Effects of oral sildenafil on exercise capacity in children with pulmonary arterial hypertension: a randomised trial

OBJECTIVE: The 16-week, randomised, double-blind Sildenafil in Treatment-Naïve Children, Aged1–17 years, with Pulmonary Arterial Hypertension (STARTS-1) study assessed the effect of sildenafil on cardiopulmonary exercise testing (CPET) in treatment-naïve paediatric patients with pulmonary arterial hypertension (PAH) and included a long-term extension (STARTS-2). CPET has rarely been performed in paediatric patients and we assessed both aerobic capacity with peak oxygen consumption (PVO(2)) and ventilatory inefficiency with the slope of ventilation to carbon dioxide production (VE/VCO(2) slope). METHODS: Patients (aged 1–17 year) were randomised to low (10 mg), medium (10–40 mg) and high (20–80 mg) sildenafil dose groups. Patients previously treated with placebo in STARTS-1 were randomised to one of three blinded sildenafil dose groups for STARTS-2. CPET was assessed by cycle ergometry at baseline, week 16, and year 1. RESULTS: Of the 234 children randomised, 115 could exercise. At week 16, the combined sildenafil dose group had a 7.7% increase in mean PVO(2) percent change from baseline compared with placebo (95% CI −0.2% to 15.6%; p=0.056); at year 1, a significant increase in mean percent change in PVO(2) from baseline was only observed in the low-dose group (mean of 12.4% and 95% CI 3% to 21.8%). For VE/VCO(2) slope, at week 16, the combined dose group had a −9.7% mean change from baseline compared with placebo (95% CI −14.9% to −4.5%; p<0.001); at year 1, there were no significant changes for any dose group. CONCLUSIONS: Sildenafil monotherapy (combined sildenafil dose group) appeared to improve short-term VE/VCO(2) slope versus placebo but did not significantly improve PVO(2) in treatment-naïve paediatric patients with PAH who were developmentally able to exercise. TRIAL REGISTRATION NUMBER: NCT00159913 for A1481131, NCT00159874 for A1481156.