Skip to main content
Log in

Prostacyclins in pulmonary arterial hypertension: the need for earlier therapy

  • Review
  • Published:
Advances in Therapy Aims and scope Submit manuscript

Abstract

Pulmonary arterial hypertension (PAH) is a rare but serious condition, which if untreated, is associated with a 2–3-year median survival time. A number of treatment options are available for PAH, leading to improvements in exercise capacity, symptoms, and hemodynamics. However, the disease remains incurable and most patients will ultimately progress to right heart failure and death. Three classes of drugs are currently available to improve PAH outcomes, although this review will focus solely on a class of potent vasodilators known as prostacyclins. Currently, four prostacyclin analogs are licensed for the treatment of PAH: epoprostenol, treprostinil, and iloprost in the USA and some European countries, and beraprost in Japan and Korea. Prostacyclins have become the treatment of choice in patients with severe PAH, but there is also evidence to suggest that their earlier use may also benefit patients with mild-to-moderate disease. This review discusses the advantages of prostacyclins in terms of their usefulness in patients whose condition has deteriorated following monotherapy with other agents, and their integral role in combination therapy. The latter appears to offer the potential for pulmonary vasculature remodeling and could be regarded as an emerging paradigm to treat and prevent the progression of PAH.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

References

  1. Galie N, Hoeper MM, Humbert M, et al. Guidelines for the diagnosis and treatment of pulmonary hypertension: the Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS), endorsed by the International Society of Heart and Lung Transplantation (ISHLT). Eur Heart J. 2009;30:2493–2537.

    Article  PubMed  Google Scholar 

  2. Simonneau G, Robbins IM, Beghetti M, et al. Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol. 2009;54:S43–S54.

    Article  PubMed  Google Scholar 

  3. Jansa P, Ambroz D, Maresova J, Polacek P, Aschermann M, Linhart A. Pulmonary arterial hypertension-contemporary management strategy. Bratisl Lek Listy. 2009;110:603–608.

    PubMed  CAS  Google Scholar 

  4. Dewachter L, Dewachter C, Naeije R. New therapies for pulmonary arterial hypertension: an update on current bench to bedside translation. Expert Opin Investig Drugs. 2010;19:469–488.

    Article  PubMed  CAS  Google Scholar 

  5. Umar S, Steendijk P, Ypey DL, et al. Novel approaches to treat experimental pulmonary arterial hypertension: a review. J Biomed Biotechnol. 2010;2010:702–836.

    Article  Google Scholar 

  6. Christman B, McPherson C, Newman J, et al. An imbalance between the excretion of thromboxane and prostacyclin metabolites in pulmonary hypertension. N Engl J Med. 1992;327:70–75.

    Article  PubMed  CAS  Google Scholar 

  7. Tuder R, Cool C, Geraci M, et al. Prostacyclin synthase expression is decreased in lungs from patients with severe pulmonary hypertension. Am J Respir Crit Care Med. 1999;159:1925–1932.

    PubMed  CAS  Google Scholar 

  8. Gomberg-Maitland M, Olschewski H. Prostacyclin therapies for the treatment of pulmonary arterial hypertension. Eur Respir J. 2008;31:891–901.

    Article  PubMed  CAS  Google Scholar 

  9. Mubarak KK. A review of prostaglandin analogs in the management of patients with pulmonary arterial hypertension. Respir Med. 2010;104:9–21.

    Article  PubMed  Google Scholar 

  10. Rubin LJ, Mendoza J, Hood M, et al. Treatment of primary pulmonary hypertension with continuous intravenous prostacyclin (epoprostenol). Results of a randomized trial. Ann Intern Med. 1990;112:485–491.

    CAS  Google Scholar 

  11. Barst R, Rubin L, Long W, et al. A comparison of continuous intravenous epoprostenol (prostacyclin) with conventional therapy for primary pulmonary hypertension. The Primary Pulmonary Hypertension Study Group. N Engl J Med. 1996;334:296–302.

    Article  PubMed  CAS  Google Scholar 

  12. Badesch DB, Tapson VF, McGoon MD, et al. Continuous intravenous epoprostenol for pulmonary hypertension due to the scleroderma spectrum of disease. A randomized, controlled trial. Ann Intern Med. 2000;132:425–434.

    PubMed  CAS  Google Scholar 

  13. Jacobs W, Boonstra A, Marcus JT, Postmus PE, Vonk-Noordegraaf A. Addition of prostanoids in pulmonary hypertension deteriorating on oral therapy. J Heart Lung Transplant. 2009;28:280–284.

    Article  PubMed  Google Scholar 

  14. Kuhn KP, Byrne DW, Arbogast PG, Doyle TP, Loyd JE, Robbins IM. Outcome in 91 consecutive patients with pulmonary arterial hypertension receiving epoprostenol. Am J Respir Crit Care Med. 2003;167:580–586.

