GRIPHON: Selexipag may reduce risk for death, complications in patients with pulmonary arterial hypertension
Patients with pulmonary arterial hypertension treated with a new oral, selective IP prostacyclin-receptor agonist had a lower risk for the primary composite endpoint of death or pulmonary arterial hypertension-related complications compared with patients who received placebo, according to results of the GRIPHON study published in The New England Journal of Medicine.
During the GRIPHON trial, a multicenter, double blind, randomized, parallel-group, placebo-controlled, event-driven, phase 3 study, Olivier Sitbon, MD, of the Université Paris-Sud, and colleagues investigated the safety and efficacy of selexipag (Uptravi, Actelion Pharmaceuticals).
The study included 1,156 patients aged 18 to 75 years who had idiopathic or heritable PAH or who had PAH associated with HIV, drug use, connective tissue disease or repaired congenital systemic-to-pulmonary shunts. The researchers collected data from 181 centers in 39 countries from December 2009 to May 2013.
All patients underwent right heart catheterization to confirm diagnosis. Other criteria included pulmonary vascular resistance of at least 5 Wood units (400 dyn.sec.cm-5) and a 6-minute walk distance of 50 m to 450 m.
Each patient was randomly assigned placebo or selexipag. Those patients assigned selexipag started with a dose of 200 µg, which was increased until adverse effects such as headache and jaw pain developed. Then, the dosage was decreased by 200 µg in both daily doses. The researchers determined that 1,600 µg twice daily was the highest dose patients could tolerate.
The primary endpoint was complications or death related to PAH. This included progression of PAH that led to hospitalization, long-term oxygen therapy or the need for lung transplantation. Markers such as a decrease of 15% or more in the 6-minute walk distance, an increase in WHO functional class and the need for more treatment were used to determine worsening of PAH.
The 582 patients in the placebo group were treated for a median length of 63.7 weeks, whereas the 574 patients assigned selexipag had a treatment period of a median length of 70.7 weeks. The primary endpoint was achieved in both groups: 41.6% of the placebo group and 27% of the selexipag group (HR = 0.6; 99% CI, 0.46-0.78). Of the primary endpoint events recorded, 81.9% were disease progression and hospitalization. According to the researchers, 23.5% of the placebo group and 17.8% of the selexipag group (HR = 0.7; 95% CI, 0.54-0.91) died from PAH or from hospitalization for disease progression. Death from any cause was 18% for the placebo group and 17.4% in the selexipag group (HR = 0.97; 95% CI, 0.74-1.28).
Among the placebo group, 7.1% of patients ended treatment early due to an adverse event vs. 14.3% of the selexipag group. In the selexipag group, 3.3% of patients discontinued because of headache, 2.3% because of diarrhea and 1.7% because of nausea. One patient had to discontinue treatment because of hyperthyroidism.
“In this event-driven study involving patients with [PAH], the risk of the primary composite endpoint of death or complication related to [PAH] was lower among those who received selexipag than among those who received placebo,” the researchers wrote. – by Tracey RomeroDisclosure: The study was supported by Actelion Pharmaceuticals. Sitbon reports receiving consulting, advisory board, lecture, committee and/or writing fees and grant support from Actelion, Bayer, GlaxoSmithKline, Pfizer and United Therapeutics. Please see the full study for a list of all other authors’ relevant financial disclosures.