Effects of Oral Sildenafil Treatment on Exercise Capacity in Pediatric Pulmonary Arterial Hypertension (PAH)

Abstract

PURPOSE: In the US, sildenafil is approved for adult but not pediatric PAH. The randomized, double‐blind STARTS‐1 study assessed the effect of sildenafil on cardiopulmonary exercise testing (CPET) in treatment‐naïve pediatric PAH patients. Although peak oxygen consumption (pVO2) has been considered the “gold standard ” CPET measurement, the ventilation to carbon dioxide output (VE/VCO2) slope also appears prognostic in various cardiopulmonary disorders including PAH (Oudiz Am J Cardiol 2010;105:1186‐1191). Further, VE/VCO2 slope may outperform pVO2 as reported in heart failure (Arena Am Heart J 2004;147:354‐60). METHODS: Children (aged 1‐17 yr) 8 kg received low‐, medium‐, or high‐dose sildenafil or placebo for 16 weeks. CPET was performed at baseline and week 16 in children able to exercise reliably. VE/VCO2 slope was assessed (posthoc) in addition to the pre‐specified primary endpoint pVO2. Treatment differences for pVO2 and VE/VCO2 slope were evaluated using analysis of covariance (covariates: treatment, etiology, weight, baseline CPET values). RESULTS: Of 115 children able to exercise, 105 had evaluable CPET data at baseline and week 16. Mean baseline pVO2 was 17.4, 18.0, and 17.4 mL/kg/min for low‐, medium‐, and high‐dose sildenafil vs 20.0 mL/kg/min for placebo. Placebo‐corrected mean (± SE) pVO2 change for combined sildenafil doses was 7.7% ± 4.0% (P=0.056). Baseline VE/VCO2 slope was 50.2, 48.0, and 50.5 for low‐, medium‐, and high‐dose sildenafil vs 45.2 for placebo. Placebo‐corrected mean (± SE) VE/VCO2 slope change for combined sildenafil doses was ‐9.7% ± 2.6% (P<0.001). Of the 50 children with an increased pVO2 and decreased VE/VCO2 slope, 43/76 (57%) were sildenafil treated vs 7/29 (24%) on placebo. Regardless of PAH etiology, children receiving sildenafil had greater improvements in pVO2 and VE/VCO2 slope vs placebo; outcomes also appeared better for idiopathic/heritable vs congenital heart defect‐associated PAH. CONCLUSIONS: Sildenafil improves VE/VCO2 slope and pVO2 in treatment‐naïve, pediatric PAH patients who are able to exercise reliably, consistent with improved functional capacity. CLINICAL IMPLICATIONS: VE/VCO2 slope may be a clinically meaningful endpoint to consider in future PAH trials.