Bosentan Improves Exercise Capacity in Adolescents and Adults After Fontan Operation: The TEMPO Study
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 (PVR) probably plays a crucial role. Elevated PVR 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 cardio-pulmonary 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 treatment with bosentan or placebo. Cardio-pulmonary exercise-test (CPET), functional class, blood samples and quality-of-life questionnaire were evaluated at baseline and at the end of treatment. Sixty-nine patients (92%) completed the study. Peak oxygen consumption increased 2.0 (from 28.7 to 30.7) ml/kg/min in the bosentan group compared to 0.6 (from 28.4 to 29.0) ml/kg/min in the placebo group, p=0.02. CPET time increased 0.48 (from 6.79 to 7.27) vs. 0.08 (from 6.94 to 7.02) minutes, p=0.04. Nine bosentan treated patients improved one 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 three-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 Information—www.clinicaltrials.gov. Identifier NCT01292551.
- randomized controlled trial
- Fontan procedure
- exercise testing
- congenital heart disease
- Received December 26, 2013.
- Revision received August 18, 2014.
- Accepted September 18, 2014.