    Article  PubMed  Google Scholar 

  15. Sitbon O, Humbert M, Nunes H, et al. Long-term intravenous epoprostenol infusion in primary pulmonary hypertension: prognostic factors and survival. J Am Coll Cardiol. 2002;40:780–788

    Article  PubMed  CAS  Google Scholar 

  16. McLaughlin VV, Shillington A, Rich S. Survival in primary pulmonary hypertension: the impact of epoprostenol therapy. Circulation. 2002;106:1477–1482.

    Article  PubMed  CAS  Google Scholar 

  17. Chin K, Channick R, de Lemos J, et al. Hemodynamics and epoprostenol use are associated with thrombocytopenia in pulmonary arterial hypertension. Chest. 2009;135:130–136.

    Article  PubMed  CAS  Google Scholar 

  18. Rich S, McLaughlin VV. The effects of chronic prostacyclin therapy on cardiac output and symptoms in primary pulmonary hypertension. J Am Coll Cardiol. 1999;34:1184–1187.

    Article  PubMed  CAS  Google Scholar 

  19. Simonneau G, Rubin LJ, Galie N, et al. Addition of sildenafil to long-term intravenous epoprostenol therapy in patients with pulmonary arterial hypertension: a randomized trial. Ann Intern Med. 2008;149:521–530.

    PubMed  Google Scholar 

  20. McLaughlin VV, Oudiz RJ, Frost A, et al. Randomized study of adding inhaled iloprost to existing bosentan in pulmonary arterial hypertension. Am J Respir Crit Care Med. 2006;174:1257–1263.

    Article  PubMed  CAS  Google Scholar 

  21. McLaughlin VV, Benza RL, Rubin LJ, et al. Addition of inhaled treprostinil to oral therapy for pulmonary arterial hypertension: a randomized controlled clinical trial. J Am Coll Cardiol. 2010;55:1915–1922.

    Article  PubMed  CAS  Google Scholar 

  22. Humbert M, Barst RJ, Robbins IM, et al. Combination of bosentan with epoprostenol in pulmonary arterial hypertension: BREATHE-2. Eur Respir J. 2004;24:353–359.

    Article  PubMed  CAS  Google Scholar 

  23. Vachiery JL, Naeije R. Treprostinil for pulmonary hypertension. Expert Rev Cardiovasc Ther. 2004;2:183–191.

    Article  PubMed  CAS  Google Scholar 

  24. Simonneau G, Barst RJ, Galie N, et al. 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;165:800–804.

    PubMed  Google Scholar 

  25. Benza RL, Rayburn BK, Tallaj JA, Pamboukian SV, Bourge RC. Treprostinil-based therapy in the treatment of moderate-to-severe pulmonary arterial hypertension: long-term efficacy and combination with bosentan. Chest. 2008;134:139–145.

    Article  PubMed  CAS  Google Scholar 

  26. Barst RJ, Galie N, Naeije R, et al. Long-term outcome in pulmonary arterial hypertension patients treated with subcutaneous treprostinil. Eur Respir J. 2006;28:1195–1203.

    Article  PubMed  CAS  Google Scholar 

  27. Lang I, Gomez-Sanchez M, Kneussl M, et al. Efficacy of long-term subcutaneous treprostinil sodium therapy in pulmonary hypertension. Chest. 2006;129:1636–1643.

    Article  PubMed  CAS  Google Scholar 

  28. Skoro-Sajer N, Lang I. Treprostinil for the treatment of pulmonary hypertension. Expert Opin Pharmacother. 2008;9:1415–1420.

    Article  PubMed  CAS  Google Scholar 

  29. Skoro-Sajer N, Lang IM, Harja E, Kneussl MP, Sing WG, Gibbs SJ. A clinical comparison of slow- and rapid-escalation treprostinil dosing regimens in patients with pulmonary hypertension. Clin Pharmacokinet. 2008;47:611–618.

    Article  PubMed  CAS  Google Scholar 

  30. Tapson VF, Gomberg-Maitland M, McLaughlin VV, et al. Safety and efficacy of IV treprostinil for pulmonary arterial hypertension: a prospective, multicenter, open-label, 12-week trial. Chest. 2006;129:683–688.

    Article  PubMed  CAS  Google Scholar 

  31. Hiremath J, Thanikachalam S, Parikh K, et al. Exercise improvement and plasma biomarker changes with intravenous treprostinil therapy for pulmonary arterial hypertension: a placebo-controlled trial. J Heart Lung Transplant. 2010;29:137–149.

    Article  PubMed  Google Scholar 

  32. Voswinckel R, Enke B, Reichenberger F, et al. Favorable effects of inhaled treprostinil in severe pulmonary hypertension: results from randomized controlled pilot studies. J Am Coll Cardiol. 2006;48:1672–1681.

