J ENDOVASC THER

2012;19:571580

^CLINICAL

571

INVESTIGATION

Lower Limb Multilevel Treatment With

Drug-Eluting Balloons: 6-Month Results From
the DEBELLUM Randomized Trial
Fabrizio Fanelli, MD; Alessandro Cannavale, MD; Emanuele Boatta, MD; Mario Corona, MD;
Pierleone Lucatelli, MD; Andrea Wlderk, MD; Carlo Cirelli, MD; and Filippo Maria Salvatori, MD
Vascular and Interventional Radiology Unit, Department of Radiological Sciences,
Sapienza University of Rome, Italy.
^

Purpose: To report 6-month results of the DEBELLUM (Drug-Eluting Balloon Evaluation for
Lower Limb MUltilevel TreatMent) randomized trial to evaluate the efficacy of a drug-eluting
balloon (DEB) to reduce restenosis after treatment of multilevel lower limb occlusive
disease vs. a conventional angioplasty balloon (AB).
Methods: Between September 2010 and March 2011, 50 consecutive patients (37 men;
mean age 6664 years) with 122 lesions (96 stenoses and 26 occlusions) of the
femoropopliteal (92, 75.4%) or below-the-knee (BTK) arteries (30, 24.6%) were enrolled
and randomly assigned to the DEB (25 patients with 57 lesions) or AB (25 patients with 65
lesions) group. Twenty patients presented multilevel lesions. Mean lesion length was
7.563.5 cm. Thirty-one (62%) of the patients were Fontaine stage IIb, while 19 (38%) were
stage III or IV. DEBs or ABs were used for dilation of de novo lesions or for postdilation after
primary stenting (superficial femoral artery only). Patients requiring provisional stenting
after angioplasty secondary to flow-limiting dissection or residual stenosis .50% were
ineligible. Primary endpoint was late lumen loss at 6 months. Secondary endpoints were
target lesion revascularization (TLR), amputation, and thrombosis.
Results: Late lumen loss was lower in the DEB group (0.561.4 vs. 1.661.7 mm, p,0.01). TLR
was necessary in 6.1% of the DEB group vs. 23.6% of the AB group (p0.02). Comparing the
DEB to AB groups, the thrombosis rates were 3.0% vs. 5.2% (p0.6), and the amputation
rates were 3.0% vs. 7.9% (p0.36). The binary restenosis rates were 9.1% (3/33 limbs) in the
DEB group vs. 28.9% (11/38 limbs) in the control group (p0.03). The ankle-brachial index
improved to a greater degree in the DEB group: 0.8760.22 vs. 0.7060.13 (p,0.05). The
Fontaine stage improved in both groups but more so in patients treated with DEBs (p0.04).
Conclusion: The DEBELLUM trial confirmed the ability of paclitaxel-eluting balloons to
reduce restenosis vs. conventional balloons at 6 months after treatment of multilevel
(femoropopliteal and BTK) arterial disease in patients affected by claudication and CLI. A
lower TLR rate and better clinical outcomes appear to be associated with the use of DEBs
regardless of stent placement.
J Endovasc Ther. 2012;19:571580
Key words: peripheral artery disease, stenosis, occlusion, critical limb ischemia, superficial
femoral artery, popliteal artery, infrapopliteal arteries, angioplasty, stent, paclitaxel, drug-eluting
balloon, restenosis, late lumen loss, amputation, thrombosis, target lesion revascularization
^
^

The authors have no commercial, proprietary, or financial interest in any products or companies described in this
article.
Corresponding author: Fabrizio Fanelli, MD, Vascular and Interventional Radiology Unit, Department of Radiological
Sciences, Sapienza University of Rome, 324 Viale Regina Elena, 00161 Rome, Italy. E-mail: fabrizio.fanelli@
uniroma1.it
2012 by the INTERNATIONAL SOCIETY

OF

ENDOVASCULAR SPECIALISTS

Available at www.jevt.org

572

DEB FOR LOWER LIMB MULTILEVEL DISEASES

Fanelli et al.

Peripheral artery disease (PAD) is a severe

and complex condition that is still a challenge
for both surgical and endovascular therapies.1
See commentary page 581
Arterial disease is known to be located mainly
in the superficial femoral artery (SFA) in cases
of claudication and in the below-the-knee
(BTK) region in patients with critical limb
ischemia (CLI). Multilevel lesion distribution
is not infrequent and requires treatment of
both the SFA and BTK vessels. Drug-eluting
devices, which inhibit neointima proliferation,
represent a novel clinical treatment modality
for PAD. Recent evidence in the literature
suggests that paclitaxel-eluting stents and
balloons are safe and effective in preventing
restenosis.28
At present, only limited data are available
on the use of drug-eluting stents (DES) in the
femoropopliteal region. In the case of BTK
disease, DES have become increasingly popular thanks to a low rate of in-stent restenosis
and occlusion in relatively short lesions.913
Moreover, the use of drug-eluting balloons
(DEBs) is gaining ground and confidence as
the most adequate therapy to deal with the
extensive and variegate complexity typical of
the peripheral vessels.12
We initiated a single-center randomized
controlled trial (RCT) to test the hypothesis
that paclitaxel-eluting balloons could reduce
restenosis after standard treatment of multilevel lower limb arterial occlusive disease.

