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Page 1 of 41Downloaded From: http://journal.publications.chestnet.org/ by a Addenbrookes 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: m.ploegstra@umcg.nl 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: http://journal.publications.chestnet.org/ by a Addenbrookes 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 41Downloaded From: http://journal.publications.chestnet.org/ by a 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: http://journal.publications.chestnet.org/ by a Addenbrookes 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: http://journal.publications.chestnet.org/ by a Addenbrookes 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: http://journal.publications.chestnet.org/ by a Addenbrookes 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