Background

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Pulmonary arterial hypertension (PAH) contributes significantly to high morbidity and mortality in diverse childhood diseases, including congenital heart disease (CHD), chronic lung disease, hematologic disorders, and others, or in its most rare but virulent form, idiopathic (IPAH) (1). Despite many advances in our understanding of the pathobiology of PAH and increasing availability of pharmacologic therapy, PAH often progresses, leading to substantial disability and in death (2).

Except for the use of inhaled nitric oxide for the treatment of newborns with persistent pulmonary hypertension of the newborn (PPHN) and severe respiratory failure (3–5), there are no PAH therapies specifically approved for children. In fact, none of the PAH-specific therapies that have been approved for adult PAH has been formally approved for use in children in the United States. Data from adult studies provide the basis for most PAH-specific therapies; however, many of these medications are commonly used in children on an off-label basis due to the life-threatening nature of PAH. In general, this approach may be appropriate, as many features of PAH in children, especially for IPAH, are similar to disease in adults (6). Despite some overlap regarding hemodynamic and pathologic features of PAH in adults, pediatric PAH has many unique clinical features due to complex maturational influences related to lung vascular development and related factors (7–9). Key differences are reflected by recent recommendations for a new classification system for pediatric PAH, which highlights the clinical impact underlying the interplay between genetic, epigenetic, and acquired factors (10). Similarly, the effects of drugs on the developing child regarding safety and efficacy may be quite different regarding drug pharmacodynamics and pharmacokinetics and mechanisms of PAH in childhood diseases.

As recently summarized from a NHLBI workshop (8), an additional barrier toward assessing drug therapy for pediatric PAH includes the lack of well-established or validated study endpoints for assessing outcomes in pediatric populations, especially regarding drug efficacy and safety. Standard endpoints commonly applied for adult drug trials in PAH, such as 6-minute walk distances, cardiopulmonary exercise testing, functional class, and others, are often not applicable or validated for use in infants and young children with PAH (11–13). Physiologic assessments, including right heart catheterization, echocardiography, magnetic resonance imaging, and serum biomarkers, have been associated with clinical outcomes in children with PAH, but their usefulness as sufficient endpoints for clinical trials remains uncertain. Thus, there is a current need for more studies in children that account for unique features of pediatric PAH, including the wide spectrum of ages and diseases associated with pediatric PAH and greater efforts toward overcoming current limitations that preclude successful drug trials in children (7, 8).

Such gaps exist throughout pediatrics, especially with rare disorders, which led to passage of the Best Pharmaceuticals in Children Act (BPCA) through the Eunice Kennedy Shriver National Institute of Child Health and Development to encourage collaborations between pharmaceuticals and clinician-scientists to promote investigations in children. Furthermore, recent legislation calls for more consultation with external experts on rare diseases and representation on U.S. Food and Drug Administration (FDA) committees to represent and advocate for interests of children with rare diseases and unmet medical needs (HR 4156). Clearly, more work and better collaborations with pediatric subspecialists in cardiopulmonary medicine are needed to optimize the efficacy and safety of drug therapies in children, especially in the setting of PAH.

Sildenafil and Pediatric PAH

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These issues and others underlie current controversies regarding the recent warning from the FDA against the use of sildenafil in pediatric PAH. Sildenafil (Revatio; Pfizer, New York, NY), a selective type 5 phosphodiesterase inhibitor, is approved by the FDA for the treatment of PAH in adults. Sildenafil has been used extensively off-label for the treatment of neonates, infants, and children with PAH associated with diverse heart and lung diseases (14–18). These studies have generally suggested favorable effects and outcomes in infants and young children with PAH, but these reports are generally uncontrolled observations except for one single-center, placebo-controlled trial for PPHN (18).

In light of a report published in Circulation (19) and subsequent long-term follow-up data from this trial (20), the FDA recently released a strong warning against the use of sildenafil for pediatric patients (ages 1 through 17) with PAH (21). The FDA warning states that “this recommendation against [sildenafil] use is based on a recent long-term clinical pediatric trial showing that: (1) children taking a high dose of Revatio had a higher risk of death than children taking a low dose and (2) the low doses of Revatio are not effective in improving exercise ability… . Revatio has never been approved for the treatment of PAH in children, and in light of the new clinical trial information, off-label (not approved by FDA) use of the drug in pediatric patients is not recommended.” This FDA warning, which is now part of the package insert, states that Revatio should not be started in patients between 1 and 17 years of age.

The FDA decision was based on findings from the published Circulation study and results of the extension study that were recently presented at an international conference (19, 20). The initial study (STARTS-1) evaluated the effects of sildenafil at low, medium, or high doses in “treatment-naive” children who were diagnosed with PAH classified as idiopathic (IPAH) or associated with CHD. Patients were randomized to placebo or one of three dosing strategies for 16 weeks. Peak VO₂ was selected as the primary endpoint; hemodynamics and World Health Organization functional class were also assessed. This study found trends for improvements in peak VO₂ (7.7 ± 4.0%; 95% confidence interval, −0.2 to 15.6%; P = 0.056), functional class, and hemodynamics with medium- and high-dose therapy; however, this effect was not found in the low- and medium-dose group at 16 weeks (19). Minor adverse events were reported, but these were mild, and no deaths occurred during the initial study. Although benefits from low-dose sildenafil therapy were not apparent at 16 weeks, clinical improvement in exercise capacity was observed at 12 months during the study extension period for combined study doses (19, 20). Higher mortality was not seen at the low dose despite evidence of efficacy at 1 year with low-dose therapy. Survival was 91% at 3 years with low-dose sildenafil monotherapy in treatment-naive children with significant PAH (e.g., mean pulmonary arterial pressure, 66 ± 23; pulmonary vascular resistance index, 22 ± 13). Overall, the data show a favorable risk–benefit profile for using low-dose sildenafil in children with PAH that is comparable to data from other patient registries.