METHODS
Study Design
The DEBELLUM (Drug-Eluting Balloon Evaluation for Lower Limb MUltilevel TreatMent)
study was a prospective, independent (no
manufacturer support) RCT designed to compare DEBs to conventional angioplasty balloons (ABs) in terms of late lumen loss 6
months after treatment of occlusive disease in
the femoropopliteal and infrapopliteal arteries. Late lumen loss was chosen to allow
sufficient sensitivity in detecting differences in
restenosis rates between the 2 arms.14 The
trial design was approved by the local ethics

J ENDOVASC THER
2012;19:571580

committee, and the study was carried out

according to the Declaration of Helsinki. All
patients were informed about the study and
the proposed treatment; all signed the consent form.
Candidates underwent clinical evaluation
including measurement of the ankle-brachial
index (ABI), duplex ultrasound, and computed
tomographic angiography (CTA) to evaluate
anatomical characteristics and morphology of
the lesions. Patients with single or multiple
lesions (stenosis or occlusion between 3 and
30 cm in length) in the native SFA, the
popliteal artery (PA), or the BTK arteries were
eligible for the study, as were those with
concomitant multilevel disease. Exclusion
criteria were in-stent restenosis, aneurysms,
acute thrombosis, pregnancy, life expectancy
,1 year, and absence of a patent crural artery.

Randomization
Patients were randomized (1:1) without
stratification using computer-generated assignments when they entered the angiographic suite. Patients, but not operators, were
blinded to the assigned intervention. Group
sizes were estimated at 24 patients each to
yield a statistical power of 90% for the
detection of an absolute difference in late
lumen loss (1 mm) of 23% of the reference
diameter between study groups at the p,0.05
level. This calculation assumed a standard
deviation for late lumen loss of 40% of the
reference diameter.

Interventions
According to protocol, the DEBs and ABs
were used for dilation of a de novo lesion at
any level or for postdilation after primary
stenting in the SFA only. The decision to
implant a nitinol stent in the SFA territory was
left to the judgment of the operator and
typically driven by lesion length and presence
of severe calcification. Patients requiring
provisional or bailout stenting after angioplasty as a result of flow-limiting dissection or
residual stenosis .50% were excluded from
the study.
Patients were placed on a standard antiplatelet regimen with aspirin (100 mg/d) and clopi-

J ENDOVASC THER
2012;19;571580

dogrel (75 mg/d) administered at least 3 days

prior to angioplasty. All procedures were
performed by the same operators in a stateof-the-art angio-suite using dedicated angiographic equipment (Artis Zee; Siemens AG
Medical Solution, Erlangen, Germany). Patients who were not on an antiplatelet medication before the procedure had a 300-mg loading
dose of clopidogrel administered. Procedures
were done via common femoral artery access
either in retrograde or antegrade fashion,
according to anatomical characteristics and
lesion location. All devices were inserted
through a 6-F, 45-cm braided introducer sheath
(Destination; Terumo, Tokyo, Japan) to ensure
the maximum protection of the DEB surface
because the amount of drug that can be lost
during navigation is still under discussion.1517
An intra-arterial 5000-unit heparin bolus was
injected immediately after sheath insertion.
The native lesion was predilated in all cases
using a non-coated angioplasty balloon undersized by 1 mm.12 Predilation was not done in
cases of primary stenting.
To keep the study as homogeneous as
possible, the same models of angioplasty
balloons (Admiral and Amphirion; Medtronic
Inc., Frauenfeld, Switzerland) were used with
the only exception being the paclitaxel coating. Balloon diameters were selected with a
1:1 ratio according to the reference vessel
diameter. In the test group, the drug-eluting
IN.PACT Admiral was used for femoropopliteal lesions and the IN.PACT Amphirion for
BTK lesions. As suggested in other studies4,18
and according to the IN.PACT Instructions for
Use, the DEBs were inflated for 60 seconds. In
long lesions requiring .1 DEB, a 1-cm overlap
area was secured between the 2 balloons.
Similarly, non-coated Admiral and Amphirion
(Medtronic Inc.) balloons were used according
to the site of the lesion in the control group.
Technical success was defined as residual
stenosis ,30% by visual estimation. After
treatment, all patients were prescribed medical
therapy consisting of aspirin (100 mg/d) indefinitely and clopidogrel (75 mg/d) for 4 weeks.

