Safety and tolerability of rapid dose-titration of subcutaneous (SC) treprostinil in pulmonary arterial hypertension (PAH)

Background: The objective of this prospective, 16-week, open-label, multi-centre trial was to evaluate the safety/tolerability of rapid dose-titration of subcutaneous (SC) treprostinil in patients with PAH. Methods: SC treprostinil therapy was initiated at 2 ng/kg/min and then up-titrated in 1-2 ng/kg/min increments every 12 hours (whilst in hospital) or 24 hours (after discharge). The aim was to achieve dose rates of at least 10, 20, and 30 ng/kg/min by the end of weeks 1, 4 and 12, respectively and a dose rate by the end of week 16 that optimised the patient9s clinical response. Six minute walking distance (6MWD), WHO functional class (FC) and right heart catheterization were performed at baseline and after 3 months. Results: Thirty-nine PAH patients were enrolled (mean age 53 years; WHO FC II/III 15%/85%; mean 6MWD 355 m; mean PAP 55 mmHg; mean CI 2.2 L/min/m 2 ) of which 90% received dual oral PAH therapy. 32 (82%) completed the study. The mean treprostinil dose rate was 19, 27, 32 and 36 ng/kg/min after 4, 8, 12 and 16 weeks, respectively. After 3 months 6MWD (mean increase 40 m, SD 72); cardiac index (mean increase 0.4 L/min/m 2 ); WHO FC II/III/IV 38%/59%/3%) and NT-pro BNP (median reduction 182 pg/mL) improved compared to baseline. Common adverse reactions included infusion site pain/reaction, diarrhoea, headache, nausea, vomiting and jaw pain and lead to discontinuation of treatment in 7 patients. Conclusions: In this study cohort of PAH-patients, rapid up-titration of SC treprostinil, had an acceptable safety profile and was generally well tolerated. The add-on treatment with SC treprostinil improved exercise capacity, haemodynamics and WHO functional class.