Article

Therapeutic Strategies in Pulmonary Arterial Hypertension

Register or Login to View PDF Permissions
Permissions× For commercial reprint enquiries please contact Springer Healthcare: ReprintsWarehouse@springernature.com.

For permissions and non-commercial reprint enquiries, please visit Copyright.com to start a request.

For author reprints, please email rob.barclay@radcliffe-group.com.
Average (ratings)
No ratings
Your rating

Keywords

Endothelin receptor antagonists, phosphodiesterase inhibitors, prostanoids, pulmonary hypertension,

Disclosure:Carmine Dario Vizza has received honoraria for sitting on advisory boards and talking at sponsored symposia from Actelion, GSK, Pfizer, United Threpeutics, Italfarmaco and Bayer. The remaining authors have no conflicts of interest to declare.

Received:

Accepted:

DOI:https://doi.org/10.15420/ecr.2012.8.3.198

Support:The publication of this article was supported by United Therapeutics. The opinions expressed are those of the authors, and not necessarily those of United Therapeutics.

Copyright Statement:

The copyright in this work belongs to Radcliffe Medical Media. Only articles clearly marked with the CC BY-NC logo are published with the Creative Commons by Attribution Licence. The CC BY-NC option was not available for Radcliffe journals before 1 January 2019. Articles marked ‘Open Access’ but not marked ‘CC BY-NC’ are made freely accessible at the time of publication but are subject to standard copyright law regarding reproduction and distribution. Permission is required for reuse of this content.

Abstract

Pulmonary arterial hypertension (PAH) is a serious and life-threatening condition for which the prognosis remains poor. Treatment options include endothelial receptor antagonists, phosphodiesterase (PDE5) inhibitors and prostanoids. Despite all demonstrating good short-term efficacy, none of the currently available drug therapies are curative. Treatment with prostanoids is complex and requires careful monitoring and management through a specialist centre. Furthermore, clinical efficacy is dependent on adequate up-titration of the drug. Treatment should be individualised and modified according to clinical response, with the addition of other therapies if required. The importance of monitoring and modifying therapeutic regimes is discussed. There appears to be reluctance among patients and physicians to employ prostanoid therapy, though an aggressive first-line therapy may be appropriate in advanced cases.

To view the full article, please click on the PDF icon.