    Article  PubMed  CAS  Google Scholar 

  33. Voswinckel R, Reichenberger F, Gall H, et al. Metered dose inhaler delivery of treprostinil for the treatment of pulmonary hypertension. Pulm Pharmacol Ther. 2009;22:50–56.

    Article  PubMed  CAS  Google Scholar 

  34. Olschewski H, Walmrath D, Schermuly R, Ghofrani A, Grimminger F, Seeger W. Aerosolized prostacyclin and iloprost in severe pulmonary hypertension. Ann Intern Med. 1996;124:820–824.

    PubMed  CAS  Google Scholar 

  35. Wensel R, Opitz CF, Ewert R, Bruch L, Kleber FX. Effects of iloprost inhalation on exercise capacity and ventilatory efficiency in patients with primary pulmonary hypertension. Circulation. 2000;101:2388–2392.

    PubMed  CAS  Google Scholar 

  36. Olschewski H, Simonneau G, Galie N, et al. Inhaled iloprost for severe pulmonary hypertension. N Engl J Med. 2002;347:322–329.

    Article  PubMed  CAS  Google Scholar 

  37. Opitz CF, Wensel R, Winkler J, et al. Clinical efficacy and survival with first-line inhaled iloprost therapy in patients with idiopathic pulmonary arterial hypertension. Eur Heart J. 2005;26:1895–1902.

    Article  PubMed  CAS  Google Scholar 

  38. Olschewski H, Hoeper MM, Behr J, et al. Longterm therapy with inhaled iloprost in patients with pulmonary hypertension. Respir Med. 2010;104:731–740.

    Article  PubMed  Google Scholar 

  39. Ikeda D, Tsujino I, Sakaue S, et al. Pilot study of short-term effects of a novel long-acting oral beraprost in patients with pulmonary arterial hypertension. Circ J. 2007;71:1829–1831.

    Article  PubMed  CAS  Google Scholar 

  40. Galie N, Humbert M, Vachiery JL, et al. Effects of beraprost sodium, an oral prostacyclin analogue, in patients with pulmonary arterial hypertension: a randomized, double-blind, placebo-controlled trial. J Am Coll Cardiol. 2002;39:1496–1502.

    Article  PubMed  CAS  Google Scholar 

  41. Barst RJ, McGoon M, McLaughlin V, et al. Beraprost therapy for pulmonary arterial hypertension. J Am Coll Cardiol. 2003;41:2119–2125.

    Article  PubMed  CAS  Google Scholar 

  42. Nagaya N, Uematsu M, Okano Y, et al. Effect of orally active prostacyclin analogue on survival of outpatients with primary pulmonary hypertension. J Am Coll Cardiol. 1999;34:1188–1192.

    Article  PubMed  CAS  Google Scholar 

  43. Nagaya N, Shimizu Y, Satoh T, et al. Oral beraprost sodium improves exercise capacity and ventilatory efficiency in patients with primary or thromboembolic pulmonary hypertension. Heart. 2002;87:340–345.

    Article  PubMed  CAS  Google Scholar 

  44. Ono F, Nagaya N, Okumura H, et al. Effect of orally active prostacyclin analogue on survival in patients with chronic thromboembolic pulmonary hypertension without major vessel obstruction. Chest. 2003;123:1583–1588.

    Article  PubMed  CAS  Google Scholar 

  45. Melian EB, Goa KL. Beraprost: a review of its pharmacology and therapeutic efficacy in the treatment of peripheral arterial disease and pulmonary arterial hypertension. Drugs. 2002;62:107–133.

    Article  PubMed  CAS  Google Scholar 

  46. Barst RJ, Gibbs JS, Ghofrani HA, et al. Updated evidence-based treatment algorithm in pulmonary arterial hypertension. J Am Coll Cardiol. 2009;54;S78–S84.

    Article  PubMed  CAS  Google Scholar 

  47. Laliberte K, Arneson C, Jeffs R, Hunt T, Wade M. Pharmacokinetics and steady-state bioequivalence of treprostinil sodium (Remodulin) administered by the intravenous and subcutaneous route to normal volunteers. J Cardiovasc Pharmacol. 2004;44:209–214.

    Article  PubMed  CAS  Google Scholar 

  48. Demolis JL, Robert A, Mouren M, Funck-Brentano C, Jaillon P. Pharmacokinetics and platelet antiaggregating effects of beraprost, an oral stable prostacyclin analogue, in healthy volunteers. J Cardiovasc Pharmacol. 1993;22:711–716.

