
From November 2010 through October 2011, all consecutive diabetic patients with CLI
undergoing angioplasty of at least one BTK vessel at our center were screened for enrollment.
4
DOI: 10.1161/CIRCULATIONAHA.113.001811
Inclusion criteria were: presence of diabetes, CLI (Rutherford class•4), stenosis or occlusion
•40mm of at least one tibial vessel with distal run off to the foot, and agreement to 12-month
angiographic evaluation. Exclusion criteria were: life expectancy < 1 year, allergy to paclitaxel,
contraindication to combined antiplatelet treatment and planned major amputation before
angiography.
Lesions were randomly assigned to one of the two study arms after successful passage of
the guidewire. Randomization was performed in blocks of ten with the use of computerDownloaded from http://circ.ahajournals.org/ by guest on September 29, 2016
generated random digits, and the assignments were placed in sealed envelopes.
Study Procedures
Interventions
nterventions were performed mainly by antegrade approach and with the use off 66-French
-F
Freenc
nchh
sheaths.
heaths. In case of failure to recanalize, a retrograde approach was attempted. In DEB group,
pre-dilatation
balloon(s)
always
performed
pr
ree-di
dila
di
lattati
la
tati
tion
on off th
thee target lesion with standard ba
ball
loon(s) was alw
wayss pe
perf
r ormed before
dilatation
The
DEB
has
previously
ddila
i ata
tation withh DE
DEB.
B. T
he D
EB uused
sedd in
se
n tthis
his sstudy
tu
udy ha
as bbeen
een pr
prev
eviiously
ly ddescribed
escrrib
ibed
ed15. Th
Thee
DEB/vessel
DE
EB/
B/ve
v ss
ve
ssel
el diameter
dia
iame
mete
me
terr ratio
rati
ra
t o was
ti
waas pl
plan
planned
anne
an
nedd to bbee 1:1.
1:1.. D
DEB
EB
B aavailable
vail
va
i ab
able
lee dduring
uriing tthe
ur
hee sstudy
tudy
tu
dy pperiod
erio
io
od ha
hadd a
diameter of 2.
2.5
.5 to 44.0
. m
.0
mm
m an
andd a le
leng
length
ngth
ng
h ooff 40 tto
o 12
1200 mm
mm.. Ra
Radi
Radiopaque
diop
di
opaq
op
aq
que rrulers
uler
ul
erss we
er
were
re uused
seed to ensure
that the zone treated with DEB consistently exceeded of at least 10mm at the proximal and distal
edges the area predilated with standard balloons, in order to avoid geographic miss. If more than
1 balloon was used per lesion, the overlap zone was at least 5 mm. Inflation time was at least 2
minutes for both DEB and PTA arms. In case of flow-limiting dissection or residual stenosis of
more than 30%, a prolonged dilation of up to 3 min was performed. Drug eluting coronary stents
(Xience V, Abbott, CA, USA) were used as a bailout. Technical success was defined as
restoration of direct flow in the target vessel with run-off to the foot and a residual stenosis of
less than 30%. Clinical success was defined as technical success without clinical events during
5
DOI: 10.1161/CIRCULATIONAHA.113.001811
hospitalization. Inflow lesions located in the femoropopliteal segment were treated by standard
techniques during the same session. In patients with bilateral CLI, an additional procedure for the
revascularization of the contralateral limb was planned in a different session to limit the risk of
x-rays exposition and contrast-induced nephropathy, maintaining the same randomization arm.
All patients were taking aspirin 100 mg daily. After sheath insertion, 70 IU/Kg heparin
was administered. Post-intervention dual antiplatelet therapy with aspirin 100 mg and
clopidogrel 75 mg once daily was given at least for 4 weeks and 100 mg aspirin was given daily
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thereafter.
Follow-up
Once discharged, patients were followed in a multidisciplinary, dedicated foot cclinic
liini
nicc to
o ffacilitate
acil
ac
ilit
il
itaate
healing process and recovery of the ambulatory function 7. Office visits were scheduled 2
daays
ys/w
/wee
/w
eekk fo
forr th
he fi
first 2 months, once a week fo
or th
he third monthh an
aand
d th
the
en every two weeks.
days/week
the
for
the
then
Minor
Minnor
no amputa
amputations
atiionss wh
whic
which
ch we
wer
were
re pplanned
re
lannne
la
nned
ed bef
before
for
ore th
the
he iinterventions
nteerv
ven
ntiion
onss were
were pperformed
erfo
fo
orm
med 22-4
-4 w
weeks
eeeks
ks af
after
fter
revascularization
eva
vasc
sccul
u ar
ariz
izat
iz
atio
ionn and
and in
incl
included:
c ud
cl
udeed: ffinger
inge
in
gerr am
amputations,
mpu
putaati
tion
on
ns,, m
metatarsal
etaata
et
tarrsal
al aamputation
mput
mp
u attio
ut
on du
duee to
necrosis/infection
necrosis/infec
eccti
t on of
of tissues
tiisssuees an
aand
d bo
bbones
n s wi
ne
with
th ppreservation
rese
re
seervvat
a io
ionn off hhealthy
ealt
ea
lthy
lt
hyy ssurrounding
urro
ur
roun
ro
undi
un
d ng ttissue.
issu
is
sue.
su
e All
patients were scheduled to be re-admitted for control peripheral angiography at 12 months.
