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Guidelines for the Treatment of Pulmonary Arterial Hypertension

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Abstract

Pulmonary arterial hypertension (PAH) is a rare form of pulmonary hypertension characterized by a progressive obliterative vasculopathy of the distal pulmonary arterial circulation that usually leads to right ventricular failure and death. Over the last 25 years, more than a dozen drugs representing five drug classes have been developed and approved for the treatment of this devastating disease. Due to the small number of patients afflicted by PAH, most health care providers have little experience with its management. To address this gap in medical knowledge, treatment guidelines have been developed by professional organizations and expert committees. Over the last few years, these guidelines have been updated to address findings from recent clinical trials and ongoing experience with these drugs. This review provides an update on the most recently published treatment guidelines for pharmacologic treatment of PAH and incorporates them into a contemporary approach to the treatment of this disease.

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References

  1. Kovacs G, Berghold A, Scheidl S, Olschewski H (2009) Pulmonary arterial pressure during rest and exercise in healthy subjects: a systematic review. Eur Respir J 34(4):888–894

    Article  CAS  PubMed  Google Scholar 

  2. Simonneau G, Montani D, Celermajer DS, Denton CP, Gatzoulis MA, Krowka M et al (2019) Haemodynamic definitions and updated clinical classification of pulmonary hypertension. Eur Respir J. https://doi.org/10.1183/13993003.01913-2018

    Article  PubMed  PubMed Central  Google Scholar 

  3. Galie N, Humbert M, Vachiery JL, Gibbs S, Lang I, Torbicki A et al (2016) 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): endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT). Eur Heart J 37(1):67–119

    Article  PubMed  Google Scholar 

  4. Humbert M, Guignabert C, Bonnet S, Dorfmuller P, Klinger JR, Nicolls MR et al (2019) Pathology and pathobiology of pulmonary hypertension: state of the art and research perspectives. Eur Respir J. https://doi.org/10.1183/13993003.01887-2018

    Article  PubMed  PubMed Central  Google Scholar 

  5. Southgate L, Machado RD, Gräf S, Morrell NW (2020) Molecular genetic framework underlying pulmonary arterial hypertension. Nat Rev Cardiol 17(2):85–95. https://doi.org/10.1038/s41569-019-0242-xEpub 2019 Aug 12

    Article  CAS  PubMed  Google Scholar 

  6. Strange G, Playford D, Stewart S, Deague JA, Nelson H, Kent A et al (2012) Pulmonary hypertension: prevalence and mortality in the Armadale echocardiography cohort. Heart 98(24):1805–1811

    Article  PubMed  PubMed Central  Google Scholar 

  7. Humbert M, Sitbon O, Chaouat A, Bertocchi M, Habib G, Gressin V et al (2006) Pulmonary arterial hypertension in France: results from a national registry. Am J Respir Crit Care Med 173(9):1023–1308

    Article  PubMed  Google Scholar 

  8. Association PH (2019) Preliminary data: demographic characteristics of participants. Pulmonary Hypertension Association. http://phassociation.org/phar/preliminary-data/demographics. Accessed 29 Oct 2019

  9. Humbert M, Sitbon O, Simonneau G (2004) Treatment of pulmonary arterial hypertension. N Engl J Med 351(14):1425–1436

    Article  CAS  PubMed  Google Scholar 

  10. Christman BW, McPherson CD, Newman JH, King GA, Bernard GR, Groves BM et al (1992) An imbalance between the excretion of thromboxane and prostacyclin metabolites in pulmonary hypertension. N Engl J Med 327(2):70–75

    Article  CAS  PubMed  Google Scholar 

  11. Tuder RM, Cool CD, Geraci MW, Wang J, Abman SH, Wright L et al (1999) Prostacyclin synthase expression is decreased in lungs from patients with severe pulmonary hypertension. Am J Respir Crit Care Med 159(6):1925–1932

    Article  CAS  PubMed  Google Scholar 

  12. Klinger JR, Abman SH, Gladwin MT (2013) Nitric oxide deficiency and endothelial dysfunction in pulmonary arterial hypertension. Am J Respir Crit Care Med 188(6):639–646

