A group of researchers reviewed the results from two clinical trials, STARTS-I and STARTS-II, testing the use of sildenafil as a therapy for children with pulmonary arterial hypertension (PAH), and concluded that additional studies are needed to fully understand sildenafil’s safety and efficacy in the long term. The review, titled “Safety and tolerability considerations in the use of sildenafil for children with pulmonary arterial hypertension” was published in the journal Drug, Healthcare and Patient Safety.
PAH induces pathological alterations in pulmonary arteries, leading to pulmonary vasoconstriction, inflammation, and remodeling of the vessel walls. These changes increase resistance to blood flow in the right side of the heart and in the arteries that supply blood to the lungs. Therefore, the heart has to work harder to pump blood through those arteries, and with time the heart muscle becomes weak.
Development of targeted PAH therapies over the last three decades have significantly improved patient outcomes. Among children with PAH, however, only two drugs have been tested in randomized controlled trials — inhaled nitric oxide (NO) and sildenafil.
Sildenafil, a phosphodiesterase type-5 inhibitor, was tested in two different trials, the Sildenafil in Treatment-Naïve Children, Aged 1 to 17 Years, With Pulmonary Arterial Hypertension (STARTS-I) trial and an extended trial, the STARTS-II. However, the results obtained in both were controversial, ranging from “safe and efficacious” to “dangerous and ineffective.”
A team of researchers now reviewed clinical presentation, diagnosis, and enrolled patients’ history of PAH. Although sildenafil was rigorously studied in adults with favorable safety and efficacy profiles, very few studies were conducted in children. In both STARTS-I and STARTS-II trials, sildenafil showed an acute adverse effect. However, at low dose, sildenafil failed to show a significant improvement in the primary trial endpoint (percent change in peak oxygen consumption) when compared to a placebo control. A high dose of sildenafil, conversely, was associated with increased mortality at long-term follow-up.
The team acknowledged that inconsistencies in both trials make the interpretation of the results difficult, and in fact, regulatory agencies have different recommendations, with the U.S. Food and Drug Administration (FDA) recommending against the use of sildenafil for treatment of PAH in children, while the European Medicines Agency supports its use when administered at “low doses.”
The authors concluded that additional studies are required to understand the long-term safety and efficacy of sildenafil, as well as other PAH therapies, to be administered in children.