Table 2.

Summary of Efficacy End Points Used to Obtain Regulatory Approval of Medicines for Use in PAH for Adults and Children

End Points Used	Study Population and Numbers of Studies	Products Approved	Limitations if Used in Pediatric Trials
Increase in 6‐min walking distance16, 17, 18, 19, 20	Adults (8 studies)	Bosentan Ambrisentan Sildenafil Tadalafil Treprostinil Iloprost Epoprostenol Riociguat	Need large sample size because of variability Not reliable in children less than 7 y
A composite of time to the first morbidity or mortality event21, 22	Adults (2 studies)	Macitentan Selexipag	To further optimize and define relevant components of clinical worsening in pediatric patients with PAH Need relatively large sample size
Increase in O2 consumption at peak exercise via CPET23	Pediatrics (1 study)	Sildenafil (EU)a	51% of children were developmentally unable to perform CPET in this trial
∆PVR/∆PVRi assessed by RHC24	Pediatrics (1 study)	Bosentan (United States and Health Canada)	End points collected by invasive RHC are not supported for the purpose of pediatric trials because of ethical concerns about the risk of death and severe adverse events related to the procedure

CPET indicates cardiopulmonary exercise testing; EU, European Union; PAH, pulmonary arterial hypertension; ∆PVR, change in pulmonary vascular resistance; ∆PVRi, ∆PVR index; RHC, right‐sided heart catheterization.

^aSildenafil is approved in the EU, but not in the United States and Canada, on the basis of the evidence that long‐term mortality showed a dose‐related adverse trend on mortality.