Clinical Worsening as Composite Study End Point in Pediatric Pulmonary Arterial Hypertension.
BACKGROUND
Clinical worsening (CW), an increasingly used composite end point 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 each separate component of CW and of the composite CW end point.


METHODS
Seventy pediatric patients with PAH from the Dutch National Network for Pediatric Pulmonary Hypertension, who started PAH-targeted therapy between January 2000 and January 2014, were included in the study and underwent standardized follow-up. The following CW components were prospectively registered: death, lung transplantation (LTx), PAH-related hospitalizations, initiation of IV prostanoids, and functional deterioration (World Health Organization functional-class deterioration, ≥ 15% decrease in 6-min walk distance, or both). The longitudinal event incidence and prognostic value were assessed for each separate component and their combination.


RESULTS
The end-point components of death, LTx, hospitalizations, initiation of IV 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 end point occurred 91.5 times per 100 person-years. The occurrences of either hospitalization, initiation of IV prostanoids, or functional deterioration were predictive of death or LTx (P < .001 for each component). In this cohort, 1-, 3-, and 5-year transplant-free survival was 76%, 64%, and 56%, respectively. Freedom from CW at 1, 3, and 5 years was 43%, 22%, and 17%, respectively.


CONCLUSIONS
CW occurred with a high event incidence and each of the soft end-point components was predictive of death or LTx. This supports the usefulness of CW as a study end point in clinical trials in pediatric PAH.
Center for Congenital Heart Diseases, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.. Electronic address: m.ploegstra@umcg.nl.
Mark-Jan
MJ
Ploegstra
Center for Congenital Heart Diseases, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
Sanne
S
Arjaans
Center for Congenital Heart Diseases, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
Willemljn M H
WMH
Zijlstra
Center for Congenital Heart Diseases, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
Johannes M
JM
Douwes
Center for Congenital Heart Diseases, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
Theresia R
TR
Vissia-Kazemier
Center for Congenital Heart Diseases, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
Marcus T R
MTR
Roofthooft
Department of Pediatric Cardiology, Beatrix Children's Hospital, and the Department of Epidemiology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
Hans L
HL
Hillege
Center for Congenital Heart Diseases, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
Rolf M F
RMF
Berger
D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D023381:Endpoint Determination; D005260:Female; D006801:Humans; D006976:Hypertension, Pulmonary / Q000401:mortality / Q000503:physiopathology*; D015994:Incidence; D008297:Male; D009426:Netherlands / Q000453:epidemiology; D011379:Prognosis; D011446:Prospective Studies; D012042:Registries; D012189:Retrospective Studies