References

  1. Simonneau G, Galiè N, Rubin LJ, et al., Clinical classification of pulmonary hypertension, J Am Coll Cardiol, 2004;43:5S–12S.
    Crossref | PubMed
  2. Galiè N, Torbicki A, Barst R, et al., Guidelines on diagnosis and treatment of pulmonary arterial hypertension. The Task Force on Diagnosis and Treatment of Pulmonary Arterial Hypertension of the European Society of Cardiology, Eur Heart J, 2004;25:2243–78.
    Crossref | PubMed
  3. Fuso L, Baldi F, Di Perna A, Therapeutic strategies in pulmonary hypertension, Front Pharmacol, 2011;2:21.
    Crossref | PubMed
  4. Houtchens J, Martin D, Klinger JR, Diagnosis and management of pulmonary arterial hypertension, Pulm Med, 2011;2011:845864.
    Crossref | PubMed
  5. Rich S, Dantzker DR, Ayres SM, et al., Primary pulmonary hypertension. A national prospective study, Ann Intern Med, 1987;107:216–23.
    Crossref | PubMed
  6. Humbert M, Morrell NW, Archer SL, et al., Cellular and molecular pathobiology of pulmonary arterial hypertension, J Am Coll Cardiol, 2004;43:13S–24S.
    Crossref | PubMed
  7. Sitbon O, Humbert M, Jaïs X, et al., Long-term response to calcium channel blockers in idiopathic pulmonary arterial hypertension, Circulation, 2005;111:3105–11.
    Crossref | PubMed
  8. Steiner MK, Preston IR, Optimizing endothelin receptor antagonist use in the management of pulmonary arterial hypertension, Vasc Health Risk Manag, 2008;4:943–52.
    Crossref | PubMed
  9. Greene S, Nunley K, Weber S, et al., ETA vs. ETB receptor selectivity of endothelin-1 receptor antagonists in human myocardial membranes, J Am Coll Cardiol, 2006;47:307A.
  10. Rubin LJ, Badesch DB, Barst RJ, et al., Bosentan therapy for pulmonary arterial hypertension, N Engl J Med, 2002;346:896–903.
    Crossref | PubMed
  11. Barst RJ, Langleben D, Frost A, et al., Sitaxsentan therapy for pulmonary arterial hypertension, Am J Respir Crit Care Med, 2004;169:441–7.
    Crossref | PubMed
  12. Galiè N, Olschewski H, Oudiz RJ, et al., 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;117:3010–9.
    Crossref | PubMed
  13. McLaughlin VV, Sitbon O, Badesch DB, et al., Survival with first-line bosentan in patients with primary pulmonary hypertension, Eur Respir J, 2005;25:244–9.
    Crossref | PubMed
  14. Oudiz RJ, Galiè N, Olschewski H, et al., Long-term ambrisentan therapy for the treatment of pulmonary arterial hypertension, J Am Coll Cardiol, 2009;54:1971–81.
    Crossref | PubMed
  15. McLaughlin VV, McGoon MD, Pulmonary arterial hypertension, Circulation, 2006;114:1417–31.
    Crossref | PubMed
  16. EMEA, Thelin (sitaxentan) to be withdrawn due to cases of unpredictable serious liver injury, Press release, 2010. Available at: www.ema.europa.eu/ema/index.jsp?curl=/pages/news_and _events/news/2010/12/news_detail_001161.jsp&murl=menu s/news_and_events/news_and_events.jsp&mid=WC0b01ac0 58004d5c1 (accessed 31 July 2012).
  17. Wilkins MR, Wharton J, Grimminger F, Ghofrani HA, Phosphodiesterase inhibitors for the treatment of pulmonary hypertension, Eur Respir J, 2008;32:198–209.
    Crossref | PubMed
  18. Galie N, Ghofrani HA, Torbicki A, et al., Sildenafil citrate therapy for pulmonary arterial hypertension, N Engl J Med, 2005;353:2148–57.
    Crossref | PubMed
  19. Galiè N, Brundage BH, Ghofrani HA, et al., Tadalafil therapy for pulmonary arterial hypertension, Circulation, 2009;119:2894–903.
    Crossref | PubMed
  20. McLaughlin VV, Genthner DE, Panella MM, Rich S, Reduction in pulmonary vascular resistance with long-term epoprostenol (prostacyclin) therapy in primary pulmonary hypertension, N Engl J Med, 1998;338:273–7.
    Crossref | PubMed
  21. Higenbottam T, Wheeldon D, Wells F, Wallwork J, Long-term treatment of primary pulmonary hypertension with continuous intravenous epoprostenol (prostacyclin), Lancet, 1984;1:1046–7.
    Crossref | PubMed
  22. Barst RJ, Rubin LJ, Long WA, 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.
    Crossref | PubMed
  23. Rubin LJ, Badesch DB, Evaluation and management of the patient with pulmonary arterial hypertension, Ann Intern Med, 2005;143:282–92.
    Crossref | PubMed
  24. Channick RN, Voswinckel R, Rubin LJ, Inhaled treprostinil: a therapeutic review, Drug Des Devel Ther, 2012;6:19–28.
    Crossref | PubMed
  25. McLaughlin VV, Gaine SP, Barst RJ, et al., Efficacy and safety of treprostinil: an epoprostenol analog for primary pulmonary hypertension, J Cardiovasc Pharmacol, 2003;41:293–9.
    Crossref | PubMed
  26. 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;165:800–4.
    Crossref | PubMed
  27. 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;40:780–8.
    Crossref | PubMed
  28. McLaughlin VV, Shillington A, Rich S, Survival in primary pulmonary hypertension: the impact of epoprostenol therapy, Circulation, 2002;106:1477–82.
    Crossref | PubMed
  29. Lang I, Gomez-Sanchez M, Kneussl M, et al., Efficacy of long-term subcutaneous treprostinil sodium therapy in pulmonary hypertension, Chest, 2006;129:1636–43.
