TY - JOUR

T1 - Bosentan Improves Exercise Capacity in Adolescents and Adults After Fontan Operation

T2 - The TEMPO (Treatment With Endothelin Receptor Antagonist in Fontan Patients, a Randomized, Placebo-Controlled, Double-Blind Study Measuring Peak Oxygen Consumption) Study

AU - Hebert, Anders

AU - Mikkelsen, Ulla Ramer

AU - Thilen, Ulf

AU - Idorn, Lars

AU - Jensen, Annette Schophuus

AU - Nagy, Edit

AU - Hanseus, Katarina

AU - Sørensen, Keld E

AU - Søndergård, Lars

N1 - © 2014 American Heart Association, Inc.

PY - 2014

Y1 - 2014

N2 - 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.

AB - 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.

KW - Adolescent

KW - Adult

KW - Child

KW - Child, Preschool

KW - Double-Blind Method

KW - Endothelin Receptor Antagonists

KW - Exercise Tolerance

KW - Female

KW - Fontan Procedure

KW - Hemodynamics

KW - Humans

KW - Infant

KW - Male

KW - Oxygen Consumption

KW - Placebos

KW - Postoperative Complications

KW - Receptor, Endothelin A

KW - Statistics, Nonparametric

KW - Sulfonamides

KW - Treatment Outcome

KW - Young Adult

U2 - 10.1161/CIRCULATIONAHA.113.008441

DO - 10.1161/CIRCULATIONAHA.113.008441

M3 - Journal article

C2 - 25446057

VL - 130

SP - 2021

EP - 2030

JO - Circulation

JF - Circulation

SN - 0009-7322

IS - 23

ER -