Adverse Events of Prostacyclin Mimetics in Pulmonary Arterial Hypertension: A Systematic Review and Meta-Analysis.

Prostacyclin mimetics (PMs) are effective for the treatment of pulmonary arterial hypertension (PAH). However, their clinical use may be limited by their adverse events. This study aims to quantify the different PM adverse events (AEs) with regard to their selectivity towards the prostacyclin (IP) receptor and their administrative routes. The study included randomised, placebo-controlled trials comparing iloprost, beraprost, treprostinil, and selexipag to placebo (published 2002–2016). We report the group efficacy differences between treatment and placebo by weighted and standardised mean difference. The probability of adverse events was determined by the odds ratio (OR). Of the 14 randomised clinical trials involving 3518 PAH patients, outcome and adverse event data were meta-analysed by drug type and route of administration. Prostacyclin mimetics comparison demonstrated a more significant discontinuation of the IP-selective agonist, selexipag, due to an adverse event (OR = 2.2; 95% CI: 1.5, 3.3). Compared to placebo, site pain associated with subcutaneously administered treprostinil was the most significant likely adverse event (OR = 17.5; 95% CI: 11.1, 27.1). Parenteral PMs were associated with fewer adverse effects overall. The overall efficacy of PMs to improve 6-minute walk distance by 16.3 meters was significant (95% CI: 13.0, 19.7). Decreases in pulmonary vascular resistance index (SMD = -5.5; 95% CI: -10.1, -0.9; I ² = 98%) and mean pulmonary arterial pressure (SMD = -1.0; 95% CI: -2.6, -0.7; I ² = 99%) in treatment groups were found to be significant. Adverse event profiles varied in response to administration route and PM type but were not negated by use of a selective IP agonist. Prostacyclin mimetics exposure to non-target IP receptors may underpin some AEs reported.
Competing Interests: C.P. is funded by a BBSRC Case PhD Studentship project which is partially funded by Lung Biotechnology, USA. Clapp has acted as a consultant and received research grants from United Therapeutics and Lung Biotechnology, USA. G.C. has received research grants from Actelion LTD (Johnson & Johnson), and honoraria and consultancy fees from Actelion; United Therapeutics; GSK; Pfizer & Bayer. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results