Addition of inhaled treprostinil to oral therapy for pulmonary arterial hypertension: a randomized controlled clinical trial.

OBJECTIVES: This study assessed the efficacy and safety of inhaled treprostinil in pulmonary arterial hypertension (PAH) patients receiving therapy with either bosentan or sildenafil.

BACKGROUND: There is no cure for PAH, despite effective treatments, and outcomes remain suboptimal. The addition of inhaled treprostinil, a long-acting prostacyclin analog, might be a safe and effective treatment addition to other PAH-specific oral therapies.

METHODS: Two hundred thirty-five PAH patients with New York Heart Association (NYHA) functional class III (98%) or IV symptoms and a 6-min walk distance (6MWD) of 200 to 450 m while treated with bosentan (70%) or sildenafil were randomized to inhaled treprostinil (up to 54 mug) or inhaled placebo 4 times daily. The primary end point was peak 6MWD at 12 weeks. Secondary end points included time to clinical worsening, Borg Dyspnea Score, NYHA functional class, 12-week trough 6MWD, 6-week peak 6MWD, quality of life, and PAH signs and symptoms. The biomarker N-terminal pro-brain natriuretic peptide (NT-proBNP) was assessed.

RESULTS: Twenty-three patients withdrew from the study prematurely (13 treprostinil, 10 placebo). The Hodges-Lehmann between-treatment median difference in change from baseline in peak 6MWD was 19 m at week 6 (p = 0.0001) and 20 m at week 12 (p = 0.0004). Hodges-Lehmann between-treatment median difference in change from baseline in trough 6MWD at week 12 was 14 m (p = 0.0066). Quality of life measures and NT-proBNP improved on active therapy. There were no improvements in other secondary end points, including time to clinical worsening, Borg Dyspnea Score, NYHA functional class, and PAH signs and symptoms. Inhaled treprostinil was safe and well-tolerated.

CONCLUSIONS: This trial demonstrates that, among PAH patients who remain symptomatic on bosentan or sildenafil, inhaled treprostinil improves exercise capacity and quality of life and is safe and well-tolerated. (TRIUMPH I: Double Blind Placebo Controlled Clinical Investigation Into the Efficacy and Tolerability of Inhaled Treprostinil Sodium in Patients With Severe Pulmonary Arterial Hypertension; NCT00147199).