Table 1.

Summary of key studies evaluating sildenafil for the treatment of children and adolescents with PAH

Study	Design	Treatment arms	Key findings
Sabri et al76	Randomized, open‐label study in 42 infants (age, 3‐24 mo) with a large septal defect and PAH	Sildenafil 1–3 mg/kg/day pre‐ and post surgery	• No significant difference in pulmonary artery‐to‐aortic pressure ratio and sPAP in the first 48 h after surgery
		Tadalafil 1 mg/kg/day pre‐ and post surgery	• No significant differences in ICU stay, mechanical ventilation time, clinical findings of low cardiac output state, and echocardiographic data
			• Both treatments were well tolerated
STARTS‐160	Randomized, placebo‐controlled trial in 235 treatment‐naïve children (age, 1‐17 y) weighing ≥8 kg with idiopathic or hPAH, or PAH associated with connective tissue disease or CHD	Low‐dose sildenafil (10 mg tid)	• Estimated mean change in PVO2 (primary endpoint) for sildenafil (pooled) vs placebo was 7.7% (95% CI, −0.2‐15.6%; P = .056)
		Medium‐dose sildenafil (10–40 mg tid)	• PVO2, FC, and hemodynamics improved with medium and high doses vs placebo; low‐dose sildenafil was ineffective
		High‐dose sildenafil (20–80 mg tid)	• Most adverse events were mild to moderate in severity
		Placebo
STARTS‐1 (sub‐analysis)77	Post hoc analysis of 48 children (age, 1‐17 y) with PAH and Down syndrome	Low‐dose sildenafil (10 mg tid)	• Sildenafil had no effect on PVRI and mPAP
		Medium‐dose sildenafil (10–40 mg tid)	• Sildenafil was well tolerated in children with Down syndrome
		High‐dose sildenafil (20–80 mg tid)
		Placebo
STARTS‐261	Long‐term open‐label extension in 220 children who completed STARTS‐1	Low‐dose sildenafil (10 mg tid)	• Deaths reported in 37 patients, of whom 28 had idiopathic or hPAH
		Medium‐dose sildenafil (10–40 mg tid)	• Deaths more likely in patients in FC III/IV (38%) than the overall cohort (15%), and in patients with worse baseline hemodynamics
		High‐dose sildenafil (20–80 mg tid)	• 3‐y survival rates: 94%, 93%, and 88% for low‐, medium‐, and high‐dose sildenafil, respectively (HR [95% CI] = 3.95 [1.46‐10.65] for high vs low and 1.92 [0.65‐5.65] for medium vs low)
Xia et al78	Open‐label, randomized, controlled study in 50 children (age, 2 mo‐2 y) with high‐altitude heart disease and severe PAH	Sildenafil 1 mg/kg/day	• Sildenafil reduced mPAP and increased arterial pO2, cardiac output, cardiac index, and oxygenation index vs controls (all P < .05)
		Conventional therapy (control)	• No significant changes in mean arterial pressure, routine blood parameters and blood biochemical parameters, and no major adverse event
Humpl et al79	Open‐label pilot study in 14 children (age, 5.3‐18 y) with symptomatic PAH who could reliably perform a 6‐min walk test	Sildenafil 0.25–0.5 mg/kg qid (0.1 mg/kg qid in 1 patient)	• 6MWD (primary endpoint) increased from 278 m to 443 m at 6 mo (P = .02) and 432 m at 12 mo (P = .005)
			• The difference between 6 and 12 mo was not significant
			• Median mPAP decreased from 60 mm Hg to 50 mm Hg (P = .014)
			• Median PVR decreased from 15 Wood units m2 to 12 Wood units m2 (P = .024)
Karatza et al80	Case series including one child with idiopathic PAH (age, 13 y) and two children with PAH‐CHD (ages, 6 and 10 y)	0.5–2.0 mg/kg 4‐hourly	• Increased exercise capacity and FC in all three patients
			• 6MWD increased by 74%, 75%, and 25%
			• Oxyhemoglobin saturations increased from 79%, 97%, and 80% to 93%, 100%, and 93%, respectively.
			• There were no side effects and no fall in systemic blood pressure
Mourani et al81	Retrospective chart review of 25 children (age, <2 y) with chronic lung disease and PH	1.5–8.0 mg/kg/day	• Hemodynamic improvement in 88% of patients (median follow‐up: 40 d) (primary endpoint) a
			• Eleven of 13 patients with interval estimates of systolic pulmonary artery pressure with echocardiogram showed clinically significant reductions in PH
			• Five deaths (20%)
			• Adverse events leading to cessation or interruption of therapy in two patients
Lunze et al82	Open‐label pilot study in 11 patients (median age, 12.9 y; range, 5.5‐54.7 y)	Sildenafil (mean dose, 2.1 mg/kg) + bosentan (mean dose, 2.3 mg/kg)	• No major liver‐ or blood pressure‐related side effects
			• FC generally improved by one NYHA class, with increased transcutaneous oxygen saturation (89.9–92.3%; P = .037), maximum oxygen uptake (18.1–22.8 mL/kg min; P = .043), and 6MWD (351–451 m; P = .039)
			• mPAP decreased (62‐46 mm Hg; P = .041)

Abbreviations: 6MWD, 6‐minute walking distance; CHD, congenital heart disease; CI, confidence interval; FC, functional class; hPAH, heritable pulmonary arterial hypertension; HR, hazard ratio; ICU, intensive care unit; mPAP, mean pulmonary artery pressure; NYHA, New York Heart Association; PAH, pulmonary arterial hypertension; PH, pulmonary hypertension; pO₂, partial pressure of oxygen; PVO₂, peak oxygen consumption; PVR, pulmonary vascular resistance; PVRI, pulmonary vascular resistance index; qid, four times daily; sPAP, systolic pulmonary artery pressure; tid, three times daily.

^aDefined as ≥20% decrease in the ratio of pulmonary to systemic systolic arterial pressure or improvement in the degree of septal flattening assessed by serial echocardiograms.