A systematic review and meta-analysis of the risk of death

and patency after application of paclitaxel-coated balloons

in the hemodialysis access
Xiyang Chen, MD,a Yang Liu, MD,a Jiarong Wang, MD,a Jichun Zhao, MD, PhD,a Niten Singh, MD,b and
Wayne W. Zhang, MD,b Sichuan, China; and Seattle, Wash

ABSTRACT
Objective: The comparison between paclitaxel-coated balloon (PCB) angioplasty and plain balloon angioplasty (PBA) for
hemodialysis (HD) access stenosis or occlusion has not been well investigated. The objectives of this systematic review
and meta-analysis were to compare all-cause mortality, HD access primary patency, and circuit primary patency after
endovascular maintenance procedures using PCB angioplasty vs PBA.
Methods: MEDLINE, Embase, and Cochrane Databases were systematically searched to identify all the relevant studies on
paclitaxel-coated devices for stenosis or thrombosis of HD access. A random effects model was applied to pool the effect
measures. Dichotomous data were presented using an odds ratio (OR). Effect data were presented using pooled hazard
ratio (HR) with 95% confidence interval (CI).
Results: A total of 16 studies were included in this meta-analysis, 12 randomized controlled trials and 4 cohort studies
involving 1086 patients who underwent endovascular treatment for HD access stenosis or occlusion. All-cause mor-
tality rates at 6, 12, and 24 months after intervention were similar between the PCB and PBA groups (6 months: OR, 1.06
[95% CI, 0.38-2.96; P ¼ .907; I2 ¼ 19.2%]; 12 months: OR, 1.20 [95% CI, 0.66-2.16; P ¼ .554; I2 ¼ 0%]; 24 months: OR, 1.43
[95% CI, 0.83-2.45; P ¼ .195; I2 ¼ 0%]). There was a significant improvement of primary patency in the PCB group
compared with the PBA group (HR, 0.47; 95% CI, 0.33-0.69; P < .001; I2 ¼ 67.3%). This benefit was consistent with the
analysis of randomized controlled trials, whereas cohort studies were excluded. Further subgroup analysis of target
lesions demonstrated that primary patency was significantly higher in the PCB group than in the PBA group, not only
for arteriovenous fistula (HR, 0.54; 95% CI, 0.30-0.98; P ¼ .041; I2 ¼ 76.8%) but also for central venous stenosis (HR, 0.39;
95% CI, 0.22-0.71; P ¼ .002; I2 ¼ 0%). The PCB group was associated with higher 6-month (OR, 0.40; 95% CI, 0.27-0.59;
P < .001) and 24-month lesion primary patency (OR, 0.28; 95% CI, 0.11-0.72; P ¼ .009) than PBA and was marginally
associated with 12-month lesion primary patency (OR, 0.52; 95% CI, 0.26-1.03; P ¼ .06). Circuit primary patency analysis
showed a marginal trend toward better outcome in the PCB group (HR, 0.63; 95% CI, 0.40-1.00) but no statistical
significance (P ¼ .052).
Conclusions: This systematic review and meta-analysis demonstrated that PCB angioplasty is associated with signifi-
cantly improved primary patency of arteriovenous fistula and central venous stenosis for HD access maintenance, with no
evidence of increasing all-cause mortality based on short-term and midterm follow-up. Further large cohort study is
needed to investigate long-term mortality. (J Vasc Surg 2020;72:2186-96.)
Keywords: Paclitaxel-coated balloon; Plain balloon angioplasty; Hemodialysis access; Meta-analysis

Endovascular procedures including percutaneous
transluminal angioplasty (PTA) and stenting have
become the mainstream treatment of peripheral artery
From the Department of Vascular Surgery, West China Hospital of Sichuan Uni-
versity, Chengdu, Sichuana; and the Division of Vascular and Endovascular
Surgery, Department of Surgery, University of Washington and Puget Sound
VA Health Care System, Seattle.b
Author conflict of interest: none.
Additional material for this article may be found online at www.jvascsurg.org.
Correspondence: Wayne W. Zhang, MD, FACS, Professor of Vascular and Endo-
vascular Surgery, University of Washington, 1660 S Columbian Way, S-112-PVS,
Seattle, WA 98018 (e-mail: wwzhang@uw.edu).
The editors and reviewers of this article have no relevant financial relationships to
disclose per the JVS policy that requires reviewers to decline review of any
manuscript for which they may have a conflict of interest.
0741-5214
Published by Elsevier Inc. on behalf of the Society for Vascular Surgery.
https://doi.org/10.1016/j.jvs.2020.04.525
disease (PAD), vein disease, and hemodialysis (HD)
access. In PAD, paclitaxel-eluting stents (PESs) and
paclitaxel-coated balloons (PCBs) have been widely
proven to improve the results of restenosis and freedom
from reintervention after the index procedure.1,2 The
correlation between paclitaxel-coated devices and mor-
tality in femoropopliteal artery disease treatment re-
mains controversial. In HD access, balloon angioplasty is
recommended for primary treatment of inflow arterial
and venous outflow stenosis of any type of vascular ac-
cess by the Kidney Disease Outcomes Quality Initiative
guidelines and the European Society for Vascular Surgery
clinical practice guideline for vascular access,3,4 despite
relatively low primary patency rates at 1 year ranging
between 26% and 62%.5,6 In the past several years, PCB
angioplasty has been extensively employed to improve
the patency of HD access in patients. It has been

