Abstract
Purpose of Review
Pulmonary arterial hypertension (PAH) leads to progressive increases in pulmonary vascular resistance (PVR), right heart failure, and death if left untreated. This review will summarize and discuss recent updates in the classification and management of patients with PAH.
Recent Findings
PAH requires careful hemodynamic assessment and is defined by a mean pulmonary artery pressure > 20 mmHg with normal left-sided filling pressures and a PVR ≥ 3 Wood units. Most patients with PAH require targeted pharmacotherapy based on multiparametric risk stratification. Significant improvements in clinical outcome have been realized through the approval of 14 unique pharmacotherapeutic options.
Summary
The latest clinical recommendations provide the updated hemodynamic definition and clinical classification as well as evidence-based treatment recommendations. An important change is the focus on initial upfront combination therapy for most patients with PAH. Structured follow-up and escalation of treatment for those not achieving low-risk status is paramount.
Similar content being viewed by others
References
Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance
Humbert M, Sitbon O, Simonneau G. Treatment of pulmonary arterial hypertension. N Engl J Med. 2004;351(14):1425–36. https://doi.org/10.1056/NEJMra040291.
Humbert M, Sitbon O, Chaouat A, Bertocchi M, Habib G, Gressin V, et al. Pulmonary arterial hypertension in France: results from a national registry. Am J Respir Crit Care Med. 2006;173(9):1023–30. https://doi.org/10.1164/rccm.200510-1668OC.
Badesch DB, Raskob GE, Elliott CG, Krichman AM, Farber HW, Frost AE, et al. Pulmonary arterial hypertension: baseline characteristics from the REVEAL Registry. Chest. 2010;137(2):376–87. https://doi.org/10.1378/chest.09-1140.
•• Galie N, Channick RN, Frantz RP, Grunig E, Jing ZC, Moiseeva O, et al. Risk stratification and medical therapy of pulmonary arterial hypertension. Eur Respir J. 2019;53(1). https://doi.org/10.1183/13993003.01889-2018 This document provides the most recent WSPH recommendations on the evaluation and management of pulmonary arterial hypertension.
D'Alonzo GE, Barst RJ, Ayres SM, Bergofsky EH, Brundage BH, Detre KM, et al. Survival in patients with primary pulmonary hypertension. Results from a national prospective registry. Ann Intern Med. 1991;115(5):343–9.
•• Simonneau G, Montani D, Celermajer DS, Denton CP, Gatzoulis MA, Krowka M, et al. Haemodynamic definitions and updated clinical classification of pulmonary hypertension. Eur Respir J. 2019;53(1). https://doi.org/10.1183/13993003.01913-2018 This document provides the most recent WSPH definitions and classification of pulmonary hypertension.
Hoeper MM, Bogaard HJ, Condliffe R, Frantz R, Khanna D, Kurzyna M, et al. Definitions and diagnosis of pulmonary hypertension. J Am Coll Cardiol. 2013;62(25 Suppl):D42–50. https://doi.org/10.1016/j.jacc.2013.10.032.
Guignabert C, Dorfmuller P. Pathology and pathobiology of pulmonary hypertension. Semin Respir Crit Care Med. 2017;38(5):571–84. https://doi.org/10.1055/s-0037-1606214.
Boucherat O, Vitry G, Trinh I, Paulin R, Provencher S, Bonnet S. The cancer theory of pulmonary arterial hypertension. Pulm Circ. 2017;7(2):285–99. https://doi.org/10.1177/2045893217701438.
VV ML, Archer SL, Badesch DB, Barst RJ, Farber HW, Lindner JR, 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. Journal of the American College of Cardiology. 2009;53(17):1573–619. https://doi.org/10.1016/j.jacc.2009.01.004.
Galie N, Corris PA, Frost A, Girgis RE, Granton J, Jing ZC, et al. Updated treatment algorithm of pulmonary arterial hypertension. J Am Coll Cardiol. 2013;62(25 Suppl):D60–72. https://doi.org/10.1016/j.jacc.2013.10.031.
•• Galie N, Humbert M, Vachiery JL, Gibbs S, Lang I, Torbicki A, et al. 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). European heart journal. 2016;37(1):67–119. https://doi.org/10.1093/eurheartj/ehv317 This statement from the ESC/ERS provides practice guidelines for pulmonary hypertension.
