848609

research-article2019
JVA0010.1177/1129729819848609The Journal of Vascular AccessTozzi et al.

Original Research Article

JVA The Journal of
Vascular Access

The Journal of Vascular Access

Drug-coated balloon angioplasty in

1­–7
© The Author(s) 2019
Article reuse guidelines:
failing haemodialysis arteriovenous shunts: sagepub.com/journals-permissions
https://doi.org/10.1177/1129729819848609
DOI: 10.1177/1129729819848609

12-month outcomes in 200 patients journals.sagepub.com/home/jva

from the Aperto Italian registry

Matteo Tozzi1, Marco Franchin1, Daniele Savio2,

Simone Comelli2, Luca Di Maggio2, Luciano Carbonari3,
Reza Ebrahimi3, Federico Fontana4, Filippo Piacentino4,
Maria Cristina Cervarolo1, Vincenzo Palermo1 and Gabriele Piffaretti1

Abstract
Background: We evaluated the safety and technical and clinical outcomes of angioplasty with a drug-coated balloon for
the management of venous stenosis in arteriovenous grafts and arteriovenous fistulas in patients undergoing haemodialysis.
Methods: Data were obtained from an ongoing prospective, non-randomised registry conducted at three Italian
centres. Patients were treated with a drug-coated balloon according to standard procedures in each participating centre.
Evaluation was by colour Doppler imaging every 3 months. The primary end-point was primary assisted patency. The
secondary end-point was the rate of assisted patency of the vascular access.
Results: A total of 311 angioplasty procedures in 200 patients, (60.4% male), were analysed. The procedural success
rate was 100%. A total of 192 treatments of restenosis were necessary in 81 patients during average 21 ± 8 months
follow-up. Kaplan–Meier estimates indicated that 88.0%, 64.2% and 40.6% of treated lesions were free from restenosis
at 6, 12 and 24 months, respectively. Including multiple angioplasty, circuit patency rates were 99.2%, 92.5% and 84.8%
at 6, 12 and 24 months, respectively. Primary patency rates were highest in shunts treated de novo with drug-coated
balloons. Risk of restenosis was associated with circuit age (p = 0.017), history of treatment with conventional angioplasty
(p < 0.001) and the kind of balloon used during pre-dilation (p = 0.001).
Conclusion: The results suggest that favourable long-term patency rates can be achieved with the drug-coated balloon
in a varied population of patients with failing haemodialysis arteriovenous shunts treated under conditions of actual care.

Keywords
Drug-coated balloon angioplasty, arteriovenous graft, arteriovenous fistulas, neointimal hyperplasia

Date received: 27 February 2018; accepted: 31 March 2019

Introduction
1Vascular Surgery Unit, Department of Medicine and Surgery, Circolo
Reliable vascular access is essential to haemodialysis. University Teaching Hospital, University of Insubria, Varese, Italy
Impaired vascular access is associated with substantial 2Interventional Radiology-Neuroradiology Department, SG Bosco

