Safety, Tolerability and Clinical Effects of a Rapid Dose Titration of Subcutaneous Treprostinil Therapy in Pulmonary Arterial Hypertension: A Prospective Multi-Centre Trial

Abstract

Background: Subcutaneous treprostinil has dose-dependent beneficial effects in patients with severe pulmonary arterial hypertension, but adverse effects like infusion site pain can lead to treatment discontinuation. Objectives: The objective of this study was to evaluate safety, tolerability and clinical effects of a rapid up-titration dosing regimen of subcutaneous treprostinil using proactive infusion site pain management. Methods: Effects of rapid up-titration dosing regimen on tolerability and clinical parameters were evaluated in this 16-week, open-label multi-centre study. Results: Thirty-nine patients with idiopathic or heritable pulmonary arterial hypertension on stable treatment with oral pulmonary arterial hypertension-approved drugs (90% on dual combination therapy) were included. Patients achieved a median treprostinil dosage of 35.7 ng/kg/min after 16 weeks. A good overall safety profile was demonstrated with 3 patients (8%) withdrawing due to infusion site pain, which occurred in 97% of patients. After 16 weeks, median 6-min walking distance, cardiac index, pulmonary vascular resistance, and tricuspid annular plane systolic excursion improved. Conclusions: Rapid up-titration of subcutaneous treprostinil was well tolerated, achieving a clinically effective dose associated with improvement of exercise capacity and haemodynamics after 16 weeks. A rapid dose titration regimen and proactive infusion site pain management may improve the handling of this therapy and contribute to better treatment outcome.

Targeted therapy of pulmonary arterial hypertension: Updated recommendations from the Cologne Consensus Conference 2018

“…The main side effect of subcutaneous treprostinil is infusion site pain, which occurs in N80% of patients and cannot always be satisfactorily treated [42]. According to a small, uncontrolled study, rapid uptitration to clinically effective dose and proactive infusion site pain management seemed to be better tolerated and improved exercise capacity and haemodynamics after 16 weeks [44].…”

Novel dose–response analyses of treprostinil in pulmonary arterial hypertension and its effects on six‐minute walk distance and hospitalizations

“…Grünig and colleagues performed an open-label study of SC treprostinil which utilized a rapid uptitration dosing regimen in 39 patients with PAH. 30 The authors did not observe an association with higher doses of SC treprostinil and longer 6MWD. The majority of patients were on dual background therapy of a PDE-5 inhibitor and ERA ( n = 35, 90%) and the lack of a dose–response finding could be explained by a diminished response in a heavily pre-treated population.…”

Titration of pulmonary arterial hypertension therapeutics: Experience-based recommendations

“…Slow up-titration was initially used as a means to address infusion site pain, but was based on an incorrect assumption of dose dependence. More recent studies have found that more rapid dose titration combined with proactive infusion site pain management leads to fewer withdrawals due to infusion site pain, along with better clinical outcomes [28].…”