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REVIEW ARTICLEPEDIATRICS Volume 139 , number 2 , February 2017 :e 20162927
Percutaneous Patent Ductus Arteriosus (PDA) Closure During Infancy: A Meta-analysisCarl H. Backes, MD, a, b, c, d Brian K. Rivera, MS, a Jeffrey A. Bridge, PhD, d, e Aimee K. Armstrong, MD, b, c, d Brian A. Boe, MD, b, c, d Darren P. Berman, MD, b, c, d Tyler Fick, MD, d Ralf J. Holzer, MD, f, g Ziyad M. Hijazi, MD, MPH, f, g Sylvia Abadir, MD, h Henri Justino, MD, i Lisa Bergersen, MD, MPH, j Charles V. Smith, PhD, k Haresh Kirpalani, BM, MScl
abstractCONTEXT: Patent ductus arteriosus (PDA) is a precursor to morbidity and mortality.
Percutaneous (catheter-based) closure is the procedure of choice for adults and older
children with a PDA, but use during infancy (<1 year) is not well characterized.
OBJECTIVE: Investigate the technical success and safety of percutaneous PDA closure during
infancy.
DATA SOURCES: Scopus, Web of Science, Embase, PubMed, and Ovid (Medline) were searched
through December 2015 with no language restrictions.
STUDY SELECTION: Publications needed to clearly define the intervention as percutaneous PDA
closure during infancy (<1 year of age at intervention) and must have reported adverse
events (AEs).
DATA EXTRACTION: The study was performed according to the Systematic Reviews and Meta-
Analysis checklist and registered prospectively. The quality of the selected studies was
critically examined. Data extraction and assignment of AE attributability and severity were
independently performed by multiple observers. Outcomes were agreed on a priori. Data
were pooled by using a random-effects model.
RESULTS: Thirty-eight studies were included; no randomized controlled trials were found.
Technical success of percutaneous PDA closure was 92.2% (95% confidence interval [CI]
88.8–95.0). Overall AE and clinically significant AE incidence was 23.3% (95% CI 16.5–30.8)
and 10.1% (95% CI 7.8–12.5), respectively. Significant heterogeneity and publication bias
were observed.
LIMITATIONS: Limitations include lack of comparative studies, lack of standardized AE reporting
strategy, and significant heterogeneity in reporting.
CONCLUSIONS: Percutaneous PDA closure during infancy is feasible and associated with
few catastrophic AEs; however, the limitations constrain the interpretability and
generalizability of the current findings.
aCenters for Perinatal Research, bCardiovascular and Pulmonary Research, and eInnovation in Pediatric Practice, and cThe Heart Center, The Research Institute at Nationwide Children’s
Hospital, Nationwide Children’s Hospital, Columbus, Ohio; dDepartment of Pediatrics, The Ohio State University, Columbus, Ohio; fDepartment of Pediatrics, Weill Cornell Medical College, New
York, New York; gCardiac Catheterization and Interventional Therapy, Sidra Cardiac Program, Sidra Medical and Research Center, Doha, Qatar; hDepartment of Pediatric Cardiology, CHU
mère-enfant Sainte-Justine, Université de Montréal, Quebec, Canada; iSection of Pediatric Cardiology, Texas Children’s Hospital, Baylor College of Medicine, Houston, Texas; jDepartment of
Cardiology, Boston Children’s Hospital, Boston, Massachusetts; kCenter for Developmental Therapeutics, Seattle Children’s Research Institute, University of Washington School of Medicine,
Seattle, Washington; and lDivision of Neonatology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania
To cite: Backes CH, Rivera BK, Bridge JA, et al. Percutaneous Patent Ductus Arteriosus (PDA) Closure During Infancy: A Meta-analysis. Pediatrics. 2017;139(2):e20162927
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BACKES et al
Patent ductus arteriosus (PDA) is
considered a significant precursor to
short- and longer-term morbidity. 1 – 3
Percutaneous PDA closure has
become the procedure of choice for
PDA closure in adults and children 4;
however, generalizable scientific
evidence to support its use during
infancy (<1 year) is limited.5, 6
Somewhat conflicting results on the
safety of percutaneous PDA closure
during infancy has led to uncertainty
regarding patient selection and
optimal timing and indications for
percutaneous PDA closure, leaving
health care providers with little
evidence-based data to guide their
clinical management. 7
Previous reviews on percutaneous
PDA closure have broadly
investigated outcomes across all
age groups, with most interventions
performed outside of infancy. 8 – 10
To our knowledge, no systematic
reviews on the feasibility and
complication rates among infants
undergoing percutaneous PDA
closure have been published.
Although percutaneous PDA
closure is considered a low-
risk intervention, 11 procedures
performed during infancy are more
complex than are those performed
during childhood or adulthood12;
thus, a separate consideration of the
potential risks and benefits in this
at-risk subgroup is needed. In view
of the increasing number of catheter-
based closures among infants, 5 – 7, 13
we conducted a systematic review
and meta-analysis of the use and
outcomes of percutaneous PDA
closure during infancy, while
attempting to characterize potential
sources of data heterogeneity.
METHODS
Data Sources
This study was performed
according to the Preferred Items
for Systematic Reviews and Meta-
Analysis 14 and registered with
the PROSPERO database, the
international prospective registry
of systematic reviews (http://
www. crd. york. ac. uk/ prospero,
identifier CRD42016033924). With
assistance from a research librarian
(A.G.), the authors performed a
comprehensive search of Scopus,
Web of Science, Embase, PubMed,
and Medline for studies investigating
percutaneous PDA closure. Search
terms are available by request to the
corresponding author. All searches
were conducted in January of 2016.
