Sildenafil for pulmonary hypertension complicating bronchopulmonary dysplasia

Abstract

Sildenafil, a phospohodiesterase-5 inhibitor, is widely used to treat pulmonary hypertension in infants with bronchopulmonary dysplasia despite a lack of evidence to support either safety or efficacy and US FDA advice against its use.

Keywords::

• bronchopulmonary dysplasia
• efficacy
• infant
• neonate
• pulmonary hypertension
• safety
• sildenafil

Bronchopulmonary dysplasia (BPD) is a common complication of preterm infants treated with mechanical ventilation. The incidence is inversely proportional to gestational age, affecting 30–40% of infants <1500 g at birth. There are 14,000 new cases per year in the USA [1]. BPD results in damage to lung parenchyma and airways, decreased alveolarization and increased airway resistance. Long-term consequences include bronchospastic (reactive airway) disease, poor growth and development and pulmonary artery hypertension (PAH), with cor pulmonale in severe cases. The latter conditions are related to proliferation of smooth muscles of the pulmonary arteries and incorporation of fibroblasts within the vessel walls, leading to high pulmonary vascular resistance and abnormally high pulmonary vasoreactivity resulting in PAH and right heart burden [1].

Despite a lack of evidence of safety or efficacy of pulmonary vasodilators, there has been an evolving tendency to aggressively treat BPD-associated PAH. Oral sildenafil (marketed as Revatio) which was approved by the US FDA in 2005 for the treatment of PAH in adults has become the pharmacologic agent of choice in neonates and infants with PAH. Its use for this indication is off-label. In Europe, sildenafil is approved by the European Medicines Agency for use in adults and children with PAH [2].

Pharmacology of sildenafil in infants

High concentrations of cyclic nucleotide phosphodiestrase-5 (PDE-5) isoenzymes present in lung tissue can rapidly degrade cyclic guanosine monophosphate (cGMP) through hydrolysis. cGMP is a secondary intracellular messenger that mediates nitric oxide activity and vascular contractility. Its concentrations are regulated within a relatively narrow range to allow fine tuning of vascular responses to oxygen, nitric oxide and other stimuli [3]. Sildenafil is a PDE-5 inhibitor that increases cGMP concentrations, thus allowing for improved pulmonary vasodilation [3].

Pharmacokinetics, metabolism & drug interactions

Pharmacokinetic information following oral and intravenous administration of sildenafil in neonates and infants is extremely limited. Enteral administration raises concern about absorption, particularly in conditions where intestinal perfusion may be compromised.

Pharmacokinetics of sildenafil and its metabolite, desmethysildenafil, were reported in newborns weighing 2–5 kg, who underwent extracorporeal membrane oxygenation. The pharmacokinetic data were obtained following decannulation and transition from the intensive care unit. Following nasogastric administration, significant variability in clearance and volume of distribution was noted, despite data being obtained after extracorporeal membrane oxygenation therapy, making it difficult to predict a typical half-life. The metabolite is also a pharmacologically active moiety, further complicating interpretation [4].

The recent introduction of an intravenous formulation may alleviate some concerns. Two recent open-label pilot trials demonstrated that intravenous sildenafil, delivered as a continuous infusion, improved oxygenation in 36 infants with persistent pulmonary hypertension of the newborn (PPHN) [5,6]. Sildenafil clearance in neonates increases rapidly through the first week of life, reflecting the relative immaturity of the hepatic CYP450 system in the early neonatal period. Hypotension was the most commonly reported adverse effect mostly associated with loading doses.

Although most infants were receiving concomitant inhaled nitric oxide (iNO), some received sildenafil alone, and all experienced a significant improvement in oxygenation within 4 hours. There are no pharmacokinetic studies available for infants older than 7 days.

A randomized controlled trial evaluating efficacy of intravenous sildenafil is currently underway [7].

The CYP4503A metabolism of sildenafil makes it more prone to interactions with other drugs commonly used in this population, including fluconazole, phenobarbital, caffeine and bosentan. Considering the maturational changes and substantial inter- and intra-patient variability in volume of distribution and drug clearance, as well as the potential for further variability in clearance from drug interactions, dose adequacy is difficult to determine. Patients may be at significant risk for adverse drug reactions.

Finally, the oral preparation for pediatric use is extemporaneously prepared since there is no commercially available preparation. This creates the potential for formulation and dispensing errors and batch-to-batch variability. Nasogastric administration increases the risk of drug–nutrient interactions, which have not been well studied.

