Real-World Study Finds Oral Combination Therapy of Macitentan, Riociguat, and Selexipag Effective in PAH

Triple oral combination therapy with macitentan, riociguat, and selexipag may be a promising strategy to treat patients with low/intermediate-risk pulmonary arterial hypertension (PAH), and possibly even patients with high-risk PAH, according to a study published in Therapeutic Advances in Respiratory Disease.

PAH is a lethal disease, and there is currently a scarcity of evidence of the efficacy and safety of triple oral combination therapy. There are 3 pathways that are targeted in PAH treatment: the endothelin pathway, nitric oxide pathway, and prostacyclin pathway.

Research has shown the effectiveness of triple therapy, but the studies analyze the use of 2 oral therapies and an infusion. However, there are 3 oral therapies targeting each of the pathways: macitentan targets the endothelin pathway; riociguat targets the nitric oxide pathway; and selexipag targets the prostacyclin therapy.

The researchers conducted a retrospective study in Keio University Hospital in Japan evaluating patients with PAH who received the triple oral combination therapy of macitentan, riociguat, and selexipag. The patients in the study were divided into 2 groups based on the REVEAL 2.0 risk score: high risk, defined as patients with a predicted 1-year survival rate of less than 90%; and low/intermediate-risk, defined as patients with a predicted 1-year survival rate of 90% or greater.

In addition, patients who were treatment-naïve when they were enrolled were independently assessed. Most of the patients (65.4%) in the study were treatment-naïve.

In total, 26 patients were enrolled in the study. Of these, 4 (15%) discontinued the oral triple combination therapy due to adverse events. “Among these four patients, one had diarrhea with selexipag, one had suspected myelosuppression with macitentan, one had nausea with riociguat, and one had hypotension with riociguat,” the authors wrote. “These patients changed their drug to another drug targeting the same pathway.”

The study found that the combination therapy improved the hemodynamics, right ventricular function, and clinical function for patients. The median follow-up period for the hemodynamic analysis was 293 days and there was a 29% decrease in the mean pulmonary arterial pressure and a 66% decrease in the pulmonary arterial resistance. Cardiac output increased by 90% over the course of the study. The median follow-up period for echocardiography was 385 days and the findings indicated right ventricular function increased significantly.

The authors concluded that most of the low/intermediate-risk patients and about half of the high-risk patients could be treated sufficiently with this combination. However, they noted that “it is difficult to generalize these findings.” The small, single-center, retrospective nature of the study was one of the limitations the authors highlighted. Additional limitations were that some patients were not treatment-naïve at baseline and the unknown nature of how each etiology of PAH may have affected the results of the study.

“In particular, this triple oral combination therapy can be a promising therapeutic strategy in patients with low/intermediate risk and possibly even in half of patients with high risk,” the authors concluded. “Further investigation is required to validate these findings.”

Reference

Momoi M, Hiraide T, Shinya Y, et al. Triple oral combination therapy with macitentan, riociguat, and selexipag for pulmonary arterial hypertension. Ther Adv Respir Dis. Jan-Dec 2021;15:1753466621995048. doi:10.1177/1753466621995048