Follow-up
Postoperative evaluation was deferred to
different physicians not informed about the

DEB FOR LOWER LIMB MULTILEVEL DISEASES

Fanelli et al.

573

assigned intervention. Six-month assessment

involved clinical evaluation to determine the
ABI and the Fontaine stage and imaging to
measure late lumen loss [duplex ultrasound
in the femoropopliteal territory and digital
subtraction angiography (DSA) for BTK lesions]. Follow-up evaluation was also planned
at 12 and 24 months after intervention.

Study Endpoints and Definitions

The primary endpoint was the late lumen
loss at 6 months as determined by duplex
ultrasound in the femoropopliteal region and
by DSA in the BTK arteries. Late lumen loss
was the difference in millimeters between the
minimum lumen diameter (MLD) immediately
after the procedure and the MLD during
follow-up. The secondary endpoints were
binary restenosis (.50%); acute thrombotic
occlusion of an artery within 48 hours of the
procedure as determined by ultrasound, angiography, or clinical evidence; any reintervention performed for thrombosis or
restenosis (.50% diameter stenosis) of the
target lesion after documentation of recurrent
ischemic symptoms (target lesion revascularization, TLR); and amputation at 6, 12, and 24
months. Minor amputation referred to loss of
only a toe or part of the foot, while major
amputation involved removal of part of the
leg, above or below the knee, in cases of
severe gangrene developing with constant
pain after angioplasty. Major adverse events
were death, TLR, amputation, and thrombosis. Calcification was estimated from axial
CTA images and/or intravascular ultrasound
(Volcano Corporation, Rancho Cordova, CA,
USA) and stratified to grade 1 (458), grade 2
(908), grade 3 (1358), or grade 4 (circumferential).

Patient Population
Enrollment began in September 2010 and
was closed in March 2011 after 50 consecutive
patients (37 men; mean age 6664 years) with
symptomatic PAD were randomized between
DEB (25 patients with 57 lesions in 33 limbs)
and AB (25 patients with 65 lesions in 38
limbs). Demographics and risk factors are
presented in Table 1; an enrollment flow chart

574

DEB FOR LOWER LIMB MULTILEVEL DISEASES

Fanelli et al.

J ENDOVASC THER
2012;19:571580

^
TABLE 1
Demographics and Risk Factors of All Patients and by Study Arm

Age, y
Men
Height, cm
Weight, kg
Diabetes
Hypercholesterolemia
Hypertension
Past/current smoker
ABI
Fontaine class
IIB
III
IV
Runoff vessels
1
2
3

All (n50)

DEB (n25)

AB (n25)

67621
37 (74%)
17068
79615
22 (44%)
29 (58%)
34 (68%)
31 (62%)
0.5660.06

6666
19 (76%)
17168
7767
13 (52%)
12 (48%)
19 (76%)
17(68%)
0.5560.06

6766
18 (72%)
16967
7867
9 (36%)
17 (68%)
15 (60%)
14 (56%)
0.5760.05

0.78
0.75
0.60
0.75
0.40
0.24
0.24
0.39
0.13

31 (62%)
14 (28%)
5 (10%)

16 (64%)
7 (28%)
2 (8%)

15 (60%)
7 (28%)
3 (12%)

0.77
1.00
0.64

9 (18%)
29 (58%)
12 (24%)

5 (20%)
16 (64%)
4 (16%)

4 (16%)
13 (52%)
8 (32%)

0.71
0.40
0.19

^
Continuous data are presented as the means6standard deviation; categorical data are given as the counts
(percentage).
AB: balloon angioplasty, ABI: ankle-brachial index, DEB: drug-eluting balloon.

is provided in Figure 1. The 122 target lesions

were located in the femoropopliteal region
(92, 75.4%) or BTK arteries (30, 24.6%).
Twenty (40%) patients had multilevel disease
with concomitant femoropopliteal and infrapopliteal lesions. According to the TASC
(TransAtlantic Inter-Society Consensus) II
classification,1 23 (18.9%) lesions were class
A, 45 (36.9%) class B, 41 (33.6%) C, and 13
(10.6%) class D (Table 2).

Statistical Analysis
All data were analyzed according to the
intention-to-treat principle and were reported
as either per patient, per limb, or per lesion as
appropriate. No patients were excluded until
they reached one of the defined endpoints.
Continuous variables were reported as the
mean6standard deviation or the median and
range as appropriate; differences were compared using the Student t test. For categorical
variables, the absolute and relative proportions were calculated and compared using the
Fisher exact test. Significance was assumed at
p,0.05. All analyses were carried out using
SPSS for Windows (IBM Corporation, Somers, NY, USA) and Excel for Mac 2008.

