American Journal of Cardiovascular Drugs

, Volume 19, Issue 2, pp 99–105 | Cite as

Improving Survival in Patients with Pulmonary Arterial Hypertension: Focus on Intravenous Epoprostenol

  • Eftychia DemeroutiEmail author
  • Panagiotis Karyofyllis
  • Athanassios Manginas
  • Anastasia Anthi
  • George Karatasakis
  • George Athanassopoulos
  • Vassilios Voudris
Leading Article


Pulmonary arterial hypertension represents a devastating disease, causing progressive increase of pulmonary vascular resistance leading to right ventricular dysfunction and death. Therapeutic management has rapidly advanced in recent years due to improved understanding of pathophysiology and new drugs have been developed; however, survival remains poor. Oral agents as phosphodiesterase type V inhibitors, the soluble guanylyl cyclase stimulator riociguat, the prostacyclin receptor agonist selexipag and the endothelin receptor antagonists have each achieved evidence-based validation and are recommended for pulmonary arterial hypertension. Initial oral monotherapy or combination therapy is recommended for patients with low or intermediate risk according to each patient’s risk stratification. Intravenous epoprostenol is a synthetic prostacyclin and the first drug approved for the disease. Although it represents the only treatment shown to reduce mortality, it is underused. Survival rates for patients treated with oral combination drug therapies are lower than those for patients treated with initial combination therapies including intravenous epoprostenol. This raises the interesting question of whether intermediate risk pulmonary arterial hypertension patients should be routinely introduced to therapies including intravenous epoprostenol rather than combination oral therapies.


Compliance with Ethical Standards


No external funding was used in the preparation of this manuscript.

Conflict of Interest

Eftychia Demerouti has received speaker honorarium and fees as advisory board member from Actelion Pharmaceutical Hellas, MSD Hellas and from Glaxo Smithkline. Panagiotis Karyofyllis has received speaker honorarium and fees as advisory board member from Actelion Pharmaceuticals Hellas and MSD Hellas.