morbidity and mortality in haemodialysis patients, and the
need for durable interventions with low restenosis rates
has long been recognised.1 A major obstacle to achieve this
goal is the limited patency of both native arteriovenous fis-
tulas (AVFs) and synthetic arteriovenous grafts (AVGs).
The 2006 Kidney Disease Outcomes Quality Initiative
(NFK-KDOQI)’s guidelines for vascular access expressed
a ‘reasonable goal’ of 50% primary patency at 6 months,
Hospital, Turin, Italy
3Vascular Surgery, Riuniti Hospitals, Ancona, Italy
4Department of Radiology, Circolo University Teaching Hospital,
University of Insubria, Varese, Italy
Corresponding author:
Matteo Tozzi, Vascular Surgery Unit, Department of Medicine and
Surgery, Circolo University Teaching Hospital, University of Insubria,
Via Guicciardini 9, 21100 Varese, Italy.
Email: matteo.tozzi@uninsubria.it
2 The Journal of Vascular Access 00(0)
which in its modesty recognised the difficulties with long-
term restenosis.2 More than a decade later, the need for
effective long-term interventions remains.
Balloon angioplasty has long been the standard percuta-
neous treatment of neointimal hyperplasia stenosis. The
procedure is rapid and easy to perform, but conventional
angioplasty balloons are often inadequate for the treatment
of haemodialysis access stenosis, particularly in native fis-
tulas.3 Blood flow is improved by the intraluminal expan-
sion of the balloon, a process that fractures the neointimal
tissue and increases the risk for venous neointimal hyper-
plasia (the healing response to the trauma of endovascular
intervention) leading to aggressive restenotic lesions after
angioplasty. This risk is well recognised at the arterio-
venous (AV) graft-venous anastomosis and in mature fis-
tulas with stenoses.4–6 New devices such as high-pressure
balloons and scoring balloons have demonstrated a poten-
tial for improved outcomes compared with conventional
angioplasty, but short-term restenosis rates with these
devices are still relatively high.
Drug-coated balloons (DCBs) are emerging as an alter-
native intervention. By delivering anti-proliferative agents
such as paclitaxel directly to the lesion, DCBs inhibit neoin-
tima formation locally, reducing intimal hyperplasia and the
risk of stenosis in coronary and peripheral vessels. However,
only limited data are available on the effectiveness of DCB
in the treatment of venous stenosis of the vascular access
circuit in patients undergoing haemodialysis.7,8 Published
trial results indicate reasonable patency rates at 6 months,9
but adequate long-term patency rates remain to be demon-
strated conclusively.10 Furthermore, as available DCB differ
in their design, it would be inadvisable to generalise results
from trials with a specific balloon to DCB stents with differ-
ent characteristics.
Aperto™ (Cardionovum, Bonn, Germany) is a drug-
coated high-pressure balloon dedicated to the treatment of
haemodialysis access stenosis and recanalisation of AV
shunt grafts. It features a delayed-delivery coating, incor-
porating nanocrystalline translucent 0.1-μm paclitaxel
particles for improved drug uptake and minimised risk of
micro-embolisation. Ammonium salt is used as as excipi-
ent to increase the resistance to mechanical influence,
minimise drug loss and improve the consistency of drug
delivery to the target lesion site. An initial study with
Aperto (Cardionovum, Bonn, Germany) for the treatment
of failing haemodialysis AV shunts reported high clinical
success rates without major complications, and primary
patency rates of 87.5% for an 8-month follow-up period.8
To obtain long-term data in a large patient population,
the Aperto Italian registry was established in September
2014. A varied population of patients treated with Aperto
in accordance to current European Renal Best Practice
(ERBP) are enrolled and followed prospectively.11,12