    Crossref | PubMed
  30. Olschewski H, Simonneau G, Galiè N, et al., Inhaled iloprost for severe pulmonary hypertension, N Engl J Med, 2002;347:322–9.
    Crossref | PubMed
  31. Hoeper MM, Schwarze M, Ehlerding S, et al., Long-term treatment of primary pulmonary hypertension with aerosolized iloprost, a prostacyclin analogue, N Engl J Med, 2000;342:1866–70.
    Crossref | PubMed
  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;48:1672–81.
    Crossref | PubMed
  33. Ewert R, Wensel R, Opitz CF, Aerosolized iloprost for primary pulmonary hypertension, N Engl J Med, 2000;343:1421–2.
    Crossref | PubMed
  34. 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;55:1915–22.
    Crossref | PubMed
  35. Barst RJ, McGoon M, McLaughlin V, et al., Beraprost therapy for pulmonary arterial hypertension, J Am Coll Cardiol, 2003;41:2119–25.
    Crossref | PubMed
  36. Simonneau G, Torbicki A, Hoeper MM, et al., Selexipag, an oral, selective IP receptor agonist for the treatment of pulmonary arterial hypertension, Eur Respir J, 2012 [Epub ahead of print].
  37. Galiè N, Manes A, Negro L, et al., A meta-analysis of randomized controlled trials in pulmonary arterial hypertension, Eur Heart J, 2009;30:394–403.
    Crossref | PubMed
  38. Rich S, McLaughlin VV, The effects of chronic prostacyclin therapy on cardiac output and symptoms in primary pulmonary hypertension, J Am Coll Cardiol, 1999;34:1184–7.
    Crossref | PubMed
  39. Benza RL, Gomberg-Maitland M, Naeije R, et al., Prognostic factors associated with increased survival in patients with pulmonary arterial hypertension treated with subcutaneous treprostinil in randomized, placebo-controlled trials, J Heart Lung Transplant, 2011;30:982–9.
    Crossref | PubMed
  40. Delcroix M, Spaas K, Quarck R. Long-term outcome in pulmonary arterial hypertension: a plea for earlier parenteral prostacyclin therapy, Eur Respir Rev, 2009;18:253–9.
    Crossref | PubMed
  41. Sadushi-Koliçi R, Skoro-Sajer N, Zimmer D, et al., Long-term treatment, tolerability, and survival with sub-cutaneous treprostinil for severe pulmonary hypertension, J Heart Lung Transplant, 2012;31:735–43.
    Crossref | PubMed
  42. Barst RJ, Gibbs JS, Ghofrani HA, et al., Updated evidencebased treatment algorithm in pulmonary arterial hypertension, J Am Coll Cardiol, 2009;54:S78–84.
    Crossref | PubMed
  43. Galiè 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;30:2493–537.
    Crossref | PubMed
  44. Provencher S, Sitbon O, Humbert M, et al., Long-term outcome with first-line bosentan therapy in idiopathic pulmonary arterial hypertension, Eur Heart J, 2006;27:589–95.
    Crossref | PubMed
  45. Benza RL, Barst RJ, Galie N, et al., Sitaxsentan for the treatment of pulmonary arterial hypertension: a 1-year, prospective, open-label observation of outcome and survival, Chest, 2008;134:775–82.
    Crossref | PubMed
  46. Vizza CD, Letizia C, Badagliacca R, et al., Relationship between baseline ET-1 plasma levels and outcome in patients with idiopathic pulmonary hypertension treated with bosentan, Int J Cardiol, 2012 Jan 18 [Epub ahead of print].
  47. Tankersley MA, D’Albini LD, Ozanich AN, Whitman AJ, A 36- Month Survival Analysis of Patients Beginning Oral PAH Monotherapy: An Indication for Escalation of Therapy? Pulmonary Hypertension Association Meeting, Houston, Texas, 2008;Poster 1062.
  48. Badagliacca R, Pezzuto B, Poscia R, et al., Prognostic factors in severe pulmonary hypertension patients who need parenteral prostanoid therapy: the impact of late referral, J Heart Lung Transplant, 2012;31:364–72.
    Crossref | PubMed
  49. Knudsen L, Schurawlew A, Nickel N, et al., Long-term effects of intravenous iloprost in patients with idiopathic pulmonary arterial hypertension deteriorating on nonparenteral therapy, BMC Pulm Med, 2011;11:56.
  50. Kemp K, Savale L, O’Callaghan DS, et al., Usefulness of firstline combination therapy with epoprostenol and bosentan in pulmonary arterial hypertension: an observational study, J Heart Lung Transplant, 2012;31(2):150–8.
    Crossref | PubMed
  51. Bai Y, Sun L, Hu S, Wei Y, Combination therapy in pulmonary arterial hypertension: a meta-analysis, Cardiology, 2012;120:157–65.
    Crossref | PubMed
  52. Simonneau G, Rubin LJ, Galiè 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;149:521–30.
    Crossref | PubMed
  53. 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;112:485–91.
    Crossref | PubMed
  54. 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;132:425–34.
    Crossref | PubMed
  55. 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;129:683–8.
    Crossref | PubMed
  56. 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;26:1895–902.
    Crossref | PubMed
  57. Barst RJ, Galie N, Naeije R, et al., Long-term outcome in pulmonary arterial hypertension patients treated with subcutaneous treprostinil, Eur Respir J, 2006;28:1195–203.
    Crossref | PubMed
Previous Volume Article Next Volume Article