RESULTS
There were no crossovers after randomization
or protocol deviations. Procedures were performed as planned using an antegrade femoral access in 37 (74%) cases and retrograde
(crossover) femoral access in the remaining
13 (26%). Patients with SFA and PA lesions
randomized in the DEB group (n44) had
angioplasty performed without stent in 19 de
novo lesions, while stents were electively
implanted in 25 lesions and postdilated with
a DEB. Similarly, the AB group (n48) included 21 lesions treated with angioplasty only
and 27 lesions in which angioplasty was done
for post-stent dilation. In the BTK region,
angioplasty was done with DEB in 13 lesions,
while 17 lesions were treated with the noncoated balloons. Technical success was
achieved in all cases. The mean residual
stenosis at the end of the procedure was
17.3%65.2% (range 8% to 26%). After 6
months of follow-up, all 50 patients were alive
The primary endpoint of mean late lumen
loss was significantly lower in the DEB group
overall (0.561.4 vs. 1.661.7 mm, p,0.01;
Table 3). Subgroup analysis of DEB vs. AB
by lesion location showed a late lumen loss of

J ENDOVASC THER
2012;19;571580

DEB FOR LOWER LIMB MULTILEVEL DISEASES

Fanelli et al.

575

Figure 1 ^ DEBELLUM study CONSORT flow chart.

0.4160.5 vs. 1.5561.3 mm in the SFA (p,0.05)

and 0.6260.9 vs. 1.6561.5 mm in the BTK
arteries (p,0.05). Subgroup analysis of stenosis treated with dilation only vs. those
treated with stenting followed by postdilation
(Table 3) also unquestionably demonstrated
better results using DEB (p,0.05). In the 30
BTK vessels (13 DEB, 17 AB), late lumen loss
was also lower in the DEB-treated vessels
(0.760.2 mm) vs. those treated with noncoated balloons (1.460.4, p,0.01).
Non-stented lesions showed a late lumen
loss of 0.560.9 mm in the DEB group vs.
1.560.6 mm in the AB group (p,0.01). In
those patients who had angioplasty performed after stent implantation (Figs. 2 and
3), late lumen loss was 0.5160.7 mm using
DEB and 1.760.2 mm with AB (p,0.01).
Target lesion revascularization (clinically
driven and imaging confirmed) at 6 months
was 6.1% (2/33 limbs) for DEB and 23.6% (9/38

limbs) for AB (p0.02). Binary restenosis was

9.1% (3/33 limbs) in the DEB group and 28.9%
(11/38 limbs) in the control group (p0.03).
Amputation rates were 3.0% (1/33 limbs;
major amputation in a patient with Fontaine
stage IV) in the DEB arm vs. 7.9% [3/38 limbs;
1 major amputation in a Fontaine stage IV
patient and 2 minor amputations (Fontaine
stages III and stage IV, respectively)] in the AB
arm (p0.36). Thrombosis at 48 hours postprocedure occurred in 1 (3.0%) limb in the
DEB arm and in 2 (5.2%) limbs in the AB arm
(p0.6).
Improvement in the ABI (Table 3) was
observed after all procedures but was to a
higher level (p,0.05) in patients treated with
DEB vs. those treated with conventional
balloons (pre/post DEB: 0.55 60.1 and
0.8760.2; pre/post AB: 0.5760.1 and post
0.7060.1). The Fontaine stage increased in
both groups but more significantly (p0.04) in

576

DEB FOR LOWER LIMB MULTILEVEL DISEASES

Fanelli et al.

J ENDOVASC THER
2012;19:571580

^
TABLE 2
Characteristics of All Lesions and by Study Arm

Location
SFA
Popliteal artery
Below the knee
Stenosis, %
Femoropopliteal
Below the knee
Occlusions
Femoropopliteal
Below the knee
Calcified lesions
1
2
3
4
TASC classification
A
B
C
D
Lesion length, cm
,7
715
.15
Reference vessel diameter, mm
Balloons per lesion

All (n122)

DEB (n57)

AB (n65)

88 (72.1%)
4 (3.3%)
30 (24.6%)
8566.4
8464.4
8665.4
26 (21.3%)
14 (11.4%)
12 (9.8%)

42 (73.7%)
2 (3.5%)
13 (22.8%)
8466.2
8364.4
8563.4
12 (21.0%)
5 (8.7%)
7 (12.2%)