Before angiography, duplex ultrasound (DUS) of the target vessel was consistently performed. In
case of clinical CLI recurrence, angiography and repeat revascularization were performed within
one week from diagnosis. In patients undergoing clinically-driven repeat angiography of the
target limb between 9 months and 12 months and who did not show evidence of restenosis of the
target lesion, scheduled angiography at 12 months was not performed if DUS evaluation was
clearly diagnostic for vessel patency with no restenosis.
Study Endpoints and Definitions
6
DOI: 10.1161/CIRCULATIONAHA.113.001811
Before, immediately after the intervention, and at follow-up, angiography of the target vessel
was performed in identical projections (2 orthogonal planes for each treated lesion). The target
lesion was identified by an image of the vascular anatomy and specific landmarks (collaterals,
bone landmarks), with a second image showing the inflated balloon(s). These images were
compared with follow-up angiograms.
The primary endpoint of the study was the comparison of 12-month binary restenosis
rates between the DEB and PTA groups. Restenosis was defined by angiography as a reduction
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in the luminal diameter >50% according to the worst angiographic view within the treated lesion
plus the 10-mm segments proximal and distal to it or, in the few patients who did not undergo
12-month angiography, as a peak systolic velocity ratio (PSVR) • 2.5 by DUS.
Pre-specified secondary endpoints of the study were: 1. Clinically-driven target lesion
revascularization
percutaneous
intervention
evaasccul
ular
arriz
izat
a ionn (TLR),
at
(T
defined as repeat percut
utan
ut
an
neous intervent
nttio
i n or ssurgical
u gical by-pass graft
ur
angiographic
due tto
due
o the ang
gio
ioggrap
graphi
h c evidence
hi
evid
evid
iden
ence
en
ce of
of restenosis
rest
re
steenossiss at level
levvell of
le
of the
the
he treated
tre
reaateed lesion
l si
le
s on
on ±10
±10
10 mm,
mm, in
in presence
pres
pr
esen
ence
en
off at
at least
leas
le
astt one
one off the
thhe
he following
fol
ollo
l wi
lo
wing
ng criteria:
cri
rite
teri
te
riaa:
a: a)
a) recurrence
recu
re
urr
r enc
ence
ce of
of pain
paiin
pa
in in
in the
the foot
f ot at
fo
at rest
reestt which
whic
hich
ch increased
inc
ncre
reas
assed
d in
the
foot
he supine position;
possit
itio
i n; b)
io
b) recurrence
r cu
re
urr
rren
e ce of
en
of fo
oot
o llesion
essio
on or
o eevidence
v deenc
vi
ncee during
duri
du
ring
ri
ng follow-up
fol
ollo
lo
oww up
u of
of fo
foot
ot llesion
esion size
decrease-increase behavior; c) appearance of new foot lesion. 2. Major amputation, defined as
unplanned amputation of the target limb where prosthesis was required for standing or walking.
3. Target vessel occlusion (either by angiography or DUS).
Acquired angiograms and DUS scans were reviewed by two blinded investigators who
did not actively participate in recruitment (I.P. and G.V.) and who had no knowledge of clinical
status and randomization group.
Post-hoc analyses was performed for the cumulative 12-month prevalence of major
adverse events (MAE: death, major amputation, TLR, and Rutherford class •4) in the two groups,
7
DOI: 10.1161/CIRCULATIONAHA.113.001811
as well as for other clinical endpoints such as rate of complete index ulcer healing, time to
complete index ulcer healing and change in ankle-brachial index between baseline and follow-up.
Further post-hoc exploratory comparisons were performed between long (>100 mm) vs. shorter
lesions, total occlusions vs. stenosis, and true lumen vs. subintimal recanalization technique.
Statistical Analysis
Values are reported as numbers with relative percentage or standard deviation. Nominal
variables were compared by Fisher’s exact test; continuous variables were compared with t-test.
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Twelve-month binary restenosis rate, the primary endpoint of the study, was compared with
Fisher’s exact test. Kaplan-Meier estimates and log-rank test survival methods were used to
assess freedom from TLR, a secondary endpoint. Cohen’s k statistics was used too compare
com
ompa
pare
pa
re
angiography and DUS for detection of restenosis. All statistical computations were performed
using
IL).
us
sin
ng SPSS
SPSS version
versi
siion 17 (SPSS Inc., Chicago, IL)
).
