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

Stuart Russell, Maurice Beghetti, Ronald Oudiz, Cecile Balagtas, Min Zhang, Dunbar Ivy, Stuart Russell, Maurice Beghetti, Ronald Oudiz, Cecile Balagtas, Min Zhang, Dunbar Ivy

Abstract

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 (PVO2) and ventilatory inefficiency with the slope of ventilation to carbon dioxide production (VE/VCO2 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 PVO2 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 PVO2 from baseline was only observed in the low-dose group (mean of 12.4% and 95% CI 3% to 21.8%). For VE/VCO2 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/VCO2 slope versus placebo but did not significantly improve PVO2 in treatment-naïve paediatric patients with PAH who were developmentally able to exercise.

Trial registration number: NCT00159913 for A1481131, NCT00159874 for A1481156.

Keywords: exercise ECG; paediatric cardiac function; pulmonary arterial hypertension (PAH).

Conflict of interest statement

Competing interests: SR was the head of the exercise core lab for this trial and received research support. MB is a consultant for Actelion Pharmaceuticals, Bayer Healthcare, GlaxoSmithKline, Eli Lilly and Pfizer; and has received grant support and personal fees from Actelion Pharmaceuticals, GlaxoSmithKline, Eli Lilly, Pfizer and Bayer Healthcare. RO is a speaker/consultant for Actelion Pharmaceuticals, Arena, Bayer Healthcare, Gilead Pharmaceuticals, Medtronic, Reata Pharmaceuticals, SteadyMed and United Therapeutics, and has received grant support for research from AAdi, Actelion Pharmaceuticals, Arena, Gilead Pharmaceuticals, GSK, Liquidia, Reata Pharmaceuticals and United Therapeutics. CB and MZ are employees of Pfizer and own Pfizer stock. DI was previously a consultant for Pfizer. The University of Colorado receives fees for DI to be a consultant for Actelion, Bayer, Lilly and United Therapeutics.

© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Figures

Figure 1
Figure 1
Patients were assigned to one of three doses or placebo by weight and developmental ability to perform exercise testing. Not all patients able to perform exercise were tested due to a variety of factors.
Figure 2
Figure 2
Mean change in peak oxygen consumption from baseline at (a) week 16 and (b) 1 year. At week 16, significant improvement was achieved in patients treated with medium-dose and high-dose sildenafil and there was no change in placebo-treated patients. At year 1, the placebo-treated patients had received sildenafil at low, medium or high dose since week 16. Only the low-dose patients had a significant increase in change in peak VO2 at 1 year.
Figure 3
Figure 3
Mean change in the VE/VCO2slope at (a) week 16 and (b) 1 year in patients. Mean VE/VCO2 slope decreased (improved) compared with baseline in all sildenafil-treated patients at week 16. The change from baseline in the sildenafil groups combined versus placebo was statistically significant overall, and within each treatment group. At year 1, the placebo-treated patients had received sildenafil at low, medium or high dose since week 16. There was a sustained mean reduction in VE/VCO2 slope in sildenafil low and medium group but was not statistically significant.

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