No date or language restrictions were
applied.
Studies that enrolled patients <1 year
of age at the time of percutaneous
PDA closure were included in this
review. To keep the number of
studies manageable, studies were
excluded if they evaluated <3 infants
undergoing attempted percutaneous
PDA closure. We excluded studies
that did not provide data on patient
age at the time of procedure.
Published studies that enrolled mixed
populations (infants and children or
adults) were included if individual
outcomes of at least 3 infants could
be ascertained. Studies were not
excluded for lack of adverse events
(AEs), but for lack of mention of
safety or AE assessment.
Eligibility Criteria
Two reviewers (C.B., B.R.) undertook
the application of inclusion/
exclusion criteria. The eligibility of
the studies was formulated according
to Participants, Interventions,
Comparator, Outcomes, and Study
Design criteria 15:
Participants: Infants (postnatal age
<12 months) who underwent
percutaneous PDA closure.
Intervention: Percutaneous PDA
closure, defined as closure with
either a device (eg, Amplatzer
ductal occluder [ADO] [St Jude
Medical, Saint Paul, MN]) or coil
(eg, Gianturco [Cook Medical,
Bloomington, IN], Flipper [Cook
Medical, Bloomington, IN],
Nit-Occlud[pfm medical ag, Köln,
Germany]).
Comparator: Any; this also included
no treatment (conservative
management) and any of the
currently available treatments
(medical therapy, surgical closure).
Outcomes: No restriction was
made according to measured
outcomes. However, technical
success (defined later in this
article), overall AEs, and clinically
significant AEs (CS-AEs) were the
primary outcomes designated a
priori.
Study Design: In the absence of
randomized controlled trials
(RCTs), the inclusion criteria were
extended to include trials that were
observational (cohort, case series).
Decisions on study inclusion were
made independently of the data
extraction and before the scrutiny of
results. Each identified citation was
designated as definitively, possibly,
or clearly not meeting inclusion
criteria by using a standardized
screening tool. Both abstracts
and full-text reviews were piloted
on sample abstracts or articles,
respectively, to ensure reviewer
consistency in judging inclusion
criteria. For each definitively
or possibly eligible citation,
full-text articles were obtained.
Disagreements were settled through
discussion, with involvement of a
third reviewer (D.B.) as necessary.
When data were unclear or missing,
the corresponding author was
contacted via e-mail at least twice
to obtain additional data to make
a final determination of inclusion
eligibility. When the same center
reported multiple eligible case series,
each of the series was included in
the review. Multiple publications
describing the same or overlapping
series of patients were combined
when feasible.
For non-English language studies
included in the full-text review,
independent reviewers with fluency
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PEDIATRICS Volume 139 , number 2 , February 2017
in the article’s language translated
and abstracted data from the article.
To ensure accurate translations,
all foreign-language articles (n =
38) were translated to English by
using computer software previously
shown to be effective for systematic
reviews. 16 All citations were
imported into an electronic database
(EndNote ×4; Thomson Reuters, New
York, NY), which was also used for
recording screening decisions and
data extraction.
Study Quality Assessment
Although the checklist of Jadad et al 17
has been widely used to determine
study quality in systematic reviews,
it was not relevant here, as no RCTs
were identified. Two reviewers (C.B.,
B.R.) independently assessed the
methodological quality of studies
by using the Newcastle-Ottawa
Scale for nonrandomized studies,
which uses a star system to assess
studies on the basis of (1) selection
of study groups, (2) comparability
of groups, and (3) ascertainment of
exposure/outcome. 18 The content
validity and interrater reliability of
the Newcastle-Ottawa Scale were
previously established, and the scale
continues to be recommended to
assess nonrandomized trials. 19 No
studies were excluded on the basis of
quality.
Data Abstraction
Authors independently extracted
data via an electronic abstraction
form, which was pilot tested for
consistency among reviewers. Data
were collected in a standardized
format, as recommended by the
Cochrane Non-Randomized Studies
Methods Group. 20
Study Outcomes
Consistent with previous reports,
technical success was defined as the
patient leaving the catheterization
laboratory (or alternative setting)
with a coil or device in the PDA.
Cases in which an implant embolized
during the procedure but was
retrieved percutaneously and the
PDA closed with a larger or different
device (during the same procedure)
were considered technical
successes, but also listed as an AE
(described later in this article). 11, 21
Procedural abandonments were
defined as cases in which the infant
left the catheterization laboratory
(or alternative setting) without
a device or coil in the ductus.
Technical failures were defined
as cases in which the device or
coil was placed and the infant
left the catheterization suite, but
subsequently required surgical or
percutaneous removal at a later time.
Residual shunting was defined as
angiographic or echocardiographic
evidence of shunting after device
placement at longest reported
follow-up. Procedural details of
the catheterization, including case
duration, access sites (arterial,
venous), and type of device/coil
were abstracted, when available.
When multiple device placements
were attempted, only the final
implant was recorded. To compare
potential changes over time in risk
of an AE, including embolization
rates, the cohort was divided into
the following epochs based on year
of study publication: “first epoch”
(1994–2009) and “second epoch”
(2010–2016).
AEs were recorded and assessed
independently by 2 pediatric
cardiac catheterization (cardiac
interventionalist) physicians (B.B.,
A.A.) based on previous work
by Bergersen and colleagues. 22
Consistent with previous work, AEs
were stratified according to severity
level (1–5). 22 AE levels 1 or 2 were
considered clinically nonsignificant
(CNS-AE), and levels 3 to 5
considered CS-AE, with levels 4 and
5 considered major and catastrophic,
respectively (Supplemental Table 4).
