Current therapies for pulmonary arterial hypertension have been adopted on the basis of short-term trials with exercise capacity as the primary end point.
The SERAPHIN trial has assessed the efficacy of Macitentan, a new dual endothelin-receptor antagonist, using a primary endpoint of morbidity and mortality in a long-term trial.
Patients with symptomatic pulmonary arterial hypertension were randomly assigned to receive placebo once daily, Macitentan at a once-daily dose of 3 mg, or Macitentan at a once-daily dose of 10 mg.
Stable use of oral or inhaled therapy for pulmonary arterial hypertension, other than endothelin-receptor antagonists, was allowed at study entry.
The primary end point was the time from the initiation of treatment to the first occurrence of a composite end point of death, atrial septostomy, lung transplantation, initiation of treatment with intravenous or subcutaneous prostanoids, or worsening of pulmonary arterial hypertension.
A total of 250 patients were randomly assigned to placebo, 250 to the 3-mg Macitentan dose, and 242 to the 10-mg Macitentan dose.
The primary endpoint occurred in 46.4%, 38.0%, and 31.4% of the patients in these groups, respectively. The hazard ratio for the 3-mg Macitentan dose as compared with placebo was 0.70 ( P=0.01 ), and the hazard ratio for the 10-mg Macitentan dose as compared with placebo was 0.55 ( P less than 0.001 ).
Worsening of pulmonary arterial hypertension was the most frequent primary end-point event. The effect of Macitentan on this endpoint was observed regardless of whether the patient was receiving therapy for pulmonary arterial hypertension at baseline.
Adverse events more frequently associated with Macitentan than with placebo were headache, nasopharyngitis, and anemia.
In conclusion, Macitentan has significantly reduced morbidity and mortality among patients with pulmonary arterial hypertension in this event-driven study. ( Xagena )
Pulido T et al, N Engl J Med 2013; 369:809-818