percutaneous patent ductus arteriosus (pda) closure during … · darren p. berman, md, db, c,...

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

2 by guest on September 18, 2020www.aappublications.org/newsDownloaded from

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


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.


PEDIATRICS Volume 139 , number 2 , February 2017 5

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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

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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



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.


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.



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.


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.



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


BACKES et al

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12

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

critically for important intellectual content; and all authors gave fi nal approval of the version to be published, and provide agreement to be accountable for all

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.

[email protected]

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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DOI: 10.1542/peds.2016-2927 originally published online January 13, 2017; 2017;139;Pediatrics

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Meta-analysisPercutaneous Patent Ductus Arteriosus (PDA) Closure During Infancy: A

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