    Article  CAS  PubMed  Google Scholar 

  13. Wharton J, Strange JW, Moller GM, Growcott EJ, Ren X, Franklyn AP et al (2005) Antiproliferative effects of phosphodiesterase type 5 inhibition in human pulmonary artery cells. Am J Respir Crit Care Med 172(1):105–113

    Article  PubMed  Google Scholar 

  14. Humbert M, Lau EM, Montani D, Jaïs X, Sitbon O, Simonneau G (2014) Advances in therapeutic interventions for patients with pulmonary arterial hypertension. Circulation 130(24):2189-2208. https://doi.org/10.1161/CIRCULATIONAHA.114.006974

    Article  PubMed  Google Scholar 

  15. Barst RJ, Rubin LJ, Long WA, McGoon MD, Rich S, Badesch DB et al (1996) A comparison of continuous intravenous epoprostenol (prostacyclin) with conventional therapy for primary pulmonary hypertension. N Engl J Med 334(5):296–301

    Article  CAS  PubMed  Google Scholar 

  16. Simonneau G, Barst RJ, Galie N, Naeije R, Rich S, Bourge RC et al (2002) 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 165(6):800–804

    Article  PubMed  Google Scholar 

  17. Jing ZC, Parikh K, Pulido T, Jerjes-Sanchez C, White RJ, Allen R et al (2013) Efficacy and safety of oral treprostinil monotherapy for the treatment of pulmonary arterial hypertension: a randomized, controlled trial. Circulation 127(5):624–633

    Article  CAS  PubMed  Google Scholar 

  18. McLaughlin VV, Benza RL, Rubin LJ, Channick RN, Voswinckel R, Tapson VF et al (2010) Addition of inhaled treprostinil to oral therapy for pulmonary arterial hypertension: a randomized controlled clinical trial. J Am Coll Cardiol 55(18):1915–1922

    Article  CAS  PubMed  Google Scholar 

  19. Olschewski H, Simonneau G, Galiè N, Higenbottam T, Naeije R, Rubin LJ et al (2002) Inhaled iloprost for severe pulmonary hypertension. N Engl J Med 347(5):322–329

    Article  CAS  PubMed  Google Scholar 

  20. Galie N, Olschewski H, Oudiz RJ, Torres F, Frost A, Ghofrani HA et al (2008) 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 117(23):3010–3019

    Article  CAS  PubMed  Google Scholar 

  21. Rubin LJ, Badesch DB, Barst RJ, Galiè N, Black CM, Keogh A et al (2002) Bosentan therapy for pulmonary arterial hypertension. N Engl J Med 346(12):896–903

    Article  CAS  PubMed  Google Scholar 

  22. Pulido T, Adzerikho I, Channick RN, Delcroix M, Galie N, Ghofrani HA et al (2013) Macitentan and morbidity and mortality in pulmonary arterial hypertension. N Engl J Med 369(9):809–818

    Article  CAS  PubMed  Google Scholar 

  23. Galiè N, Ghofrani HA, Torbicki A, Barst RJ, Rubin LJ, Badesch D et al (2005) Sildenafil citrate therapy for pulmonary arterial hypertension. N Engl J Med 353(20):2148–2157

    Article  PubMed  Google Scholar 

  24. Simonneau G, Rubin LJ, Galie N, Barst RJ, Fleming TR, Frost AE et al (2008) Addition of sildenafil to long-term intravenous epoprostenol therapy in patients with pulmonary arterial hypertension: a randomized trial. Ann Intern Med 149(8):521–530

    Article  PubMed  Google Scholar 

  25. Galie N, Brundage BH, Ghofrani HA, Oudiz RJ, Simonneau G, Safdar Z et al (2009) Tadalafil therapy for pulmonary arterial hypertension. Circulation 119(22):2894–2903

    Article  CAS  PubMed  Google Scholar 

  26. Ghofrani HA, Galie N, Grimminger F, Grunig E, Humbert M, Jing ZC et al (2013) Riociguat for the treatment of pulmonary arterial hypertension. N Engl J Med 369(4):330–340

    Article  CAS  PubMed  Google Scholar 

  27. Sitbon O, Channick R, Chin KM, Frey A, Gaine S, Galiè N et al (2015) Selexipag for the Treatment of Pulmonary Arterial Hypertension. N Engl J Med 373(26):2522–2533