    Article  PubMed  CAS  Google Scholar 

  49. Vachiery JL, Simonneau G. Management of severe pulmonary arterial hypertension. Eur Respir Rev. 2010;19:279–287.

    Article  PubMed  Google Scholar 

  50. McLaughlin VV, Archer SL, Badesch DB, et al. ACCF/AHA 2009 expert consensus document on pulmonary hypertension: a report of the American College of Cardiology Foundation Task Force on Expert Consensus Documents and the American Heart Association: developed in collaboration with the American College of Chest Physicians, American Thoracic Society, Inc., and the Pulmonary Hypertension Association. Circulation. 2009;119:2250–2294.

    Article  PubMed  Google Scholar 

  51. Benza R, Miller D, Gomberg-Maitland M, et al. Predicting survival in pulmonary arterial hypertension. Insights From the Registry to Evaluate Early and Long-Term Pulmonary Arterial Hypertension Disease Management (REVEAL). Circulation. 2010;122:164–172.

    Article  PubMed  Google Scholar 

  52. Humbert M, Sitbon O, Yaici A, et al. Survival in incident and prevalent cohorts of patients with pulmonary arterial hypertension. Eur Respir J. 2010;36:549–555.

    Article  PubMed  CAS  Google Scholar 

  53. Gessler T, Seeger W, Schmehl T. Inhaled prostanoids in the therapy of pulmonary hypertension. J Aerosol Med Pulm Drug Deliv. 2008;21:1–12.

    Article  PubMed  CAS  Google Scholar 

  54. Buckley MS, Feldman JP. Inhaled epoprostenol for the treatment of pulmonary arterial hypertension in critically ill adults. Pharmacotherapy. 2010;30:728–740.

    Article  PubMed  CAS  Google Scholar 

  55. Rich J, Hoeper MM. The search for an oral prostanoid to treat pulmonary arterial hypertension continues. Are we getting any closer? Int J Clin Pract Suppl. 2009;161:17–18.

    Article  PubMed  Google Scholar 

  56. Skoro-Sajer N, Lang I, Naeije R. Treprostinil for pulmonary hypertension. Vasc Health Risk Manag. 2008;4:507–513.

    PubMed  CAS  Google Scholar 

  57. Hart CM. The Role of PPARgamma in pulmonary vascular disease. J Investig Med. 2008;56:518–521.

    PubMed  CAS  Google Scholar 

  58. Rabinovitch M. PPARgamma and the pathobiology of pulmonary arterial hypertension. Adv Exp Med Biol. 2010;661:447–458.

    Article  PubMed  CAS  Google Scholar 

  59. Crossno JT, Jr., Garat CV, Reusch JE, et al. Rosiglitazone attenuates hypoxia-induced pulmonary arterial remodeling. Am J Physiol Lung Cell Mol Physiol. 2007;292:L885–L897.

    Article  PubMed  CAS  Google Scholar 

  60. Nisbet RE, Bland JM, Kleinhenz DJ, et al. Rosiglitazone attenuates chronic hypoxia-induced pulmonary hypertension in a mouse model. Am J Respir Cell Mol Biol. 2010;42:482–490.

    Article  PubMed  Google Scholar 

  61. Falcetti E, Flavell DM, Staels B, Tinker A, Haworth SG, Clapp LH. IP receptor-dependent activation of PPARgamma by stable prostacyclin analogues. Biochem Biophys Res Commun. 2007;360:821–827.

    Article  PubMed  CAS  Google Scholar 

  62. Rosen CJ. Revisiting the rosiglitazone story-lessons learned. N Engl J Med. 2010;363:803–806.

    Article  PubMed  CAS  Google Scholar 

  63. Benza RL, Park MH, Keogh A, Girgis RE. Management of pulmonary arterial hypertension with a focus on combination therapies. J Heart Lung Transplant. 2007;26:437–446.

    Article  PubMed  Google Scholar 

  64. Stenmark KR, Rabinovitch M. Emerging therapies for the treatment of pulmonary hypertension. Pediatr Crit Care Med. 2010;11:S85–S90.

    Article  PubMed  Google Scholar 

  65. Olsson KM, Hoeper MM. Novel approaches to the pharmacotherapy of pulmonary arterial hypertension. Drug Discov Today. 2009;14:284–290..

    Article  PubMed  CAS  Google Scholar 

  66. Humbert M, Sitbon O, Chaouat A, et al. Survival in patients with idiopathic, familial, and anorexigenassociated pulmonary arterial hypertension in the modern management era. Circulation. 2010;122:156–163.

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Jean-Luc Vachiéry.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Vachiéry, JL. Prostacyclins in pulmonary arterial hypertension: the need for earlier therapy. Adv Therapy 28, 251–269 (2011). https://doi.org/10.1007/s12325-011-0005-5

Download citation

  • Received:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12325-011-0005-5

Keywords

Navigation