Although treatment options exist, patients with pulmonary arterial hypertension have a poor prognosis. Current recommendations include combination therapies that target the endothelin, nitric oxide, and prostacyclin pathways. The burden and risks of the administration of intravenous prostacyclin therapy likely contribute to the many patients who die before receiving this treatment. Selexipag, an oral selective IP prostacyclin-receptor agonist, is structurally different from prostacyclin. A previous phase 2 trial showed that selexipag increased the cardiac index and significantly reduced pulmonary vascular resistance by 33% in patients who were already receiving treatment for pulmonary arterial hypertension.
To further explore these results, Olivier Sitbon, MD, Hôpitaux de Paris, Hôpital de Bicêtre, INSERM Unité Mixte de Recherche en Santé 999, Université Paris-Sud, Universite Paris-Saclay, Le Kremlin-Bicêtre, France, and colleagues conducted a phase 3 trial, the Prostacyclin (PGI2) Receptor Agonist in Pulmonary Arterial Hypertension (GRIPHON) study, to investigate the safety and efficacy of selexipag in patients with pulmonary arterial hypertension who were and were not already receiving therapy at baseline. Selexipag was shown to be beneficial for this patient population.
The GRIPHON study was an event-driven, randomized, double-blind, multicenter, parallel-group, placebo-controlled trial from December 2009 through May 2013 wherein the study authors randomly designated 1156 patients with pulmonary arterial hypertension to receive placebo (582 patients) or selexipag (574 patients) in customized doses, with a maximum dose of 1600 µg twice daily. Study participants were aged 18 to 75 years, and had idiopathic or heritable pulmonary arterial hypertension. Patients eligible for enrollment included those not receiving treatment for pulmonary arterial hypertension, and those who were receiving an endothelin receptor antagonist and/or a phosphodiesterase type 5 inhibitor at a stable dose for ≥3 months. Patients receiving prostacyclin analogues were ineligible. The primary end point was death from any cause, or a complication related to pulmonary arterial hypertension up to 7 days after the last intake of selexipag or placebo. Secondary end points included the change in 6-minute walking distance from baseline to week 26, no worsening of the World Health Organization (WHO) functional class status from baseline to week 26, and death as a result of pulmonary arterial hypertension.
A total of 242 (41.6%) patients in the placebo group and 155 (27.0%) patients in the selexipag group experienced a primary end point event; disease progression and hospitalization caused 81.9% of the primary end point events. From baseline, the 6-minute walk distance had decreased by a median of 9.0 meters in the placebo group, and increased by 4.0 meters in the selexipag group at week 26. There was no significant variance in worsening of WHO functional class status between the groups. Death as a result of pulmonary arterial hypertension or hospitalization for worsening of pulmonary arterial hypertension occurred in 137 (23.5%) patients in the placebo group and in 102 (17.8%) patients in the selexipag group. In the selexipag group, the most frequent adverse events leading to discontinuation were headache (3.3%), diarrhea (2.3%), and nausea (1.7%).
The risk for death or a complication related to pulmonary arterial hypertension was lower among patients who received selexipag than those who received placebo. There was no significant difference in mortality between the 2 groups, and the results of selexipag were consistent in all prespecified patient subgroups. "Among patients with pulmonary arterial hypertension, the risk of the primary composite end point of death or a complication related to pulmonary arterial hypertension was significantly lower among patients who received selexipag than among those who received placebo," Dr Sitbon and colleagues concluded.
- Sitbon O, Channick R, Chin KM, et al. Selexipag for the treatment of pulmonary arterial hypertension. N Engl J Med. 2015;373:2522-2533.