The current communication presents procedural and
follow-up data in the cohort of 200 patients for whom
follow-up data at ⩾12 months are available at the time of
writing.
Methods
Aperto registry
The data were obtained from an ongoing prospective, non-
randomised registry conducted at three Italian centres. The
objective of the registry is to evaluate the safety and tech-
nical and clinical outcomes of Aperto DCB angioplasty for
the management of venous stenosis in AVGs and AVFs.
Study population
Both AVF and AVG are treated. In accordance with single-
centre dialysis protocol, patients routinely underwent clin-
ical evaluation and ultrasound examination in order to
detect signs or images of stenosis. The absence of thrill
and pulsatility, increasing bleeding time after needle
removal, swelling or oedema were considered the com-
monest signs of stenosis. Ultrasound examination included
morphological assessment in B-mode, colour Doppler
examination and Doppler ultrasound assessment of the fis-
tula. Evaluation focused on arterial flow and Doppler flow
volume estimation, study of the anastomotic chamber or
graft anastomosis and finally study of the venous outflow.
In addition, haemodynamic data (arterial and vein line
pressure and blood flow rate – QB) were collected. In par-
ticular, attention was given to the trend of pressure of vein
line and arterial line besides the blood flow rate (QB).
Patients are enrolled if they have been treated with the
Aperto balloon for the indications specified in the NFK-
KDOQI 2006 guidelines:2 asymptomatic ⩾50% stenosis,
uncomplicated symptomatic stenosis causing malfunc-
tions of the vascular access, or symptomatic stenosis com-
plicated by thrombosis. The stenoses were classified as
restenosis or de novo. We excluded cases of AVF matura-
tion failure. Young underage patients, complex stenosis
needing for a more extensive surgical revision and non-
acceptance of participating to the study were considered as
the exclusion criteria.
Interventions
All subjects in the registry are treated with the Aperto
DCB according to standard procedures in each partici-
pating centre. Pre-dilatation was always performed, and
the balloon diameter was chosen in accordance to that of
the nearest healthy vessel. Drug-coated balloons 5–7 mm
in diameter were used. The balloon was inflated for 180 s
at 15 atm. Post-operatively, all patients started anticoag-
ulant therapy with enoxaparin sodium 2000 IU once
daily for 7 days after the procedures and antiplatelet
therapy.
Tozzi et al. 3
Follow up and outcomes
Subjects enrolled in the Aperto registry are followed up
prospectively for an indefinite period of time. During fol-
low up, routine assessments are performed on the afore-
mentioned NFK-KDOQI clinical and haemodynamic
criteria. Changes in haemodynamical data trends recorded
during haemodialysis are investigated with ultrasound
examination. Otherwise, a routine evaluation by colour
Doppler imaging is performed in all subjects every
3 months. Every episode of AVF failure is recorded,
assessed and treated at the same centre.
End-points
In this analysis, the primary end-point was primary assisted
patency of the critical restenosis target lesion. The second-
ary end-point was the rate of assisted patency of the vascu-
lar access. In addition, success rates were calculated as
follows: technical success, defined as the achievement of a
lumen diameter of ⩾70% of the nominal diameter by vis-
ual estimate and without bail-out stenting; clinical success,
defined as resumption of ⩾1 session of normal dialysis
after angioplasty; and procedural success, defined as tech-
nical success without the occurrence of major adverse
events (MAEs) during the index hospitalisation/day of
treatment. As MAEs were recorded death, stroke, throm-
botic occlusion, allergic reaction and pulmonary events,