Clinical experience

The first use of sildenafil in infants was reported in 1999 to facilitate weaning from iNO after corrective cardiac surgery [8]. Enteral sildenafil increased circulating cGMP and allowed two of three infants to wean without rebound PAH. Subsequently, the use of sildenafil has expanded to include primary PPHN secondary to meconium aspiration and congenital diaphragmatic hernia, pulmonary hypertension accompanying BPD and postoperative PAH, as well as other applications [9–11]. However, the evidence for use of sildenafil in treatment of PAH secondary to BPD is limited to one retrospective case series. None of the eight currently active clinical trials are designed to evaluate the efficacy of sildenafil in PAH/BPD. In the single retrospective study, 25 infants <2 years of age with PAH/BPD received sildenafil at 1.5–8 mg/kg/day, and it was reported to be safe and effective [9].

The FDA warning

In August 2012, the FDA placed a safety warning on prescription of sildenafil in pediatric patients with PAH [12]. The ruling, now part of the package insert for Revatio, states that it should not be initiated in patients 1–17 years of age, based on results of the sildenafil monotherapy sildenafil in treatment-naive children aged 1–17 years with pulmonary arterial hypertension (STARTS) trials [13]. Patients randomized to high-dose sildenafil had an overall increased mortality at 3 years compared to the lower dose groups. The study included several types of PAH patients, including idiopathic and heritable PAH and PAH associated with congenital heart disease, but none associated with BPD. The safety and/or efficacy of combination therapies used in children with PAH are unknown, as all of the children studied were only treated with sildenafil monotherapy. Recently, the FDA has further clarified its warning regarding use of Revatio in pediatric patients with PAH. According to this clarification, while Revatio is FDA-approved only to treat PAH in adults, and not in children, health care professionals must consider whether the benefits of treatment with the drug are likely to outweigh its potential risks in the individual patient [14].

While acknowledging and respecting the FDA’s decision, the Scientific Leadership Council of the Pulmonary Hypertension Association provided some perspectives, arguing that results do not account for the differences in disease severity at the time of enrollment or subgroup differences. With respect to survival, there was no control group. The overall survival for the sildenafil-treated patients was favorable compared to historical controls. Survival is also favorable in current cohorts of treated patients despite the reported association between high-dose sildenafil and increased mortality [2].

Expert commentary

Details of the results of the STARTS study have just been published. The Kaplan–Meier estimated 3-year survival rates from start of sildenafil were 94%, 93% and 88% for patients randomized to low-, medium- and high-dose sildenafil, respectively; actual survival rates were 87%, 89% and 80%. Hazard ratios for mortality were 3.95 (95% CI: 1.46–10.65) for high versus low and 1.92 (95% CI: 0.65–5.65) for medium versus low dose; however, multiple analyses raised uncertainty about the survival/dose relationship. Nevertheless, mortality was higher in the high-dose group. It is our opinion that there is no benefit to using the high-dose regimen of sildenafil in any circumstance, since the risks outweigh the benefits.

There are several concerns regarding the use of sildenafil in neonates. First, the only randomized, placebo-controlled trials studied patients >8 kg and used oral sildenafil. Second, it is difficult to extrapolate these results, responses or doses to neonates and smaller infants, since oral absorption is unpredictable and especially so in those with cardiovascular compromise. Even in the older population, the dose–response relationships are not well established. Third, dose escalation is based on surrogate responses such as blood pressure or oxygenation index, and not estimates of pulmonary arterial pressure. Fourth, effects of sildenafil in infants with PAH/BPD have not been well studied. Infants with BPD have complex pathophysiology and are often receiving multiple pharmacologic agents. Pilot data examining the effects of oral sildenafil in infants and children <2 years of age with PAH/BPD suggest that sildenafil is well tolerated and paves the way for further studies in this challenging population. However, recent literature suggests that serious side effects – such as hypoxia – may also occur with the use of sildenafil in infants with BPD [15–17]. The FDA has recently also warned about hearing loss (mainly in adults) and vision abnormalities in patients treated with sildenafil [18–20]. Little is known of the true effect of sildenafil on retinopathy of prematurity [21,22] Clinicians treating pediatric patients with sildenafil should be aware of these complications as well. Based on the most recent evidence on adverse effects available for adults, it behooves pediatric clinicians to exercise caution while treating infants with PAH secondary to BPD with sildenafil, paying special attention to dosing, response measures and drug interactions when long-term use is planned.

Commentary

Work to date has been unsatisfactory in addressing safety and efficacy of sildenafil in neonates with BPD/PAH. Moreover, significant meaningful endpoints have not been addressed in any of the trials. Given the vagaries of orally administered preparations, it is unlikely that this approach will be fruitful. The recent advent of an intravenous preparation may allow us to address this question, but only if clinically significant outcome variables are chosen and investigators retain equipoise. There are two trials underway. One is examining safety and efficacy of sildenafil in term and late preterm infants with PPHN, while the other is evaluating the pharmacokinetics of sildenafil in premature infants. However, neither study includes babies with PAH/BPD and thus will be unable to address this issue. Until such information is forthcoming, we would be wise to honor the oath we took. First, do no harm.

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.