  1. 1.
    Farber HW, Miller DP, Poms AD, Badesch DB, Frost AE, Muros-Le Rouzic E, Romero AJ, Benton WW, Elliott CG, McGoon MD, Benza RL. Five-year outcomes of patients enrolled in the REVEAL registry. Chest. 2015;148(4):1043–54.CrossRefGoogle Scholar
  2. 2.
    Barst RJ, Chung L, Zamanian RT, Turner M, McGoon MD. Functional class improvement and 3-year survival outcomes in patients with pulmonary arterial hypertension in the REVEAL registry. Chest. 2013;144(1):160–8.CrossRefGoogle Scholar
  3. 3.
    D’Alonzo GE, Barst RJ, Ayres SM, Bergofsky EH, Brundage BH, Detre KM, Fishman AP, Goldring RM, Groves BM, Kernis JT, et al. Survival in patients with primary pulmonary hypertension. Results from a national prospective registry. Ann Intern Med. 1991;115(5):343–9.CrossRefGoogle Scholar
  4. 4.
    Galiè N, Humbert M, Vachiery J, Gibbs S, Lang I, Torbicki A, Simonneau G, Peacock A, Noordegraaf AV, Beghetti M, Ghofrani A, Gomez Sanchez MA, Hansmann G, Klepetko W, Lancellotti P, Matucci M, McDonagh T, Pierard LA, Trindade PT, Zompatori M, Hoeper M. 2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension. The Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS). Eur Respir J. 2015;46:903–75.CrossRefGoogle Scholar
  5. 5.
    Boucly A, Weatherald J, Savale L, et al. Risk assessment, prognosis and guideline implementation in pulmonary arterial hypertension. Eur Respir J. 2017;50(2):1700889.CrossRefGoogle Scholar
  6. 6.
    Kylhammar D, Kjellstrom B, Hjalmarsson C, et al. A comprehensive risk stratification at early follow-up determines prognosis in pulmonary arterial hypertension. Eur Heart J. 2017. Scholar
  7. 7.
    Hoeper MM, Kramer T, Pan Z, et al. Mortality in pulmonary arterial hypertension: prediction by the 2015 European pulmonary hypertension guidelines risk stratification model. Eur Respir J 2017 Aug 3 [E-pub ahead of print].Google Scholar
  8. 8.
    Nickel N, Golpon H, Greer M, et al. The prognostic impact of follow-up assessments in patients with idiopathic pulmonary arterial hypertension. Eur Respir J. 2012;39:589–96.CrossRefGoogle Scholar
  9. 9.
    Frost AE, Badesch DB, Miller DP, et al. Evaluation of the predictive value of a clinical worsening definition using 2-year outcomes in patients with pulmonary arterial hypertension: a REVEAL registry analysis. Chest. 2013;144:1521–9.CrossRefGoogle Scholar
  10. 10.
    Arif SA, Poon H. Tadalafil: a long-acting phosphodiesterase-5 inhibitor for the treatment of pulmonary arterial hypertension. Clin Ther. 2011;33(8):993–1004.CrossRefGoogle Scholar
  11. 11.
    Galiè N, Ghofrani HA, Torbicki A, Barst RJ, Rubin LJ, Badesch D, Fleming T, Parpia T, Burgess G, Branzi A, Grimminger F, Kurzyna M, Simonneau G, Sildenafil Use in Pulmonary Arterial Hypertension (SUPER) Study Group. Sildenafil citrate therapy for pulmonary arterial hypertension. N Engl J Med. 2005;353(20):2148–57.CrossRefGoogle Scholar
  12. 12.
    Ghofrani HA, Galiè N, Grimminger F, Grünig E, Humbert M, Jing ZC, Keogh AM, Langleben D, Kilama MO, Fritsch A, Neuser D, PATENT-1 Study Group. Riociguat for the treatment of pulmonary arterial hypertension. N Engl J Med. 2013;369(4):330–40.CrossRefGoogle Scholar
  13. 13.
    Channick RN, Simonneau G, Sitbon O, Robbins IM, Frost A, Tapson VF, Badesch DB, Roux S, Rainisio M, Bodin F, Rubin LJ. Effects of the dual endothelin-receptor antagonist bosentan in patients with pulmonary hypertension: a randomised placebo-controlled study. Lancet. 2001;358:1119–23.CrossRefGoogle Scholar
  14. 14.
    Rubin LJ, Badesch DB, Barst RJ, Galie N, Black CM, Keogh Keogh A, Pulido T, Frost A, Roux S, Leconte I, Landzberg M, Simonneau G. Bosentan therapy for pulmonary arterial hypertension. N Engl J Med. 2002;346:896–903.CrossRefGoogle Scholar
  15. 15.
    McLaughlin VV, Sitbon O, Badesch DB, Barst RJ, Black C, Galiè N, Rainisio M, Simonneau G, Rubin LJ. Survival with first-line bosentan in patients with primary pulmonary hypertension. Eur Respir J. 2005;25:244–9.CrossRefGoogle Scholar
  16. 16.
    Galiè N, Lj Rubin, Hoeper M, Jansa P, Al-Hiti H, Meyer G, Chiossi E, Kusic-Pajic A, Simonneau G. Treatment of patients with mildly symptomatic pulmonary arterial hypertension with bosentan (EARLY study): a double-blind, randomised controlled trial. Lancet. 2008;371(9630):2093–100.CrossRefGoogle Scholar