46 (70.8%)
2 (3.1%)
17 (26.1%)
8766.7
8666.7
8865.4
14 (21.5%)
9 (13.8%)
5 (7.6%)

0.70
0.89
0.67
0.70
0.70
0.60
0.94
0.64
1.00

19
49
32
22

11
20
12
14

(19.3%)
(35.1%)
(21.1%)
(24.5%)

8 (12.3%)
29 (44.6%)
20 (30.7%)
8 (12.3%)

0.19
0.29
0.22
0.08

11 (19.3%)
21 (36.8%)
18 (31.6%)
7 (12.3%)
7.660.6
17 (29.8%)
31 (54.4%)
9 (15.8%)
4.060.9
1.560.5

12 (18.5%)
24 (36.9%)
23 (35.4%)
6 (9.2%)
7.860.7
21 (32.3%)
32 (49.2%)
12 (18.5%)
3.960.8
1.060.0

0.71
0.77
0.77
0.61
0.10
0.20
0.19
0.70
0.50
0.06

(15.5%)
(40.1%)
(26.2%)
(18.1%)

23 (18.9%)
45 (36.9%)
41 (33.6%)
13 (10.6%)
7.563.5
38 (31.2%)
63 (51.6%)
21 (17.2%)
3.961.0
2.560.5

^
Continuous data are presented as the means6standard deviation; categorical data are given as the counts
(percentage).
AB: balloon angioplasty, DEB: drug-eluting balloon, SFA: superficial femoral artery, TASC: TransAtlantic InterSociety Consensus.

patients treated with DEB [Fontaine stage I:

22/25 (88%) vs. 16/25 (64%) in the control
group].
Patients who received treatment with DEB
alone (without stents) were analyzed to correlate results with the amount of calcium on
the arterial wall (Table 4) estimated from CTA
axial images and stratified into 4 categories
(grade 4 represented the highest calcium
burden). Late lumen loss was 0.4960.2 mm
in grade 1 patients, 0.6360.3 mm in grade 2,
0.760.2 mm in grade 3, and 0.7560.2 mm in
grade 4. TLR was more frequent in patients
with grades 3 (1 case) and 4 (1 case)
calcification; the previously mentioned thrombotic event occurred in a patient with significant (grade 4) calcification, as did the only
major amputation.

DISCUSSION
Studies of early DEB technology (Paccocath)
in the SFA were followed by trials that
confirmed the role of DEB in both SFA and
BTK districts.2,4,8,19 The DEBELLUM trial was
intended to investigate the efficacy of DEB in
reducing restenosis (rates and entity) after
treatment of lower limb disease in both
claudicants and patients with CLI. Different
from previous studies, which focused on SFA
or BTK vascular beds alone, the DEBELLUM
trial addressed lower limb arterial disease as
it presents in clinical practice, thus including
multilevel treatment of SFA and/or BTK
lesions as clinically indicated. Moreover, the
effect of DEB as standalone therapy vs. a
combination of stentDEB was also explored,
but limited to SFA lesions.

J ENDOVASC THER
2012;19;571580

Figure 2 ^ (A) Angiography shows multiple severe

stenoses in the left SFA of a 67-year-old man with
diabetes, hypertension, and severe left limb claudication (,50 m). (B) After primary stenting (6360mm Maris; Medtronic) of the diseased segment,
postdilation was performed using a conventional
angioplasty balloon (Admiral 5360 mm). (C) The
final angiogram shows good flow within the stent.
(D) Ultrasound at 6 months shows the presence of
consistent intimal hyperplasia within the inner
lumen of the stent (1.6 mm).

The trial results showed a consistently

lower late lumen loss with DEB in both the
SFA and BTK territories. Moreover, these
good results were also observed in the SFA
when DEB was employed either without
stents or for postdilation after primary stenting. This angiographic outcome at 6 months
was associated with an improvement in
hemodynamic and clinical endpoints.

DEB FOR LOWER LIMB MULTILEVEL DISEASES

Fanelli et al.

577

Figure 3 ^ (A) Angiography confirms a 5-cm-long

SFA obstruction and shows a large collateral vessel
perfusing the distal tract in a 63-year-old man with
hypertension, diabetes, and severe left limb claudication. After recanalization, a stent (6360-mm
Maris; Medtronic) is positioned. (B) Postdilation
was performed with a DEB balloon (5360-mm
IMPACT Admiral) inflated for 60 seconds. (C)
Control angiography shows the artery completely
patent. The patients clinical condition soon improved, with the ABI increased to 0.9. (D) Ultrasound at 6 months shows complete patency of the
stent with minimal intimal hyperplasia (0.5 mm).

