Anders Hebert1, Ulla R Mikkelsen2, Ulf Thilen2, Lars Idorn2, Annette S Jensen2, Edit Nagy2, Katarina Hanseus2, Keld E Sørensen2, Lars Søndergaard2. 1. From the Department of Cardiology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark (A.H., L.I., A.S.J., L.S.); Institute of Sports Medicine, Department of Orthopedic Surgery, Bispebjerg Hospital and Center for Healthy Ageing, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark (U.R.M.); Departments of Cardiology (U.T.) and Pediatric Cardiology (K.H.), Lund University Hospital, Lund, Sweden; Department of Cardiology/Department of Medicine, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden (S.N.); and Department of Cardiology, Skejby, Aarhus University Hospital, Aarhus, Denmark (K.E.S.). andershebert@gmail.com. 2. From the Department of Cardiology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark (A.H., L.I., A.S.J., L.S.); Institute of Sports Medicine, Department of Orthopedic Surgery, Bispebjerg Hospital and Center for Healthy Ageing, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark (U.R.M.); Departments of Cardiology (U.T.) and Pediatric Cardiology (K.H.), Lund University Hospital, Lund, Sweden; Department of Cardiology/Department of Medicine, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden (S.N.); and Department of Cardiology, Skejby, Aarhus University Hospital, Aarhus, Denmark (K.E.S.).
Abstract
BACKGROUND: The Fontan procedure has improved survival in children with functionally univentricular hearts. With time, however, complications such as reduced exercise capacity are seen more frequently. Exercise intolerance is multifactorial, but pulmonary vascular resistance probably plays a crucial role. Elevated pulmonary vascular resistance has been associated with raised levels of endothelin-1, which are common both before and after Fontan operations. Treatment with endothelin-1 receptor antagonists could theoretically improve cardiopulmonary hemodynamics and exercise capacity. The aim of this study was therefore to examine the efficacy and safety of bosentan in Fontan patients. METHODS AND RESULTS: Seventy-five adolescents and adults were randomized 1:1 to 14 weeks of treatment with bosentan or placebo. Cardiopulmonary exercise test, functional class, blood samples, and quality-of-life questionnaires were evaluated at baseline and at the end of treatment. Sixty-nine patients (92%) completed the study. Peak oxygen consumption increased 2.0 mL·kg(-1)·min(-1) (from 28.7 to 30.7 mL·kg(-1)·min(-1)) in the bosentan group compared with 0.6 mL·kg(-1)·min(-1) (from 28.4 to 29.0 mL·kg(-1)·min(-1)) in the placebo group (P=0.02). Cardiopulmonary exercise test time increased by 0.48 minute (from 6.79 to 7.27 minutes) versus 0.08 minute (from 6.94 to 7.02 minutes; P=0.04). Nine bosentan-treated patients improved 1 functional class, whereas none improved in the placebo group (P=0.0085). Side effects were mild and occurred equally in both groups. No serious adverse effects were seen, and no patients had liver enzyme levels above the 3-fold upper limit. CONCLUSIONS: Bosentan improves exercise capacity, exercise time, and functional class in Fontan patients without serious adverse events or hepatotoxicity. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT01292551.
RCT Entities:
BACKGROUND: The Fontan procedure has improved survival in children with functionally univentricular hearts. With time, however, complications such as reduced exercise capacity are seen more frequently. Exercise intolerance is multifactorial, but pulmonary vascular resistance probably plays a crucial role. Elevated pulmonary vascular resistance has been associated with raised levels of endothelin-1, which are common both before and after Fontan operations. Treatment with endothelin-1 receptor antagonists could theoretically improve cardiopulmonary hemodynamics and exercise capacity. The aim of this study was therefore to examine the efficacy and safety of bosentan in Fontan patients. METHODS AND RESULTS: Seventy-five adolescents and adults were randomized 1:1 to 14 weeks of treatment with bosentan or placebo. Cardiopulmonary exercise test, functional class, blood samples, and quality-of-life questionnaires were evaluated at baseline and at the end of treatment. Sixty-nine patients (92%) completed the study. Peak oxygen consumption increased 2.0 mL·kg(-1)·min(-1) (from 28.7 to 30.7 mL·kg(-1)·min(-1)) in the bosentan group compared with 0.6 mL·kg(-1)·min(-1) (from 28.4 to 29.0 mL·kg(-1)·min(-1)) in the placebo group (P=0.02). Cardiopulmonary exercise test time increased by 0.48 minute (from 6.79 to 7.27 minutes) versus 0.08 minute (from 6.94 to 7.02 minutes; P=0.04). Nine bosentan-treated patients improved 1 functional class, whereas none improved in the placebo group (P=0.0085). Side effects were mild and occurred equally in both groups. No serious adverse effects were seen, and no patients had liver enzyme levels above the 3-fold upper limit. CONCLUSIONS:Bosentan improves exercise capacity, exercise time, and functional class in Fontan patients without serious adverse events or hepatotoxicity. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT01292551.
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