Assuming
group,
reported
with
Assumi
minng a rrestenosis
esteeno
nosi
siis ra
rate
tee ooff 660%
0% inn tthe
he PT
PTA gr
grou
oup,
p, aass re
epo
port
rted
ed ffor
orr ppatients
atie
at
ieent
ntss wi
w
th
h
extensive
infrapopliteal
ex
xte
tens
nsiv
ns
i e in
iv
nfr
frap
apop
opli
op
lite
teaal ddisease
iseaase10, we
is
we hypothesized
hyp
ypot
othhesi
ot
hesi
size
zeed th
that
a D
at
DEB
EB w
would
ould ha
ould
halve
alv
ve th
the
he re
rrestenosis
stten
enossis rrate
atee to
at
o
30% on the basis
bas
a is
i of
of the
th
he extremely
extr
ex
trem
tr
emel
em
elyy positive
el
posiiti
po
tive
ve result
res
esul
u t reported
ul
reepo
portted for
for DEB
DEB in
in the
th
he superficial
supe
su
peerffic
icia
iaal femoral
f moral
fe
artery.18,19 A minimum of 63 evaluable lesions per group were considered necessary to have an
90% power (2-sided 5% significance level) to detect a 50% relative risk reduction (RRR) in the
DEB group. The number of lesions per group was further increased to 70 in order to maximize
study power.
Assuming a rate of eligible lesions/patient=1.3, a minimum of 110 patients had to be
enrolled in the study. The number of patients was increased to 130 considering a drop-out rate of
20% due to the expected high morbidity and mortality in CLI patients.
8
DOI: 10.1161/CIRCULATIONAHA.113.001811
Results
Patients and Lesions
During the study period, 156 patients were screened for study enrolment and 132 met the
inclusion criteria and were randomized, 65 patients (80 lesions in 71 limbs) to DEB and 67 (78
lesions in 72 limbs) to PTA (Figure 1). Baseline clinical characteristics were similar between
study groups (Table 1). Ten per cent of the patients in each study arm were on chronic dialysis
and the majority of patients had 0-1 patent tibial arteries at baseline.
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Procedural and angiographic characteristics are reported in Table 2. The most frequently
treated vessel was the anterior tibial artery (ATA). Treated lesions had a high degree of
more
complexity in both study arms, as 80% of the lesions were total occlusions and m
orre th
than
an
n 220%
0%
0%
were heavily calcified. Subintimal recanalization was performed in one fifth of the lesions.
About
underwent
lesion
treatment.
Ab
Abou
outt 50
ou
50%
% of
o patients
pat
atiient
ien s in both study arms under
rwent inflow lesio
on trea
eaatm
tment. Technical and
clinical
was
cl
lin
nic
ical success
ss w
as obtained
obt
btai
aine
ai
nedd in
ne
in aall
l ppatients.
ll
atieents..
Follow-up
Fo
Foll
llow
ll
ow-u
ow
-up
p an
aand
d cclinical
liinic
iniccal ooutcome
u co
ut
come
me
No major adverse
adv
dvver
erse
se event
eve
v nt occurred
occ
ccur
cc
urreed in-hospital.
ur
in
n-h
-hos
ospi
os
pita
pi
tal.
ta
l Eight
l.
Eig
ght patients
pat
atie
ient
ie
ntss died
nt
died during
dur
urin
ur
ingg follow-up:
in
foll
fo
llow
ll
ow
w-uup: causes
cau
a ses of
death included sudden death (n=3), respiratory failure (n=1), stroke (n=1), heart failure (n=1),
and sepsis (n=1). Percentages of cardiac vs. noncardiac death in the two groups were not
significantly different.
Of the 124 patients alive at 12 months (60 patients with 74 lesions in DEB group vs. 64
patients with 74 lesions in PTA group), angiographic follow-up could not be obtained in 13
patients (5 patients for worsening of pre-existing renal failure, 2 for major stroke, 2 for
congestive heart failure and 4 patients refused the examination), who underwent DUS. In the 135
lesions with both angiographic and DUS follow-up assessment, agreement for restenosis
9
DOI: 10.1161/CIRCULATIONAHA.113.001811
detection (see Methods for definitions) was good, with a k value of 0.88. Among the 73 lesions
with angiographic restenosis, DUS revealed Doppler restenosis in 67 (91.7%). All cases of DUSdefined restenosis were confirmed by angiography. Among those patients who could not undergo
12-month angiography, only 2 lesions in 2 patients (1 in each group) were found to have
restenosis, which was of the occlusive pattern in both.
Angiograms were thus available for 67 of 74 (91%) and 68 of 74 (92%) eligible lesions in
the DEB and PTA arms, respectively. No patient was lost to follow-up.
Downloaded from http://circ.ahajournals.org/ by guest on September 29, 2016
Clinical and angiographic data of 12-month follow-up are presented in Table 3. The
primary endpoint, 12-month binary restenosis, occurred in 20(27%) and 55(75%) lesions in the
DEB and PTA groups (p<0.001), respectively. Freedom from TLR was significa
significantly
antly
ntly
y hhigher
ighe
ig
herr in
he
in
the
he DEB group (Figure 2). Thirty six (mainly planned) minor amputations were performed, 19 in
the
occurred, in the
he PTA
PTA and
and 17 in
in the
th DEB arm, respectively (p=0.8).
