Abstract: Objective Analysis of the occurrence characteristics of adverse events of macitentan, ambrisentan and bosentan, in order to provide a reference for the clinical selection of endothelin receptor antagonists. Methods Based on all adverse event reports in the FDA Adverse Event Reporting System(FAERS) and Japanese Adverse Drug Event Report(JADER) database from October 1, 2013 through December 31, 2023. We used the reporting odds ratio (ROR) method and the information component (IC) method to calculate the signals of endothelin receptor antagonist-associated adverse events. The positive signals were analyzed and compared. Log-rank test and nonparametric test were used to compare the differences in the time to induce ADE of endothelin receptor antagonists. Results Based on two database, total of 35 150 adverse event reports were obtained for macitentan, 75 177 for ambrisentan, and 22 707 for bosentan. Macitentan and ambrisentan-induced anaemia was reported in highest numbers in JADER, and macitentan, ambrisentan and bosentan-induced fluid retention was reported in highest numbers in FAERS. Bosentan hepatic impairment PT signal intensity was significantly higher than that of macitentan and irisentan. Anemia signal ranked highest in JADER and fluid retention signal ranked highest in FAERS. Bosentan hepatic impairment PT signal strength was significantly higher than that of macitentan and irisentan. Macitentan anemia PT signal strength was significantly higher than that of anrisentan and bosentan. Anlisentan fluid retention PT signal strength was significantly higher than that of macitentan and bosentan. Adverse event signalling in minor patients revealed that bosentan was more likely to induce liver function test abnormalities in minor patients than other endothelin receptor antagonists. Ambrisentan was more likely to induce nasopharyngeal discomfort in minor patients. The use of macitentan in underage patients should focus on anaemia, thrombocytopenia, abnormal liver function tests, epistaxis, decreased blood pressure, and hypokalaemia. Macitentan combined with nitric oxide synthase inhibitor [173 (IQR 40~544)] is the fastest combination regimen to induce adverse events, and bosentan combined with prostacyclin receptor antagonistsa [632.5 (IQR 222.75~1 225.5)] had the longest time for the induction of adverse events. Conclusion There are differences in the signal intensity of risk of adverse events and the time of adverse event induction for different endothelin receptor antagonists. Individualized dosing and monitoring of patients should be carried out to reduce possible adverse events and ensure patient safety.

Key words: endothelin receptor antagonists, macitentan, ambrisentan, bosentan, adverse drug reaction/event, data mining, FAERS, JADER