Revatio at Low Doses Safe and of Benefit to Children with PH, Study Reports

Revatio (sildenafil) in low doses is safe and can be of benefit to children with pulmonary hypertension (PH), particularly those with early lung disease, a study reports.

With this work, the researchers weighed in on a controversy, coming down in favor of the treatment. Revatio is approved to treat adults with pulmonary arterial hypertension (PAH) in the U.S., and commonly used off-label to treat PH in infants and children because approved treatments are lacking for these young patients. But the FDA warns against pediatric use, and a clinical trial linked its use to a higher mortality risk in some.

The single-site study, “Sildenafil Use in Children with Pulmonary Hypertension,” was published in The Journal of Pediatrics.

Revatio is an phosphodiesterase (PDE) type 5 inhibitor, marketed by Pfizer, that works by dilating pulmonary artery walls to increase blood flow and reduce pressure in the heart. In adult PAH patients in the U.S., Revatio is given to improve exercise ability and delay clinical worsening.

But across the European Union, the treatment is approved for adults and children, 1 year and older,  with PAH.

A long-term extension study (STARTS-2; NCT00159874) that ended in 2012 tested three Revatio doses (low, medium and high) in toddlers and adolescents (ages 1–17) with idiopathic (of unknown cause) PAH. It associated an increase in mortality in those given the high-dose at three years.

Review of the study’s data led the EU to recommend a maximum dose of Revatio at 20 mg three times a day for children weighing more than 20 kg, and 10 mg three times daily for those weighing 20 kg or less.

The FDA responded with a warning against Revatio’s use in children, regardless of the dose prescribed. This 2012 warning was later changed to allow that risk-benefit consideration might be in favor of treatment in individual cases like a lack of treatment options, provided the child is closely monitored.

Despite the controversy, Revatio “has been extensively used off-label for pediatric PH since 2005” in the U.S., the new study’s researchers noted.

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A team of pediatricians and PH specialists at the New York Presbyterian Hospital decided to evaluate and to share their experiences in treating infants and children with Revatio at their center.

As the team noted, this medication “has been extensively used off-label for pediatric PH since 2005” in the U.S., with physicians largely basing their decision on trial results in adults, since little or contradictory information is available for pediatric PH patients.

The retrospective study looked at 269 patients under age 18 who began treatment with Revatio between 2004 and 2015; some had or were using another PH therapy. Patients were given a low-dose Revatio (1 mg per kg of body weight every eight hours). Data was analyzed at the start of treatment (baseline) and through follow-up. All children were followed for at least one year, with the median follow-up time 3.1 years.

The children’s median age at treatment initiation was 6 months (age range was 1 week old to 17.1 years), and the median time on Revatio was 1.7 years. 

Almost half  — 135 patients — had PH associated with bronchopulmonary dysplasia (BPD), 53 had PH associated with congenital heart disease (CHD), 47 had idiopathic PAH (IPAH), 24 had PH associated with congenital diaphragmatic hernia (CDH), three had PH associated with connective tissue disease. PH in seven others was linked to other causes.

Revatio was given as a sole therapy to most patients (84.8%), and as an add-on therapy to the remaining 15.2%.

At the completion of follow-up, 99 children either were still using Revatio (33%) or switched to Adcirca (tadalafil) — 4% — a PAH medicine also prescribed off-label to children; 93 (35%) had stopped treatment “owing to improvement in PH”; 54 (20%) had died (18 deaths were related to PH, the other 36 were attributed to respiratory failure or an infection); and 20 (7%) were lost to follow-up. Two patients interrupted treatment due to side effects, specifically, airway spasms.

Children with PH associated with lung disease (BPD or CDH; WHO group 3) were the most likely to experience a relief in PH symptoms with Revatio. Among those with BPD, 45% improved enough to withdraw from the medication, a significantly higher proportion than was seen in other groups. Similar outcomes were reported in half of the children with PF linked with CDH.

While mortality was also highest in both these patient groups (26% among those with BPD, and 21% for CHD in WHO group 3), researchers emphasized that others treated “have a high likelihood of weaning off PH medications owing to improvement in PH associated with lung growth and maturation.”  

Overall, survival was better in children with WHO group 1 PH (idiopathic PAH, CHD, and connective tissue disease). Among group 3 patients, survival rates at one, three and five years after starting Revatio were 84%, 80%, and 78%, respectively. In group 1 children, they were 98%, 94%, and 90%, respectively.

Children with idiopathic PAH were more likely to require additional medications — 83% of them needed Revatio plus another kind of PH therapy, the researchers reported.

“In this retrospective experience in children with mainly World Health Organization groups 1 and 3 PH, low-dose sildenafil was well-tolerated, safe, and had an acceptable side effect profile. Although patients with group 3 PH have high mortality, survivors have a high likelihood of PH improving,” the team concluded.