(p
p=0.8). Only 1 major
maajo
j r amputation
am
mputation
pu
PTA
(p=0.9).
Target
vessel
13(17%)
DEB-treated
vs.
41(55%)
PTA
A group (p
p=0
0.99). T
arge
ar
gett ve
ge
ves
ssell oocclusion
ssel
c lu
cc
lussionn ooccurred
ccu
urr
rreed iin
n 13
13(1
(17%
7%
%) DE
DEBB treaate
tedd vs
s. 41
41(5
(55%
(5
5%))
5%
PTA-treated
vessels
(p<0.001).
Twelve-month
MAE
less
DEB
PT
TAA-tr
trea
tr
eate
teed ve
ves
ssels (p
(p<
<0.001
<0.0
011). T
welve
elvee-m
mon
onth
hM
AE ooccurred
cccur
urre
redd le
esss ffrequently
r quen
re
quentl
tlyy in
tl
i tthe
he D
EB ((31%)
31%
%)
%)
than
(51%)
group
(p=0.02),
mainly
TLR
han in PTA (5
51%
1%)) gr
grou
oupp (p
ou
(p=0
= .002)
2 , ma
main
inly
in
ly ddriven
riv
ven by
by a reduction
redu
re
duct
du
ctio
ct
ionn in
io
nT
LR aand
n bbetter
nd
ette
et
terr ul
te
uulcer
cer
healing. Rate of complete healing of the index ulcer was higher and time to index ulcer healing
was shorter in the DEB group (Table 3).
Subanalyses for lesion length, baseline vessel status (stenosis or occlusion) and
revascularization technique (intraluminal vs. subintimal) yielded similar comparative results
(Figure 3). Three vessels treated with DEB showed an increase •30% in reference vessel
diameter at follow-up: interestingly, no angiographically evident flaps were visible during the
initial procedure in these 3 cases.
Examples of DEB-treated lesions are shown in Figures 4 and 5.
10
DOI: 10.1161/CIRCULATIONAHA.113.001811
Discussion
The DEBATE-BTK is the first randomized study evaluating the efficacy, in terms of 12-month
restenosis and TLR, of DEB vs. standard PTA in diabetic patients with CLI undergoing
revascularization of BTK arteries. DEB significantly reduce 12-month restenosis, with a relative
risk reduction (RRR) of 64%. This advantage was irrespective of lesion length, revascularization
technique and baseline vessel conditions. When DEB failed to match 12-month vessel patency,
the length of reocclusion was significantly shorter compared to that observed after standard PTA,
Downloaded from http://circ.ahajournals.org/ by guest on September 29, 2016
facilitating re-intervention. Our findings confirm, in a randomized fashion, those previously
reported in a single center registry15, which evaluated 3-month binary restenosis in unselected
CLI patients treated with the same DEB platform as in our study. Our data show
w tthe
hee ppersistence
ersi
er
sist
si
sten
st
e ce
en
c
of the results at 12 months and add important clinical endpoints. Moreover, the high frequency oof
angiographic
an
ngi
giog
ogrraph
og
raph
phic
ic fol
follow-up
llo
low
w-up and the very low rate off ba
bbail-out
il-out treatment
n wit
nt
with
itth ddrug-eluting
rug-eluting stents
ensure
en
nsuure
r the reliability
relia
iabi
b liity
bi
y ooff ou
ourr res
rresults.
esult
sults.
s
s.
Thee ad
conferred
DEB
restenosis
Th
aadvantage
dva
vaanttag
agee co
onf
n errre
redd by D
EB oon
n re
est
s en
enoosiis rresulted
esuulte
es
teed in
i a significant
sig
gnifi
fica
cant
ca
nt ddecrease
ecrreas
ec
asse in
clinically-driven
value
clinically-dri
ive
venn TLR,
TLR, a secondary
sec
econ
ec
o da
on
dary
r endpoint
ry
end
dpo
poin
intt of tthe
in
he sstudy.
t dy
tu
dy.. TL
TLR
R ha
hhass an iimportant
mpor
mp
o taant pprognostic
or
rogn
ro
g ostic valu
gn
ue
in CLI patients, as early failure of endovascular recanalization was found to predict limb loss and
poor prognosis20, and repeat interventions with multiple contrast exposures are harmful in these
very sick patients with frequent life-threatening comorbidities. Besides major amputation, our
study did not have pre-planned endpoints of minor amputation and healing due to the fact that
vessel patency alone is considered necessary but not sufficient to guarantee amputation-free
survival.2,8,21 However, post hoc analysis revealed that DEB are likely to provide significant
improvement in the rate of complete index ulcer healing at 12 months. The possibility that
treatment with DEB might result in significant clinical benefit is further compounded by the
11
DOI: 10.1161/CIRCULATIONAHA.113.001811
more favorable distribution of Rutherford classes at follow-up and faster index ulcer healing in
the DEB group.