2186
Journal of Vascular Surgery
Volume 72, Number 6
documented that PCB angioplasty is a promising strat-
egy for the inhibition of neointimal hyperplasia, which
is the primary cause of HD access stenosis.7 Updated
research including several randomized controlled trials
(RCTs) revealed similar clinical outcomes of PCB use in
HD access compared with PAD treated with PCB, which
showed significant improvement in patency of HD ac-
cess at 3, 6, and 12 months, but no significant benefit
was identified for central venous stenosis (CVS).8-10
The issue of longer term safety of paclitaxel-coated de-
vices in the treatment of femoropopliteal artery occlusive
disease was first raised by a meta-analysis11 that revealed
a possible association between paclitaxel-coated devices
and increased mortality for the treatment of femoropo-
pliteal artery disease. In addition, the authors reported
a significant relationship between exposure to paclitaxel
(dose-time product) and absolute risk of death. However,
another study did not show the possible relationship be-
tween paclitaxel-coated devices and all-cause mortal-
ity.12 Paclitaxel-coated devices have been extensively
used in patients with venous diseases, including HD ac-
cess maintenance. Previous investigation demonstrated
favorable safety and efficacy results of PCB angioplasty
in the management of dysfunctional HD access.9,13,14
However, the promising results of PCB use in HD access
patients were mainly focused on long-term patency
and freedom from reintervention. The short- and long-
term mortality after PCB angioplasty has not been well
documented. In addition, the difference of mortality be-
tween PAD and HD access stenosis after PCB treatment
has not been compared. We conducted a systematic re-
view and quantitative meta-analysis of paclitaxel-coated
devices in HD access maintenance to analyze the risk of
death associated with paclitaxel and the patency of HD
access in patients with end-stage renal disease (ESRD).
METHODS
This systematic review and meta-analysis was
performed according to the Cochrane Handbook for
Systematic Reviews of Interventions (version 5.2.0) and
the Preferred Reporting Items for Systematic Reviews
and Meta-Analyses statement.15
Search strategy. A literature search was conducted
using MEDLINE, Embase, and Cochrane Library for all
relevant studies published in English. The following
terms were used in different combinations with the op-
erators AND and OR: “Fistula,” “Venous Thrombosis,”
“Postthrombotic Syndrome,” “Drug-Eluting Stents,”
“Angioplasty, Balloon” (Medical Subject Headings),
“Venous Thrombos*s,” “Vein Thrombos*s,” “Vein Compres-
sion,” “Venous Compression,” “paclitaxel-eluting balloons,”
“paclitaxel-coated balloons,” “paclitaxel-eluting stents,”
“paclitaxel-coated stents,” “paclitaxel-eluting stents,”
“drug-coated balloons,” and “drug-eluting stents.” Filters
were used to restrict the search to human studies only
Chen et al 2187
and to articles in English, and some potentially related
publications listed in the references were retrieved by a
computer-aided manual search. The literature search
was last updated in April 2019.
Selection criteria. Review articles, case reports, and
editorial comments were excluded. Studies with dupli-
cate data were excluded as well. All retrospective, pro-
spective, and observational studies were included. All
abstracts were reviewed for a first selection of the eligible
studies. Trials were considered for inclusion if they ful-
filled the following inclusion criteria: investigation of
PCB or PES vs plain balloon angioplasty (PBA) in the
HD access (arteriovenous fistula [AVF], arteriovenous
graft [AVG], or CVS); population of patients with ESRD
needing long-term HD; clinical follow-up of at least
6 months available; and studies having sufficient data to
pool the effect estimate. Comparative studies that
compared target lesion interventions with previous in-
terventions on the same target lesion as a control were
excluded. Studies with a sample size of fewer than 10
patients were excluded as well. The flow chart for this
work is presented in Fig 1.
Quality assessment. Two review authors evaluated the
risk of bias of each included study independently.
Discrepancies were resolved by consensus. The
Newcastle-Ottawa Scale (www.ohri.ca/programs/clinical_
epidemiology/oxford.asp) for cohort studies was adopted
for assessing the quality of the included nonrandomized
studies. This scale developed a star system ranging from
0 to 9 stars that covers three broad perspectives: selection
of cohorts, comparability of groups, and adequacy of
outcome assessment and reporting. The Cochrane
Collaboration tool for RCTs was adopted for assessing risk
of bias, which evaluates seven key design items of an RCT:
random sequence generation, allocation concealment,
blinding of participants and personnel, blinding of
outcome assessment, incomplete outcome data, selective
outcome reporting, and other potential sources of bias.16
After quality assessment, only cohort studies with low
risk of bias were retained in this meta-analysis.
Data extraction and outcomes of interest. All the avail-
able data were carefully extracted and collected by two
independent reviewers, such as first author, year, study
