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Int J Cardiol. 2019 Aug 15;289:110-115. doi: 10.1016/j.ijcard.2019.04.062. Epub 2019 Apr 25.

Meaningful and feasible composite clinical worsening definitions in paediatric pulmonary arterial hypertension: An analysis of the TOPP registry.

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Paediatric Cardiology Unit, and Centre Universitaire Romand de Cardiologie et Chirurgie Cardiaque Pédiatrique, University of Lausanne and Geneva, Switzerland. Electronic address:
Global Medical Science and Epidemiology, Actelion Pharmaceuticals Ltd, Allschwil, Switzerland.
Center for Congenital Heart Diseases, Department of Paediatric Cardiology, Beatrix Children's Hospital, University Medical Center Groningen, University of Groningen, Groningen, Netherlands.
Division of Cardiology, Hospital for Sick Children, University of Toronto, Toronto, Canada.
Quanticate Ltd, London, UK.
Department of Pediatrics, Children's Hospital Colorado, University of Colorado School of Medicine, Aurora, CO, USA.
M3C-Necker, Paediatric Cardiology, Reference Centre for Complex Congenital Heart Diseases, Hôpital Necker Enfants Malades, Université Paris Descartes, Paris, France.



Composite clinical worsening (cCW) outcomes might allow measurement of disease progression in paediatric pulmonary arterial hypertension (PAH). This TOPP registry analysis investigated three cCW outcomes and their predictive strength for lung transplantation/death.


Patients ≤17 years with idiopathic/familial PAH or PAH-associated congenital heart disease diagnosed ≤3 months before enrolment were included. cCW outcomes included the following variables at enrolment and/or follow-up: all-cause death, PAH-related hospitalisation, lung transplantation, atrial septostomy (cCW1, 2 and 3), WHO FC deterioration, intravenous/subcutaneous prostanoids initiation, syncope (cCW2,3) and occurrence/worsening of ≥2 PAH symptoms (cCW3). The predictive value of CW (excluding transplantation and death) to transplantation or death was assessed. Predictive values of each cCW for lung transplantation/death were analysed by Cox proportional hazards models.


From 255 patients, first-event rate/100 person-years (95% CI) were cCW1: 23.1(19.3,27.6), cCW2: 43.6(37.6,50.6), and cCW3: 46.3(40.0,53.7) with PAH-related hospitalisation as the most frequent first event in each. The cCW definitions comprised from endpoints (excluding transplantation and death), were associated with higher risk [hazard ratio (95% CI)] for lung transplantation/death [4.23(2.27,7.91), 3.25(1.65,6.39), 2.74(1.41,5.34), respectively]; individual parameters with higher risks were WHO FC deterioration [3.49(1.47,8.29)], PAH-related hospitalisation [2.62(1.32,5.20)] and occurrence/worsening of ≥2 PAH symptoms [2.13(1.02,4.45)].


These data support the use of cCW outcomes in paediatric PAH research. WHO FC deterioration, PAH-related hospitalisation, occurrence/worsening of ≥2 PAH symptoms may be important for risk assessment during clinical management.


Clinical endpoints; Clinical worsening; Disease worsening; Paediatric PAH

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