Treatment with DEB, however, did not translate to a significantly higher rate of limb
salvage due to the very low rate of major amputations (1 limb out of 143). This low rate of limb
loss may depend on several factors: 1) patients were enrolled in the study only after successful
wiring of the target vessel and, therefore, the rate of major amputation observed cannot be
compared to that derived from studies designed on an intention-to-treat basis; 2) we established a
Downloaded from http://circ.ahajournals.org/ by guest on September 29, 2016
dedicated multidisciplinary team providing wound care and continuous surveillance regimen of
the foot lesion and vessel patency, including fast-track angiography and re-intervention when
clinically needed8,21. We previously showed the long-term benefit of this integra
integrated
ated
t ed
multidisciplinary framework in this high-risk subset of patients7.
Th
saafeety ooff DEB, moreover, was similar
simillar tto
o conventiona
al ball
llloo
oons
n , as no acute
Thee safety
conventional
balloons,
thrombosis
hro
omb
m osis occ
occurred
ccuurreed oon
n1m
month
onth
on
th ddual
ual an
ua
antiplatelet
ntipllat
ateelet th
therapy
herap
apyy in
ap
n bboth
othh aarms.
ot
rms
ms. IIn
n ffew
ew ccases,
assess, DE
DEB
B we
were
r
associated
as
sso
soci
ciat
ci
a ed with
at
with
ith a llimited
imi
mittedd in
incr
increase
crrea
ease
se iin
n re
reference
efeere
rennce
nce vessel
v sse
ve
ssel diameter
diaame
meteer att follow-up.
fol
ollo
l wlo
w-up
up. Longer
Long
Lo
nger
ng
err follow-up
foollo
ol oww-uup
up
will clarify iff th
this
is pphenomenon
h no
he
nomeeno
non is ooff cl
clin
clinical
inic
in
iccal rrelevance.
elev
el
ev
van
ance
c .
ce
Study Limitations
Like many device trials in interventional cardiology, this is not a blinded study. In addition,
patients were enrolled only in a single, high-volume center that might have a unique patient
referral pattern and interventional technique. In addition, this study had no financial support and
no external angiography or DUS core laboratory was available for adjudication of the endpoints.
However, the size of the observed effect and the additional evidence in favor of DEB in the
femoropopliteal district14 leaves few chances for these results to be controverted in a multicenter
randomized study. We used everolimus drug-eluting stents as a bailout, which could have
12
DOI: 10.1161/CIRCULATIONAHA.113.001811
potentially affected the study results and interacted with DEB leading to excessive neointimal
inhibition. However, only two DES were implanted (one in each study group) and we did not
observe any sign of positive remodelling in the single patient that was eventually treated with
DEB+DES. Finally, clinical results achieved by an integrated multidisciplinary approach to CLI
may not reproduced with DEB in other centers with different organization.
Conclusions
Downloaded from http://circ.ahajournals.org/ by guest on September 29, 2016
DEB angioplasty of tibial vessel in diabetic patients with CLI is associated with a significant
reduction in binary restenosis, TLR and vessel occlusion at 12 months. The higher vessel patency
single-center
provided by DEB translated into some clinical advantage, although our single-cen
en
nteer tria
ttrial
ria
iall do
does
es
not have the power to evaluate more patient-centered outcomes. Large multicenter randomized
trials
ria
ials
ls will
wil
illl be needed
neeede
dedd to assess whether the increased
increaase
s d patency of limb
lim
im
mb arteries
arrte
terries afforded by DEB
promotes
survival.
prom
motes clear
ar iimprovement
mpro
mp
rovveme
ment
me
nt iin
n li
limb
mb ssalvage
alvvagee aand
al
nd su
urviivaal.
l
Conflict
None.
Conf
Co
nfli
nf
lict
li
ct of
of Interest
Inte
In
tere
te
rest
re
st Disclosures:
Dis
iscl
clos
cl
osur
os
ures
ur
es:: N
es
onee.
on
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57..
Larsson
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Stenstrom
A.. De
Decreasing
major
221.
1. L
arsson J,, Ape
pelqvvistt J, Ag
pe
Agar
a dh
d C
D, S
tennsttrom
mA
Dec
creas
cre
easingg iincidence
nciddennce
nce ooff m
ajjorr aamputation
mputaatiion
mp
inn diabetic
patients:
consequence
multidisciplinary
care
approach?
Diabet
Med.
diaabe
b ti
ticc pa
pati
tien
en
ntss: A co
ons
nseq
queenc
ncee off a m
ul idi
ulti
disc
sccip
pli
l nary
ry ffoot
oo
ot ca
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appr
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pr
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iabbet M
ed
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1995;12:770-776.
