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Hospital Useron 08/13/20151 Text word count: 2785Abstract word
count: 247Running head: Clinical worsening in pediatric PAH
Clinical Worsening as Composite Study Endpoint in Pediatric
Pulmonary Arterial Hypertension Mark-Jan Ploegstra, MD*; Sanne
Arjaans, BSc*; Willemijn M.H. Zijlstra, BSc; Johannes M. Douwes,
MD; Theresia R. Vissia-Kazemier, RN, MANP; Marcus T.R. Roofthooft,
MD, PhD; Hans L. Hillege, MD, PhD; Rolf M.F. Berger, MD, PhD *These
authors contributed equally to this manuscript Center for
Congenital Heart Diseases, Department of Pediatric Cardiology,
Beatrix Childrens Hospital, University Medical Center Groningen,
University of Groningen, The Netherlands. Correspondence to: M.
Ploegstra, MD. Center for Congenital Heart Diseases, University
Medical Center Groningen Hanzeplein 1, PO Box 30.001. 9700 RB
Groningen, The Netherlands.E-mail: [email protected] Summary
conflict of interest: The authors report no conflicts of interest
related to the manuscript. Funding Source: The Sebald Foundation
Prior publication / presentation: Results from this study were
presented at the European Society of Cardiology congress 2014,30
Aug 2014, Barcelona. Page 2 of 41Downloaded From:
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Hospital Useron 08/13/20152 ABSTRACT Background: Clinical Worsening
(CW), an increasingly used composite endpoint in adult pulmonary
arterial hypertension (PAH), has not yet been evaluated in
pediatric PAH. This study aims to evaluate the usefulness of CW in
pediatric PAH, by assessing the event incidence and prognostic
value of (1) each separate component of CW and (2) the composite
CW-endpoint. Methods: Seventy pediatric PAH-patients from the Dutch
National Network for Pediatric Pulmonary Hypertension who started
PAH-targeted therapy between January 2000 and January 2014 were
included and underwent standardized follow-up. The following
CW-components were prospectively registered: death,
lung-transplantation (LTx), PAH-related hospitalizations,
initiation of intravenous prostanoids and functional deterioration
(WHO-functional-class deterioration and/or 15% decrease in
6-minute-walk-distance). The longitudinal event incidence and
prognostic value were assessed for each separate component and
their combination. Results: The endpoint-components death, LTx,
hospitalizations, initiation of intravenous prostanoids and
functional deterioration occurred with a longitudinal event rate of
10.1, 2.5, 21.4, 9.4 and 48.1 events per 100 person-years,
respectively. The composite CW-endpoint occurred 91.5 times per 100
person-years. The occurrences of either hospitalization, initiation
of intravenous prostanoids or functional deterioration were
predictive of death/LTx (p7 years old.14,15 However, in the current
era with accumulating23 treatment modalities, more ambitious
treatment effects such as improved morbidity and24 Page 6 of
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Addenbrookes Hospital Useron 08/13/20156 mortality are desired.
Recent evidence suggests that changes in 6MWD are not accurate25
surrogates for disease-progression or survival, neither in adults
nor children.13,16,17 This26 challenges the usefulness of 6MWD as
an endpoint and has led to a call for alternative,27 more
clinically meaningful endpoints.28 Clinical worsening (CW) has been
suggested as an alternative endpoint in PAH.18-29 21 CW consists of
a combination of hard unambiguous events such as death and lung- 30
transplantation (LTx), and softer events including
hospitalizations, need for additional31 therapy and worsening of
function. Although CW is being used already for some time as32 a
primary or secondary endpoint in adult trials,22-39 its validity
has only recently been33 evaluated in adults.40 Using 2-year
outcome data from the Registry to Evaluate Early and34 Long-term
PAH Disease Management (REVEAL), it was shown that the soft CW- 35
endpoint-components were highly predictive of subsequent
mortality.36 As 6MWD is not reliable in young children, this
endpoint is not feasible for the37 pediatric age group. Although
not yet evaluated, CW might be an appealing clinical38 endpoint in
pediatric PAH, since it provides a patient-centered composite
endpoint that39 decreases the required study participants and it
would be applicable in different age40 groups. Moreover, it would
account for the risk of rapid clinical deterioration in41
children.8 However, before CW can be used in clinical trials,
essential evaluation steps42 are required, that would include a
description of how frequent the endpoint-components43 of CW occur,
how the soft endpoint-components relate to mortality and what the
timing44 of CW is compared to mortality.10 Therefore, the primary
aim of this study was to45 evaluate the usefulness of CW in
pediatric PAH, by assessing event incidence and46 prognostic value
of (1) each separate component-endpoint and (2) the composite CW-
47 Page 7 of 41Downloaded From:
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Hospital Useron 08/13/20157 endpoint. The secondary aim was to
describe the timing of CW compared to death or LTx48 in pediatric
PAH.49 50 Page 8 of 41Downloaded From:
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Hospital Useron 08/13/20158 METHODS51 52 Study design and
population. 53 This study is a retrospective analysis of data from
a prospective clinical registry.54 In the Netherlands, all children
with PAH are referred to the University Medical Center55 Groningen,
which serves as the national referral center of the Dutch National
Network for56 Pediatric Pulmonary Hypertension.41 Children are
followed and registered prospectively57 according to a standardized
protocol. Ethical approval for this ongoing registry was58 obtained
from the institutional review board (Medical Ethics Review Board of
the59 University Medical Center Groningen, approval number
M11.097816) and the subjects60 and/or their guardians provided
written informed consent at enrolment. All treatment- 61 naive
patients in whom PAH-targeted therapy was initiated between January
1st 2000 and62 January 1st 2014 were included in this study.63 64
Endpoint definition and data collection.65 The definition of CW
included the following endpoint-components: (1) death, (2)66 LTx,
(3) non-elective PAH-related hospitalizations including
hospitalizations for atrial67 septostomies, (4) initiation of
intravenous prostanoids and (5) functional deterioration,68 defined
as either worsening of World Health Organization functional class
(WHO-FC)69 and/or 15% decrease in 6MWD. This CW-definition is in
line with various CW- 70 endpoints used in adult PAH-trials and as
proposed in recent consensus statements.42, 4371 As the change in
6MWD as an endpoint has been challenged, a sensitivity analysis
was72 performed with defining functional deterioration as worsening
of WHO-FC only. The73 Page 9 of 41Downloaded From:
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Hospital Useron 08/13/20159 CW-components were longitudinally
registered from initiation of PAH-targeted therapy74 until the last
follow-up visit before January 1st 2014. 75 76 Data analysis. 77
Data are presented as meanSD, median (interquartile range) or
frequencies78 (percentage). Statistical analysis was performed
using IBM SPSS version 22.0 (IBM,79 Armonk, NY). All statistical
tests were two-sided and p-values