Comparative Safety and Tolerability of Prostacyclins in Pulmonary Hypertension

Prostacyclin (PGI₂) is a prostaglandin derived from arachidonic acid in the endothelium and smooth muscle which causes vasodilation, inhibits platelet aggregation, and has anti-inflammatory, anti-thrombotic and anti-proliferative effects. In pulmonary arterial hypertension (PAH), PGI₂ levels and PGI₂ synthase expression are reduced, contributing to the vasoconstriction and vascular smooth muscle cell proliferation seen in the disease. Based on these findings, PGI₂ analogues were developed to target this pathway. Epoprostenol was the first targeted therapy available for treating PAH. Due to the short half-life of this drug, it requires administration via a continuous intravenous infusion, and therefore it carries the risks of central line infections and thrombosis. However, it remains the treatment of choice in patients with severe PAH as it has a proven survival benefit as well as improved functional class and exercise capacity. Subsequently, several other PGI₂ analogues have been developed with differing modes of administration and varying degrees of efficacy. Beraprost is an oral PGI₂ analogue for which a sustained efficacy has not been demonstrated. Iloprost is a nebulised PGI₂ analogue that requires administration six to nine times a day and leads to improved functional class, exercise capacity and haemodynamics. There are inhaled, oral, subcutaneous and intravenous forms of treprostinil. Subcutaneous treprostinil avoids the risks of a continuous intravenous administration; however, this drug can cause intractable pain at the injection site. Selexipag is the new oral non-prostanoid IP prostacyclin receptor agonist that has shown improved haemodynamics and good tolerance in a phase II study. Initial results of the phase III trial are promising. Comparison of the different PGI₂ agents is limited by a lack of head-to-head clinical trials. However, the development of PGI₂ analogues has improved survival in patients with PAH and remains the main treatment option in advanced disease. While PGI₂ analogues have good efficacy in PAH, they are not interchangeable, and their delivery systems have many limitations; in particular, they are associated with significant deleterious consequences. In the future, it is hoped that the elusive goal of developing an effective oral PGI₂ analogue will be achieved. This would increase the number of people who could benefit from the treatment while reducing the associated adverse events, and as a result improve the survival and quality of life for these patients.