design, number of patients, mean age, target lesion,
lesion type, paclitaxel dose, PCB intervention, follow-up
period, and outcomes of interest. Outcomes of interest
included mortality in 6 months, mortality in 12 months,
mortality in 24 months, lesion primary patency, and cir-
cuit primary patency. Lesion primary patency is defined
as absence of any repeated intervention at the target
lesion from the index PTA during the follow-up period.
Circuit primary patency is defined as the interval from
the index PTA to the next access intervention anywhere
in the HD access. When the extracted data were
2188 Chen et al
Fig 1. Flow chart of the literature search and selection of
included studies.
insufficient to calculate the effect estimates, we e-mailed
the corresponding authors to obtain the necessary
information.
Statistical analysis. We employed Stata version 15.0
(Stata Corp LLC, College Station, Tex) to conduct all the
statistical analyses in this review. For dichotomous data,
such as mortality and lesion primary patency in 6 months,
12 months, and 24 months, we reconstructed the overall
odds ratios (ORs) with 95% confidence intervals (95% CIs)
using total numbers and event numbers according to
the Mantel-Haenszel method.17 For the effect data, as
for lesion primary patency, we reconstructed the pooled
hazard ratio (HR) with 95% CI using the individual HRs
for lesion primary patency according to the generic
inverse variance method. The individual HRs with 95%
CIs were extracted from the results of original studies or
the Kaplan-Meier survival curve according to the
methods introduced by Tierney et al.18
We applied the c2 test to assess potential heterogeneity
of publications and the random effect model to pool all
the effect measures. We also performed subgroup
analyses according to the HD access type (AVF, AVG, or
CVS) to search for the source of heterogeneity. At the
same time, we adopted the funnel plot symmetry and
Egger linear regression method to explore the presence
of potential publication bias. We used sensitivity analysis
to assess the robustness of overall effect measures by
omitting one study at a time. It was considered statisti-
cally significant if P < .05 in this review.
Journal of Vascular Surgery
December 2020
RESULTS
Study selection and description of included studies. A
total of 1653 records were identified through initial electronic
database search and manual search. After removal of dupli-
cate records and screening of abstracts, 16 candidate studies
fulfilling the selection criteria were analyzed in quality
assessment and included in the final meta-analysis.14,19-33
Twelve studies were RCTs,14,20-22,24-26,29-33 three studies
were retrospective investigations,19,27,28 and one study was a
prospective cohort.23 Most of studies focused on the target
lesions of AVF and AVG, and some studies paid attention to
CVS. The paclitaxel doses of the PCB for all 16 studies were
2.0 mg/mm2, 3.0 mg/mm2, and 3.5 mg/mm2. A flow chart of
the literature search and selection is presented in Fig 1, and
the main characteristics of the included studies are listed in
Table I. The results of the Cochrane Collaboration tool for
assessing risk of bias are shown in Supplementary Table I
(online only), and the results of the Newcastle-Ottawa
Scale are shown in Supplementary Table II (online only).
Mortality. A total of seven studies reported mortality
within 6 months.20-22,26,29,30,32 Thirteen of the 282 (4.6%)
patients treated with PCB died compared with 13 of the
283 (4.6%) patients in the PBA group. Three of the seven
studies documented zero deaths; the pooled result from
the remaining four studies showed no significant differ-
ence of 6-month mortality between the PCB and PBA
groups, with a low level of heterogeneity (OR, 1.06; 95%
CI, 0.38-2.96; P ¼ .907; I2 ¼ 19.2%).20-22,32
Eight studies documented 12-month mortality, with a
total of 680 patients included.20-25,29,30 There were 27
deaths among 338 (8.0%) patients in the PCB group
and 24 of 342 (7.0%) patients in the PBA group. Apart
from two studies with zero deaths at 12 months, the over-
all pooled estimate from the remaining six studies sug-
gested that PCB was not associated with increased 12-
month mortality compared with PBA (OR, 1.20; 95% CI,
0.66-2.16; P ¼ .554). The heterogeneity test showed no
heterogeneity across studies (I2 ¼ 0; P ¼ .702).20-25
Three studies reported 24-month mortality.19,21,23 The
pooled rates of 24-month mortality were 20.5% (38/185)
in the PCB treatment group and 15.4% (29/188) in the
PBA group. The overall pooled OR was 1.43 (95% CI,
0.83-2.45; P ¼ .195), suggesting a trend that PCB angio-
plasty might increase the risk of 24-month mortality
compared with PBA, with a low level of heterogeneity
(I2 ¼ 0%; P ¼ .837; Fig 2; Table II).
Lesion primary patency. Thirteen original studies pre-
sented results of lesion primary patency during follow-
up.14,19-21,23,24,26-31,33 Based on pooled analysis with indi-
vidual HRs, we found that PCB angioplasty was associ-
ated with higher lesion primary patency than PBA (HR,
0.47; 95% CI, 0.33-0.69; P < .001; I2 ¼ 67.3%). To explore
the potential heterogeneity of publications, we con-
ducted a subgroup analysis according to study design.
Journal of Vascular Surgery Chen et al 2189
Volume 72, Number 6