Rich JD, Shah SJ, Swamy RS, Kamp A, Rich S. Inaccuracy of Doppler echocardiographic estimates of pulmonary artery pressures in patients with pulmonary hypertension: implications for clinical practice. Chest. 2011;139(5):988–93. https://doi.org/10.1378/chest.10-1269.
Raymond RJ, Hinderliter AL, Willis PW, Ralph D, Caldwell EJ, Williams W, et al. Echocardiographic predictors of adverse outcomes in primary pulmonary hypertension. J Am Coll Cardiol. 2002;39(7):1214–9.
Benza RL, Miller DP, Foreman AJ, Frost AE, Badesch DB, Benton WW, et al. Prognostic implications of serial risk score assessments in patients with pulmonary arterial hypertension: a registry to evaluate early and Long-term pulmonary arterial hypertension disease management (REVEAL) analysis. J Heart Lung Transplant. 2015;34(3):356–61. https://doi.org/10.1016/j.healun.2014.09.016.
Benza RL, Gomberg-Maitland M, Elliott CG, Farber HW, Foreman AJ, Frost AE, et al. Predicting survival in patients with pulmonary arterial hypertension: the REVEAL risk score calculator 2.0 and comparison with ESC/ERS-based risk assessment strategies. Chest. 2019;156(2):323–37. https://doi.org/10.1016/j.chest.2019.02.004.
Kylhammar D, Kjellstrom B, Hjalmarsson C, Jansson K, Nisell M, Soderberg S, et al. A comprehensive risk stratification at early follow-up determines prognosis in pulmonary arterial hypertension. Eur Heart J. 2018;39(47):4175–81. https://doi.org/10.1093/eurheartj/ehx257.
Hoeper MM, Kramer T, Pan Z, Eichstaedt CA, Spiesshoefer J, Benjamin N, et al. Mortality in pulmonary arterial hypertension: prediction by the 2015 European pulmonary hypertension guidelines risk stratification model. Eur Respir J. 2017;50(2). https://doi.org/10.1183/13993003.00740-2017.
Boucly A, Weatherald J, Savale L, Jais X, Cottin V, Prevot G, et al. Risk assessment, prognosis and guideline implementation in pulmonary arterial hypertension. Eur Respir J. 2017;50(2). https://doi.org/10.1183/13993003.00889-2017.
Leuchte HH, El Nounou M, Tuerpe JC, Hartmann B, Baumgartner RA, Vogeser M, et al. N-terminal pro-brain natriuretic peptide and renal insufficiency as predictors of mortality in pulmonary hypertension. Chest. 2007;131(2):402–9. https://doi.org/10.1378/chest.06-1758.
Pezzuto B, Badagliacca R, Poscia R, Ghio S, D'Alto M, Vitulo P, et al. Circulating biomarkers in pulmonary arterial hypertension: update and future direction. J Heart Lung Transplant. 2015;34(3):282–305. https://doi.org/10.1016/j.healun.2014.12.005.
Gomberg-Maitland M, Glassner-Kolmin C, Watson S, Frantz R, Park M, Frost A, et al. Survival in pulmonary arterial hypertension patients awaiting lung transplantation. J Heart Lung Transplant. 2013;32(12):1179–86. https://doi.org/10.1016/j.healun.2013.08.016.
George MG, Schieb LJ, Ayala C, Talwalkar A, Levant S. Pulmonary hypertension surveillance: United States, 2001 to 2010. Chest. 2014;146(2):476–95. https://doi.org/10.1378/chest.14-0527.
Frantz RP, Schilz RJ, Chakinala MM, Badesch DB, Frost AE, McLaughlin VV, et al. Hospitalization and survival in patients using epoprostenol for injection in the PROSPECT observational study. Chest. 2015;147(2):484–94. https://doi.org/10.1378/chest.14-1004.
Frost AE, Badesch DB, Miller DP, Benza RL, Meltzer LA, McGoon MD. 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(5):1521–9. https://doi.org/10.1378/chest.12-3023.
Cogswell R, Pritzker M, De Marco T. Performance of the REVEAL pulmonary arterial hypertension prediction model using non-invasive and routinely measured parameters. J Heart Lung Transplant. 2014;33(4):382–7. https://doi.org/10.1016/j.healun.2013.12.015.