Several trials have compared paclitaxelcoated balloons with conventional uncoated

balloon catheters to investigate how the
restenosis rate in peripheral vascular diseases
can be reduced. In the Thunder trial,2 154
patients with stenosis or occlusions of the
SFA or PA were enrolled, including a third
treatment arm with paclitaxel dissolved in the
contrast medium. At 6-month follow-up, treatment of patients with Paccocath balloons
significantly reduced late lumen loss compared to patients treated with an uncoated
balloon or to patients treated with paclitaxel
dissolved in the contrast medium. The TLR
rate at 6, 12, and 24 months post intervention

578

DEB FOR LOWER LIMB MULTILEVEL DISEASES

Fanelli et al.

J ENDOVASC THER
2012;19:571580

^
TABLE 3
Results at 6 Months in 50 Patients With 122 Treated Lesions
DEB (patients/limbs)
Overall
(25/33)

Minimum lumen diameter, mm 4.2261.1

Femoropopliteal
5.1160.5
Below the knee
2.4160.1
Late lumen loss, mm
0.5061.4
Femoropopliteal
0.4160.5
Below the knee
0.6260.9
ABI
0.8760.2
Fontaine class
I
22 (88%)
IIa
1 (4%)
IIb
1 (4%)
III
1 (4%)
Death
0
TLR, per limb
2 (6%)
Amputation, per limb
1 (3%)
Thrombosis, per limb
1 (3%)
4 (16%)
Aggregate MAEs

AB (patients/limbs)

DEB Only StentDEB

(13/21)
(12/12)

p*

Overall
(25/38)

AB
(15/24)

ABStent
(10/14)

p*

3.1261.2
3.6160.3
1.5160.1
1.6061.7
1.5561.3
1.6561.5
0.7060.1

2.4160.7
3.3160.2
1.5160.1
1.5060.6
1.5461.1
1.6561.5
0.6860.4

3.8160.4
3.8160.4

1.7060.2
1.7060.2

0.7560.3

0.045
0.7

0.8
0.7

0.04

,0.05
,0.05
,0.05
,0.01
,0.05
,0.05
0.02

3.4260.9
5.1160.2
2.4160.1
0.5060.9
0.3860.4
0.6260.9
0.8860.2

5.2260.6
5.2260.6

0.5160.7
0.5160.7

0.8260.7

0.05
0.9

0.5
0.9

0.25

12
1
0
0

10
0
1
1

0.34 16 (64%) 10 (67%)

0.4
3 (12%) 2 (13%)
0.4
2 (8%)
1 (7%)
0.4
4 (16%) 2 (13%)

0
0
0.34 9 (24%) 6 (25%)
0.3
3 (8%)
2 (8%)
1
2 (5%)
1 (4%)
0.27 14 (56%) 9 (60%)

1
1
0
2

(92%)
(8%)
(0%)
(0%)
0
(5%)
(5%)
(0%)
(15%)

1
0
1
2

(83%)
(0%)
(8%)
(8%)
0
(8%)
(0%)
(8%)
(17%)

6
1
1
2
3
1
1
5

(60%)
(10%)
(10%)
(20%)
0
(21%)
(7%)
(7%)
(50%)

0.2
0.4
0.5
0.5

0.4
0.1
0.5
0.37

0.04
0.10
0.30
0.40

0.02
0.36
0.60
0.008

^
Data are presented as the means6standard deviation.
AB: balloon angioplasty, ABI: ankle-brachial index, DEB: drug-eluting balloon, MAEs: major adverse events, TLR:
target lesion revascularization.
* No stent vs. stent.
Overall DEB vs. overall AB.

remained significantly lower in the Paccocath

group compared with the other 2 groups.
In the FemPac trial,4 87 patients were
randomly assigned to treatment either with
standard balloon angioplasty or with the
Paccocath balloon. At 6-month follow-up,
patients treated with the Paccocath balloon
had significantly reduced late lumen loss
compared with the control group. The number
of target lesion revascularizations was significantly lower in the Paccocath group than in
control group subjects, and the difference
between both treatment groups was maintained 18 to 24 months after intervention. In
addition, patients in the coated-balloon group
showed improvement in Rutherford class,
whereas no improvement was observed in
the ABI.
The Levant I trial was a randomized 2-arm
study comparing the Moxy drug-coated balloon vs. standard balloon angioplasty for the
treatment of stenosis in the femoropopliteal
arteries of 101 patients. The primary endpoint,
late lumen loss at 6 months, was significantly

