Endothelin receptor antagonism in single ventricle physiology with fontan palliation: A systematic review and meta-analysis

Background The prevalence of single ventricle patients palliated with Fontan operation continues to grow worldwide. This study systematically reviewed existing evidence and performed a meta-analysis to determine the safety and efficacy of endothelin receptor antagonism in single ventricle physiology with Fontan palliation. Methods Keyword and reference search was conducted in PubMed Cochrane Library, Web of Science, Google Scholar, and ClinicalTrials.gov databases. Inclusion criteria were - study design: randomized controlled trials, cohort studies, prospective studies, or retrospective studies; subjects: single ventricle patients with Fontan palliation; main outcome: exercise or functional capacity; language: English; and article type: peer-reviewed publications. Results Five studies met the inclusion criteria, including three pre-post studies, one randomized crossover open label clinical trial, and one double-blind randomized controlled clinical trial. Study durations ranged from 3.5 to 6 months, with a total sample size of 123. Bosentan was the single endothelin receptor blocker used in all studies. No significant increase in liver toxicity or other serious adverse events were reported in these studies. Meta-analysis found bosentan use to be associated with improvement in functional class (p = 0.0007); whereas no significant change in six-minute walk distance, resting oxygen saturation, and maximal oxygen consumption was identified. Conclusions Bosentan was found to be a safe and well tolerated endothelin receptor antagonist in Fontan patients over 3-6 months of therapy. Bosentan use was associated with improved functional capacity. Future studies with larger sample size and longer duration are warranted to examine the long-term safety and efficacy of endothelin blockade in Fontan physiology.