Table I. Characteristics of included cohorts

No. of patients

Author Year Design PCB PBA Age, yearsa Target lesion

19
Haave 2019 Retrospective 14 13 76 vs 64 AVF
Bjorkman20 2019 RCT 18 18 67.0 vs 67.4 AVF
Trerotola 21
2018 RCT 141 144 62.0 6 14 AVF
Swinnen14 2018 RCT 68 60 64.9 6 13.7 AVF
Maleux22 2018 RCT 33 31 68.1 6 15.9 AVF
ev23
Luc 2018 Prospective 31 31 64.9 6 13.6 AVF
Irani 24
2018 RCT 59 60 59.2 6 10.3 AVF, AVG, CVS
Roosen25 2017 RCT 16 18 81.6 AVF
Kitrou26 2017 RCT 20 20 57 CVS
 27
Çildag 2016 Retrospective 26 26 65.8 AVF
Massmann 28
2015 Retrospective 10 15 66 6 13.8 CVS
Kitrou29 2015 RCT 20 20 61 6 14.63 AVF
Kitrou30 2015 RCT 20 20 64 6 14.3 AVF, AVG
Lai31 2014 RCT 10 10 67.2 6 9.4 AVF
32
Teo 2013 RCT 30 30 58.4 AVF
Katsanos33 2012 RCT 20 20 64.1 6 14.3 AVF, AVG
AVF, Arteriovenous fistula; AVG, arteriovenous graft; CVS, central venous stenosis; NA, not available; PBA, plain balloon angioplasty; PCB, paclitaxel-
coated balloon; RCT, randomized controlled trial.
a
Data are expressed as mean or mean 6 standard deviation.
b
Outcome of interest: 1, 6-month mortality; 2, 12-month mortality; 3, 24-month mortality; 4, lesion primary patency; 5, circuit primary patency.

The pooled results from nine RCTs indicated that PCB
angioplasty had a significantly lower risk of target lesion
restenosis (HR, 0.51; 95% CI, 0.31-0.82; P ¼ .005), still with a
high level of heterogeneity (I2 ¼ 76.8%; P < .001), which
could also be seen in retrospective studies (HR, 0.42; 95%
CI, 0.23-0.77; P ¼ .005; I2 ¼ 0). Eight studies focused on
AVF and two on CVS, in which 7- to 14-mm balloons were
used for CVS.26,28 Subgroup analysis suggested that PCB
angioplasty had a better performance in lesion primary
patency compared with PBA not only in AVF (HR, 0.54;
95% CI, 0.30-0.98; P ¼ .041; I2 ¼ 76.8%) but also in CVS
(HR, 0.39; 95% CI, 0.22-0.71; P ¼ .002; I2 ¼ 0%; Fig 3;
Table II). The Egger linear regression showed that there
was no presence of potential publication bias (t ¼ 0.93;
P ¼ .375); however, we noticed that one study deviated
from the axis of symmetry in the funnel plot, which
might have a potential effect on the results of our meta-
analysis. Therefore, we conducted sensitivity analyses by
omitting one study at a time to explore potential
changes in the final outcomes. The results of sensitivity
analysis demonstrated that there were not any changes
in the overall effect measures, which means the results
were robust in our meta-analysis (Fig 4). We also recon-
structed the ORs with 95% CIs for lesion primary patency
in 6 months, 12 months, and 24 months. A total of 13
studies reported the lesion primary patency in
6 months.14,19,21-24,26-31,33 Of the 471 patients treated with
PCB, 126 (26.7%) had loss of lesion primary patency
compared with 222 of the 485 (45.7%) patients in the
PBA group. The overall pooled results revealed that PCB
angioplasty was associated with higher lesion primary
patency than PBA (OR, 0.40; 95% CI, 0.27-0.59; P < .001;
I2 ¼ 31.0%). Eleven studies documented 12-month lesion
primary patency.14,19,20,22-24,26-30 There was loss of lesion
primary patency in 157 of 318 (49.3%) patients in the PCB
group and 199 of 314 (63.3%) patients in the PBA group.
The overall pooled estimate showed that PCB was
marginally associated with increased 12-month lesion
primary patency (OR, 0.52; 95% CI, 0.26-1.03; P ¼ .06; I2 ¼
69.6%). Only two studies reported the 24-month lesion
primary patency. The pooled rates of 24-month lesion
primary patency loss were 52.2% (23/44) in the PCB
treatment group and 79.5% (35/44) in the PBA group. The
overall pooled OR was 0.28 (95% CI, 0.11-0.72; P ¼ .009;
I2 ¼ 0%; Fig 5; Table II).19,23
Circuit primary patency. Analysis of the four studies
that described the circuit primary patency21,24,29,33
showed a marginal trend toward better circuit primary
patency in the PCB group (HR, 0.63; 95% CI, 0.40-1.00);
however, it did not have statistical significance (P ¼ .052).
Because of the limited numbers of studies, we did not
perform any subgroup analyses and sensitivity analyses
(Fig 6; Table II).
2190 Chen et al Journal of Vascular Surgery
December 2020

Table I. Continued.

