A multicenter, double-blind, randomized, placebo-controlled, event-driven, phase 3 trial investigated whether long-term treatment with macitentan reduces clinical worsening events among patients with PAH.34 Patients ≥ 12 years of age who had IPAH or PAH related to connective tissue disease, repaired congenital systemic-to-pulmonary shunts, HIV infection, or drug use or toxin exposure were eligible for inclusion. Confirmation of PAH by right-sided heart catheterization was required, as was a 6MWD ≥ 50 m and WHO FC II, III, or IV. At the time of entry into the study, > 60% of patients were on treatment with oral phosphodiesterase-5 (PDE5) inhibitors, oral or inhaled prostanoids, CCBs, or l-arginine. Patients receiving IV or subcutaneous prostanoids were excluded. Patients were randomly assigned in a 1:1:1 ratio to receive placebo once daily (n = 250), macitentan at a once-daily dose of 3 mg (n = 250), or macitentan at a once-daily dose of 10 mg (n = 242). The composite primary end point was the time from the initiation of treatment to the first event related to PAH (worsening of PAH, initiation of treatment with IV or subcutaneous prostanoids, lung transplantation, or atrial septostomy) or death from any cause up to the end of treatment. Secondary end points included the change from baseline to month 6 in the 6MWD, the percentage of patients with an improvement in WHO FC at month 6, death due to PAH or hospitalization for PAH up to the end of treatment, and death from any cause up to the end of treatment and up to the end of the study. A total of 287 patients had a primary end point event over a median treatment period of 115 weeks: 116 patients (46.4%) in the placebo group, 95 patients (38.0%) in the group that received 3 mg of macitentan, and 76 patients (31.4%) in the group that received 10 mg of macitentan. Worsening of PAH was the most frequent primary end point event. The HR for the primary end point with the 3-mg dose of macitentan vs placebo was 0.70 (97.5% CI, 0.52-0.96; P = .01), and the HR with the 10-mg dose of macitentan vs placebo was 0.55 (97.5% CI, 0.39-0.76; P < .001). At month 6, the 6MWD had decreased by a mean of 9.4 m in the placebo group and increased by a mean of 7.4 m in the group that received 3 mg of macitentan (treatment effect with 3-mg dose vs placebo, 16.8 m; 97.5% CI, −2.7 to 36.4; P = .01) and by a mean of 12.5 m in the group that received 10 mg of macitentan (treatment effect with 10-mg dose vs placebo, 22.0 m; 97.5% CI, 3.2-40.8; P = .008). The number of patients in the placebo, 3-mg macitentan, and 10-mg macitentan groups who discontinued the study drug owing to adverse events was 31 (12.4%), 34 (13.6%), and 26 (10.7%), respectively. The incidences of peripheral edema and of alanine aminotransferase or aspartate aminotransferase levels that were more than three times the upper limit of the normal range were similar across the three groups. As compared with patients who received placebo, higher percentages of patients in the two macitentan groups had nasopharyngitis, headache, and anemia. Three patients, one in each group, discontinued treatment because of anemia.