PURPOSE: Pulmonary arterial hypertension (PAH) is a debilitating, progressive condition with diverse etiologies. Combining treatments that target different PAH disease pathways (prostacyclin; nitric oxide; endothelin) may be critical in reducing PAH morbidity. The purpose of this study was to evaluate the safety and efficacy of adding continuous intravenous (IV) or subcutaneous (SC) treprostinil sodium to existing therapy with a phosphodiesterase type 5 inhibitor (PDE5I), an endothelin receptor antagonist (ERA), or the combination of a PDE5I and ERA.
METHODS: This was a multicenter, parallel group, open-label, 12-week study in patients with PAH receiving one of three therapies (PDE5I, ERA or PDE5I & ERA). All patients were declining in functional status and required prostanoid therapy. Following the addition of treprostinil, safety and efficacy were assessed by the six minute walk (6MW) test, Borg dyspnea score and adverse events (AEs).
RESULTS: Twenty patients enrolled in the study; 6 PDE5I, 7 ERA, and 7 PDE5I & ERA. Baseline mean (SEM) 6MW distance for all groups was 280(±20) meters. Overall, treprostinil improved mean 6MW distance by 35 (±24) meters at Week 12 (p=0.04). Mean improvement of 6MW for treprostinil added to PDE5I, ERA or the combination was 63 (±24), 5 (±40), and 36 (±49) meters, respectively. The Borg dyspnea score trended toward improvement with a mean reduction of 0.8 (p=0.06). Most AEs were those commonly associated with PAH therapies. Three patients discontinued prematurely: one central line infection (ERA), one death with worsening PAH (ERA), one lost to follow-up (PDE5I). The mean treprostinil dose was 24 ng/kg/min at Week 12.
CONCLUSION: Treprostinil, in combination with oral PAH therapies, has a satisfactory profile and appears to support improved 6MW and Borg dyspnea scores in patients deteriorating on oral therapies. Combination therapy was generally well tolerated. These results suggest that the low dose of treprostinil achieved in 12 weeks provided measurable benefit.
CLINICAL IMPLICATIONS: Few studies report the clinical effects of combining PAH therapies. More studies are needed to determine the optimal approach to combination therapies in PAH.
DISCLOSURE: Jeremy Feldman, No Financial Disclosure Information; No Product/Research Disclosure Information