Lesion type PCB intervention Paclitaxel dose Follow-up, months Outcome of interestb
Recurrent IN.PACT Admiral (Medtronic) 3 mg/mm2 24 3, 4
Primary/recurrent IN.PACT Admiral (Medtronic) 3.5 mg/mm2 12 1, 2, 4, 5
Primary/recurrent Lutonix (Bard) 2 mg/mm2 6 1, 2, 3, 4
Recurrent IN.PACT Admiral (Medtronic) 3 mg/mm2 12 4
Primary/recurrent IN.PACT Admiral (Medtronic) NA 12 1, 2
Primary IN.PACT Admiral (Medtronic) 3 mg/mm2 24 2, 3, 4
Primary/recurrent IN.PACT Admiral (Medtronic) 3 mg/mm2 12 2, 4, 5
Recurrent IN.PACT Admiral (Medtronic) NA 12 2
Primary/recurrent Lutonix (Bard) 2 mg/mm 2
6 1, 4
Primary/recurrent Freeway (Eurocor) NA 12 4
Primary/recurrent Elutax-SV (Aachen Resonance) 2 mg/mm2 18.4 4
NA IN.PACT Admiral (Medtronic) 3 mg/mm2 12 1, 2, 4, 5
Primary/recurrent IN.PACT Admiral (Medtronic) 3 mg/mm2 12 1, 2, 4
Primary/recurrent SeQuent Please (B. Braun) NA 12 4
NA NA NA 6 1, 2
Primary/recurrent IN.PACT Admiral (Medtronic) 3 mg/mm2 6 4, 5

DISCUSSION patency. We extracted the individual HRs with 95% CIs

ESRD has been a major health care issue during the last
40 years and is still rising in incidence.34 HD access is
widely used for renal replacement therapy. AVF is recom-
mended as the best conduit for HD; however, access
dysfunction has been a major cause of morbidity in the
ESRD population.34-36 It is well documented that PTA is
the first choice for treatment of dysfunctional AVFs
despite reported 1-year patency rates lower than
65%.10,13 The major cause of HD access dysfunction is
neointimal hyperplasia, which leads to venous outflow
stenosis. The PCB has been proven to be able to reduce
neointimal hyperplasia significantly in PAD and coronary
artery disease (CAD). Compared with PAD, stenotic le-
sions in AVF are more often manifested as neointimal hy-
perplasia, not calcification.37 Therefore, in theory, clinical
benefit from hyperplasia inhibition by paclitaxel should
be more effective than PBA in the treatment of AVF ste-
nosis.38-40
Our analysis, based on previous studies, showed that
the PCB was associated with a significant improvement
of HD access primary patency at 3, 6, 12, and
24 months.8,38 One publication summarized the pooled
ORs of primary patency after PCB angioplasty and PBA
in treatment of HD access, which revealed a similar result
to ours.8 Nevertheless, that study might bring potential
bias to the conclusion when employing ORs as the out-
comes of meta-analysis because the time of AVF is also
an important prognostic indicator. As we know, HR,
which was related to time, had a better efficacy in assess-
ing time-to-event or effect data, such as lesion primary
from the results of original studies or the Kaplan-Meier
survival curve and reconstructed the pooled HR with
95% CI. We believed that the use of HR would make
the conclusion more convincing.
With respect to the analyses of lesion primary patency,
we noticed the high level of heterogeneity across the
studies. Although we tried to explore the potential het-
erogeneity by performing subgroup analyses to investi-
gate study design and target lesions, the results still
had a high level of heterogeneity. In this systematic re-
view, Bjorkman et al20 suggested that the target lesion
revascularization-free survival after PCB angioplasty was
clearly worse with 1-year follow-up compared with PBA,
which was different from the rest of the studies. After
removal of this study, the pooled estimate presented a
similar result that PCB is associated with a higher lesion
primary patency than PBA (HR, 0.44; 95% CI, 0.35-0.55;
P < .001), with a low level of heterogeneity (I2 ¼ 11.9%;
P ¼ .329). For the 12-month primary lesion patency, the
OR showed that PCB angioplasty is marginally associ-
ated with increased 12-month lesion primary patency,
but there was no statistical significance (P ¼ .06). When
Bjorkman’s study was removed, the result revealed that
PCB angioplasty could improve the 12-month lesion pri-
mary patency (OR, 0.41; 95% CI, 0.26-0.67; P < .001;
Fig 7). Although the reasons for an unfavorable result of
PCB angioplasty in Bjorkman’s study remain unknown,
it was hypothesized that the PCB was harmful to the
young native AVFs because the venous wall may be
more susceptible to the local potential toxic effects of
Journal of Vascular Surgery
Volume 72, Number 6
Fig 2. Forest plot showing the odds ratios (ORs) for all-
cause mortality at 6 months (A), 12 months (B), and
24 months (C). CI, Confidence interval; DCB, drug-coated
balloon; PBA, plain balloon angioplasty.
paclitaxel. It might lead to immediate damage (the sur-
vival plot of PCBs decreased early after intervention).
This hypothesis is also supported by Yildiz,13 whose find-
ings revealed a higher likelihood of postoperative AVF
dysfunction recurrence in patients with younger age
AVF (<6 months), regardless of the angioplasty method.
Since the meta-analysis published in December 2018
identified higher mortality rates in patients with femoro-
popliteal artery disease treated with PCB or PES
compared with PBA,11 the debates on the safety of PCB
and PES have never ceased. Katsanos et al11 revealed
that all-cause mortality at 2 years and up to 5 years was
significantly increased in the group of paclitaxel patients
vs controls. However, Schneider et al12 subsequently per-
formed another independent patient-level study of PCB
angioplasty in direct response to the former one. This in-
dependent patient-level research demonstrated no cor-
relation between level of paclitaxel exposure and
mortality for the treatment of femoropopliteal arterial
disease in IN.PACT global clinical studies. Besides PAD,
Chen et al 2191
safety and efficacy of paclitaxel-coated devices have
been previously discussed in CAD. The TAXUS clinical tri-
als41 demonstrated that cardiac death or myocardial
infarction between 1 year and 5 years was increased in
the PES group (6.7% vs 4.5%; P ¼ .01). Another patient-
level meta-analysis with long-term follow-up identified
no significant difference between PESs and bare-metal
stents in mortality after primary percutaneous coronary
intervention (9.2% vs 11.9%; HR, 0.84; 95% CI, 0.67-1.06;
P ¼ .15; heterogeneity, 0.59).42 However, the safety of
paclitaxel-coated devices for HD access maintenance in
ESRD patients has not been well documented. In
contrast to the findings of PCB in PAD, our study identi-
fied no such association in those ESRD patients undergo-
ing treatment of failing HD access. Individual time point
analysis of 6, 12, and 24 months confirmed that mortality
was similar between PCB and PBA groups.
Although the potential causes of late increased inci-
dence of death remain unknown in both PAD meta-an-
alyses,11,12 the association between payload of paclitaxel
and mortality is the major concern. Katsanos et al11
revealed a significant relationship between exposure to
paclitaxel (dose-time product) and absolute risk of death.
Schneider et al12 performed a survival analysis that strat-
ified the mean level of paclitaxel received by patients
from the PCB by low, mid, and upper terciles (5.0 mg,
10.0 mg, and 20.0 mg, respectively), which identified no
correlation between level of paclitaxel exposure and
mortality.
Paclitaxel is a lipophilic cytotoxic preventing neointimal
hyperplasia by causing cellular apoptosis and inhibition
of vascular smooth muscle cell migration into the in-
tima.43-45 It is commonly used in drug-coated balloons.
Preclinical studies identified that paclitaxel is detected
at 180 days after intervention. The drug level at
180 days could still be in the therapeutic range and pro-
vide biologic effect.46,47 A hypothesis was postulated that
late paclitaxel toxicity may be the cause of the observed
increased late mortality. With the limitation of insuffi-
cient studies and PCB data (diameter and length), the
estimation of paclitaxel exposure is not feasible in
ESRD patients, let alone actual calculations of individual
patient doses.
However, 90% of paclitaxel is metabolized by hepatic
metabolism, biliary excretion, fecal elimination, or exten-
sive tissue binding.43 Renal clearance contributes a small
proportion (1%-8%) to overall clearance of paclitaxel;
therefore, dose modification does not appear to be
necessary in patients with renal dysfunction.48 Limited
research revealed the independence of the pharmacoki-
netic parameters for paclitaxel from the extent of renal
dysfunction.49,50 Baur et al51 demonstrated that the
peak plasma concentration of the 300 mg/m2 dose
before and after dialysis was 23.05 ng/mL and 21.01 ng/
mL, respectively, which indicated that paclitaxel is not
dialyzable. In addition, most PCBs used for the HD access
2192 Chen et al Journal of Vascular Surgery
December 2020