reduced to 0.46 from 1.09 mm in the Moxy

group.20 In the DEB Italian Registry, Micari et
al.19 reported an 83.7% primary patency rate
at 1 year with a low (12.3%) stent rate in 105
patients treated for claudication and pain at
rest. These results were associated with a
significant improvement in ABI, walking capacity, and quality of life at 12 months. In
sum, the 0.5-mm late lumen loss at 6 months
in the treatment arm of the DEBELLUM trial
was very similar to the data reported by these
other trials (Thunder2 0.40 mm, FemPac4 0.50
mm, Levant I20 0.46 mm, and Pacifier21 0.01
mm). Moreover, all studies confirmed that
exposure of the target lesion to paclitaxel
inhibits restenosis.12
The use of DEB can also be advantageous in
infrapopliteal vessels as initially investigated
by Schmidt et al.,8 who reported a 3-month
angiographic restenosis rate of 27% in long
BTK lesions and occlusions, an appreciable
difference vs. the results obtained from a
historical cohort22 of similar patients treated
with standard angioplasty (restenosis rate

J ENDOVASC THER
2012;19;571580

DEB FOR LOWER LIMB MULTILEVEL DISEASES

Fanelli et al.

^
TABLE 4
Analysis of Lesion Calcium Burden in Patients
Treated With Drug-Eluting Balloons
Calcium Grade*

Number of patients
Late lumen loss, mm
Target lesion
revascularization
Thrombosis, per limb
Amputation, per limb

12

34

14
0.4960.12
0

11
0.7360.27
2

0.41
0.03
0.35

0
0

1
1

0.30
0.30

^
Continuous data are presented as the mean6standard deviation; categorical data are given as the
counts.
* Estimated from axial CTA images and defined as
grade 1 (458), grade 2 (908), grade 3 (1358), or
grade 4 (circumferential).

69% at 3 months). Our trial also comes to the

conclusion that DEB in the BTK area can help
achieve a successful outcome. In fact, if we
look at the 30 lesions (13 DEB, 17 AB) in the
BTK vessels, amputation was necessary at 6
months in only 1 DEB patient but 2 from the
AB group. Late lumen loss was also significantly lower (p,0.01).
As observed in DEBELLUM and in other
trials, the advantage of DEB for the treatment
of lower limb arterial disease lies in achieving
low restenosis rates with very limited or no
need to implant a foreign body. This is
particularly important for some critical vessel
districts in which the high mechanical stress
can lead to stent fractures (femoropopliteal)
and for extensively diseased small vessels
with slow blood flow (BTK). In addition, a nonstent strategy can leave the door open to
future treatment options, especially in case of
claudicants with a long life expectancy. While
long-term results of DEB trials are awaited to
confirm such hypotheses, we consider it
reasonable and advisable to avoid any chronic stress to the vessel like the one exerted by
the stents radial force. Such a guideline is a
potential advantage to maintaining patency
beyond 1 year. Last but not least, we have
shown that dual antiplatelet therapy limited to
4 weeks is effective.
We used DEB also for postdilation after
primary stenting in the SFA. Despite the
limited number of patients, results were quite

579

interesting because DEB proved to be effective under any circumstance, with a 6-month
late lumen loss two thirds lower than using
conventional non-coated balloons. Similar
results were reported in the Levant I trial that
studied Moxy balloon efficacy in case of poststent dilation; no differences were noticed in
DEB when employed as a standalone therapy
vs. postdilation after primary stenting.20
Our subanalysis of calcified lesions signaled a higher late lumen loss with increased
calcium (grades 3 and 4), which may confirm
the hypothesis that severe calcification behaves as a barrier to optimal drug absorption.
In that case, the potential role of debulking
prior to DEB may be justified and should be
further investigated in specific trials.

Limitations
This study involved a small sample size
which, although sufficient to detect differences in the primary endpoint of late lumen loss,
did not support any real conclusion in reference to other clinically important secondary
endpoints.

Conclusion
The DEBELLUM trial demonstrated and
confirmed the ability of paclitaxel-eluting
balloons to reduce restenosis vs. conventional
balloons at 6 months after treatment of
multilevel (femoropopliteal and BTK) arterial
disease in patients affected by claudication
and CLI. A lower TLR rate and better clinical
outcomes appear to be associated with the
use of DEBs regardless of stent placement.
Further studies including a larger number of
patients are expected to corroborate these
results.

REFERENCES
1. Norgren L, Hiatt WR, Dormandy JA, et al. InterSociety Consensus for the Management of
Peripheral Arterial Disease (TASC II). Eur J
Vasc Endovasc Surg. 2007;33 Suppl 1:S175.
2. Tepe G, Zeller T, Albrecht T, et al. Local delivery
of paclitaxel to inhibit restenosis during angioplasty of the leg. N Engl J Med. 2008;358:689
699.

580

DEB FOR LOWER LIMB MULTILEVEL DISEASES

Fanelli et al.

