Bosentan for treatment of inoperable chronic thromboembolic pulmonary hypertension: BENEFiT (Bosentan Effects in iNopErable Forms of chronIc Thromboembolic pulmonary hypertension), a randomized, placebo-controlled trial.

OBJECTIVES: Our goal was to investigate the effect of treatment with the oral dual endothelin receptor antagonist bosentan on the hemodynamics and exercise capacity of patients with chronic thromboembolic pulmonary hypertension (CTEPH).

BACKGROUND: CTEPH is characterized by vascular obstruction and remodeling, leading to increased pulmonary vascular resistance (PVR). Although pulmonary endarterectomy (PEA) is potentially curative, medical therapy is needed in patients with inoperable disease or persistent/recurrent pulmonary hypertension after PEA.

METHODS: The BENEFiT (Bosentan Effects in iNopErable Forms of chronIc Thromboembolic pulmonary hypertension) study was a double-blind, randomized, placebo-controlled study in CTEPH including patients with either inoperable CTEPH or persistent/recurrent pulmonary hypertension after PEA (>6 months after PEA). Independent coprimary end points were change in PVR as a percentage of baseline and change from baseline in 6-min walk distance after 16 weeks of treatment with bosentan or placebo. Secondary end points included change from baseline in World Health Organization functional class and other hemodynamic parameters.

RESULTS: One hundred fifty-seven patients were enrolled and randomized: 80 to placebo, 77 to bosentan. A statistically significant treatment effect (TE) of bosentan over placebo on PVR was demonstrated: -24.1% of baseline (95% confidence interval [CI]: -31.5% to -16.0%; p < 0.0001). Total pulmonary resistance (TE: -193 dynxsxcm(-5); 95% CI: -283 to -104 dyn.s.cm(-5); p < 0.0001) and cardiac index (TE: 0.3 lxmin(-1)xm(-2); 95% CI: 0.14 to 0.46 lxmin(-1)xm(-2); p = 0.0007) improved. Mean TE on 6-min walk distance was +2.2 m (95% CI: -22.5 to 26.8 m; p = 0.5449). Bosentan treatment was well tolerated.

CONCLUSIONS: This study demonstrated a positive TE of bosentan on hemodynamics in this patient population. No improvement was observed in exercise capacity. Further trials are needed to define the role of medical therapy in patients with CTEPH (Bosentan Effects in Inoperable Forms of Chronic Thromboembolic Pulmonary Hypertension; NCT00313222).