    Article  CAS  PubMed  Google Scholar 

  28. Galie N, Barbera JA, Frost AE, Ghofrani HA, Hoeper MM, McLaughlin VV et al (2015) Initial use of ambrisentan plus tadalafil in pulmonary arterial hypertension. N Engl J Med 373(9):834–844

    Article  CAS  PubMed  Google Scholar 

  29. Tongers J, Schwerdtfeger B, Klein G, Kempf T, Schaefer A, Knapp JM et al (2007) Incidence and clinical relevance of supraventricular tachyarrhythmias in pulmonary hypertension. Am Heart J 153(1):127–132

    Article  PubMed  Google Scholar 

  30. Klinger JR, Elliott CG, Levine DJ, Bossone E, Duvall L, Fagan K et al (2019) Therapy for pulmonary arterial hypertension in adults: update of the CHEST guideline and expert panel report. Chest 155(3):565–586

    Article  PubMed  Google Scholar 

  31. Weiss BM, Zemp L, Seifert B, Hess OM (1998) Outcome of pulmonary vascular disease in pregnancy: a systematic overview from 1978 through 1996. J Am Coll Cardiol 31(7):1650–1657

    Article  CAS  PubMed  Google Scholar 

  32. Lim K, Chang SA, Oh SY, Lee JH, Song J, Kang IS et al (2019) Pulmonary arterial hypertension and pregnancy: single center experience in current era of targeted therapy. Korean Circ J 49(6):545–554

    Article  PubMed  PubMed Central  Google Scholar 

  33. Galie N, McLaughlin VV, Rubin LJ, Simonneau G (2019) An overview of the 6th world symposium on pulmonary hypertension. Eur Respir J. https://doi.org/10.1183/13993003.02148-2018

    Article  PubMed  PubMed Central  Google Scholar 

  34. Sitbon O, Humbert M, Jais X, Ioos V, Hamid AM, Provencher S et al (2005) Long-term response to calcium channel blockers in idiopathic pulmonary arterial hypertension. Circulation 111(23):3105–3111

    Article  CAS  PubMed  Google Scholar 

  35. Montani D, Savale L, Natali D, Jais X, Herve P, Garcia G et al (2010) Long-term response to calcium-channel blockers in non-idiopathic pulmonary arterial hypertension. Eur Heart J 31(15):1898–1907

    Article  CAS  PubMed  Google Scholar 

  36. Palmer SM, Robinson LJ, Wang A, Gossage JR, Bashore T, Tapson VF (1998) Massive pulmonary edema and death after prostacyclin infusion in a patient with pulmonary veno-occlusive disease. Chest 113(1):237–240

    Article  CAS  PubMed  Google Scholar 

  37. Preston IR, Klinger JR, Houtchens J, Nelson D, Mehta S, Hill NS (2002) Pulmonary edema caused by inhaled nitric oxide therapy in two patients with pulmonary hypertension associated with the CREST syndrome. Chest 121(2):656–659

    Article  PubMed  Google Scholar 

  38. Morrell NW, Aldred MA, Chung WK, Elliott CG, Nichols WC, Soubrier F et al (2019) Genetics and genomics of pulmonary arterial hypertension. Eur Respir J. https://doi.org/10.1183/13993003.01899-2018

    Article  PubMed  PubMed Central  Google Scholar 

  39. Vonk Noordegraaf A, Chin KM, Haddad F, Hassoun PM, Hemnes AR, Hopkins SR et al (2019) Pathophysiology of the right ventricle and of the pulmonary circulation in pulmonary hypertension: an update. Eur Respir J. https://doi.org/10.1183/13993003.01900-2018

    Article  PubMed  PubMed Central  Google Scholar 

  40. Sitbon O, Gomberg-Maitland M, Granton J, Lewis MI, Mathai SC, Rainisio M et al (2019) Clinical trial design and new therapies for pulmonary arterial hypertension. Eur Respir J. https://doi.org/10.1183/13993003.01908-2018

    Article  PubMed  PubMed Central  Google Scholar 

  41. Frost A, Badesch D, Gibbs JSR, Gopalan D, Khanna D, Manes A et al (2019) Diagnosis of pulmonary hypertension. Eur Respir J. https://doi.org/10.1183/13993003.01904-2018