3. Dake MD, Scheinert D, Tepe G, et al.; Zilver PTX

Single-Arm Study Investigators. Nitinol stents
with polymer-free paclitaxel coating for lesions
in the superficial femoral and popliteal arteries
above the knee: twelve-month safety and
effectiveness results from the Zilver PTX single-arm clinical study. J Endovasc Ther. 2011;
18:613623.
4. Werk M, Langner S, Reinkensmeier B, et al.
Inhibition of restenosis in femoropopliteal
arteries: paclitaxel-coated versus uncoated balloon: femoral paclitaxel randomized pilot trial.
Circulation. 2008;118:13581365.
5. Scheller B. Opportunities and limitations of
drug-coated balloons in interventional therapies. Herz. 2011;36:232239.
6. Chan YC, Cheng SW. Drug-eluting stents and
balloons in peripheral arterial disease: evidence so far. Int J Clin Pract. 2011;65:664668.
7. Dake MD, Ansel GM, Jaff MR, et al. Paclitaxeleluting stents show superiority to balloon
angioplasty and bare metal stents in femoropopliteal disease: twelve-month Zilver PTX
randomized study results. Circ Cardiovasc
Interv. 2011;4:495504.
8. Schmidt A, Piorkowski M, Werner M, et al. First
experience with drug-eluting balloons in infrapopliteal arteries: restenosis rate and clinical
outcome. J Am Coll Cardiol. 2011;58:1105
1109.
9. Feiring AJ, Krahn M, Nelson L, et al. Preventing
leg amputations in critical limb ischemia with
below-the-knee drug-eluting stents: the PaRADISE (PReventing Amputations using Drug
eluting StEnts) trial. J Am Coll Cardiol. 2010;
55:15801589.
10. Balzer JO, Zeller T, Rastan A, et al. Percutaneous interventions below the knee in patients
with critical limb ischemia using drug eluting
stents. J Cardiovasc Surg (Torino). 2010;51:
183191.

11. Rastan A, Schwarzwalder

U, Noory E, et al.
Primary use of sirolimus-eluting stents in the
infrapopliteal arteries. J Endovasc Ther. 2010;
17:480487.
12. Diehm NA, Hoppe H, Do DD. Drug eluting
balloons. Tech Vasc Interv Radiol. 2010;13:59
63.
13. Bosiers M, Scheinert D, Peeters P, et al.
Randomized comparison of everolimus-eluting

J ENDOVASC THER
2012;19:571580

14.

15.

16.

17.

18.

19.

20.

21.

22.

versus bare-metal stents in patients with

critical limb ischemia and infrapopliteal arterial
occlusive disease. J Vasc Surg. 2012;55:390
398.
Mauri L, Orav EJ, Candia SC, et al. Robustness
of late lumen loss in discriminating drugeluting stents across variable observational
and randomized trials. Circulation. 2005;112:
28332939.
Baumann F, Willenberg T, Do DD, et al.
Endovascular revascularization of below-theknee arteries: prospective short-term angiographic and clinical follow-up. J Vasc Interv
Radiol. 2011;22:16651673.
Sharma S, Kukreja N, Christopoulos C, et al.
Drug-eluting balloon: new tool in the box.
Expert Rev Med Devices. 2010;7:381388.
Cremers B, Speck U, Kaufels N, et al. Drugeluting balloon: very short-term exposure and
overlapping. Thromb Haemost. 2009;101:201
206.
Scheller B, Speck U, Abramjuk C, et al.
Paclitaxel balloon coating, a novel method for
prevention and therapy of restenosis. Circulation. 2004;110:810814.
Micari A, Cioppa A, MD, Vadala` G, et al. Clinical
evaluation of a paclitaxel-eluting balloon for
treatment of femoropopliteal arterial disease.
12-month results from a multicenter Italian
Registry. JACC Cardiovasc Interv. 2012;5:331
338.
Zeller T, Schmitmeier S, Tepe G, et al. Drugcoated balloons in the lower limb. J Cardiovasc
Surg (Torino). 2011;52:235243.
Werk M, Albrecht T, Meyer DR, et al. The
PACIFIER trial: a randomized multicenter trial
evaluating prevention of restenosis with paclitaxel-coated PTA balloon catheters in stenosis
or occlusion of femoropopliteal arteries. Presented at LINC 2012 held in Leipzig, Germany,
January 2528, 2012. Available at: http://www.
leipzig-interventional-course.com/index.php?
optioncom_docman&taskdoc_download&
gid1053. Last accessed June 6, 2012.
Schmidt A, Ulrich M, Winkler B, et al. Angiographic patency and clinical outcome after
balloon-angioplasty for extensive infrapopliteal
arterial disease. Catheter Cardiovasc Interv.
2010;76:10471054.