Study With an Endothelin Receptor Antagonist in Pulmonary Arterial Hypertension to Improve Clinical Outcome | Clinical Trial - SERAPHIN


The goal of the trial was to evaluate the safety and efficacy of macitentan, a dual endothelin-receptor antagonist, in patients with pulmonary arterial hypertension (PAH).

Contribution to the Literature: The SERAPHIN trial showed that high and low doses of macitentan are safe and efficacious compared with placebo in improving hemodynamics, symptoms, and intermediate-term morbidity.

Study Design

Patients with PAH were randomized to macitentan 10 mg daily (n = 242), macitentan 3 mg daily (n = 250), or placebo (n = 250).

Inclusion criteria:

  • Idiopathic or heritable PAH
  • PAH related to connective tissue disease (CTD), repaired congenital systemic-to-pulmonary shunts, human immunodeficiency virus infection, or drug use or toxin exposure
  • 6-minute walk distance of 50 m or more
  • World Health Organization (WHO) class II, III, or IV symptoms

Exclusion criteria:

  • Use of intravenous or subcutaneous prostanoids
  • Total number of enrollees: 742
  • Duration of follow-up: 115 weeks
  • Mean patient age: 45.6 years
  • Percentage female: 76%

Other salient features/characteristics:

  • Idiopathic PAH: 55%, CTD-associated PAH: 31%
  • Baseline 6-minute walk distance: 360 m
  • WHO class II: 52%, III: 46%
  • Hemodynamics: pulmonary artery pressure 53.9 mm Hg, pulmonary capillary wedge pressure 9.6 mm Hg, cardiac index (CI) 2.39 L/min/m2, pulmonary vascular resistance (PVR) 1026 dynes/sec/cm5
  • Background pulmonary hypertension treatment: 64% (phosphodiesterase 5 inhibitors in 61%)

Principal Findings:

The primary outcome, first event related to PAH (worsening of PAH, initiation of treatment with intravenous or subcutaneous prostanoids, lung transplantation, or atrial septostomy) or death from any cause, occurred in 31.4% of the macitentan 10 mg group versus 38.0% of the macitentan 3 mg group versus 46.4% of the placebo group (hazard ratio [HR] 0.70, p < 0.001 for 10 mg vs. placebo; HR 0.55, p = 0.01 for 3 mg vs. placebo). This was driven predominantly by worsening of PAH (24.4% vs. 28.8% vs. 37.2%); all-cause mortality was similar (6.6% vs. 8.4% vs. 6.8%).

Secondary outcomes: All-cause hospitalization: 37.2% vs. 41.6% vs. 46.8%, hospitalization for PAH: 18.6% vs. 22.4% vs. 31.6%. At 6 months, change in 6-minute walk distance: +12.5 m vs. +7.4 m vs. -9.4 m (p < 0.05 for both groups vs. placebo). In the subset that had hemodynamic measurements on follow-up (n = 147), PVR had reduced in the macitentan arms (680 vs. 736 vs. 1042 dynes/sec/cm5), while CI had increased (2.93 vs. 2.69 vs. 2.21). Adverse events were overall similar, with events such as upper respiratory infection, nasopharyngitis, headache, bronchitis, and anemia being more common in the macitentan arms.


Among patients with PAH, macitentan reduced PVR and increased CI and improved 6-minute walk distance at 6 months, and reduced morbidity among patients with PAH; overall mortality was unchanged. The higher dose (10 mg) appeared to have greater benefit than low-dose macitentan (3 mg). Macitentan is a novel designer medication, developed by modifying the structure of bosentan, and functions as a dual endothelin-receptor antagonist.

These results are encouraging and add to the available shorter-term data with macitentan. Further longer-term data are necessary since PAH is a life-long disorder that tends to affect younger patients. Although patients with both on-treatment and treatment-naïve PAH were enrolled, the incremental benefit/role of macitentan when compared with other existing therapies is unknown. Cost-effectiveness analyses are also necessary.


Channick RN, Delcroix M, Ghofrani HA, et al. Effect of Macitentan on Hospitalizations: Results From the SERAPHIN Trial. JACC Heart Fail 2015;3:1-8.

Pulido T, Adzerikho I, Channick RN, et al., on behalf of the SERAPHIN Investigators. Macitentan and Morbidity and Mortality in Pulmonary Arterial Hypertension. N Engl J Med 2013;369:809-18.

Clinical Topics: Heart Failure and Cardiomyopathies, Prevention, Pulmonary Hypertension and Venous Thromboembolism, Vascular Medicine, Acute Heart Failure, Pulmonary Hypertension, Hypertension

Keywords: Hypertension, Hypertension, Pulmonary, Pulmonary Artery, Vascular Resistance, Connective Tissue Diseases, Endothelins, Hospitalization, Heart Failure, Venous Thromboembolism, Phosphodiesterase 5 Inhibitors, Nasopharyngitis

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