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Bosentan for Inoperable Chronic Thromboembolic Pulmonary Hypertension: A Randomized, Placebo-Controlled Trial (BENEFiT)

X. Jais

Hossein-Ardeschir Ghofrani

Marius Hoeper

Irene Lang

Eckhard Mayer

Joanna Pepke-Zaba

Lewis Rubin

G. Simmoneau


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Conference: 2008 International PHA Conference and Scientific Sessions

Release Date: 06.20.2008

Presentation Type: Abstracts

Jaïs X.1, Ghofrani A.2, Hoeper M.M.3, Lang I.4, Mayer E.5, Pepke-Zaba J.6, Rubin L.J.7, Simonneau G.1

1. Hôpital Antoine Béclère, Université Paris-Sud, Clamart, France
2. University of Giessen Lung Center, Giessen, Germany
3. University of Hannover Medical School, Hannover, Germany
4. Medical University of Vienna, Vienna, Austria
5. Johannes Gutenberg University Medical School, Mainz, Germany
6. Papworth Hospital, Cambridge, UK
7. University of California, San Diego, La Jolla, CA, USA

BACKGROUND: Chronic thromboembolic pulmonary hypertension (CTEPH) is a life-threatening condition characterized by the presence of organized thrombotic material in the pulmonary arteries causing increased pulmonary vascular resistance (PVR) and progressive pulmonary hypertension (PH). Pulmonary endarterectomy (PEA) is the treatment of choice and is potentially curative. However, PEA is not an option for up to 50% of patients and 10-15% of patients experience persistent or recurrent PH post-PEA. Since the vascular features of CTEPH are similar to those of idiopathic pulmonary arterial hypertension (PAH), the efficacy and safety of the dual endothelin receptor antagonist, bosentan, was evaluated in patients with inoperable CTEPH or with persistent or recurrent post-operative PH.

METHODS: BENEFiT is the first multi-center, prospective, double-blind, placebo-controlled study of medical treatment for inoperable CTEPH or persistent/recurrent PH after PEA. Patients were randomized 1:1 to receive bosentan or placebo for 16 weeks (62.5 mg bid increasing to 125 mg bid after 4 weeks). Two independent co-primary endpoints were included: percentage change from baseline in PVR at rest at week 16 and change from baseline to week 16 in 6MWD. Patients were excluded from the primary analysis if they were considered ‘operable’ following randomization or if they had a missing baseline or post-baseline assessment. Other endpoints included: change from baseline to week 16 in WHO functional class, hemodynamics, time to clinical worsening, mixed venous oxygen saturation, change from baseline in N-terminal-prohormone-brain natriuretic peptide and Borg dyspnea index.

RESULTS: 157 patients were randomized to bosentan or placebo. Twenty patients were excluded from the PVR analysis (9 placebo, 11 bosentan) and 17 from the 6MWD analysis (7 placebo, 10 bosentan). Change in PVR from baseline to week 16 was +30 dyn·sec·cm-5 in the placebo group, compared with -146 dyn·cm·sec-5 in the bosentan group, which corresponds to a significant treatment effect of -24.1% (95% CI: -31.5, -16.0; p<0.0001). 6MWD increased in the placebo group at week 16 by 0.8 m vs 2.9 m in the bosentan group: a treatment effect of +2.2 m (95% CI: -22.5, 26.8; p = 0.5449). Hemodynamic parameters improved. Safety and tolerability were consistent with the established safety profile of bosentan.

CONCLUSIONS: These results suggest that bosentan improves hemodynamics in patients with inoperable CTEPH or with persistent or recurrent PH after PEA.