    Article  PubMed  PubMed Central  Google Scholar 

  42. Rosenzweig EB, Abman SH, Adatia I, Beghetti M, Bonnet D, Haworth S et al (2019) Paediatric pulmonary arterial hypertension: updates on definition, classification, diagnostics and management. Eur Respir J. https://doi.org/10.1183/13993003.01916-2018

    Article  PubMed  PubMed Central  Google Scholar 

  43. McGoon MD, Ferrari P, Armstrong I, Denis M, Howard LS, Lowe G et al (2019) The importance of patient perspectives in pulmonary hypertension. Eur Respir J. https://doi.org/10.1183/13993003.01919-2018

    Article  PubMed  PubMed Central  Google Scholar 

  44. Kim NH, Delcroix M, Jais X, Madani MM, Matsubara H, Mayer E et al (2019) Chronic thromboembolic pulmonary hypertension. Eur Respir J. https://doi.org/10.1183/13993003.01915-2018

    Article  PubMed  PubMed Central  Google Scholar 

  45. Galie N, Channick RN, Frantz RP, Grunig E, Jing ZC, Moiseeva O et al (2019) Risk stratification and medical therapy of pulmonary arterial hypertension. Eur Respir J. https://doi.org/10.1183/13993003.01889-2018

    Article  PubMed  PubMed Central  Google Scholar 

  46. Hoeper MM, Benza RL, Corris P, de Perrot M, Fadel E, Keogh AM et al (2019) Intensive care, right ventricular support and lung transplantation in patients with pulmonary hypertension. Eur Respir J. https://doi.org/10.1183/13993003.01906-2018

    Article  PubMed  PubMed Central  Google Scholar 

  47. Vachiery JL, Tedford RJ, Rosenkranz S, Palazzini M, Lang I, Guazzi M et al (2019) Pulmonary hypertension due to left heart disease. Eur Respir J. https://doi.org/10.1183/13993003.01897-2018

    Article  PubMed  PubMed Central  Google Scholar 

  48. Nathan SD, Barbera JA, Gaine SP, Harari S, Martinez FJ, Olschewski H et al (2019) Pulmonary hypertension in chronic lung disease and hypoxia. Eur Respir J. https://doi.org/10.1183/13993003.01914-2018

    Article  PubMed  PubMed Central  Google Scholar 

  49. Badesch DB, Abman SH, Ahearn GS, Barst RJ, McCrory DC, Simonneau G et al (2004) Medical therapy for pulmonary arterial hypertension: ACCP evidence-based clinical practice guidelines. Chest 126(1 Suppl):35s–62s

    Article  PubMed  Google Scholar 

  50. Balshem H, Helfand M, Schunemann HJ, Oxman AD, Kunz R, Brozek J et al (2011) GRADE guidelines: 3. Rating the quality of evidence. J Clin Epidemiol 64(4):401–406

    Article  PubMed  Google Scholar 

  51. Galie N, Muller K, Scalise AV, Grunig E (2015) PATENT PLUS: a blinded, randomised and extension study of riociguat plus sildenafil in pulmonary arterial hypertension. Eur Respir J 45(5):1314–1322

    Article  CAS  PubMed  Google Scholar 

  52. Hoeper MM, Simonneau G, Corris PA, Ghofrani HA, Klinger JR, Langleben D et al (2017) RESPITE: switching to riociguat in pulmonary arterial hypertension patients with inadequate response to phosphodiesterase-5 inhibitors. Eur Respir J. https://doi.org/10.1183/13993003.02425-2016

    Article  PubMed  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. Division of Pulmonary, Sleep and Critical Care Medicine, Rhode Island Hospital, Alpert Medical School of Brown University, 593 Eddy St., POB 224, Providence, RI, 02806, USA

    Zoë G. S. Vazquez & James R. Klinger

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  1. Zoë G. S. Vazquez
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  2. James R. Klinger
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Correspondence to James R. Klinger.

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Dr. Klinger's institution receives grant funding for pulmonary hypertension studies from United Therapeutics and Actelion, and he serves as a non-paid committee member on a pulmonary hypertension clinical trial for Bayer.

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Vazquez, Z.G.S., Klinger, J.R. Guidelines for the Treatment of Pulmonary Arterial Hypertension. Lung 198, 581–596 (2020). https://doi.org/10.1007/s00408-020-00375-w

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