title: Comparative Safety and Tolerability of Prostacyclins in Pulmonary Hypertension.
abstract: Prostacyclin (PGI2) is a prostaglandin derived from arachidonic acid in the endothelium and smooth muscle which causes vasodilation, inhibits platelet aggregation, and has anti-inflammatory, anti-thrombotic and anti-proliferative effects. In pulmonary arterial hypertension (PAH), PGI2 levels and PGI2 synthase expression are reduced, contributing to the vasoconstriction and vascular smooth muscle cell proliferation seen in the disease. Based on these findings, PGI2 analogues were developed to target this pathway. Epoprostenol was the first targeted therapy available for treating PAH. Due to the short half-life of this drug, it requires administration via a continuous intravenous infusion, and therefore it carries the risks of central line infections and thrombosis. However, it remains the treatment of choice in patients with severe PAH as it has a proven survival benefit as well as improved functional class and exercise capacity. Subsequently, several other PGI2 analogues have been developed with differing modes of administration and varying degrees of efficacy. Beraprost is an oral PGI2 analogue for which a sustained efficacy has not been demonstrated. Iloprost is a nebulised PGI2 analogue that requires administration six to nine times a day and leads to improved functional class, exercise capacity and haemodynamics. There are inhaled, oral, subcutaneous and intravenous forms of treprostinil. Subcutaneous treprostinil avoids the risks of a continuous intravenous administration; however, this drug can cause intractable pain at the injection site. Selexipag is the new oral non-prostanoid IP prostacyclin receptor agonist that has shown improved haemodynamics and good tolerance in a phase II study. Initial results of the phase III trial are promising. Comparison of the different PGI2 agents is limited by a lack of head-to-head clinical trials. However, the development of PGI2 analogues has improved survival in patients with PAH and remains the main treatment option in advanced disease. While PGI2 analogues have good efficacy in PAH, they are not interchangeable, and their delivery systems have many limitations; in particular, they are associated with significant deleterious consequences. In the future, it is hoped that the elusive goal of developing an effective oral PGI2 analogue will be achieved. This would increase the number of people who could benefit from the treatment while reducing the associated adverse events, and as a result improve the survival and quality of life for these patients.
authors.affiliation: Univ. Paris-Sud, Faculté de Médecine, Université Paris-Saclay, Le Kremlin-Bicêtre, France.|AP-HP, Hôpital Bicêtre, Service de Pneumologie et Soins Intensifs, Centre de Référence del'Hypertension Pulmonaire Sévère, DHU Thorax Innovation, Le Kremlin-Bicêtre, France.|INSERM UMR_S999, LabEx LERMIT, Centre Chirurgical Marie Lannelongue, Le Plessis Robinson, France.
authors.forename: Caroline
authors.initials: C
authors.lastname: O'Connell
authors.affiliation: Univ. Paris-Sud, Faculté de Médecine, Université Paris-Saclay, Le Kremlin-Bicêtre, France.|AP-HP, Hôpital Bicêtre, Service de Pneumologie et Soins Intensifs, Centre de Référence del'Hypertension Pulmonaire Sévère, DHU Thorax Innovation, Le Kremlin-Bicêtre, France.|INSERM UMR_S999, LabEx LERMIT, Centre Chirurgical Marie Lannelongue, Le Plessis Robinson, France.
authors.forename: David
authors.initials: D
authors.lastname: Amar
authors.affiliation: Univ. Paris-Sud, Faculté de Médecine, Université Paris-Saclay, Le Kremlin-Bicêtre, France.|AP-HP, Hôpital Bicêtre, Service de Pneumologie et Soins Intensifs, Centre de Référence del'Hypertension Pulmonaire Sévère, DHU Thorax Innovation, Le Kremlin-Bicêtre, France.|INSERM UMR_S999, LabEx LERMIT, Centre Chirurgical Marie Lannelongue, Le Plessis Robinson, France.
