Objective

To describe the safety and tolerability of treatment with ambrisentan and tadalafil in pediatric pulmonary hypertension (PH).

Study Design

This retrospective observational two center study included subjects(<18 years of age)with PH receiving combination therapy with ambrisentan and tadalafil. Prior to initiating this therapy,many patients were on other therapies for PH. At baseline,patients either received no therapy or monotherapy with a phosphodiesterase 5 inhibitor(PDE5i) or endothelin receptor antagonist(ERA)(Group A),switched from a different PDE5i and ERA(Group B),or were on prostanoid therapy with or without a PDE5i and/or ERA(Group C and D). Demographics,symptoms, and adverse effects were collected. Pre and post values for exercise capacity,hemodynamics and biomarkers were compared.

Results

There were 43 subjects(26F, 17M) ages 4-17.5years (median 9.3) with World Symposium of PH group 1,3 and 5. Significant improvements were seen in change scores at follow-up in the entire sample and Group A for 6-minute walk distance: +37.0(6.5–71.0)[P=.022], mean pulmonary artery pressure:-6.0(-14.0 – -3.5)[P=.002], pulmonary vascular resistance: -1.7 (-6.2 – -1.0)[P=.003], NT-proBNP -32.9(-148.9– -6.7)[P=.025]. WHO functional class improved in 39.5% and was unchanged in 53.5%;PH risk scores improved in 16%; were unchanged in 56%; and declined in 14%. Three patients discontinued therapy (2 headaches,1 peripheral edema). Seven patients were hospitalized for worsening disease (2/7 had a Potts shunt placed,2/7 had an atrial septostomy). There were no deaths or lung transplantation.

Conclusions

Combination therapy with ambrisentan and tadalafil was well-tolerated,with an acceptable safety profile in a select group of children. This therapy was associated with improved exercise capacity and hemodynamics in children who were treatment naïve or on monotherapy with a PH medication prior to the initiation of ambrisentan and tadalafil. Based on these early data,further study of combination therapy in pediatric PH is warranted.

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