AEs were further categorized into
4 subheadings: (1) access-related,
(2) sedation or airway, (3) general
catheterization, and (4) device/
coil-related (Supplemental
Table 5). 23 The degree of association
between the intervention and the
AE was assessed independently
(A.A., B.B.) by using the causality
algorithm used by the World Health
Organization Collaborating Centre
for International Drug Monitoring;
terminology was modified for
use for a device rather than for a
pharmacological product. 24 Only AEs
adjudicated as probable, probable/
likely, or certain were included.
Disagreements between reviewers
on the assignment of AE, or the
degree of causality, were resolved by
discussion, and, if necessary, a third
party was consulted (D.B.).
Synthesis of Results and Statistical Analysis
A random-effects meta-analysis
model was selected a priori based
on the assumption that treatment
effects were heterogeneous based
on expected differences in study
designs and patient characteristics
among studies. However, by using a
fixed effects model, results did not
consistently change (data available
on request). Denominators were
adjusted, where appropriate, to
include the number of reported cases
or outcome of interest. For each
primary outcome, the incidence and
95% confidence interval (CI) were
calculated. A forest plot was used
to illustrate the individual study
findings and the random-effects
meta-analysis results for primary
outcomes. Although traditional meta-
analysis methods for calculating
prevalence is based on the inverse
variance method, this puts undue
weight on the studies with small
or large prevalence; therefore, we
used MetaXL data analysis software
(EpiGear International Pty Ltd,
Queensland, Australia) with the
double arcsine transformation. 25
For presentation, the pooled
transformation and its CI were back
transformed to a proportion. 25
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BACKES et al
The I2 statistic was used to estimate
heterogeneity of effects across
studies. Consistent with previous
studies, values of ≤25%, 25% to
75%, and ≥75% represented low,
moderate, and high heterogeneity,
respectively. 26 Publication bias was
visually assessed with funnel and Doi
plots (not shown, data available on
request) and quantitatively assessed
by using the LFK Index (no bias,
index within ±1; minor bias, index
exceeds ±1 but within ±2; major bias,
index exceeds ±2). 27 –30
Subgroup analyses (χ2 or Fisher’s
exact test) were undertaken to
explore potential differences
and sources of heterogeneity in
outcomes. Consistent with previous
studies, 31 – 33 we compared outcomes
among infants <6 kg versus those
≥6 kg. Although our objective was to
evaluate percutaneous PDA closure
as a generic technique, embolization
rates from device and coil arms were
compared. Differences in the overall
AE rates between first and second
epochs were also compared. A P < .05
was considered significant for overall
effect.
RESULTS
The flow diagram ( Fig 1) summarizes
the identified, screened, eligible, and
included studies. The most common
reason for exclusion in the full-text
review was <3 infants included in the
study. Interrater agreement on the
inclusion/exclusion of articles was
good (κ = 0.82).
Study characteristics, representing
635 infants, are summarized in
Table 1. The sample sizes from the
studies meeting inclusion criteria
ranged from 3 to 94 patients. No
RCTs comparing percutaneous PDA
closure with alternative management
strategies (surgical ligation,
conservative management, drug
therapy) were found. Included studies
were highly diverse with regard
to the participants, interventions,
and outcome measures. Interrater
agreement on the methodological
quality of included articles was good
(κ = 0.74). Studies ranged from 4 to 9
stars on the Newcastle-Ottawa Scale
(range, 0–9; a lower score indicates
methodological weakness).
Aggregate data synthesis of the
included studies is shown in Table 2.
Included studies reported outcomes
from 18 countries, with 9 studies
performed in the United States.
Although 1 study reported on factors
associated with length of stay and
hospital charges, an economic
evaluation of direct health care
utilization costs, or nonmedical costs
assumed by affected parties (parents,
families) was not performed by any
of the included studies.
Technical Success (Feasibility)
Technical success with percutaneous
PDA closure was 92.2% (95%
CI 88.8%–95.0%) with modest
heterogeneity (I2 = 32%, P = .03;
Fig 2); minor publication bias was
evident (LFK Index = 1.80). Among
40 cases designated as procedural
abandonments, the reasons for
this included an AE (n = 15), device
malposition within the aorta (n = 10),
device malposition within the left
pulmonary artery (n = 3), technical
failure (n = 10), or unknown/
undisclosed (n = 2).
Four cases (0.6%) were considered
technical failures. In 1 case, the
patient had successful catheter
placement of coils in the PDA, which
were surgically removed 3 days later
due to persistent ductal shunting and
hemolysis. In the remaining cases,
4
FIGURE 1Article selection for inclusion fl ow diagram. Flow diagram showing the process for identifi cation and selection of articles for inclusion in this systematic review and meta-analysis. From: Moher D, Liberati A, Tetzlaff J, Altman DG, The PRISMA Group. Preferred Reporting Items for Systematic Reviews and Meta-Analyses: The PRISMA Statement. PLoS Med. 2009;6(6):e1000097.
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PEDIATRICS Volume 139 , number 2 , February 2017 5
TABL
E 1
Ch
arac
teri
stic
s an
d Q
ual
ity
of In
clu
ded
Stu
die
s (n
= 3
8)
Sou
rce:
Las
t N
ame
of F
irst
Au
thor
,
Year
of
Pu
blic
atio
n
Incl
usi
on C
rite
ria
or P
atie
nt
Ch
arac
teri
stic
s
Excl
usi
on C
rite
ria
No.
