Bosentan Improves Exercise Capacity in Adolescents and Adults After Fontan Operation

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.

Emerging Research Directions in Adult Congenital Heart Disease

“…Some small biological studies have explored organ physiology, such as the gastrointestinal system in protein-losing enteropathy or the respiratory system and mechanics related to functional capacity. There are also case reports, small series, and a few trials assessing outcomes with medications used to improve physiology or hemodynamics, such as anti-inflammatories or pulmonary vasodilators (51,52). Gathering clinical and biological data from a multicenter longitudinal cohort would be beneficial in understanding the multiorgan interactions; however, data may be more quickly available from a diverse cross-sectional cohort of patients of different ages.…”

D-optimal Design for Preparation and Optimization of Fast Dissolving Bosentan Nanosuspension

“…4 Bosentan is an orally active, selective and competitive non-peptide dual endothelin receptor (both ET A and ET B ) antagonist and usually used in cure of PAH. 5 Bosentan is also being considered for treatment of other conditions such as Eisenmenger syndrome, 6 persistent pulmonary hypertension of the newborn, 7 digital ulcer prevention in patients with systemic sclerosis, 8 adolescent and adult patients who have undergone Fontan operation, 9 vascular remodeling and dysfunctional angiogenesis in diabetes 10 and possibly even depression. 11 For treatment of PAH, bosetan is currently administered at the daily dose of 125-250 mg. 12 The maximum plasma peak is seen within 3-5 h after oral intake and the half-life of drug is 5.4 h. 13 Moreover, the bioavailability of bosentan after oral administration is approximately low (50%) 14 and variability is seen in bosentan absorption which may get back to its poor water solubility.…”

Fontan Circulation

“…In this study, the authors evaluate the effect of bosentan, an endothelin-1 receptor antagonist, on exercise performance in adolescents and young adults with Fontan physiology. 6 The authors demonstrate a small but statistically significant improvement in oxygen consumption during peak exercise after 14 weeks of treatment compared with placebo. The TEMPO trial is well designed and well executed and adds significantly to the growing literature evaluating the potential role of modulators of pulmonary vascular resistance (PVR) in those who have undergone the Fontan operation.…”