all complications were recorded.
Definition and outcomes criteria were defined as per
the Committee on Reporting 21 Standards of the Society
for Vascular Surgery and the American Association for
Vascular Surgery 22 (SVS/AAVS) on AV accesses.13
Ethical standards
All procedures performed in human participants were in
accordance with the ethical standards of the institutional
and/or national Italian research committee, and with the
1964 Helsinki Declaration and its later amendments.14 All
participants in the study provided informed consent.
Statistical methods
Clinical data were recorded and tabulated in a Microsoft
Excel (Microsoft Corp, Redmond, WA) database.
Statistical analysis was computed with SPSS, version 23.0
for Windows (IBM SPSS Inc, Chicago, IL). Results are
presented as mean ± standard deviation for continuous
variables and as number and percentages for categorical
variables. Between-groups comparisons were performed
with Student’s t-test for continuous variables and chi-
square or Fisher’s exact test for categorical variables.
Kaplan–Meier analysis was used to estimate survival.
Comparison between the survival distributions of cohorts
was done with the Mantel–Cox log-rank test. Univariate
and multivariate analyses were used to identify factors
affecting the primary outcome and the composite end-
point. A p value <0.05 was considered significant.
Results
Patient characteristics
A total of 200 patients, 121 (60.4%) of whom were male,
were treated between December 2014 and January 2018.
Mean age was 68 ± 13 (range: 37–87; interquartile range:
(IQR) 62–77) years. Demographic data and comorbidities
are reported in Table 1. In 124 cases (57.0%) stenosis was
identified on haemodynamic intra-dialysis evidence. The
remaining lesions were documented during routine ultra-
sonographic circuit evaluation (n = 48; 24.0%), or intraop-
eratively by angiography after vascular access thrombectomy
(n = 34; 17.0%).
Autogenous vascular access was involved in 86 cases
(43%) and prosthetic vascular access in 114 cases (57%).
Detailed information about vascular access characteristics
are reported in Table 1. A total of 98 (49%) vascular
accesses were created >1 year before stenosis treatment. A
total of 51 (26%) lesions had been treated with conven-
tional angioplasty within the previous 12 months.
Procedural and safety data
A total of 311 angioplasty procedures were performed. The
procedural success rate was 100%. Pre-dilation was done
using a high-pressure balloon in 115 cases (57.5%), a focal
force balloon in 54 (27.0%) and a cutting balloon in 18 cases
(9.0%). Average in-hospital stay was 16 ± 6 (range: 5–24;
IQR 7–14) h; shorter for patients hospitalised for angiography
(7 ± 3; range: 5–12; IQR 6–9) h and longer in patients treated
during thrombectomy (15 ± 3; range: 9–24; IQR: 12–18) h.
Over the 37 months’ follow-up, a total of 192 treatments
of restenosis were necessary in 81 patients. Most patients
(n = 61; 30.5% of the total population) needed two redo
procedures, with three redos performed in 13 (6.5%), four
in 4 (2.2%) and five in 3 (1.4%) patients. It is notable that
only 24 (12.5%) cases of restenosis occurred within the
first 3 months after angioplasty, potentially associated with
the procedure. Intraoperative complications occurred in 7
(2.3%) cases: four cases of circuit thrombosis, treated with
surgical thrombectomy and three vein ruptures treated
with redo angioplasty (n = 2) or positioning with stent-
graft (n = 1, excluded from further analysis). In no case
was vascular access lost, and no central line placement
was necessary. Other main complication such as haema-
toma, pseudo-aneurysm or infection were not reported.
Follow-up data
No patient was lost during follow up. Mean follow up was
21 ± 8 (range: 2–37) months. Follow-up index was 0.86,
4 The Journal of Vascular Access 00(0)

