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Comparative Safety and Tolerability of Prostacyclins in Pulmonary Hypertension

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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.

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Authors and Affiliations

  1. Univ. Paris-Sud, Faculté de Médecine, Université Paris-Saclay, Le Kremlin-Bicêtre, France

    Caroline O’Connell, David Amar, Athénaïs Boucly, Laurent Savale, Xavier Jaïs, David Montani, Marc Humbert, Gérald Simonneau & Olivier Sitbon

  2. AP-HP, Hôpital Bicêtre, Service de Pneumologie et Soins Intensifs, Centre de Référence del’Hypertension Pulmonaire Sévère, DHU Thorax Innovation, Le Kremlin-Bicêtre, France

    Caroline O’Connell, David Amar, Athénaïs Boucly, Laurent Savale, Xavier Jaïs, David Montani, Marc Humbert, Gérald Simonneau & Olivier Sitbon

  3. INSERM UMR_S999, LabEx LERMIT, Centre Chirurgical Marie Lannelongue, Le Plessis Robinson, France

    Caroline O’Connell, David Amar, Athénaïs Boucly, Laurent Savale, Xavier Jaïs, Marie-Camille Chaumais, David Montani, Marc Humbert, Gérald Simonneau & Olivier Sitbon

  4. Univ. Paris-Sud, Faculté de Pharmacie, Université Paris-Saclay, Chatenay-Malabry, France

    Marie-Camille Chaumais

  5. APHP, Hôpital Antoine Béclère, Service de Pharmacie, Clamart, France

    Marie-Camille Chaumais

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  1. Caroline O’Connell
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Correspondence to Olivier Sitbon.

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No funding was obtained to write this article.

Conflicts of interest

Caroline O’Connell, David Amar, Athénaïs Boucly and Marie-Camille Chaumais have no conflicts of interest to disclose.

Laurent Savale has relationships with pharmaceutical companies including Actelion Pharmaceuticals, Bayer HealthCare, GlaxoSmithKline and Pfizer. In addition to being an investigator in clinical studies involving these companies, relationships include membership of scientific advisory boards and fees for lectures.

Xavier Jaïs has relationships with pharmaceutical companies including Actelion Pharmaceuticals, Bayer HealthCare, GlaxoSmithKline and Pfizer. In addition to being an investigator in clinical studies involving these companies, relationships include membership of scientific advisory boards and fees for lectures.

David Montani has relationships with pharmaceutical companies including Actelion Pharmaceuticals, Bayer HealthCare, GlaxoSmithKline and Pfizer. In addition to being an investigator in clinical studies involving these companies, relationships include membership of scientific advisory boards and fees for lectures.

Marc Humbert has relationships with pharmaceutical companies including Actelion, Aires, Bayer HealthCare, Gilead, GlaxoSmithKline, Novartis and Pfizer. In addition to being an investigator in clinical studies involving these companies, relationships include consulting services, fees for lectures and funds for research.

Gérald Simonneau has relationships with pharmaceutical companies including Actelion, Bayer HealthCare, GlaxoSmithKline, Novartis and Pfizer. In addition to being an investigator in clinical studies involving these companies, relationships include consulting services, fees for lectures and funds for research.

Olivier Sitbon has relationships with pharmaceutical companies including Actelion, Bayer HealthCare, GlaxoSmithKline, Pfizer and United Therapeutics. In addition to being an investigator in clinical studies involving these companies, relationships include consulting services, fees for lectures and funds for research.

The authors have no other relevant affiliations or financial involvement with any organisation or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

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O’Connell, C., Amar, D., Boucly, A. et al. Comparative Safety and Tolerability of Prostacyclins in Pulmonary Hypertension. Drug Saf 39, 287–294 (2016). https://doi.org/10.1007/s40264-015-0365-x

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