5017Subcutaneous treprostinil for the treatment of non-operable chronic thromboembolic pulmonary hypertension: a randomized, controlled trial (CTREPH)

Abstract

Background: Treprostinil, a prostacyclin analogue, is efective for the treatment of pulmonary arterial hypertension (PAH), but little information exists on treprostinil treatment of non-operable chronic thromboembolic pulmonary hypertension (CTEPH). Methods: In a phase III, double-blind, randomized, con-trolled, multicenter trial (ClinicalTrials.gov: NCT01416636) 105 patients (mean age 64 years, 46.7% females) with severe, non-operable CTEPH were randomly assigned to low-dose subcutaneous treprostinil (scTRE, target dose 3 ng/kg/min at week 12) or high-dose scTRE (target dose 30 ng/kg/min at week 12) in several European expert centers. Primary study endpoint was change from baseline in 6-minute walking distance (6MWD) at week 24. Secondary endpoints included clinical worsening and the change from baseline in hemodynamics, World Health Organization functional class (WHO FC), Borg dyspnea score, oxygen saturation, heart rate, NT-proBNP, quality of life and safety. Results: Patients predominantly in WHO FC class III and IV with a mean baseline 6MWD of 304 ± 78 m, a mean pulmonary artery pressure (mPAP) of 49 ± 11 mmHg and a mean pulmonary vascular resistance (PVR) of 827 ± 343 dyn.s.cm-5 were randomized to low dose scTRE (n = 52) or to high dose scTRE (n = 53). Four patients (three in the low-dose and one in the high-dose group) stopped treatment prior to week 24 because of infusion site pain and 5 patients were withdrawn because of clinical worsening (three in the high-dose and two in the low-dose group). Tree deaths occurred within the study period, two of which were in the high-dose group. By 24 weeks 6MWD had increased by a mean of 45 m in the high-dose group and by a mean of 4 m in the low-dose group (P = 0.0003). PVR decreased by a mean of 214 dyn.s.cm-5 in the high-dose group and increased by a mean of 73 dyn.s.cm-5 in the low-dose group (P = 0.00001). Mean PAP decreased by a mean of 3.5 mmHg in the high-dose group and by 0.4 mmHg in the low-dose group (P = 0.029). High-dose treprostinil was asso-ciated with a signifcant improvement of WHO FC (P = 0.003). Conclusions: Treatment with subcutaneous treprostinil was safe, and improved exercise capacity, hemodynamics, and WHO FC in patients with severe, non-operable CTEPH.