Cas
esAg
e, m
o, M
ean
± S
D o
r
Med
ian
(R
ange
)
New
cast
le-O
ttaw
a S
cale
34
Sel
ecti
on, o
f 4
Sta
rsC
omp
arab
ility
, of
2 S
tars
Ou
tcom
e, o
f 3
Sta
rs
Abu
Haz
eem
, 201
3 13<
4 kg
, pos
itiv
e p
ress
ure
ven
tila
tion
Oth
er h
eart
dis
ease
83.
7 (1
.0–
5.3)
****
****
*
Adel
man
n, 2
010 35
Pre
term
, 24–
35 w
k ge
stat
ion
Non
e5
8.4
± 3
.3
***
N/A
***
Abad
ir, 2
009 31
≤6 k
g, c
linic
ally
sym
pto
mat
ic
PD
A
Pu
lmon
ary
hyp
erte
nsi
on56
5.2
± 2
.1
***
N/A
***
Bac
kes,
201
6 21Ve
ry p
rete
rm; <
4 kg
Non
e52
1.2
(0.3
–2.
3)**
*N
/A**
*
Bas
pin
ar, 2
015 33
<6
kg, c
linic
ally
sig
nifi
can
t
PD
A sy
mp
tom
s
Non
e16
1.0
± 0
.7
***
N/A
**
Bas
pin
ar, 2
013 36
<10
kg,
clo
sure
wit
h A
DO
-
dev
ice
PD
A cl
osu
re w
ith
oth
er
met
hod
s
83.
4 ±
2.0
**
*N
/A**
*
Bay
kan
, 201
5 37P
DA
>1.
0 m
m, c
losu
re w
ith
ADO
-I
Dev
ice
oth
er t
han
AD
O-I
126.
9 ±
2.8
**
*N
/A**
*
Ben
tham
, 201
1 38a
Non
e3
1.9
± 0
.8
**N
/A**
Bu
tera
, 200
4 39M
oder
ate-
larg
e P
DA,
>4.
5 kg
Non
e7
8.5
± 1
.8
***
N/A
***
Cas
tald
i, 20
12 6
<12
mo
<1
mo
and
/or
wei
ght
<3.
5 kg
697.
7 ±
2.7
**
*N
/A**
*
Fisc
her
, 200
1 40S
ign
ifi ca
nt
PD
A w
ith
vol
um
e
over
load
Non
e12
4.7
(0.7
5–11
)**
*N
/A**
*
Fors
ey, 2
009 41
>4.
5 kg
, PD
A m
urm
ur
con
fi rm
ed o
n
ech
ocar
dio
grap
hy
Non
e5
8.5
± 2
.9
***
N/A
***
Fran
cis,
201
0 42Lo
w w
eigh
t (>
0.8
to <
2 kg
),
pre
term
PD
A si
ze >
3.5
mm
,
<0.
8 kg
81.
5 ±
1.0
**
*N
/A**
*
Gam
boa
, 200
7 43C
linic
al/e
choc
ard
iogr
aph
ic
dia
gnos
is o
f is
olat
ed P
DA
Non
e4
8.8
± 2
.2
***
N/A
***
Gild
ein
, 199
9 44>
5.0
kgN
one
35.
6 ±
1.4
**
*N
/A**
*
Gro
ss, 2
013 45
AVP
-II, h
emod
ynam
ical
ly
sign
ifi ca
nt
PD
A
Non
e8
3.0
± 2
.3
***
N/A
**
Hija
zib ,
199
4, 19
96 46
, 47C
linic
al a
nd
ech
ocar
dio
grap
hic
PD
A
Non
e7
6.8
± 3
.1
***
N/A
***
Hija
zi, 1
996 48
≤8.0
kg,
clin
ical
or
ech
ocar
dio
grap
hic
PD
A
Non
e15
6.6
± 3
.5
***
N/A
***
Knir
sch
, 200
4 49≤8
.0 k
gN
one
186.
1 ±
2.9
**
*N
/A**
*
Kob
ayas
hi,
2005
50P
DA
>3.
0 m
mN
one
67.
5 ±
3.6
**
N/A
**
Lee,
199
9 51P
DA
occl
usi
on u
sin
g G
ian
turc
o
coils
Pre
term
or,
fu
ll-te
rm
infa
nts
<3
mo
125.
4 ±
1.7
**
*N
/A**
*
Lin
, 200
9 52Te
rm in
fan
ts ≤
3 m
o, P
DA
>3.
0-m
m d
iam
eter
wit
h
sym
pto
ms
Pre
term
infa
nts
<36
wk
201.
7 ±
0.7
**
****
***
Mas
ura
, 199
8 53C
linic
al a
nd
ech
ocar
dio
grap
hic
PD
A
Non
e3
7.6
± 3
.0
***
N/A
***
Moy
sich
, 201
5 54<
10 k
g, m
oder
ate/
larg
e P
DA,
Nit
-Occ
lud
er
Non
e7
5.9
± 3
.1
***
N/A
***
Ow
ada,
199
7 55P
DA ≥3
.5 m
mN
one
86.
2 ±
2.6
**
*N
/A**
Pra
da,
200
9 56<
1 y
Add
itio
nal
hea
rt d
isea
se15
6.6
± 3
.1
***
N/A
***
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BACKES et al
evidence of late embolizations (>24
hours after successful placement)
necessitated device (n = 1) or coil
(n = 2) retrieval.
Among 28 studies reporting the
incidence of residual shunting
after coil or device placement, the
incidence of immediate ductal
occlusion after device or coil
placement was 76.7% (95% CI
65.2%–83.3%) with significant
heterogeneity among studies
(I2 = 70%, P < .01); major publication
bias was evident (LFK Index = 2.87).
Among cases (n = 83) with residual
ductal shunting, most (n = 68/83,
82%) subsequently closed within
24 hours. Eight (10%) cases
remained patent at longest reported
follow-up (range 3–36 months).