Sitbon O, Humbert M, Jais X, Ioos V, Hamid AM, Provencher S, et al. Long-term response to calcium channel blockers in idiopathic pulmonary arterial hypertension. Circulation. 2005;111(23):3105–11. https://doi.org/10.1161/CIRCULATIONAHA.104.488486.
Galie N, Ghofrani HA, Torbicki A, Barst RJ, Rubin LJ, Badesch D, et al. Sildenafil citrate therapy for pulmonary arterial hypertension. N Engl J Med. 2005;353(20):2148–57. https://doi.org/10.1056/NEJMoa050010.
Galie N, Brundage BH, Ghofrani HA, Oudiz RJ, Simonneau G, Safdar Z, et al. Tadalafil therapy for pulmonary arterial hypertension. Circulation. 2009;119(22):2894–903. https://doi.org/10.1161/CIRCULATIONAHA.108.839274.
Revatio (sildenafil) [package insert]. New York, NY: Pfizer Labs; 2014.
Adcirca (tadalafil) [package insert]. Indianapolis, IN: Eli Lilly and Company; 2017.
Ghofrani HA, Galie N, Grimminger F, Grunig E, Humbert M, Jing ZC, et al. Riociguat for the treatment of pulmonary arterial hypertension. N Engl J Med. 2013;369(4):330–40. https://doi.org/10.1056/NEJMoa1209655.
Adempas (riociguat) [package insert]. Whippany, NJ: Bayer HealthCare Pharmaceuticals Inc; 2017.
Rubin LJ, Badesch DB, Barst RJ, Galie N, Black CM, Keogh A, et al. Bosentan therapy for pulmonary arterial hypertension. N Engl J Med. 2002;346(12):896–903. https://doi.org/10.1056/NEJMoa012212.
Galie N, Olschewski H, Oudiz RJ, Torres F, Frost A, Ghofrani HA, 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(23):3010–9. https://doi.org/10.1161/CIRCULATIONAHA.107.742510.
Pulido T, Adzerikho I, Channick RN, Delcroix M, Galie N, Ghofrani HA, et al. Macitentan and morbidity and mortality in pulmonary arterial hypertension. N Engl J Med. 2013;369(9):809–18. https://doi.org/10.1056/NEJMoa1213917.
Opsumit (macitentan) [package insert]. South San Francisco, CA: Actelion Pharmaceuticals US, Inc; 2019.
Letairis (ambrisentan) [package insert]. Foster City, CA: Gilead Sciences, Inc; 2018.
Tracleer (bosentan) [package insert]. South San Francisco, CA: Actelion Pharmaceuticals US, Inc; 2019.
Barst RJ, Rubin LJ, Long WA, McGoon MD, Rich S, Badesch DB, et al. A comparison of continuous intravenous epoprostenol (prostacyclin) with conventional therapy for primary pulmonary hypertension. N Engl J Med. 1996;334(5):296–301. https://doi.org/10.1056/NEJM199602013340504.
Simonneau G, Barst RJ, Galie N, Naeije R, Rich S, Bourge RC, 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(6):800–4. https://doi.org/10.1164/ajrccm.165.6.2106079.
Remodulin (treprostinil) [package insert]. Research Triange Park, NC: United Therapeutics Corp; 2019.
Califf RM, Adams KF, McKenna WJ, Gheorghiade M, Uretsky BF, McNulty SE, et al. A randomized controlled trial of epoprostenol therapy for severe congestive heart failure: the Flolan International Randomized Survival Trial (FIRST). Am Heart J. 1997;134(1):44–54.
Jing ZC, Parikh K, Pulido T, Jerjes-Sanchez C, White RJ, Allen R, et al. Efficacy and safety of oral treprostinil monotherapy for the treatment of pulmonary arterial hypertension: a randomized, controlled trial. Circulation. 2013;127(5):624–33. https://doi.org/10.1161/CIRCULATIONAHA.112.124388.
Tapson VF, Jing ZC, Xu KF, Pan L, Feldman J, Kiely DG, et al. Oral treprostinil for the treatment of pulmonary arterial hypertension in patients receiving background endothelin receptor antagonist and phosphodiesterase type 5 inhibitor therapy (the FREEDOM-C2 study): a randomized controlled trial. Chest. 2013;144(3):952–8. https://doi.org/10.1378/chest.12-2875.
