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(Circulation. 2006;114:48-54.)
© 2006 American Heart Association, Inc.

Vascular Medicine

Bosentan Therapy in Patients With Eisenmenger Syndrome

A Multicenter, Double-Blind, Randomized, Placebo-Controlled Study

Nazzareno Galiè, MD; Maurice Beghetti, MD; Michael A. Gatzoulis, MD; John Granton, MD; Rolf M.F. Berger, MD; Andrea Lauer, PhD; Eleonora Chiossi, MSc; Michael Landzberg, MD, for the Bosentan Randomized Trial of Endothelin Antagonist Therapy-5 (BREATHE-5) Investigators

From the Istituto di Cardiologia, Università di Bologna, Bologna, Italy (N.G.); Cardiology Unit, Hôpital des Enfants, Geneva, Switzerland (M.B.); Adult Congenital Heart Centre, Royal Brompton Hospital, and the National Heart and Lung Institute, Imperial College, London, UK (M.A.G.); Toronto General Hospital, Toronto, Ontario, Canada (J.G.); University Medical Center of Groningen, Groningen, the Netherlands (R.M.F.B.); Actelion Pharmaceuticals Ltd, Allschwil, Switzerland (A.L., E.C.); and Boston Adult Congenital Heart and Pulmonary Hypertension Group, Children’s Hospital, BWH and BIDMC, Boston, Mass (M.L.).

Reprint requests to Nazzareno Galiè, MD, Istituto di Cardiologia, Università di Bologna, Via Massarenti, 9 IT-40138, Bologna, Italy. E-mail nazzareno.galie{at}unibo.it

Received March 30, 2006; revision received April 26, 2006; accepted April 28, 2006.

Background— Eisenmenger syndrome is characterized by the development of pulmonary arterial hypertension with consequent intracardiac right-to-left shunt and hypoxemia in patients with preexisting congenital heart disease. Because Eisenmenger syndrome is associated with increased endothelin expression, patients may benefit from endothelin receptor antagonism. Theoretically, interventions that have some effect on the systemic vascular bed could worsen the shunt and increase hypoxemia.

Methods and Results— The Bosentan Randomized Trial of Endothelin Antagonist Therapy-5 (BREATHE-5) was a 16-week, multicenter, randomized, double-blind, placebo-controlled study evaluating the effect of bosentan, a dual endothelin receptor antagonist, on systemic pulse oximetry (primary safety end point) and pulmonary vascular resistance (primary efficacy end point) in patients with World Health Organization functional class III Eisenmenger syndrome. Hemodynamics were assessed by right- and left-heart catheterization. Secondary end points included exercise capacity assessed by 6-minute walk distance, additional hemodynamic parameters, functional capacity, and safety. Fifty-four patients were randomized 2:1 to bosentan (n=37) or placebo (n=17) for 16 weeks. The placebo-corrected effect on systemic pulse oximetry was 1.0% (95% confidence interval, –0.7 to 2.8), demonstrating that bosentan did not worsen oxygen saturation. Compared with placebo, bosentan reduced pulmonary vascular resistance index (–472.0 dyne · s · cm^–5; P=0.0383). The mean pulmonary arterial pressure decreased (–5.5 mm Hg; P=0.0363), and the exercise capacity increased (53.1 m; P=0.0079). Four patients discontinued as a result of adverse events, 2 (5%) in the bosentan group and 2 (12%) in the placebo group.

Conclusions— In this first placebo-controlled trial in patients with Eisenmenger syndrome, bosentan was well tolerated and improved exercise capacity and hemodynamics without compromising peripheral oxygen saturation.

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