Severity of residual shunting was
trivial (n = 5) or was unknown/not
reported (n = 3).
AEs
Overall AE rate was 23.3% (95%
CI 16.5%–30.8%; Fig 3). Significant
heterogeneity in AE rates was
identified among studies (I2 = 82%,
P < .01); mild publication bias was
evident (LFK Index = 1.16). Among
140 AEs, causality was assessed as
probably (n = 3), probably/likely
(n = 57), or certain (n = 80).
Interrater agreement on causality of
AEs was good (κ = 0.86). Among AEs,
most were CNS-AE (80/140, 57.1%).
The rate of CS-AE was 10.1% (95%
CI 7.8%–12.5%; Fig 4), with low
heterogeneity (I2 = 0%, P = .51), and
evidence of mild publication bias
(LFK Index = 1.44). Most CS-AEs
(78.3%, 47/60) were level 3 AEs.
Among all procedures, level 4 AE
(major) or 5 AE (catastrophic)
occurred in 1.6% (10/635) and
<0.5% (3/635) of cases, respectively.
Most major or catastrophic events
(92.3%, 12/13) occurred among
infants <6 kg. Additional details
on level 4 or 5 AEs are provided
in Supplemental Table 6. The
prevalence of embolization (both
coils and devices) was 5.0% (95%
6
Sou
rce:
Las
t N
ame
of F
irst
Au
thor
,
Year
of
Pu
blic
atio
n
Incl
usi
on C
rite
ria
or P
atie
nt
Ch
arac
teri
stic
s
Excl
usi
on C
rite
ria
No.
Cas
esAg
e, m
o, M
ean
± S
D o
r
Med
ian
(R
ange
)
New
cast
le-O
ttaw
a S
cale
34
Sel
ecti
on, o
f 4
Sta
rsC
omp
arab
ility
, of
2 S
tars
Ou
tcom
e, o
f 3
Sta
rs
Rob
erts
, 200
6 57P
rete
rm, L→
R s
hu
nt
Non
e10
8.9
± 0
.6
***
N/A
**
Rot
hm
an, 1
997 58
≤4.0
mm
“re
stri
ctiv
e” P
DA,
coil
clos
ure
Non
e3
10.4
± 0
.7
***
N/A
***
Sal
iba,
200
9 59≥3
.0 k
g fo
r co
ils a
nd
≥5.
0 kg
for
ADO
<3
kg20
3 to
<12
**
*N
/A**
*
San
dh
u, 2
001 60
Infa
nts
wit
h P
DA
<5.
0 kg
, PVR
(>
8 w
ood
s
un
its)
127.
8 ±
2.5
**
*N
/A**
*
Sen
ga, 2
013 61
>4.
5 kg
; car
dia
c fa
ilure
or
cyan
osis
Non
e3
N/A
***
N/A
**
Siv
aku
mar
, 200
8 62≤6
.0 k
g, P
DA ≥4
.0-m
m
dia
met
er, P
H
Pre
term
, coa
rcta
tion
255.
2 ±
2.4
**
*N
/A**
*
Su
ngu
r, 2
013 63
PD
A ≤4
.0-m
m d
iam
eter
, AD
O-II
AS
Add
itio
nal
car
dia
c
anom
alie
s
354.
0 ±
2.4
**
*N
/A**
*
Than
opol
ous,
200
0 64L→
R s
hu
nt
LA d
ilati
on A
DO
clos
ure
<4
kg, c
ard
iac
anom
alie
s, P
DA
<2
mm
dia
met
er
36.
0 ±
2.0
**
*N
/A**
*
Tom
ita,
200
9 5<
1 y,
coi
lN
one
327
(1–
11)
***
N/A
**
Vija
yala
ksh
mi,
2006
65≤8
kg,
larg
e P
DA,
AD
O u
sed
Non
e8
7.3
± 2
.4
***
N/A
**
Vija
yala
ksh
mi,
2014
66>
2.5
mm
PD
A d
iam
eter
,
pu
lmon
ary
hyp
erte
nsi
on
Oth
er c
omp
lex
CH
D
req
uir
ing
surg
ery
94N
/A**
*N
/A**
*
Zah
n, 2
015 67
<32
wk
GA,
AVP
-II u
sed
Non
e6
1.0
± 0
.8
***
N/A
***
AVP
-II, A
mp
latz
Vas
cula
r P
lug;
CH
D, c
onge
nit
al h
eart
dis
ease
; EC
HO
, ech
ocar
dio
gram
; GA,
ges
tati
onal
age
; LA,
left
atr
ium
; N/A
, not
ap
plic
able
(n
o co
mp
arat
ive
grou
p);
PH
, pu
lmon
ary
hyp
erte
nsi
on; P
VR, p
ulm
onar
y va
scu
lar
resi
stan
ce.
a C
ases
wer
e se
lect
ed b
ased
on
agr
eed
cri
teri
a of
clin
ical
, rad
iogr
aph
ic, a
nd
ech
ocar
dio
grap
hic
ass
essm
ents
.b C
omb
ined
cas
es f
rom
2 s
tud
ies.
46, 47
TABL
E 1
Con
tin
ued
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PEDIATRICS Volume 139 , number 2 , February 2017
CI 3.5%–8.5%), with moderate
heterogeneity (I2 = 34%; P = .02) and
evidence of major publication bias
(LFK Index = 2.6).
Nature of AEs
Device or Coil-Related AEs (Embolization, Malposition)
Device or coil-related complications
were the most frequent AEs,
occurring in 12.3% (95% CI 7.9%–
17.6%). Moderate heterogeneity
in device or coil-related AE rates
was identified among studies (I2 =
57%, P < .01) with evidence of major
publication bias (LFK Index = 2.18).
