Comparative efficacy and acceptability of endothelin receptor antagonists for pulmonary arterial hypertension: A network meta-analysis.

BACKGROUND: Endothelin receptor antagonists (ERAs) such as ambrisentan, sitaxsentan, bosentan and macitentan are primary drug therapies for pulmonary arterial hypertension (PAH) patients. However, the optimal drugs for PAH remained controversial due to heterogeneous nature of randomized control trials (RCTs). METHODS: Apart from traditional meta-analysis, network meta-analysis (NMA) was performed in this study for multiple comparisons among PAH therapies. The 6 minute walking distance (6MWD) and clinical worsening were efficacy outcomes whereas serious adverse effects (SAE) and all-cause discontinuation were acceptability outcomes. The weighted mean difference (WMD) and odds ratio (OR) along with their 95% confidence interval (95% CI) or 95% credible interval (95% CrI) were used to evaluate the positive and negative effects of these therapies on PAH patients. RESULTS: By synthesizing direct evidence from 10 studies with a total number of 2172 patients, we discovered that all of the four PAH therapies significantly increased the average 6MWD in comparison to the placebo (P-value<0.05). Moreover, bosentan and ambrisentan both showed significant association with a decrease in the risk of clinical worsening compared to placebo. Regarding of all-cause discontinuation, ambrisentan is the only therapy which was significantly associated with a risk decrease compared to placebo. However, there was no sufficient evidence suggesting significant difference in any efficacy or acceptability outcomes between any two of the PAH therapies (P-value>0.05). CONCLUSION: Ambrisentan could be considered as the most appropriate therapy among the four ERAs for PAH patients. Bosentan also behaved well, but it is not as safe as ambrisentan.

Endothelin.

The endothelins comprise three structurally similar 21-amino acid peptides. Endothelin-1 and -2 activate two G-protein coupled receptors, ETA and ETB, with equal affinity, whereas endothelin-3 has a lower affinity for the ETA subtype. Genes encoding the peptides are present only among vertebrates. The ligand-receptor signaling pathway is a vertebrate innovation and may reflect the evolution of endothelin-1 as the most potent vasoconstrictor in the human cardiovascular system with remarkably long lasting action. Highly selective peptide ETA and ETB antagonists and ETB agonists together with radiolabeled analogs have accurately delineated endothelin pharmacology in humans and animal models, although surprisingly no ETA agonist has been discovered. ET antagonists (bosentan, ambrisentan) have revolutionized the treatment of pulmonary arterial hypertension, with the next generation of antagonists exhibiting improved efficacy (macitentan). Clinical trials continue to explore new applications, particularly in renal failure and for reducing proteinuria in diabetic nephropathy. Translational studies suggest a potential benefit of ETB agonists in chemotherapy and neuroprotection. However, demonstrating clinical efficacy of combined inhibitors of the endothelin converting enzyme and neutral endopeptidase has proved elusive. Over 28 genetic modifications have been made to the ET system in mice through global or cell-specific knockouts, knock ins, or alterations in gene expression of endothelin ligands or their target receptors. These studies have identified key roles for the endothelin isoforms and new therapeutic targets in development, fluid-electrolyte homeostasis, and cardiovascular and neuronal function. For the future, novel pharmacological strategies are emerging via small molecule epigenetic modulators, biologicals such as ETB monoclonal antibodies and the potential of signaling pathway biased agonists and antagonists.