Tapson VF, Torres F, Kermeen F, Keogh AM, Allen RP, Frantz RP, et al. Oral treprostinil for the treatment of pulmonary arterial hypertension in patients on background endothelin receptor antagonist and/or phosphodiesterase type 5 inhibitor therapy (the FREEDOM-C study): a randomized controlled trial. Chest. 2012;142(6):1383–90. https://doi.org/10.1378/chest.11-2212.
Chakinala MM, Feldman JP, Rischard F, Mathier M, Broderick M, Leedom N, et al. Transition from parenteral to oral treprostinil in pulmonary arterial hypertension. J Heart Lung Transplant. 2017;36(2):193–201. https://doi.org/10.1016/j.healun.2016.06.019.
Rahaghi FF, Feldman JP, Allen RP, Tapson V, Safdar Z, Balasubramanian VP, et al. Recommendations for the use of oral treprostinil in clinical practice: a Delphi consensus project pulmonary circulation. Pulm Circ. 2017;7(1):167–74. https://doi.org/10.1086/690109.
Sitbon O, Channick R, Chin KM, Frey A, Gaine S, Galie N, et al. Selexipag for the treatment of pulmonary arterial hypertension. N Engl J Med. 2015;373(26):2522–33. https://doi.org/10.1056/NEJMoa1503184.
Galie N, Barbera JA, Frost AE, Ghofrani HA, Hoeper MM, McLaughlin VV, et al. Initial use of ambrisentan plus tadalafil in pulmonary arterial hypertension. N Engl J Med. 2015;373(9):834–44. https://doi.org/10.1056/NEJMoa1413687.
Weill D, Benden C, Corris PA, Dark JH, Davis RD, Keshavjee S, et al. A consensus document for the selection of lung transplant candidates: 2014—an update from the Pulmonary Transplantation Council of the International Society for Heart and Lung Transplantation. J Heart Lung Transplant. 2015;34(1):1–15. https://doi.org/10.1016/j.healun.2014.06.014.
Khush KK, Cherikh WS, Chambers DC, Goldfarb S, Hayes D Jr, Kucheryavaya AY, et al. The International Thoracic Organ Transplant Registry of the International Society for Heart and Lung Transplantation: thirty-fifth adult heart transplantation report-2018; focus theme: multiorgan transplantation. J Heart Lung Transplant. 2018;37(10):1155–68. https://doi.org/10.1016/j.healun.2018.07.022.
Sitbon O, Jais X, Savale L, Cottin V, Bergot E, Macari EA, et al. Upfront triple combination therapy in pulmonary arterial hypertension: a pilot study. Eur Respir J. 2014;43(6):1691–7. https://doi.org/10.1183/09031936.00116313.
Actelion. The efficacy and safety of initial triple versus initial dual oral combination therapy in patients with newly diagnosed pulmonary arterial hypertension (TRITON). ClinicalTrialsgov. 2017:NCT02558231.
Hill NS, Cawley MJ, Heggen-Peay CL. New therapeutic paradigms and guidelines in the management of pulmonary arterial hypertension. J Manag Care Spec Pharm. 2016;22(3 Suppl A):S3–21. https://doi.org/10.18553/jmcp.2016.22.3-a.s3.
McCollister DHWP, Badesch DB. Depression: beyond description as an important comorbidity in PAH—the next steps. Adv Pulm Hypertens. 2012;10(4):227–32.
Post MC, van der Wall E. Pulmonary hypertension: the importance of a multidisciplinary approach. Neth Heart J. 2016;24(6):369–71.
Vachiery JL, Tedford RJ, Rosenkranz S, Palazzini M, Lang I, Guazzi M, et al. Pulmonary hypertension due to left heart disease. Eur Respir J. 2019;53(1). https://doi.org/10.1183/13993003.01897-2018.
Aras MA, Psotka MA, De Marco T. Pulmonary hypertension due to left heart disease: an update. Curr Cardiol Rep. 2019;21(7):62. https://doi.org/10.1007/s11886-019-1149-1.
Medrek SK, Sharafkhaneh A, Spiegelman AM, Kak A, Pandit LM. Admission for COPD exacerbation is associated with the clinical diagnosis of pulmonary hypertension: results from a retrospective longitudinal study of a veteran population. COPD. 2017;14(5):484–9. https://doi.org/10.1080/15412555.2017.1336209.