  17. 17.
    Galiè N, Olschewski H, Oudiz RJ, Torres F, Frost A, Ghofrani HA, Badesch DB, McGoon MD, McLaughlin VV, Roecker EB, Gerber MJ, Dufton C, Wiens BL, Rubin LJ. Ambrisentan for the treatment of pulmonary arterial hypertension: results of the ambrisentan in pulmonary arterial hypertension, randomized, double-blind, placebo-controlled, multicenter, efficacy (ARIES) study 1 and 2. Circulation. 2008;117(23):3010–9.CrossRefGoogle Scholar
  18. 18.
    Manes A, Palazzini M, Leci E, Bacchi Reggiani ML, Branzi A, Galiè N. Current era survival of patients with pulmonary arterial hypertension associated with congenital heart disease: a comparison between clinical subgroups. Eur Heart J. 2014;35(11):716–24.CrossRefGoogle Scholar
  19. 19.
    Galiè N, Palazzini M, Manes A. Pulmonary arterial hypertension: from the kingdom of the near-dead to multiple clinical trial meta-analyses. Eur Heart J. 2010;31(17):2080–6.CrossRefGoogle Scholar
  20. 20.
    Galiè N, Negro L, Simonneau G. The use of combination therapy in pulmonary arterial hypertension: new developments. Eur Respir J. 2009;18(113):148–53.CrossRefGoogle Scholar
  21. 21.
    Pulido T, Adzerikho I, Channick RN, Delcroix M, Galiè N, Ghofrani HA, Jansa P, Jing ZC, Le Brun FO, Mehta S, Mittelholzer CM, Perchenet L, Sastry BK, Sitbon O, Souza R, Torbicki A, Zeng X, Rubin LJ, Simonneau G, SERAPHIN Investigators. Macitentan and morbidity and mortality in pulmonary arterial hypertension. N Engl J Med. 2013;369(9):809–18.CrossRefGoogle Scholar
  22. 22.
    Sitbon O, Channick R, Chin KM, Frey A, Gaine S, Galiè N, Ghofrani HA, Hoeper MM, Lang IM, Preiss R, Rubin LJ, Di Scala L, Tapson V, Adzerikho I, Liu J, Moiseeva O, Zeng X, Simonneau G, McLaughlin VV, GRIPHON Investigators. Selexipag for the treatment of pulmonary arterial hypertension. N Engl J Med. 2015;373(26):2522–33.CrossRefGoogle Scholar
  23. 23.
    Burger CD, Long PK, Shah MR, McGoon MD, Miller DP, Romero AJ, Benton WW. Safford RE Characterization of first-time hospitalizations in patients with newly diagnosed pulmonary arterial hypertension in the REVEAL registry. Chest. 2014;146(5):1263–73.CrossRefGoogle Scholar
  24. 24.
    McLaughlin VV, Hoeper MM, Channick RN, Chin KM, Delcroix M, Gaine S, Ghofrani HA, Jansa P, Lang IM, Mehta S, Pulido T, Sastry BKS, Simonneau G, Sitbon O, Souza R, Torbicki A, Tapson VF, Perchenet L, Preiss R, Verweij P, Rubin LJ, Galiè N. Pulmonary arterial hypertension-related morbidity is prognostic for mortality. J Am Coll Cardiol. 2018;71(7):752–63.CrossRefGoogle Scholar
  25. 25.
    Galiè N, Barberà JA, Frost AE, Ghofrani HA, Hoeper MM, McLaughlin VV, Peacock AJ, Simonneau G, Vachiery JL, Grünig E, Oudiz RJ, Vonk-Noordegraaf A, White RJ, Blair C, Gillies H, Miller KL, Harris JH, Langley J, Rubin LJ, AMBITION Investigators. Initial use of ambrisentan plus tadalafil in pulmonary arterial hypertension. N Engl J Med. 2015;373(9):834–44.CrossRefGoogle Scholar
  26. 26.
    Hoeper MM, McLaughlin VV, Barberá JA, Frost AE, Ghofrani HA, Peacock AJ, Simonneau G, Rosenkranz S, Oudiz RJ, White RJ, Miller KL, Langley J, Harris JHN, Blair C, Rubin LJ, Vachiery JL. Initial combination therapy with ambrisentan and tadalafil and mortality in patients with pulmonary arterial hypertension: a secondary analysis of the results from the randomised, controlled AMBITION study. Lancet Respir Med. 2016;4(11):894–901.CrossRefGoogle Scholar
  27. 27.
    Sitbon O, Sattler C, Bertoletti L, Savale L, Cottin V, Jaïs X, Groote P, Chaouat A, Chabannes C, Bergot E, Bouvaist H, Dauphin C, Bourdin A, Bauer F, Montani D, Humbert M. Simonneau G Initial dual oral combination therapy in pulmonary arterial hypertension. Eur Respir J. 2016;47:1727–36.CrossRefGoogle Scholar
  28. 28.
    Rubin LJ, Groves BM, Reeves JT, Frosolono M, Handel F. Cato AE Prostacyclin-induced acute pulmonary vasodilation in primary pulmonary hypertension. Circulation. 1982;66(2):334–8.CrossRefGoogle Scholar
  29. 29.
