title: Bosentan improves exercise capacity in adolescents and adults after Fontan operation: the TEMPO (Treatment With Endothelin Receptor Antagonist in Fontan Patients, a Randomized, Placebo-Controlled, Double-Blind Study Measuring Peak Oxygen Consumption) study.
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.
  
  
  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.
  
  
  BACKGROUND
  http://www.clinicaltrials.gov. Unique identifier: NCT01292551.
authors.affiliation: 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.
authors.forename: Anders
authors.initials: A
authors.lastname: Hebert
authors.affiliation: 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.).
authors.forename: Ulla R
authors.initials: UR
authors.lastname: Mikkelsen
authors.affiliation: 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.).
authors.forename: Ulf
authors.initials: U
authors.lastname: Thilen
authors.affiliation: 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.).
authors.forename: Lars
authors.initials: L
authors.lastname: Idorn
authors.affiliation: 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.).
authors.forename: Annette S
authors.initials: AS
authors.lastname: Jensen
authors.affiliation: 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.).
authors.forename: Edit
authors.initials: E
authors.lastname: Nagy
authors.affiliation: 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.).
authors.forename: Katarina
authors.initials: K
authors.lastname: Hanseus
authors.affiliation: 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.).
authors.forename: Keld E
authors.initials: KE
authors.lastname: Sørensen
authors.affiliation: 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.).
authors.forename: Lars
authors.initials: L
authors.lastname: Søndergaard
mesh_terms: D000293:Adolescent; D000328:Adult; D000077300:Bosentan; D002648:Child; D002675:Child, Preschool; D004311:Double-Blind Method; D065128:Endothelin Receptor Antagonists / Q000008:administration & dosage* / Q000009:adverse effects; D017079:Exercise Tolerance / Q000187:drug effects*; D005260:Female; D018729:Fontan Procedure / Q000009:adverse effects*; D006439:Hemodynamics; D006801:Humans; D007223:Infant; D008297:Male; D010101:Oxygen Consumption / Q000187:drug effects*; D010919:Placebos; D011183:Postoperative Complications / Q000188:drug therapy*; D044022:Receptor, Endothelin A / Q000097:blood; D018709:Statistics, Nonparametric; D013449:Sulfonamides / Q000008:administration & dosage* / Q000009:adverse effects; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D065128:Endothelin Receptor Antagonists; D010919:Placebos; D044022:Receptor, Endothelin A; D013449:Sulfonamides; D000077300:Bosentan
keywords: Fontan procedure; bosentan; exercise test; heart defects, congenital; vasodilation