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7700 77
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15
DOI: 10.1161/CIRCULATIONAHA.113.001811
Table 1. Patients baseline characteristics
Downloaded from http://circ.ahajournals.org/ by guest on September 29, 2016
Number of patients
Age — yr
Male gender — no. (%)
Diabetes — no. (%)
Hypertension — no. (%)
Smoking — no. (%)
Hypercholesterolemia — no. (%)
Dialysis — no. (%)
Serum creatinine — mg/dl
eGFR— ml/min/1.73m2
Coronary artery disease — no. (%)
Cerebrovascular disease — no. (%)
Number of limbs
Patent tibial vessels — no. (%):
0
1
2
ABII
AB
Inflow
nfl
floow
ow lesio
lesion
ionn tr
treatment
reaatm
t en
nt — no
no.. (%
(%))
M
Mean
ean
an Rutherf
Rutherford
for
ordd Class
Classs
Clas
Rutherford
R
utherfo
ord Class
Claass 4 — no.
no. (%)
(%)
%
Ruth
Ru
Rutherford
ther
th
erfo
er
ford
fo
rd C
Class
laass 5 — nno.
o.. ((%)
%)
Ruth
Ru
Rutherford
ther
th
erfo
er
ford
fo
rd C
Class
lass
la
ss 6 — nno.
o. ((%)
%)
Plus–minus val
values
allue
uess ar
aree me
m
means
anss ±S
an
±SD.
SD.
ABI
kl b hi l i d
ABI: A
Ankle-brachial-index
16
DEB
65
74±9.4
54 (83.1)
65 (100)
46 (70.8)
13 (20.0)
23 (35.4)
7 (10.8)
1.2±0.4
51±27
12 (18.5)
5 (7.7)
71
PTA
67
75±9.6
52 (77.6)
67 (100)
52 (77.6)
7 (10.4)
16 (23.9)
7 (10.4)
1.2±0.5
54±23
10 (14.9)
7 (10.4)
72
23 (35.4)
30 (46.2)
12 (18.5)
0.31±0.2
32
32(49.2)
2(4
(499.2)
9.2)
5.15±0.4
5 15±
5.
15±0.4
.4
2 (2.8)
(2.8))
(2.
56 ((78.9)
78.9
78
.99)
13 (18.3)
(18.3)
3)
19 (28.4))
37 (55.2)
11 (16.4)
0.
0.29±0.3
335
5 (5
(52.2)
52.
2.2)
2)
55.09±0.4
.0
09±
9±0.
0.44
3 (4.2)
(4.2)
(4.2
59(8
59
59(81.9)
(81.
1 9)
1.
10 (13.9)
(13.9)
9)
P value
0.7
0.5
1
0.4
0.1
0.1
1
0.9
0.8
0.6
0.7
0.5
0.6
00.8
.88
00.4
.44
0.7
7
DOI: 10.1161/CIRCULATIONAHA.113.001811
Table 2. Procedural and angiographic characteristics
Downloaded from http://circ.ahajournals.org/ by guest on September 29, 2016
Number of lesions
Vessel location — no. (%):
ATA
PTA
PA
TPT
Complete vessel occlusion — no. (%)
Lesion length — mm
Severe calcification — no. (%)
RVD — mm
MLD — mm
DS — %
Predilatation — no. ((%))
Subintimal recanalization — no. (%)
Antegrade recanalization — no. (%)
Retrograde recanalization — no. (%)
Balloon inflation time — sec
Ball
Ba
Balloon
lloo
ll
oonn di
oo
diam
diameter
ameter
am
err — mm
Ball
Ba
loon leng
ngtth — m
m
Balloon
length
mm
B
ail
illou
o t stenting
ng — nno.
o. ((%)
%)
Bailout
Te
Technical
ech
hni
n cal su
success
ucc
c esss — no
no. (%
(%)
%)
Proc
Pr
occed
edur
ural
ur
al ssuccess
ucce
uc
cess
ce
sss — no.
no.
o. (%)
%)
Procedural
DEB
80
PTA
78
37 (46.3)
13 (16.3)
14 (17.5)
16 (20.0)
62 (77.5)
129±83
20 (25.0)
2.91±0.27
0.06±0.14
97.2±7.7
(
)
80 (100.0)
17 (21.3)
78 (97.5)
2 (2.5)
142±38
2.90±0.39
14
48±
8±83
8
148±83
1 (1
(1.
.3))
(1.3)
80 ((100)
1000)
65(1
65
(100
(1
00))
00
65(100)
32 (41.0)
18 (23.1)
21 (26.9)
7 (9.0)
64 (82.1)
131±79
22 (28.2)
2.87±0.29
0.05±0.14
97.1±8.0
17 (21.8
(21.8)
8)
75 (96.2)
(96.2
2)
3 (3.8)
140±50
22.85±0.36
2.85
.8 ±0.36
1140±79
400±7
±799
1 (1.3
((1.3)
1.3))
778
8 (1
(100
(100)
00)
6 (1
67
100
00))
67(100)
P value
0.5
0.5
0.9
0.5
0.7
0.6
0.9
00.8
0.