Importantly, increased mortality was reported in patients randomized to high-dose sildenafil monotherapy at 3 years when compared with the lower-dose groups (19, 20). There were 35 deaths (15% mortality) during the extension phase: 26 patients died while still on therapy and 9 after completing treatment. Deaths appeared to be dose related, with mortality rates of 9, 14, and 20% for patients randomized to low-, medium-, or high-dose strategies, respectively. Risk factors for death included patients with IPAH. Children with PAH associated with CHD had few deaths, and patients weighing less than 20 kg did not have an increased risk with high-dose sildenafil. There were also important differences in baseline (pretreatment) parameters in the high-dose group, including higher mean pulmonary artery and right atrial pressures and pulmonary vascular resistance. Forty percent of patients who died were initially classified as functional class III or IV at baseline (in contrast with 15% in the remainder of the study group) and had higher N-terminal pro–brain natriuretic peptide levels (19). The unfavorable findings presented in the original publication and extension study do not take into account these differences in disease severity at the time of enrollment.

The safety and/or efficacy in children with PAH on combination therapy is unknown, because all of the children studied were only treated with sildenafil monotherapy per study protocol. With respect to long-term survival, there was no control (untreated) group for comparison, and the overall survival for the treated patients is very favorable when compared with historical control subjects (that is, untreated patients reported in previous studies) (1, 22–24). Recent reports of 3-year survival in children with PAH from registries in the United States, Netherlands, and United Kingdom range from 80 to 84% (1, 22–24). In this study, conservative estimates of survival at 3 years after the initiation of sildenafil treatment were similar for patients in the extension study.

Several problems exist regarding these mortality data. First, during the follow-up period after the initial 16-week trial, clinical care was not standardized, and information regarding the clinical course is not available beyond survival. Substantial center-to-center variability regarding frequency of clinic visits, added therapies, and related decisions may have affected the outcomes of this study. This is especially important in light of the large number of study sites and the international nature of study. It is not clear whether additional therapies beyond sildenafil monotherapy were available at all sites as the severity of PAH progressed in these patients. The lack of detailed data beyond survival during follow-up and the intention-to-treat analysis is somewhat limiting regarding the ability to discern factors associated with deaths in the study.

Recommendations

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Despite these concerns, the European Medicines Agency (EMA) approved sildenafil therapy for use in children with PAH but added caveats regarding dosage (25). In contrast, the FDA expressed a strong warning against the use of sildenafil therapy for pediatric PAH (21). Members of the Pediatric Pulmonary Hypertension Network (PPHNet), which includes leaders of pediatric pulmonary hypertension programs throughout North America, recently discussed these important issues. Although these data certainly warrant further discussion and analysis, we have several major concerns regarding this announcement by the FDA.

First, sudden withdrawal of PAH drug therapy can prove fatal in patients with severe disease, whether therapy is halted due to fears induced by the FDA or through the loss of insurance coverage of drug costs. This decision will likely lead to insurance denials in existing and new patients with PAH and places the prescribing physician potentially at medical-legal risk. Furthermore, other PAH-specific therapies may be used in patients who may otherwise have been treated with sildenafil, such as earlier treatment with chronic continuous intravenous prostacyclin analogs. Although strongly recommended for children with severe PAH, continuous intravenous prostacyclin therapy is associated with significant additional risks, such as bloodstream line infections, thrombosis, and higher costs.

Our European colleagues remind us that the EMA reviewed the same data and concluded that the data are highly supportive that sildenafil should be made available for pediatric PH, with the caveat that “higher sildenafil doses are not recommended” (from the EMA website [25]). Certainly, warnings of high-dose use are warranted; overall, the high doses used in this study are above the doses we generally use for older children with severe PAH. Similarly, none of these data address critical questions regarding our approach to sick newborns or infants, which warrants further study for both safety and efficacy.

Overall, we make the following recommendations:

1. We recommend that families of children with PAH who are currently treated with sildenafil should be contacted by the prescribing physician for review of the potential risks and benefits of sildenafil therapy for their child;

2. We warn against abruptly stopping sildenafil, as this may be associated with severe clinical worsening or death;

3. We strongly recommend avoiding high doses of sildenafil and recommend that adjusting sildenafil dosage in patients currently on sildenafil should be made with close monitoring to target the following ranges in accordance with the EMA-approved dosing:

   • 10 mg three times a day doses for children between 8 and 20 kg

   • 20 mg three times a day for all children more than 20 kg

4. Current treatment of PAH in children less than 8 kg is generally 0.5 to 2.0 mg/kg three times a day, but the safety and efficacy of this strategy are uncertain, and the use of sildenafil in younger infants has not been specifically addressed by the FDA or EMA;

5. For patients with PAH who are currently stable but on higher doses of sildenafil, sildenafil therapy should be decreased, with frequent and cautious assessments of clinical status and echocardiogram studies or perhaps after the addition of a second PAH medication;

6. We recommend initiating sildenafil therapy cautiously in new patients until there is further review of the data;

7. We recommend consultation or referral to experienced PH teams regarding sildenafil therapy for children with PH;

8. Because these findings are based on a study of long-term follow-up after chronic therapy for monotherapy only, the current FDA review is not relevant regarding the short-term use of sildenafil in the critical care setting (neonatal intensive care unit [ICU], pediatric ICU, or cardiac ICU). The use of sildenafil in these settings also warrants further investigation for safety and efficacy but constitute a distinct patient population and indication.