authors.forename: Athénaïs
authors.initials: A
authors.lastname: Boucly
authors.affiliation: Univ. Paris-Sud, Faculté de Médecine, Université Paris-Saclay, Le Kremlin-Bicêtre, France.|AP-HP, Hôpital Bicêtre, Service de Pneumologie et Soins Intensifs, Centre de Référence del'Hypertension Pulmonaire Sévère, DHU Thorax Innovation, Le Kremlin-Bicêtre, France.|INSERM UMR_S999, LabEx LERMIT, Centre Chirurgical Marie Lannelongue, Le Plessis Robinson, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Savale
authors.affiliation: Univ. Paris-Sud, Faculté de Médecine, Université Paris-Saclay, Le Kremlin-Bicêtre, France.|AP-HP, Hôpital Bicêtre, Service de Pneumologie et Soins Intensifs, Centre de Référence del'Hypertension Pulmonaire Sévère, DHU Thorax Innovation, Le Kremlin-Bicêtre, France.|INSERM UMR_S999, LabEx LERMIT, Centre Chirurgical Marie Lannelongue, Le Plessis Robinson, France.
authors.forename: Xavier
authors.initials: X
authors.lastname: Jaïs
authors.affiliation: INSERM UMR_S999, LabEx LERMIT, Centre Chirurgical Marie Lannelongue, Le Plessis Robinson, France.|Univ. Paris-Sud, Faculté de Pharmacie, Université Paris-Saclay, Chatenay-Malabry, France.|APHP, Hôpital Antoine Béclère, Service de Pharmacie, Clamart, France.
authors.forename: Marie-Camille
authors.initials: MC
authors.lastname: Chaumais
authors.affiliation: Univ. Paris-Sud, Faculté de Médecine, Université Paris-Saclay, Le Kremlin-Bicêtre, France.|AP-HP, Hôpital Bicêtre, Service de Pneumologie et Soins Intensifs, Centre de Référence del'Hypertension Pulmonaire Sévère, DHU Thorax Innovation, Le Kremlin-Bicêtre, France.|INSERM UMR_S999, LabEx LERMIT, Centre Chirurgical Marie Lannelongue, Le Plessis Robinson, France.
authors.forename: David
authors.initials: D
authors.lastname: Montani
authors.affiliation: Univ. Paris-Sud, Faculté de Médecine, Université Paris-Saclay, Le Kremlin-Bicêtre, France.|AP-HP, Hôpital Bicêtre, Service de Pneumologie et Soins Intensifs, Centre de Référence del'Hypertension Pulmonaire Sévère, DHU Thorax Innovation, Le Kremlin-Bicêtre, France.|INSERM UMR_S999, LabEx LERMIT, Centre Chirurgical Marie Lannelongue, Le Plessis Robinson, France.
authors.forename: Marc
authors.initials: M
authors.lastname: Humbert
authors.affiliation: Univ. Paris-Sud, Faculté de Médecine, Université Paris-Saclay, Le Kremlin-Bicêtre, France.|AP-HP, Hôpital Bicêtre, Service de Pneumologie et Soins Intensifs, Centre de Référence del'Hypertension Pulmonaire Sévère, DHU Thorax Innovation, Le Kremlin-Bicêtre, France.|INSERM UMR_S999, LabEx LERMIT, Centre Chirurgical Marie Lannelongue, Le Plessis Robinson, France.
authors.forename: Gérald
authors.initials: G
authors.lastname: Simonneau
authors.affiliation: Univ. Paris-Sud, Faculté de Médecine, Université Paris-Saclay, Le Kremlin-Bicêtre, France. olivier.sitbon@bct.aphp.fr.|AP-HP, Hôpital Bicêtre, Service de Pneumologie et Soins Intensifs, Centre de Référence del'Hypertension Pulmonaire Sévère, DHU Thorax Innovation, Le Kremlin-Bicêtre, France. olivier.sitbon@bct.aphp.fr.|INSERM UMR_S999, LabEx LERMIT, Centre Chirurgical Marie Lannelongue, Le Plessis Robinson, France. olivier.sitbon@bct.aphp.fr.
authors.forename: Olivier
authors.initials: O
authors.lastname: Sitbon
mesh_terms: D000081:Acetamides / Q000008:administration & dosage / Q000627:therapeutic use; D011464:Epoprostenol / Q000009:adverse effects / Q000627:therapeutic use; D006801:Humans; D006976:Hypertension, Pulmonary / Q000188:drug therapy*; D044062:Prostaglandins I / Q000009:adverse effects* / Q000627:therapeutic use*; D011719:Pyrazines / Q000008:administration & dosage / Q000627:therapeutic use; D016032:Randomized Controlled Trials as Topic; D011982:Receptors, Prostaglandin / Q000819:agonists
chemical_list: D000081:Acetamides; D044062:Prostaglandins I; D011719:Pyrazines; D011982:Receptors, Prostaglandin; C523468:selexipag; D011464:Epoprostenol