Table II. Summary of the main overall results in this meta-analysis

Outcomes No. of cohorts Effect measure Effect estimate 95% CI P value I2 (Q). %
6-month mortality 4 OR 1.06 0.38-2.96 .907 19.2
1-year mortality 6 OR 1.20 0.66-2.16 .554 0
2-year mortality 3 OR 1.43 0.83-2.45 .195 0
Lesion primary patency 13 HR 0.47 0.33-0.69 <.001 67.3
RCT 9 HR 0.51 0.31-0.82 .005 76.8
Retrospective 3 HR 0.42 0.23-0.77 .005 0
AVF 8 HR 0.54 0.30-0.98 .041 76.8
CVS 2 HR 0.39 0.22-0.71 .002 0
6-month primary patency 13 OR 0.40 0.27-0.59 <.001 31.0
1-year primary patency 11 OR 0.52 0.26-1.03 .060 69.6
2-year primary patency 2 OR 0.28 0.11-0.72 .009 0
Circuit primary patency 4 HR 0.63 0.40-1.00 .052 58.7
AVF, Arteriovenous fistula; CI, confidence interval; CVS, central venous stenosis; HR, hazard ratio; OR, odds ratio; RCT, randomized controlled trial.

contained a lower payload of paclitaxel in comparison

Fig 3. Forest plot showing the hazard ratios (HRs) for
lesion primary patency by study design (A) and lesion type
(B) in subgroup analyses. AVF, Arteriovenous fistula; AVG,
arteriovenous graft; CI, confidence interval; CVS, central
venous stenosis; RCT, randomized controlled trial.
with PCB used in femoropopliteal artery disease. PCBs
used in HD access commonly ranged from 4 to 7 mm
in diameter and 40 to 80 mm in length, compared
with PCBs used in PAD with averages of 6 mm in diam-
eter and 120 mm in length. Therefore, in theory, the dose
of paclitaxel delivered is less in HD patients than that in
PAD patients. The metabolism of paclitaxel in ESRD pa-
tients is consistent with that in PAD patients, mainly
from the hepatobiliary system. However, although artery
and vein share similar general features in their structure,
artery has much thicker tunica media than vein. Smooth
muscle cells and elastic fibers predominate in the tunica
media layer, indicating that quantity of smooth muscle
cell is quite different between artery and vein. This anat-
omy difference may influence the distribution of pacli-
taxel of the blood vessel. Kim et al52 reported that the
venous smooth muscle cells were substantially more sus-
ceptible to inhibition by antiproliferative drugs including
paclitaxel than the aortic smooth muscle cells in the
methylthiazole tetrazolium assay. Lee et al53 also pre-
sented the difference of signaling responses to antiproli-
ferative agents in human aortic and venous smooth
muscle cells. Furthermore, the hemodynamic and bio-
logic circumstances in HD access are more complex
compared with PAD. Multiple factors will influence the
susceptibility of vein to paclitaxel; these factors include
blood flow velocity, AVF age, vascular manipulation dam-
age, shear stress, uremia, hypoxia, and cytomegalovirus
infection.41,42 All these variables can be seen in HD access
but not in PAD, which may affect the dose of paclitaxel
released into the systemic circulation and the local
drug level and lasting concentration at the target lesion.
ESRD is associated with adverse postoperative out-
comes in peripheral vascular intervention. It has been
Journal of Vascular Surgery
Volume 72, Number 6
Fig 4. A, Funnel plot for lesion primary patency. B, Results of sensitivity testing for lesion primary patency by
removing cohorts one by one. CI, Confidence interval; HR, hazard ratio.
Fig 5. Forest plot showing the odds ratios (ORs) for lesion
primary patency at 6 months (A), 12 months (B), and
24 months (C). CI, Confidence interval; DCB, drug-coated
balloon; PBA, plain balloon angioplasty.
Chen et al 2193
documented that severe chronic kidney disease (CKD)
increased the risk of late mortality after a peripheral
vascular intervention (HR, 2.4; 95% CI, 1.8-3.2; P <
.01).54,55 Ozaki et al56 evaluated the relationship between
the degree of renal function (four groups divided into
normal glomerular filtration rate, mild CKD, moderate
CKD, and dialysis) and long-term clinical outcomes in
CAD patients who underwent PES treatment. The inci-
dence of 2-year major adverse cardiovascular events
was 9.7%, 15.2%, 30%, and 31% in the control, mild CKD,
moderate CKD, and dialysis groups, respectively. Cardiac
death rates were significantly higher in CKD and ESRD
patients after PES implantation. However, ESRD patients
have a high mortality rate even without any endovascu-
lar or surgical intervention. The mortality of the patients
receiving HD is affected by many factors, including pre-
existing comorbidities, modalities of dialysis, economic
condition, and ESRD itself, which makes the adverse ef-
fect of PCB less important if it exists at all.
Cardiovascular death accounts for the main proportion
of all-cause mortality, followed by infection. HD is most
widely used for renal replacement therapy. It is reported
that yearly mortality in HD patients remains at 5% to
27% in developed countries. It is estimated that life expec-
tancy for HD patients aged 65 to 74 years is only 5 years.57-59
In regard to the mortality of CKD patients after vascular
surgery, it has been reported that approximately 50% of
the patients with CKD would develop acute kidney injury
after major vascular surgery, which significantly predicts
90-day mortality.58 Compared with ESRD patients, the