We observed a higher proportion
of coil than device embolizations
(21/216, 9.7% vs 11/419, 2.6%;
P < .01). Most coil (16/21,
76.2%) and device embolizations
(8/11, 72.7%) were retrieved
percutaneously. Embolizations
(n = 32) were observed to the
following: pulmonary arteries
(n = 19), aorta (n = 5), internal/
external iliac arteries (n = 1), or
uncertain/not provided (n = 7). In 10
of these cases (31.3%), the implant
was retrieved in the catheterization
laboratory and the PDA closed by
using a larger device during the same
procedure. In 2 cases (Supplemental
Table 6 for details), a device embolized
and, despite successful percutaneous
retrieval, the patients did not recover
from the hemodynamic compromise
and died. 31, 65
Access-Related AEs
The rate of access-related
complications was 8.2% (95%
CI 5.6%–11.2%) with moderate
heterogeneity (I2 = 37%, P = .37)
among studies. We observed no
evidence of publication bias (LFK
Index = 0.57). Access-related
complications were the second most
frequent AEs (50/140, 35.7%), and
included hematoma or transient
pulse loss not requiring therapy
(n = 19), pulse loss or thrombosis
requiring therapy (n = 23), or blood
transfusion for vascular compromise
(n = 8).
Sedation/Airway AEs
Two AEs were sedation/airway-
related, occurring in 0.3% (2/635)
of attempted PDA closures and
comprising <1% of reported AEs. One
sedation/airway-related AE was the
need to reposition an endotracheal
tube during the catheterization, 21
whereas a second was need for
transient bag-and-mask ventilation
for apnea during the procedure. 42
General Catheterization AEs
Among 16 general catheterization
AEs, 1 death was attributed to the
catheterization. In this case, a 1.5-kg
premature infant with multiple
7
TABLE 2 Aggregate Data Synthesis for 38 Included Studies
Characteristics No. of Studies (%)
Location of studya
United States 9 (24)
Europe 18 (47)
Asia 9 (24)
Africa 1 (3)
South America 1 (3)
Age of included patients
All <1 y 13 (34)
Mixed cohortb 25 (66)
Medical treatment of PDA before catheterization
All cases 3 (8)
Yes, in some cases 8 (21)
Not specifi ed 27 (71)
Indications provided for PDA closure
Left-sided volume loading 13 (24)
Pulmonary hypertension 2 (5)
Persistent oxygen requirement 2 (5)
Multiple indications for closure 12 (32)
No indications provided 9 (27)
Vascular access
Venous only 13 (34)
Arterial and venous 25 (66)
Sheath sizes used, French
Arterial, range 3–7
Venous, range 4–7
Implants
ADO (all types) 23 (61)
AVP 5 (13)
Cook, Gianturco, or Flipper coils 4 (11)
Nit-Occlud coils 2 (5)
Mix (devices or coils) 4 (11)
Reported the cost of the intervention 0 (0)
No. of Cases (%)
Weight at time of procedure, c kg
<3 103 (19)
3–6 255 (48)
>6 171 (32)
Krichenko 68 classifi cationsd
Type A 157 (50)
Type B 10 (3)
Type C 100 (32)
Type D 8 (3)
Type E 39 (12)
Mixed Type 4 (1)
AVP, Amplatzer Vascular Plug.a According to location of fi rst author.b Studies that included patients ≥1 y at time of intervention; only infants <1 y were included in present analysis.c Data from 2 studies with missing weight at time of catheterization were excluded. 60, 65
d Among studies with cases (n = 318) reporting Krichenko classifi cation.
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BACKES et al
comorbidities had a suspected
cardiac perforation and underwent
emergent pericardiocentesis;
however, the infant did not respond
to resuscitation and died. 33
Subgroup Analysis of Outcomes
Subgroup analyses were performed
to explore potential sources of
heterogeneity in primary outcomes
( Table 3). No variables influenced
the rate of technical success
(feasibility). The incidence of CS-AEs
was more than twofold to threefold
higher among studies with infants
weighing <6 kg (14.0% vs 4.8%).
Many comparisons were limited
by nonreporting of the variables of
interest.
DISCUSSION
This study reports the largest known
meta-analysis among infants treated
percutaneously for PDA. In 38 studies
encompassing 635 procedures,
percutaneous closure was associated
with 92.2% technical success, 23.3%
overall AE rate, and 10.1% CS-AE
rate. Although a better understanding
of risks associated with percutaneous
closure is an important first step, lack
of comparative trials (percutaneous
closure versus surgical ligation)
precludes determination of the
optimal treatment of PDA closure
during infancy. 69 Pragmatic clinical
trials using strict inclusion criteria,
well-defined treatment thresholds,
standardized protocols for AE
surveillance, and long-term follow-up
are needed to generate relevant
and generalizable data to develop
evidence-based standards for PDA
treatment during infancy. 69 – 71 This
goal is achievable, but will require
a high level of interdisciplinary
(neonatology, cardiology,
interventional medicine) and multi-
institutional collaboration.
Traditionally, PDA treatments (eg,
prophylactic drug therapy) have
been applied broadly, irrespective
8
FIGURE 2Technical success forest plot. Feasibility (technical success) with percutaneous PDA closure. I2 for heterogeneity = 32% (P = .03). LFK Index for publication bias = 1.80.
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PEDIATRICS Volume 139 , number 2 , February 2017
of markers of disease burden.