Table 1.  Population and access characteristics. of restenosis and age of the circuit (p = 0.017), history of
previous treatment with conventional angioplasty
Number of patients 200
(p < 0.001) and the kind of balloon used during pre-dila-
Male, n (%) 121 (60.4) tion (p = 0.001) (Figure 2). The best pre-dilation results
Age, years mean ± SD 68 ± 13 were obtained with focal force balloon and cutting bal-
IQR 62–77 loons. The rate of restenosis with the use of scoring bal-
Risk factors, n (%) loons was 94.9% at 6 months and 84.0% subsequently.
 Hypertension 136 (68) Multivariate analysis confirmed that a history of previous
 Smoking 46 (23) treatment (hazard ratio (HR): 3.86, 95% confidence inter-
 Hypercholesterolaemia 76 (38) val (CI): 1.94–7.72, p < 0.001) and type of balloon used
 IHD 120 (60) during pre-dilation (HR: 0.592, CI: 0.369–0.950, p = 0.030)
Diabetes mellitus, n (%) 68 (34)
were independently associated with increased risk of reste-
BMI > 30, n (%) 32 (16)
nosis. Type of access (prosthetic or autogenous) had no
COPD, n (%) 54 (27)
significant influence on patency rates.
Vascular access 98 (49)
created > 1 year ago, n (%)
Vascular access age 3 ± 2 years (range Discussion
2 months – 8 years)
Dialysis vintage 7 ± 5 years (range The need for improved treatments of impaired vascular
2 months – 38 years) access to reduce morbidity and mortality in patients with
Recurrent stenosis, n (%)a 51 (25.5) AVF or AVG is well recognised. The recent increase of the
De novo stenosis, n (%) 149 (74.5) use of DCBs is driven by the belief that these devices are
Vascular access, n (%) more effective than conventional angioplasty. Randomised
Autogenous, n (%) 86 (43) trials with paclitaxel-coated balloons have shown improved
  Venous outflow 45 (52.3) results compared with uncoated balloons.9,10 These data
 Perianastomotic 48 (47.7) support smaller single-centre experiences and retrospec-
Prosthetic, n (%) 114 (57) tive records.16,17 Nevertheless, Trerotola et al.18 in a recent
  Venous anastomosis 66 (57.8) randomised controlled trial questioned the superiority of
  Venous outflow 33 (29) DCBs over conventional angioplasty in terms of target
 Prosthesis 12 (10.6)
lesion patency at 180  days (DCB: 71.4%  ± 4% vs
  Arterial anastomosis 3 (2.6)
63.5% ± 4%, p = 0.06), recognising fewer interventions to
SD: Standard deviation; IQR: interquartile range; IHD: ischaemic heart maintain patency in DCB group at 6 months. However, as
disease; BMI: body mass index; COPD: chronic obstructive pulmonary noted in a recent review,19 the body of evidence remains
disease. moderate, and more data are needed, particularly from
aTreated at least once in the last year.
real-life situations and with follow-up times that are rele-
vant to actual care. The data presented here, from a large
indicating that follow up was satisfactorily conducted.15 multicentre registry and with follow-up times of
The mortality rate was 7.2%, but no causes of death were >12 months, provide support for the benefits of DCBs as
associated with the treatment. During follow up, 15 vascu- well as some insights into how procedural differences may
lar accesses (7.5%) were abandoned for reasons of multi- influence outcomes.
ple recurrent stenosis and consequent thrombosis (n = 9), The data from the Aperto registry confirm the safety of
aneurysms (n = 4) and vascular access lesion due to wrong DCBs in angioplasty of failing haemodialysis AV shunts in
cannulation (n  = 2). Survival estimates indicated that the largest population to date for which 1 year patency
88.0%, 64.2%, 40.6% and 40.6% of treated lesions were rates are available. Katsanos et al.20 in a recent paper docu-
free from restenosis at 6, 12, 24 and 36 months, respec- mented an increased risk of mortality following applica-
tively (Figure 1(a)). Including multiple angioplasty, circuit tion of paclitaxel-coated balloons in femoropopliteal
patency rates were 99.2%, 92.5%, 84.8% and 84.8% at 6, artery. However, according to our registry, mortality rate
12, 24 and 36 months, respectively (Figure 1(b)). Primary was 7.2%, comparable to that reported in literature2 and
patency rates were higher in shunts treated de novo with causes of death were not associated to the procedure.
DCBs than in older shunts (Figure 2). Rates at 12 months Notably, Fanelli et al. in a recent editorial commented
were 79.1% vs 48.2%, and the difference remained over Katsanos’s paper underlining many critical issues.
the duration of follow up with de novo treated circuits Remarkably, Katsanos considered death from all causes as
maintaining 67.6% patency at 31 months. The univariate primary safety measure ignoring the relationship between
analysis excluded a relationship between demographic the procedure and the event.21 These results are in line with
characteristics or comorbidities and outcome. On the rank other reports. More notably, and importantly for greater
test, a strong statistical association was found between risk use of the therapy, our 1-year patency rates were greater
Tozzi et al. 5
Figure 1.  Kaplan–Meier plots of (a) freedom from restenosis and (b) circuit patency including multiple angioplasty.
Figure 2.  Kaplan–Meier plot of freedom from restenosis in
shunts treated de novo and previously treated with angioplasty,