8
0.7
07
0.
0.7
0.5
0.4
0.5
0.
5
00.9
0.
9
1
1
Plus–minus
Plus
Pl
us–m
us
min
inus
us vvalues
alue
al
uess ar
ue
aree me
mean
means
anss ±S
an
±SD.
SD.
D.
ATA: anteriorr ti
ttibial
bial
bi
al artery,
art
rter
ery,
er
y, PTA:
PTA
A: posterior
postter
po
erio
i r tibial
io
t biial artery,
ti
art
r er
e y, PA:
PA: peroneal
pero
pe
r neeal
ro
a artery,
art
rter
ery,
er
y, T
TPT:
PT
T: tibioperoneal
tibi
ti
biop
bi
oper
op
eron
er
onea
eall trunk,
ea
trrun
unk,
k, RVD:
reference
minimal
lumen
efe
fere
renc
ncee vessel
vess
ve
ssel
el diameter,
dia
iame
mete
terr MLD:
MLD
LD:: mi
mini
nima
mall lu
lume
menn diameter,
diam
di
amet
eter
er %D
%DS:
S: ppercentage
erce
er
cent
ntag
agee diameter
diam
di
amet
eter
er sstenosis
teno
te
nosi
siss
17
DOI: 10.1161/CIRCULATIONAHA.113.001811
Table 3. Clinical and angiographic outcome at 12 months
Downloaded from http://circ.ahajournals.org/ by guest on September 29, 2016
DEB
5(7.7)
0(0.0)
2 (3.1)
3 (4.6)
20 (31)
66
0.78±0.22
0.90±1.8
57 (86.3)
0 (0)
8 (12.2)
1 (1.5)
56/65 ((86))
4.4±1.5
74
20(27.0)
13(17.6)
87±88
Death — no. (%)
Major Amputation — no. (%)
CVA — no. (%)
AMI — no. (%)
MAE — no. (%)
Limbs available for 12-month follow-up
ABI
Mean Rutherford class category
Rutherford Class 0-3 — no. (%)
Rutherford Class 4 — no. (%)
Rutherford Class 5 — no. (%)
Rutherford Class 6 — no. (%)
p
g*— no. ((%))
Complete
index ulcer healing
Time to index ulcer healing*— months
Lesions available for 12-month follow-up
Binary Restenosis (>50%) — no. (%)†
Vessel
el Occlusion
Occlu
lusi
s onn — no. (%)†
Occlusion
Occcl
cluusio
on le
leng
length
gth — mm†
PTA
3(4.5)
1 (1.5)
3 (4.5)
3 (4.5)
34 (51)
67
0.47±0.28
2.0±2.3
44 (65.7)
2 (3)
19 (28.3)
2 (3)
43/64 ((67))
5.2±1.6
6
74
55(74.3)
441(55.4)
1(55.4)
1128±75
12
8±75
P value
0.4
0.9
0.9
0.9
0.05
<0.001
0.004
0.06
0.01
00.01
.0
01
<0.001
<0.001
<0.001
Pllus–
Plus–minus
–m
–minus
val
values
alue
uess ar
aree me
mean
means
anss ±S
±SD.
D
D.
CVA:
C
VA
A: cerebrovascular
A:
cerebrovascuularr accident,
acc
cciideent, AMI:
AMI: acute
acu
cutte
cu
te myocardial
myocard
diaal infarction,
inffar
farctioon,
n, M
MAE:
AE: ma
AE
major
ajo
or ad
adverse
dversse ev
eve
events.
ents
ts.
*
Refers
R
efe
fers to limb
fe
limbs
mbss ava
available
aillablee fo
for
or 12
12-month
2-month
on h fol
follow-up
olllo
low
w-up with
w-u
withh Rutherford
Rutther
therfo
ford
rd cclass
lasss 5-6 att basel
la
baseline
linne
†P
†Per
Per llesion
esio
es
ion analysis
anal
an
alys
al
ysis
is
Figure Legends:
Figure 1. Study Flow.
Figure 2. Kaplan-Meyer analysis for survival free from target lesion revascularization (TLR) in
both study groups.
Figure 3. Post-hoc analysis of restenosis (%) in different subgroups of the 2 study groups.
18
DOI: 10.1161/CIRCULATIONAHA.113.001811
Figure 4. Right limb below the knee (BTK) vessels in a 76-year old male with critical limb
ischemia. Panel A: stenosis in the proximal segment of the peroneal artery (PA); long diseased
segment of the posterior tibial artery (PTA, black arrows). Panel B: patent plantar arteries. Panel
C: Dilatation of the proximal segment of the tibioperoneal trunk and PTA with a 3.0x120mm
drug-eluting balloon (DEB, Amphirion In.Pact, Medtronic, Santa Rosa, CA). Panel D: Dilatation
of the mid-distal segment of the PTA with a 3.0x120mm DEB (Amphirion In.Pact, Medtronic,
Santa Rosa, CA) overlapping for 10mm with the segment previously treated with the other DEB.
