The Real World of Medical Treatment of Pulmonary Arterial Hypertension―Small Evidence, but Heavy Cornerstone―

A variety of pulmonary vasodilators are now on the market; however, little is known about their use in children, as over the past two decades, only a limited number of clinical pediatric trials have been conducted in the US and EU. Pulmonary arterial hypertension (PAH) is a rare disease characterized by sustained elevation of pulmonary vascular resistance and pressure, resulting in refractory right ventricular dysfunction. Clinical trials using agents that act on three major pathways, prostacyclin PGI2/cAMP, NO/cGMP activation by phosphodiesterase (PDE)-5 inhibitors, and suppression of the activity of endothelin (ET)-1 by ET receptor antagonists (ERAs), have been performed mainly in adults. Most pediatric cardiologists treat PAH in children by conversion of normal adult dosages. However, such dosage modification in children is not always safe or effective. In addition, management of pediatric PAH is complex because of the variety of formulations, classes, and nature of the three major types of agent. The current trend in drug therapy for PAH recommends a so-called combination therapy; however, any pulmonary vasodilative agent has not been approved by their efficacy and safety for background disease-related PAH. PGI2 or epoprostenol (Flolan, GSK) has been recommended in NYHA-FC III and IV. However, some cases have been withdrawn from continuous infusion of Flolan in combination with inhaled PG12 (iloprost, treprostinil), subcutaneous PG12 (treprostinil), oral PGI2, (beraprost), ERA (bosetan, ambrisentan), or PDE5-I (sildenafil, tadalafil). Careful consideration and assessment of PK/PD and interactions of each class of drug are essential in children with PAH on a case-by-case basis. Clinical trials of bosentan, ambrisentan, sildenafil, and tadalafil for children have been conducted in Japan since 2012; however, no conclusive results have been obtained till date. In general, the efficacy and side effects seem to be similar to those in adults. Other critical drugs used in the treatment of PAH include sGC agonists; riociguat, a Rho-kinase inhibitor; Fasudil macitentan Opsumit, and inhaled iloprost, all of which have undergone clinical trials in adults. This chapter presents the current standard for medications used for pediatric PAH.