respectively.
than those reported in most earlier studies. In two well-
designed RCTs in patients with dysfunctional AVFs (n = 40
in each trial), circuit primary patency rates at 6 and
12 months after the procedure were 70%9 and 35%,10
respectively. In the Aperto registry experience, 88% of fis-
tulas were free from restenosis at 6 months and 64% at
12 months, almost twice the rates of the RCTs. Any com-
parison between published data is of course precarious,
given the differences in study design, patient populations,
end points and, not the least, DCB designs.
Coming from a registry, our data are highly relevant to
actual care. In this context, we note that circuit patency
rates at 36 months, including multiple angioplasty were
84.5%. Arguably, such long-term rates are more important
to patients than patency rates after single procedures. It is
also noteworthy that only 10% of our subjects required ⩾3
redo dilations over 36 months. Restenosis is a particularly
acute problem in patients on haemodialysis, who usually
have more complex or calcified lesions, and/or multivessel
disease, than non-haemodialysis patients.22–24 If the long-
term results from the Aperto registry are confirmed by
other studies, there will be a strong case for the use of
DCBs in this patient population.
The multivariate analysis revealed a number of poten-
tial factors associated with risk of stenosis, some of which
were not identified in earlier studies. The greater resteno-
sis risk in subjects with a history of previous conventional
angioplasty is in agreement with the view that the endothe-
lial disruption by angioplasty may promote progress of
stenosis.25 More interesting for clinical practice is the find-
ing of reduced long-term patency from procedures in older
circuits. It has been shown that the mitotic activity of
inflammatory and matrix cells in traumatised vessels
diminishes progressively with time.26,27 Thus, the potential
for restenosis inhibition by paclitaxel may well be greatest
in younger fistulas, as seen in our data set. In the Aperto
registry, 12-month primary patency rates in older circuits
were 48.2% (compared with 79.1% in circuits treated de
novo). The rates in older circuits are within the same mag-
nitude as rates with plain balloon in an early study by
Beathard28 in 1992, who reported 38.2% primary patency
rates at 12 months in 285 patients. A direct comparison is
not possible, and the numbers still indicate benefits from
the DCB, but the observation deserves attention. It would
be interesting to see if similar analyses in subgroups of
lesions treated with DCBs in other indications would sup-
port our findings.
A third consideration highlighted by the multivariate
analysis is the importance of pre-dilation and the choice of
6 The Journal of Vascular Access 00(0)
device. Pre-dilation with scoring or cutting balloons is
thought to facilitate balloon expansion and concentrate the
dilating force, which provides a greater control over lumi-
nal expansion, a lower rate of uncontrolled dissections and
less barotrauma while increasing the exposure to subse-
quent paclitaxel delivery by the DCB.29
An open question is whether the greater 6- and 12-month
patency rates in the Aperto registry than in reported RCTs
are attributable to the device or to other factors. Registries
are often associated with improved outcomes than RCTs,
and all results should be viewed with appropriate caution.
Procedural differences may be important in neither of the
two RCTs, with DCBs pre-dilation performed systemati-
cally10 or at all.9 A class effect is a reasonable assumption,
since all DCBs are based on the same principle that block-
ing neointimal hyperplasia will maintain long-term
patency. The use of micronized paclitaxel particles may
improve outcomes, but given the lack of direct comparator
trials, such hypotheses are devoid of supporting evidence
at present.
The study has limitations. As the data are gathered in a
non-randomised registry, the Aperto population reflects
patients as treated in conditions of actual clinical care, that
is, a heterogeneous population presenting with distal and
proximal lesions and treated with autogenous and pros-
thetic vascular access. The lack of comparator group pre-
cludes any statement on patency rates in this population
using alternative interventions. The low number of pre-
dilation with cutting balloons should be mentioned as a
caveat in the multivariate analysis. A strength of the analy-
sis is the size of the population, the completeness of the
follow-up data and the long follow-up times available.
In summary, the results from the Aperto multicentre
registry suggest that favourable long-term patency rates
can be achieved with the Aperto DCB in a varied popula-
tion of patients with failing haemodialysis AV shunts
treated under conditions of actual care. Further studies on
this intervention would be needed to answer outstanding
questions.
Declaration of conflicting interests
The author(s) declared no potential conflicts of interest with
respect to the research, authorship and/or publication of this
article.
Funding
The author(s) received no financial support for the research,
authorship and/or publication of this article.
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