Downloaded from http://circ.ahajournals.org/ by guest on September 29, 2016
Panel E: immediate angiographic result with good patency of the PTA without residual stenosis.
The PA lesion could not be enrolled in the study (length <40 mm) and was dilated with
conventional, non-eluting balloon (not shown). Panel D: Twelve-month follow-u
follow-up
up aangiography
up
nggio
iogr
grap
gr
aphy
ap
hy
showing
howing optimal patency of the PTA without restenosis.
Figure
knee
male
limb
Figu
gure
u 5. Right
Rig
ght llimb
im
mb be
bbelow
low
lo
w th
thee kn
nee ((BTK)
BTK)) vvessels
BT
esseelss inn a 778-year
8-yyear
yearr oold
ld m
alle wi
with
th ccritical
riti
ri
tiica
c l li
imb
ischemia:
artery
(upper
sch
chem
em
mia
ia:: Panel
Pane
Pa
nell A: proximal
pro
oxima
xim l occlusion
occl
oc
clus
cl
usiion
us
ion of the
the anterior
anteeriior
o ttibial
ib
bia
iall ar
arte
t ry
te
ry ((ATA)
ATA
TA)) (u
upp
pper
e bblack
er
lack
la
k aarrow)
rrow
rrow
w)
with filling of
of the
the dorsalis
dors
do
rssal
alis pedis
ped
ediss artery
a teery (lower
ar
(lo
owe
werr black
b ac
bl
a k arrow)
a roow) by
ar
by the
the peroneal
pero
pe
rone
ro
neal
ne
al artery
artter
eryy (PA),
(PA)
(P
A , which
shows significant stenosis in the proximal segment (white arrows); occlusion of the posterior
tibial artery (PTA) with collateral filling of the plantar arteries by the PA. Panel B: Immediate
results after drug-eluting balloon (DEB, Amphirion In.Pact, Medtronic, Santa Rosa, CA) dilation
of both ATA (3.5x120mm+3x120mm+3x80mm) and PA (3,5x120mm). Panel B: immediate
angiographic result with no residual stenosis of both ATA and PA. Panel C: Twelve-month
follow-up angiography showing good patency of both ATA and PA arteries. Black arrow
indicates focal ectasia of the ATA in the segment previously treated with DEB.
19
Downloaded from http://circ.ahajournals.org/ by guest on September 29, 2016
156 diabetic patients with CLI
(Rutherford class•4) with at least one
•50% stenosis of tibial vessels
vessels •40mm in length with distal
run-off
24 excluded
16 did not meet angiographic inclusion criteria
2 need for major amp
amputation
utat
tatio
ion
n
4 lack of consent
2 life expectancy < 1 year
yea
132 patients with 158 lesions
in 143 limbs e
enrolled
n olled
nr
1:1
1:
1
1 Randomization
R nd
Ra
n omiz
i attio
ion
12-month
FUP
Figure 1
DEB
DEB
65 patients, 80 lesions in
71 limbs
PTA
PTA
67 patients, 78 lesions in
72 limbs
Death = 5
Death = 3
67 lesions Angio FUP1
7 lesions DUS FUP2
68 lesions Angio FUP1
6 lesions DUS FUP2
1 Angio FUP performed
at 12 months or at the
time of TLR
2
DUS=Doppler
Ultrasoud imaging
Downloaded from http://circ.ahajournals.org/ by guest on September 29, 2016
Figure 2
Downloaded from http://circ.ahajournals.org/ by guest on September 29, 2016
Figure 3
Downloaded from http://circ.ahajournals.org/ by guest on September 29, 2016
Figure 4
Downloaded from http://circ.ahajournals.org/ by guest on September 29, 2016
Figure 5
Drug-Eluting Balloon in peripherAl inTErvention for Below the Knee Angioplasty Evaluation
(DEBATE-BTK): A Randomized Trial in Diabetic Patients with Critical Limb Ischemia
Francesco Liistro, Italo Porto, Paolo Angioli, Simone Grotti, Lucia Ricci, Kenneth Ducci, Giovanni
Falsini, Giorgio Ventoruzzo, Filippo Turini, Guido Bellandi and Leonardo Bolognese
Downloaded from http://circ.ahajournals.org/ by guest on September 29, 2016
Circulation. published online June 24, 2013;
Circulation is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
Copyright © 2013 American Heart Association, Inc. All rights reserved.
Print ISSN: 0009-7322. Online ISSN: 1524-4539
The online version of this article, along with updated information and services, is located on the
World Wide Web at:
http://circ.ahajournals.org/content/early/2013/06/24/CIRCULATIONAHA.113.001811
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