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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

Xavier Jaïs, MD^_*,_*, Andrea M. D'Armini, MD, Pavel Jansa, MD, Adam Torbicki, MD, Marion Delcroix, MD^||, Hossein A. Ghofrani, MD^¶, Marius M. Hoeper, MD^#, Irene M. Lang, MD^_**, Eckhard Mayer, MD, Joanna Pepke-Zaba, MD, Loïc Perchenet, PhD, Adele Morganti, MSc, Gérald Simonneau, MD^_*, Lewis J. Rubin, MD^|||| for the BENEFiT Study Group

^_* Antoine Béclère Hospital, Clamart, France
Division of Cardiac Surgery, St. Matteo Hospital, University of Pavia School of Medicine, Pavia, Italy
Charles University, 1st Faculty of Medicine, 2nd Medical Department–Clinical Department of Cardiology and Angiology, Prague, Czech Republic
Department of Chest Medicine, Institute of Tuberculosis and Lung Diseases, Warsaw, Poland
^|| Department of Pulmonology, University Hospital Gasthuisberg, Leuven, Belgium
^¶ University of Giessen Lung Center, Giessen, Germany
^# Hannover Medical School, Hannover, Germany
^_** Medical University of Vienna, Vienna, Austria
Catholic Academic Hospital, Mainz, Germany
Papworth Hospital, Cambridge, United Kingdom
Actelion Pharmaceuticals Ltd., Allschwil, Switzerland
^|||| University of California, San Diego, La Jolla, California

Manuscript received May 22, 2008; revised manuscript received July 23, 2008, accepted August 12, 2008.

^_* Reprint requests and correspondence: Dr. Xavier Jaïs, Service de Pneumologie et Réanimation Respiratoire, Hôpital Antoine Béclère, 157 rue de la Porte de Trivaux, 92140 Clamart, France (Email: xavier.jais{at}abc.aphp.fr).

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

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