Macitentan did not significantly improve peak oxygen consumption compared to placebo in adolescents and adults with Fontan physiology over 52 weeks.
RCT (n=211)
Double-blind in some trials, crossover in others
Randomized
Sí
Do endothelin-receptor antagonists improve functional capacity and stabilize circulation in patients with failing Fontan physiology?
Endothelin-1 plays a key role in the pathophysiology of the failing Fontan circulation, and targeted therapies may improve outcomes if future trials utilize physiologically aligned endpoints like ventilatory efficiency rather than peak oxygen consumption.
Estimación del efecto: Neutral effect on peak VO2
The Fontan circulation, devised as definitive palliation for single-ventricle congenital heart disease, imposes systemic venous hypertension, loss of pulmonary arterial pulsatility, and restricted preload reserve. These hemodynamic trade-offs progressively injure the pulmonary vasculature, liver, and lymphatic system, producing late morbidities including elevated pulmonary vascular resistance, Fontan-associated liver disease (FALD), protein-losing enteropathy, and arrhythmias. Endothelin-1 (ET-1), a potent vasoconstrictor and profibrotic mediator, plausibly unifies these complications. Mechanistic studies demonstrate ET-1 upregulation in failed Fontan lungs, activating PLC–Ca 2+ , RhoA/ROCK, and MAPK/ERK cascades to drive vasoconstriction and remodeling. In cirrhotic livers, ET-1 localizes to stellate cells, promoting contraction and fibrogenesis, mechanisms biologically relevant to congestive FALD. Clinical cohorts consistently show elevated ET-1 correlating with hospitalization, exercise intolerance, and arrhythmias. Trials of endothelin-receptor antagonists (bosentan, ambrisentan, macitentan) demonstrate reassuring safety and suggest benefit when outcomes emphasize ventilatory efficiency or hepatic endpoints rather than peak oxygen consumption, which is physiologically constrained in Fontan physiology. Given the mixed results of existing trials, a framework is outlined that stratifies Fontan patients into pulmonary-inefficiency, congestive-hepatic, lymphatic, and arrhythmia-dominant phenotypes, using co-primary endpoints such as VE/VCO 2 slope, elastography, and biomarker panels. By linking ET-1 biology to pragmatic trial design, this approach emphasizes targeted strategies that may stabilize the circulation, extend transplant candidacy, and improve long-term outcomes.
Iman Maiza (Thu,) conducted a rct in Adolescents and adults with Fontan physiology (n=211). Macitentan vs. Placebo was evaluated on Peak oxygen consumption (peak VO2) (Neutral effect on peak VO2). Macitentan did not significantly improve peak oxygen consumption compared to placebo in adolescents and adults with Fontan physiology over 52 weeks.