    Rubin LJ, Mendoza J, Hood M, McGoon M, Barst R, Williams WB, Diehl JH, Crow J, Long W. Treatment of primary pulmonary hypertension with continuous intravenous prostacyclin (epoprostenol). Results of a randomized trial. Ann Intern Med. 1990;112(7):485–91.CrossRefGoogle Scholar
  30. 30.
    Barst RJ, Rubin LJ, Long WA, McGoon MD, Rich S, Badesch DB, Groves BM, Tapson VF, Bourge RC, Brundage BH, Koerner SK, Langleben D, Keller CA, Murali S, Uretsky BF, Clayton LM, Jöbsis MM, Blackburn SD, Shortino D, Crow JW, Primary Pulmonary Hypertension Study Group. A comparison of continuous intravenous epoprostenol (prostacyclin) with conventional therapy for primary pulmonary hypertension. N Engl J Med. 1996;334(5):296–301.CrossRefGoogle Scholar
  31. 31.
    Shapiro SM, Oudiz RJ, Cao T, Romano MA, Beckmann XJ, Georgiou D, Mandayam S, Ginzton LE, Brundage BH. Primary pulmonary hypertension: improved long-term effects and survival with continuous intravenous epoprostenol infusion. J Am Coll Cardiol. 1997;30(2):343–9.CrossRefGoogle Scholar
  32. 32.
    McLaughlin VV, Shillington A, Rich S. Survival in primary pulmonary hypertension: the impact of epoprostenol therapy. Circulation. 2002;106(12):1477–82.CrossRefGoogle Scholar
  33. 33.
    Sitbon O, Humbert M, Nunes H, Parent F, Garcia G, Hervé P, Rainisio M, Simonneau G. Long-term intravenous epoprostenol infusion in primary pulmonary hypertension: prognostic factors and survival. J Am Coll Cardiol. 2002;40(4):780–8.CrossRefGoogle Scholar
  34. 34.
    Bergot E, Sitbon O, Cottin V, Prévot G, Canuet M, Bourdin A, de Groote P, Rottat L, Gressin V, Jaïs X, Humbert M, Simonneau G. Current epoprostenol use in patients with severe idiopathic, heritable or anorexigen-associated pulmonary arterial hypertension: data from the French pulmonary hypertension registry. Int J Cardiol. 2014;172(3):561–7.CrossRefGoogle Scholar
  35. 35.
    Sitbon O, Jaïs X, Savale L, Cottin V, Bergot E, Macari EA, Bouvaist H, Dauphin C, Picard F, Bulifon S, Montani D, Humbert M, Simonneau G. Upfront triple combination therapy in pulmonary arterial hypertension: a pilot study. Eur Respir J. 2014;43(6):1691–7.CrossRefGoogle Scholar
  36. 36.
    Ogawa A, Ejiri K, Matsubara H. Long-term patient survival with idiopathic/heritable pulmonary arterial hypertension treated at a single center in Japan. Life Sci. 2014;118(2):414.CrossRefGoogle Scholar
  37. 37.
    Ogawa A, Satoh T, Tamura Y, Fukuda K, Matsubara H. Survival of Japanese patients with idiopathic/heritable pulmonary arterial hypertension. Am J Cardiol. 2017;119(9):1479–84.CrossRefGoogle Scholar
  38. 38.
    Sitbon O, Vonk Noordegraaf A. Epoprostenol and pulmonary arterial hypertension: 20 years of clinical experience. Eur Respir Rev. 2017;26(143):160055.CrossRefGoogle Scholar
  39. 39.
    Badesch DB, Tapson VF, McGoon MD, Brundage BH, Rubin LJ, Wigley FM, Rich S, Barst RJ, Barrett PS, Kral KM, Jöbsis MM, Loyd JE, Murali S, Frost A, Girgis R, Bourge RC, Ralph DD, Elliott CG, Hill NS, Langleben D, Schilz RJ, McLaughlin VV, Robbins IM, Groves BM, Shapiro S, Medsger TA Jr. Continuous intravenous epoprostenol for pulmonary hypertension due to the scleroderma spectrum of disease. A randomized, controlled trial. Ann Intern Med. 2000;132(6):425–34.CrossRefGoogle Scholar
  40. 40.
    Humbert M, Barst RJ, Robbins IM, Channick RN, Galiè N, Boonstra A, Rubin LJ, Horn EM, Manes A, Simonneau G. Combination of bosentan with epoprostenol in pulmonary arterial hypertension: BREATHE-2. Eur Respir J. 2004;24(3):353–9.CrossRefGoogle Scholar
  41. 41.
    Kemp K, Savale L, O’Callaghan DS, Jaïs X, Montani D, Humbert M, Simonneau G, Sitbon O. Usefulness of first-line combination therapy with epoprostenol and bosentan in pulmonary arterial hypertension: an observational study. J Heart Lung Transplant. 2012;31(2):150–8.CrossRefGoogle Scholar
  42. 42.
    Tokunaga N, Ogawa A, Ito H, Matsubara H. Rapid and high-dose titration of epoprostenol improves pulmonary hemodynamics and clinical outcomes in patients with idiopathic and heritable pulmonary arterial hypertension. J Cardiol. 2016;68:542e547.CrossRefGoogle Scholar
  43. 43.
