Clinical Research
Clinical Trial
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

https://doi.org/10.1016/j.jacc.2008.08.059Get rights and content
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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 dyn·s·cm−5; 95% CI: −283 to −104 dyn·s·cm−5; p < 0.0001) and cardiac index (TE: 0.3 l·min−1·m−2; 95% CI: 0.14 to 0.46 l·min−1·m−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).

Key Words

pulmonary endarterectomy
bosentan
operability
hemodynamics

Abbreviations and Acronyms

CI
confidence interval
CTEPH
chronic thromboembolic pulmonary hypertension
ET
endothelin
mPAP
mean pulmonary arterial pressure
NT-proBNP
N-terminal pro-brain natriuretic peptide
PAH
pulmonary arterial hypertension
PCWP
pulmonary capillary wedge pressure
PEA
pulmonary endarterectomy
PH
pulmonary hypertension
PVR
pulmonary vascular resistance
WHO
World Health Organization
6MWD
6-min walk distance

Cited by (0)

This study was funded by Actelion Pharmaceuticals. Dr. Jaïs has received consulting fees, speaking fees, and honoraria from Actelion and GlaxoSmithKline. Dr. D'Armini has received consulting fees for service as a Steering Committee member for Actelion Pharmaceuticals. Dr. Jansa has received honoraria from Actelion Pharmaceuticals and fees for consultancies from Actelion, Pfizer, GlaxoSmithKline, and AOP Orphan Pharmaceuticals. Dr. Torbicki has received speaker fees and honoraria for consultations from Actelion, Bayer-Schering, and GlaxoSmithKline. Dr. Delcroix has received consulting fees and research grants from Actelion. Dr. Ghofrani has received honoraria from Actelion, Bayer, Encysive Pharmaceuticals, Ergonex, Pfizer, and GlaxoSmithKline. Dr. Hoeper has received speaker fees and honoraria for consultations from Actelion Pharmaceuticals, Encysive Pharmaceuticals, Pfizer, and Bayer-Schering. Dr. Lang has received honoraria from Actelion, Bayer-Schering, Pfizer, AstraZeneca, GlaxoSmithKline, AOP Orphan Pharmaceuticals, and Encysive Pharmaceuticals, and grant support from Actelion Pharmaceuticals, the EU, and the Austrian government. Dr. Mayer has received speaker fees from Actelion and Bayer. Dr. Pepke-Zaba has received honoraria from Actelion, Encysive Pharmaceuticals, Pfizer, GlaxoSmithKline, and Bayer-Schering, and also holds educational grants funded in part or whole from Actelion, Lung Rx, Pfizer, and Schering. Dr. Simonneau has received honoraria for consultations and/or lecture fees from Pfizer, GlaxoSmithKline, Actelion, Lilly, United Therapeutics, and Bayer, and industry sponsored grants from Pfizer, GlaxoSmithKline, Actelion, Lilly, and United Therapeutics. Dr. Rubin has received consulting fees for service as a Steering Committee member and advisor, and honoraria for lectures from Actelion. Dr. Perchenet and Adele Morganti are employees of Actelion Pharmaceuticals Ltd. Valerie V. McLaughlin, MD, served as Guest Editor for this article.