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.
DISCLOSURE: Robyn Barst: Consultant fee, speaker bureau, advisory committee, etc.: Robyn Barst has been a consultant and on the advisory committee for Pfizer Inc.
Stuart Russell: Consultant fee, speaker bureau, advisory committee, etc.: Stuart Russell has been a consultant to Pfizer Inc.
Ronald Oudiz: Consultant fee, speaker bureau, advisory committee, etc.: Ronald Oudiz has been a consultant for Pfizer.
D. Dunbar Ivy: Consultant fee, speaker bureau, advisory committee, etc.: D. Dunbar Ivy has been a consultant for Pfizer.
Gary Layton: Employee: Gary Layton is a full-time employee of Pfizer Inc., Shareholder: Gary Layton is a shareholder of Pfizer Inc.
Irina Konourina: Employee: Irina Konourina is a full-time employee of Pfizer Inc., Shareholder: Irina Konourina is a shareholder of Pfizer Inc.
Stephen Watt: Employee: Stephen Watt is a full-time employee of Pfizer Inc.
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