Objective: To investigate the efficacy and safety of sildenafil added to inhaled nitric oxide (iNO) for newborn infants with persistent pulmonary hypertension of newborn (PPHN) or hypoxic respiratory failure (HRF) at risk of PPHN.
Study design: Part A of a multinational, randomized, double-blind, placebo-controlled trial. Infants ≤96hrs-old, >34 weeks of gestation, receiving iNO (10-20ppm on ≥50% FiO2) for PPHN or HRF at risk of PPHN, and oxygen index >15-<60, were randomized (1:1) to IV sildenafil (loading: 0.1mg/kg, over 30 mins; maintenance: 0.03mg/kg/h) or placebo, for up to 14 days. Coprimary endpoints were treatment failure rate (day 14/discharge) and time on iNO without treatment failure. Secondary endpoints included time on ventilation and oxygenation measures.
Results: Of 87 infants screened, 29 were randomized to IV sildenafil and 30 to placebo; 13 discontinued treatment (sildenafil, n=6; placebo: n=7), including 3 deaths (sildenafil: n=2; placebo: n=1). Treatment failure rates did not differ with sildenafil (27.6%) vs. placebo (20.0%; P=0.4935). Mean time on iNO was not different with sildenafil (4.1-days) vs placebo (4.1-days; P=0.9850). No differences were noted in secondary endpoints. Most common adverse events (AEs) with sildenafil (≥10% infants) were: hypotension (n=8/29), hypokalemia (n=7/29), anemia, drug withdrawal syndrome (n=4/29, each), bradycardia (n=3/29). One serious AE (hypotension) was considered treatment-related.
Conclusion: IV sildenafil added to iNO was not superior to placebo in infants with PPHN or HRF at risk of PPHN. A review of AEs did not identify any pattern of events indicative of a safety concern with IV sildenafil. Infants will have developmental follow-up (Part B).