Rather than an “all-or-none
approach, ” efforts to develop more
individualized approaches to PDA
management that take into account
markers (clinical, echocardiographic)
of adverse ductal sequelae and
the natural history of the disease
(rates of spontaneous closure) may
improve outcomes. 72 For example,
using conservative management
(fluid restriction, diuretics, positive
pressure ventilation) to reduce
symptoms from the PDA, recent
data show that approximately two-
thirds of infants spontaneously
close their ductus before hospital
discharge, 73 thereby avoiding the
risks of an unnecessary intervention,
without evidence of increasing
risk associated with conservative
management. Targeted use of
percutaneous PDA closure in the
subset of infants whose ductus fails
to close after conservative treatment,
and who continue to show evidence
of adverse ductal consequences
(clinical, echocardiographic,
serum biomarkers), would enable
clinicians to minimize risk and
yield the greatest benefits. 72 In the
present review, neither the primary
indications for PDA closure, nor the
nature and extent of management
before referral for closure, were
reported consistently; thus,
optimal timing and thresholds for
percutaneous PDA closure remain
unknown and can vary greatly
according to age, weight, and clinical
condition. 74
In adults and children with a
persistent ductus warranting closure,
percutaneous techniques provide
clear advantages over surgical
ligation and comprise the treatment
of choice for PDA closures beyond
the first year of life. 4, 11 Given growing
concerns on the merits and safety
of surgical ligation during infancy, 75
percutaneous PDA closure represents
a potentially attractive alternative.
However, consistent with previous
studies, higher rates of overall AEs
and CS-AE were observed among
a subgroup of low weight (<6 kg)
infants. 11 At these lower weights,
providers must be careful not to
9
FIGURE 3Overall AE forest plot. Overall AE rate with percutaneous PDA closure. I2 for heterogeneity = 82% (P < .01). LFK Index for publication bias = 1.16.
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BACKES et al
trade the risks of surgical ligation for
those associated with percutaneous
closure without producing and
examining the necessary evidence
base. Early (<7 days of life) surgical
PDA ligation seems to have fallen
out of favor in recent years, 76, 77 but
surgery remains an important option
in the treatment of symptomatic low
weight infants, particularly in centers
without a dedicated pediatric team of
cardiac interventionists. 78, 79
Consistent with previous reports,
we observed that access-related
injuries are frequently observed in
percutaneous PDA closure during
infancy. 21, 80 However, inconsistent
reporting precluded a better
understanding of the possible link
between sheath size and access-
related injuries. Approaches that
limit or avoid arterial access, such
as the use of fluoroscopy and
transthoracic echocardiography to
guide transvenous PDA closure, will
likely reduce such complications. 67
Our findings suggest that outcomes
for percutaneous PDA closure
have changed over time, which
is likely attributable to new
techniques, approaches, and
available technologies. Recent device
modifications to the ADO-II AS (St
Jude Medical, Minneapolis, MN; not
available in the United States) 81 and
reports on the safety and feasibility
of a new, flexible, self-shaping device
(Occlutech PDA occluder; Occlutech
International AB, Helsingborg,
Sweden; not available in the United
States) 82 suggest that risk/benefit
profiles are likely to continue
to change. Thus, we encourage
investigators to document and
publish their results to further the
collective knowledge.
The inclusion of data from
nonrandomized, noncontrolled,
and retrospective studies may
have introduced bias in the results.
Observational studies may report
outcomes in “best-case scenarios, ” in
which the health care providers feel
personally committed to the success
10
FIGURE 4CS-AE forest plot. CS-AE rate with percutaneous PDA closure. I2 for heterogeneity = 0% (P < .51). LFK Index for publication bias = 1.44.
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PEDIATRICS Volume 139 , number 2 , February 2017
of an intervention; thus, reported
AE rates may not accurately reflect
those events encountered in clinical
practice (publication bias). In the
absence of therapy randomization,
defining any link between
percutaneous PDA closure and AEs
was not feasible. Although front-
line providers (pediatric cardiac
interventionalists) determined the
attributability and severity level
of AEs based on previous criteria
with strong interrater agreement,
no formal certifying training was
provided. One of the critical steps
in remedying the gaps identified in
this review is the standardization
of definitions and research
methodologies for AEs after cardiac
catheterization. 12, 23
Within the meta-analysis,
heterogeneity and publication bias
were observed frequently, which
confounded data interpretation.
Marked variation in the completeness
of data reported among studies limited
data synthesis. Limited descriptions
of patient-selection procedures,
including how infants were drawn
from the eligible population, likely
increased the risk of selection bias
among included studies.
Studies in the present review
provided limited or no description
of sedation- or anesthesia-related
procedures; however, data showing
infants to be at the greatest risk
for such complications among all
pediatric populations 83 suggest
that thoughtful consideration of
optimal anesthesia and sedation
practices are necessary. Although
we evaluate percutaneous PDA
closure among infants <1 year at
time of intervention, risk/benefit
ratios are likely to be continuous in
nature and dependent on a number
of patient- and procedural-related
factors beyond age at intervention.
Given the interrelatedness of health
and resource utilization, lack of
available data on resource use and
cost associated with percutaneous
PDA closure is noteworthy.
It is possible that relevant published
peer-reviewed evidence was not
identified, and disagreements about
whether specific articles should have
been included may be reasonable.
To minimize this risk, we performed
a sensitive literature search with
assistance from a research librarian,
by using a diverse set of databases
without language restrictions.
Although percutaneous PDA closure
may be feasible in some centers,
broad generalizability has yet to be
demonstrated.
CONCLUSIONS
Percutaneous PDA closure during
infancy is feasible and is associated
with few major or catastrophic
AEs; however, the absence of high-
quality studies and significant
heterogeneity for main outcomes
limits interpretability and
generalizability of current findings.
