• Olivier Sitbon, Richard Channick, Kelly M Chin, Aline Frey, Sean Gaine, Nazzareno Galiè, Hossein-Ardeschir Ghofrani, Marius M Hoeper, Irene M Lang, Ralph Preiss, Lewis J Rubin, Lilla Di Scala, Victor Tapson, Igor Adzerikho, Jinming Liu, Olga Moiseeva, Xiaofeng Zeng, Gérald Simonneau, Vallerie V McLaughlin, and GRIPHON Investigators.
• From Assistance Publique-Hôpitaux de Paris, Hôpital de Bicêtre, INSERM Unité Mixte de Recherche en Santé 999, Université Paris-Sud, Université Paris-Saclay, Le Kremlin-Bicêtre, France (O.S., G.S.); Massachusetts General Hospital, Boston (R.C.); UT Southwestern Medical Center, Dallas (K.M.C.); Actelion Pharmaceuticals, Allschwil, Switzerland (A.F., R.P., L.D.S.); National Pulmonary Hypertension Unit, Mater Misericordiae University Hospital, Dublin (S.G.); the Department of Experimental, Diagnostic and Specialty Medicine (DIMES) University of Bologna, Bologna, Italy (N.G.); University of Giessen and Marburg Lung Center, German Center of Lung Research, Giessen (H.-A.G), and the Department of Respiratory Medicine, Hannover Medical School and German Center of Lung Research, Hannover (M.M.H.) - both in Germany; the Department of Medicine, Imperial College London, London (H.-A.G.); Medical University of Vienna, Department of Internal Medicine II, Division of Cardiology, Allgemeines Krankenhaus, Vienna (I.M.L.); the Division of Pulmonary and Critical Care Medicine, University of California, San Diego (L.J.R.); the Division of Pulmonary and Critical Care Medicine, Cedars-Sinai Medical Center, Los Angeles (V.T.); Minsk Regional Clinical Hospital, Minsk, Belarus (I.A.); the Department of Pulmonary Circulation, Shanghai Pulmonary Hospital, Shanghai (J.L.), and the Department of Rheumatology, Peking Union Medical College Hospital, Beijing (X.Z.) - both in China; Federal Almazov North-West Medical Research Center, St. Petersburg, Russia (O.M.); and the Department of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan Health System, Ann Arbor (V.V.M.).
• N. Engl. J. Med. 2015 Dec 24;373(26):2522-33.

BackgroundIn a phase 2 trial, selexipag, an oral selective IP prostacyclin-receptor agonist, was shown to be beneficial in the treatment of pulmonary arterial hypertension.MethodsIn this event-driven, phase 3, randomized, double-blind, placebo-controlled trial, we randomly assigned 1156 patients with pulmonary arterial hypertension to receive placebo or selexipag in individualized doses (maximum dose, 1600 μg twice daily). Patients were eligible for enrollment if they were not receiving treatment for pulmonary arterial hypertension or if they were receiving a stable dose of an endothelin-receptor antagonist, a phosphodiesterase type 5 inhibitor, or both. The primary end point was a composite of death from any cause or a complication related to pulmonary arterial hypertension up to the end of the treatment period (defined for each patient as 7 days after the date of the last intake of selexipag or placebo).ResultsA primary end-point event occurred in 397 patients--41.6% of those in the placebo group and 27.0% of those in the selexipag group (hazard ratio in the selexipag group as compared with the placebo group, 0.60; 99% confidence interval, 0.46 to 0.78; P<0.001). Disease progression and hospitalization accounted for 81.9% of the events. The effect of selexipag with respect to the primary end point was similar in the subgroup of patients who were not receiving treatment for the disease at baseline and in the subgroup of patients who were already receiving treatment at baseline (including those who were receiving a combination of two therapies). By the end of the study, 105 patients in the placebo group and 100 patients in the selexipag group had died from any cause. Overall, 7.1% of patients in the placebo group and 14.3% of patients in the selexipag group discontinued their assigned regimen prematurely because of adverse events. The most common adverse events in the selexipag group were consistent with the known side effects of prostacyclin, including headache, diarrhea, nausea, and jaw pain.ConclusionsAmong 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 with selexipag than with placebo. There was no significant difference in mortality between the two study groups. (Funded by Actelion Pharmaceuticals; GRIPHON ClinicalTrials.gov number, NCT01106014.).

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