Introduction and objectives Macitentan, a novel dual endothelin receptor antagonist with sustained receptor binding, significantly reduced the risk of morbidity and mortality in pulmonary arterial hypertension (PAH) patients in the SERAPHIN trial (NCT00660179), the first event-driven outcomes trial in PAH. The effect of macitentan on the risk of PAH-related hospitalisation was evaluated in this study.
Methods In SERAPHIN, a multicentre, double-blind, placebo-controlled trial in PAH, patients (aged =12 years) in WHO functional class II–IV were randomised (1:1:1) to oral macitentan 3mg, 10mg, or placebo once-daily. Time to death due to PAH or hospitalisation for PAH up to end of treatment (EOT), and time to hospitalisation for PAH up to EOT were evaluated (Kaplan–Meier analysis). Treatments were compared using log-rank tests. Annual rates of PAH-related hospitalisations and inpatient hospital days up to EOT were also assessed.
Results For the 742 patients randomised, the median treatment duration was >2 years. The risk of death due to PAH or hospitalisation for PAH was reduced vs placebo by 33% (97.5% CL: 3–54%; P = 0.0146) in the macitentan 3mg group and 50% (97.5% CL: 25–67%; P < 0.0001) in the macitentan 10mg group. Risk of hospitalisation for PAH was reduced by 39% (97.5% CL: 10–58%; P = 0.0040) with macitentan 3mg and 50% (97.5% CL: 24–66%; P = 0.0001) with macitentan 10mg. Overall, 33% (n = 82), 23% (n = 58), and 20% (n = 49) of patients randomised to placebo, macitentan 3mg, and macitentan 10mg, respectively, were hospitalised at least once for PAH. Compared with placebo, the rate of PAH-related hospitalisations and number of inpatient hospital days per year were reduced by 43% (P = 0.0068) and 33% (P = 0.2707), respectively, with macitentan 3mg, and by 55% (P = 0.0002) and 52% (P = 0.0416), respectively, with macitentan 10mg (Table). Macitentan was well tolerated, with similar incidences of elevated liver aminotransferases and peripheral oedema across groups. Adverse events more frequently associated with macitentan vs placebo were headache, nasopharyngitis, and anaemia.
Conclusions Macitentan significantly reduced the risk of hospitalisation for PAH and the number of PAH-related hospitalisations and inpatient days (10mg only). These data offer further evidence that macitentan has beneficial effects on long-term outcomes in PAH.