Large, pragmatic, multicenter studies
that systematically evaluate existing
PDA treatments (percutaneous
closure, surgical ligation) are needed
to address the fundamental gaps in
knowledge documented by this review.
ACKNOWLEDGMENTS
The authors recognize and thank
Dr Michael Borenstein, PhD, a
member of the Development Team
for Comprehensive Meta-Analysis
software and author of Introduction to Meta-Analysis, for his willingness
to provide statistical consultation to
the current study. The authors also
thank Alison Gehred, MS, clinical
librarian at Nationwide Children’s
Hospital for her assistance in
conducting the database searches to
locate articles for possible inclusion.
11
ABBREVIATIONS
ADO: Amplatzer ductal occluder
AE: adverse event
CI: confidence interval
CNS-AE: clinically nonsignificant
adverse event
CS-AE: clinically significant
adverse event
PDA: patent ductus arteriosus
RCT: randomized controlled trial
TABLE 3 Subgroup Analysis of Baseline Factors on Primary Outcomes
No. of
Studies
No. of Cases Technical Success
(Feasibility)
Any AEs CS-AEs
Study design
Prospective 17 138 125 (90.6) 47 (34.1)a 15 (10.9)
Retrospective 21 497 467 (94.0) 93 (18.7) 45 (9.1)
No. of centers
Single center 31 502 470 (93.6) 106 (21.1) 51 (10.2)
Multicenter 7 133 122 (91.7) 34 (25.6) 9 (6.8)
Cohort size
<10 20 113 102 (90.3) 30 (26.5) 11 (9.7)
≥10 18 522 490 (93.9) 110 (21.1) 49 (9.4)
Weight at time of procedureb
<6 kg 18 299 274 (91.6) 92 (30.8)a 42 (14.0)a
≥6 kg 18 230 213 (92.6) 40 (17.4) 11 (4.8)
Year of publication
Pre 2010 23 301 271 (90.0) 94 (31.2)a 28 (9.3)
2010–2016 15 334 321 (96.1) 46 (13.8) 32 (9.6)
Occluder type usedc
Coil 12 115 98 (85.2) 40 (34.8)a 8 (7.0)
Device 21 410 388 (94.6) 90 (22.0) 47 (11.5)
Outcome reporting
<1 y 26 321 291 (90.7) 89 (27.7)a 29 (9.0)
≥1 y 12 314 301 (95.9) 51 (16.2) 31 (9.9)
Data shown as n (% of cases).a P < .01.b Excluded 2 studies in which weight at the time of procedure could not be determined. 60, 66
c Excluded studies (n = 5) that used coil and devices. 37, 43 –46
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BACKES et al
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Dr Backes was involved in the acquisition of data, analysis and interpretation of data, conception and design of manuscript, drafting the article, and revising it
critically for important intellectual content; Mr Rivera and Drs Fick and Holzer were involved in substantial contributions to conception and design of manuscript,
analysis and interpretation of data, drafting the article, and revising it critically for important intellectual content; Dr Bridge was involved in the analysis and
interpretation of data, drafting the article, and revising it critically for important intellectual content; Drs Armstrong and Boe were involved in the acquisition of
data and analysis and interpretation of data analysis, drafting the article, and revising it critically for important intellectual content; Dr Berman was involved in
substantial contributions to conception and design and analysis and interpretation of data, drafting the article, and revising it critically for important intellectual
content; Drs Hijazi, Abadir, and Justino were involved in the acquisition of data, drafting the article, and revising it critically for important intellectual content;
Drs Bergersen, Smith, and Kirpalani was involved in substantial contributions to conceptualization and design of the study, drafting the article, and revising it
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aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.
DOI: 10.1542/peds.2016-2927
Accepted for publication Oct 31, 2016
Address correspondence to Carl Backes, MD, Center for Perinatal Research, Nationwide Children’s Hospital, 700 Children’s Dr, Columbus, OH 43205. E-mail: carl.
backesjr@nationwidechildrens.org
PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275).
Copyright © 2017 by the American Academy of Pediatrics
FINANCIAL DISCLOSURE: The authors have indicated they have no fi nancial relationships relevant to this article to disclose.
FUNDING: No external funding.
POTENTIAL CONFLICT OF INTEREST: Dr Hijazi is a consultant for NuMED and Occlutech, and has ownership/partnership of the Colibri Heart Valve. He is also
chairman of the PICS Foundation. Dr Armstrong reports the following potential confl icts of interest: Medtronic Inc, research grants; Edwards Lifesciences,
consultant, proctor, research grant; Siemens Healthcare AX, consultant; St Jude Medical, consultant, proctor, research grant; B. Braun Interventional Systems Inc,
proctor; and Pfm Medical, Inc, research grant. Dr Justino is a consultant for St Jude Medical, B-Braun Interventional Systems, and Janssen Pharmaceutical. Dr
Bergersen is a consultant for 480 Biomedical. The other authors have indicated they have no potential confl icts of interest to disclose.
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DOI: 10.1542/peds.2016-2927 originally published online January 13, 2017; 2017;139;Pediatrics
Henri Justino, Lisa Bergersen, Charles V. Smith and Haresh KirpalaniBoe, Darren P. Berman, Tyler Fick, Ralf J. Holzer, Ziyad M. Hijazi, Sylvia Abadir, Carl H. Backes, Brian K. Rivera, Jeffrey A. Bridge, Aimee K. Armstrong, Brian A.
Meta-analysisPercutaneous Patent Ductus Arteriosus (PDA) Closure During Infancy: A
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Meta-analysisPercutaneous Patent Ductus Arteriosus (PDA) Closure During Infancy: A
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