    Akagi S, Nakamura K, Miyaji K, Ogawa A, Kusano KF, Ito H, Matsubara H. Marked hemodynamic improvements by high-dose epoprostenol therapy in patients with idiopathic pulmonary arterial hypertension. Circ J. 2010;74:2200–5.CrossRefGoogle Scholar
  44. 44.
    Kingman MS, Tankersley MA, Lombardi S, et al. Prostacyclin administration errors in pulmonary arterial hypertension patients admitted to hospitals in the United States: a national survey. J Heart Lung Transplant. 2010;29:841–6.CrossRefGoogle Scholar
  45. 45.
    Kingman MS, Chin K. Safety recommendations for administering intravenous prostacyclins in the hospital. Crit Care Nurse. 2013;33:32–9.CrossRefGoogle Scholar
  46. 46.
    Doran AK, Ivy DD, Barst RJ, et al. Guidelines for the prevention of central venous catheter-related blood stream infections with prostanoid therapy for pulmonary arterial hypertension. Int J Clin Pract Suppl. 2008;160:5–9.CrossRefGoogle Scholar
  47. 47.
    Opitz CF, Wensel R, Winkler J, Halank M, Bruch L, Kleber FX, Höffken G, Anker SD, Negassa A, Felix SB, Hetzer R, Ewert R. Clinical efficacy and survival with first-line inhaled iloprost therapy in patients with idiopathic pulmonary arterial hypertension. Eur Heart J. 2005;26(18):1895–902.CrossRefGoogle Scholar
  48. 48.
    Del Pozo R, Blanco I, Hernández-González I, López-Meseguer M, López-Reyes R, Lázaro-Salvador M, Elías-Hernández T, Álvarez-Vega P, Pérez-Peñate GM, Martínez-Meñaca A, Bedate P, Escribano-Subias P, REHAP investigators. Real-life experience of inhaled iloprost for patients with pulmonary arterial hypertension: insights from the Spanish REHAP registry. Int J Cardiol. 2018. Scholar
  49. 49.
    Simonneau G, Barst RJ, Galie N, Naeije R, Rich S, Bourge RC, Keogh A, Oudiz R, Frost A, Blackburn SD, Crow JW, Rubin LJ, Treprostinil Study Group. Continuous subcutaneous infusion of treprostinil, a prostacyclin analogue, in patients with pulmonary arterial hypertension: a double-blind, randomized, placebo-controlled trial. Am J Respir Crit Care Med. 2002;165(6):800–4.CrossRefGoogle Scholar
  50. 50.
    Hiremath J, Thanikachalam S, Parikh K, Shanmugasundaram S, Bangera S, Shapiro L, Pott GB, Vnencak-Jones CL, Arneson C, Wade M, White RJ. Exercise improvement and plasma biomarker changes with intravenous treprostinil therapy for pulmonary arterial hypertension: a placebo-controlled trial. J Heart Lung Transpl. 2010;29:137–49.CrossRefGoogle Scholar
  51. 51.
    Richter M, Harutyunova S, Bollmann T, Classen S, Gall H, Gerhardt F, Grimminger F, Grimminger J, Grunig E, Guth S, Halank M, Heine A, Hoeper M, Klose H, Lange T, Meyer K, Neurohr C, Nickolaus K, Olsson K, Opitz C, Rosenkranz S, Seyfarth H, Warnke C, Wiedenroth C, Hossein A, Ewert R. Long-term safety and outcome of intravenous treprostinil via an implanted pump in pulmonary hypertension. J Heart Lung Transpl. 2018;37(10):1235–44.CrossRefGoogle Scholar
  52. 52.
    Benza RL, Miller DP, Barst RJ, et al. An evaluation of long-term survival from time of diagnosis in pulmonary arterial hypertension from the REVEAL Registry. Chest. 2012;142:448–56.CrossRefGoogle Scholar
  53. 53.
    Humbert M, Sitbon O, Chaouat A, et al. Survival in patients with idiopathic, familial, and anorexigen-associated pulmonary arterial hypertension in the modern management era. Circulation. 2010;122(2):156–63.CrossRefGoogle Scholar
  54. 54.
    Farber HW, Miller DP, Meltzer LA, McGoon MD. Treatment of patients with pulmonary arterial hypertension at the time of death or deterioration to functional class IV: insights from the REVEAL Registry. J Heart Lung Transplant. 2013;32(11):1114–22.CrossRefGoogle Scholar
  55. 55.
    Burks M, Stickel S, Galiè N. Pulmonary arterial hypertension: combination therapy in practice. Am J Cardiovasc Drugs. 2017;18(4):249–57.CrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Noninvasive Department of CardiologyOnassis Cardiac Surgery CenterAthensGreece
  2. 2.Interventional Department of CardiologyOnassis Cardiac Surgery CenterAthensGreece
  3. 3.Interventional Cardiology and Cardiology DepartmentMediterraneo HospitalAthensGreece
  4. 4.Intensive Care Unit DepartmentAttikon University HospitalAthensGreece

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