life expectancy of PAD patients with claudication is
more optimistic. The all-cause 5-year mortality ranged
from 8.6% to 26.7%, of which cardiovascular causes
accounted for 21% to 54%.60,61 In our meta-analysis, there
were 27 deaths of 338 patients (8.0% crude risk of death)
during 12-month follow-up and 38 deaths of 185 patients
(20.5% crude risk of death) during 24-month follow-up of
patients with failing HD access treated with PCB. These
rates were not higher than the all-cause mortality of HD
patients not receiving PCB intervention.
Notably, our study observed an interesting finding con-
cerning overall mortality, that is, no significant difference
2194 Chen et al
Fig 6. Forest plot showing the hazard ratio (HR) for circuit
primary patency. CI, Confidence interval.
Fig 7. Sensitivity analysis of lesion primary patency at
12 months after removal of Bjorkman’s study. CI, Confi-
dence interval; DCB, drug-coated balloon; OR, odds ratio;
PBA, plain balloon angioplasty.
was found in short-term mortality within 1 year after
intervention, but there may be a trend that PCB was
associated with worse mortality at 2 years after interven-
tion. Because of limited sample size, we did not achieve a
statistically significant association between application
of PCB and 24-month mortality. Further studies with
larger sample size are warranted to confirm this issue.
This finding was similar to that of other studies concern-
ing the application of PCB in PAD, namely, PCB had a
possible association with increased mortality for the
treatment of femoropopliteal artery disease.11
The latest review calculated that the 12-month and 24-
month mortality was 2.3% and 7.2% in patients with
PAD after PCB or PES treatment.11 The IN.PACT Global
Study, focusing on PCB treatment of femoropopliteal
lesions for patients with intermittent claudication and
ischemic rest pain, showed that the 12-month and 24-
month mortality was 3.5% and 7.6%, respectively.62
Our meta-analysis showed that PCB angioplasty did
Journal of Vascular Surgery
December 2020
not increase all-cause mortality compared with PBA in
the group of patients with ESRD. It is suggested that
the observed higher mortality at 12 months and
24 months after PCB treatment in ESRD patients
compared with PAD patients is mainly due to ESRD it-
self and associated complications including failed HD
access, but not the toxicity of paclitaxel. The benefit of
PCB in improving HD access patency exceeds the
concern of paclitaxel-related mortality.
Study limitation. There are some limitations in our
study. First, the number of reports and patients enrolled
in this meta-analysis are smaller than in the analysis of
PCB-associated all-cause mortality in PAD patients.
Follow-up time in all the studies was within 24 months.
The time point of follow-up and number of deaths in
each group were not clearly documented in two
studies.14,28 Thus, we included them in HD access
patency analysis but had to exclude them from the
mortality analysis. Second, target lesion and lesion type
were varied in different publications. AVF was the only
type of HD access in most enrolled studies; the others
included AVF, AVG, and CVS. Two studies evaluated only
CVS patients.26,28 Third, some studies provided informa-
tion only on lesion length without PCB length. Therefore,
it is not possible to calculate the nominal device dose
and treated vessel surface area according to the equa-
tion used for calculation of paclitaxel dose-time product.
Finally, because there were fewer than 400 patients in
this analysis, a type II statistical error cannot be excluded.
Further large cohort studies will be needed.
CONCLUSIONS
This meta-analysis showed a significant improvement
of short-term and midterm primary patency of HD ac-
cess after treatment with PCB angioplasty. This favorable
outcome was observed in both AVF and CVS. There was
no association between paclitaxel and all-cause mortal-
ity in HD patients at 6-, 12-, and 24-month follow-up in
this analysis. However, there was a trend suggesting
that PCB angioplasty might increase the risk of 24-
month mortality compared with PBA if the sample size
is large enough. The benefit of PCB angioplasty for dial-
ysis access maintenance exceeds the concern of
paclitaxel-related mortality based on short-term and
midterm follow-up. Further studies on long-term mortal-
ity are needed to investigate the safety of PCB angio-
plasty in patients with ESRD.
AUTHOR CONTRIBUTIONS
Conception and design: XC, WZ
Analysis and interpretation: XC, YL, JW, JZ, NS, WZ
Data collection: XC, YL, JW
Writing the article: XC, YL, JW, JZ, NS, WZ
Critical revision of the article: XC, YL, JW, JZ, NS, WZ
Final approval of the article: XC, YL, JW, JZ, NS, WZ
Journal of Vascular Surgery
Volume 72, Number 6
Statistical analysis: XC, YL, JW, JZ, WZ
Obtained funding: Not applicable
Overall responsibility: WZ
XC and YL participated equally and share co-first
authorship.
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Submitted Jan 19, 2020; accepted Apr 10, 2020.
Additional material for this article may be found online
at www.jvascsurg.org.
Journal of Vascular Surgery Chen et al 2196.e1
Volume 72, Number 6

Supplementary Table I (online only). Results of Cochrane Collaboration tool for assessing risk of bias
Blinding of
Random participants Blinding of Incomplete
sequence Allocation and outcome outcome Selective Other
Author Year generation concealment personnel assessment data reporting bias
Bjorkman20 2019 þ þ þ þ þ þ þ
Trerotola21 2018 þ þ ?  þ þ þ
Swinnen14 2018 þ ? þ þ þ þ þ
Maleux22 2018 þ þ   þ þ ?
Irani 24
2018 þ þ   þ þ ?
Roosen25 2017 þ þ  þ þ þ þ
Kitrou26 2017 þ þ  þ þ þ 
Kitrou29 2015 þ þ   þ þ þ
Kitrou30 2015 þ þ   þ þ ?
Lai31 2014 ? ?   þ þ ?
Teo32 2013 þ ?   þ þ ?
Katsanos33 2012 þ þ   þ þ þ
þ, Low risk of bias; , high risk of bias; ?, unclear risk of bias.
2196.e2 Chen et al Journal of Vascular Surgery
December 2020

Supplementary Table II (online only). Results of Newcastle-Ottawa Scale

Representativeness Selection of the Outcome of interest
of the exposed nonexposed Ascertainment was not present at
Author Year cohort cohort of exposure start of study
19
Haave 2019 1 1 1 1
 ev23
Luc 2018 1 0 1 1
 27
Çildag 2016 1 1 1 1
Massmann28 2015 1 1 1 1
Journal of Vascular Surgery Chen et al 2196.e3
Volume 72, Number 6

Supplementary Table II (online only). Continued.

Comparability of cohorts on Was follow-up long Adequacy of
the basis of the design enough for outcomes follow-up
or analysis Assessment of outcome to occur? of cohorts Total
1 1 1 1 8
0 1 1 1 6
0 1 1 1 7
0 1 1 1 7