• Nathan SD, Barbera JA, Gaine SP, Harari S, Martinez FJ, Olschewski H, et al. Pulmonary hypertension in chronic lung disease and hypoxia. Eur Respir J. 2019;53(1). https://doi.org/10.1183/13993003.01914-2018 This document provides the most recent WSPH recommendations on the evaluation and management of pulmonary hypertension due to chronic lung disease.
Wells JM, Washko GR, Han MK, Abbas N, Nath H, Mamary AJ, et al. Pulmonary arterial enlargement and acute exacerbations of COPD. N Engl J Med. 2012;367(10):913–21. https://doi.org/10.1056/NEJMoa1203830.
Olschewski H, Behr J, Bremer H, Claussen M, Douschan P, Halank M, et al. Pulmonary hypertension due to lung diseases: updated recommendations from the Cologne Consensus Conference 2018. Int J Cardiol. 2018;272S:63–8. https://doi.org/10.1016/j.ijcard.2018.08.043.
• Kim NH, Delcroix M, Jais X, Madani MM, Matsubara H, Mayer E, et al. Chronic thromboembolic pulmonary hypertension. Eur Respir J. 2019;53(1). https://doi.org/10.1183/13993003.01915-2018 This document provides the most recent WSPH recommendations on the evaluation and management of chronic thromboembolic pulmonary hypertension.
Simonneau G, Torbicki A, Dorfmuller P, Kim N. The pathophysiology of chronic thromboembolic pulmonary hypertension. Eur Respir Rev. 2017;26(143). https://doi.org/10.1183/16000617.0112-2016.
Delcroix M, Lang I, Pepke-Zaba J, Jansa P, D'Armini AM, Snijder R, et al. Long-term outcome of patients with chronic thromboembolic pulmonary hypertension: results from an International Prospective Registry. Circulation. 2016;133(9):859–71. https://doi.org/10.1161/CIRCULATIONAHA.115.016522.
Gavilanes-Oleas FAAJ, Fernandes CJC, Prada LFL, Salibe Filho W, Terra Filho M, et al. Use of direct oral anticoagulants for chronic thromboembolic pulmonary hypertension. Clinics (Sao Paulo). 2018;73:e216.
Jais X, D'Armini AM, Jansa P, Torbicki A, Delcroix M, Ghofrani HA, et al. Bosentan for treatment of inoperable chronic thromboembolic pulmonary hypertension: BENEFiT (Bosentan Effects in iNopErable Forms of chronIc Thromboembolic pulmonary hypertension), a randomized, placebo-controlled trial. J Am Coll Cardiol. 2008;52(25):2127–34. https://doi.org/10.1016/j.jacc.2008.08.059.
Ghofrani HA, Simonneau G, D'Armini AM, Fedullo P, Howard LS, Jais X, et al. Macitentan for the treatment of inoperable chronic thromboembolic pulmonary hypertension (MERIT-1): results from the multicentre, phase 2, randomised, double-blind, placebo-controlled study. Lancet Respir Med. 2017;5(10):785–94. https://doi.org/10.1016/S2213-2600(17)30305-3.
Ghofrani HA, D'Armini AM, Grimminger F, Hoeper MM, Jansa P, Kim NH, et al. Riociguat for the treatment of chronic thromboembolic pulmonary hypertension. N Engl J Med. 2013;369(4):319–29. https://doi.org/10.1056/NEJMoa1209657.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of Interest
James C. Coons reports a grant from United Therapeutics.
Kristen Pogue reports no conflicts of interest.
Andrew R. Kolodziej reports no conflicts of interest.
Glenn A. Hirsch reports no conflicts of interest.
Marjorie Patricia George reports a grant from Actelion, and personal fees from Actelion, Gilead, Bayer.
Human and Animal Rights and Informed Consent
This article does not contain any studies with human or animal subjects performed by any of the authors.
Additional information
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
This article is part of the Topical Collection on Heart Failure
Rights and permissions
About this article
Cite this article
Coons, J.C., Pogue, K., Kolodziej, A.R. et al. Pulmonary Arterial Hypertension: a Pharmacotherapeutic Update. Curr Cardiol Rep 21, 141 (2019). https://doi.org/10.1007/s11886-019-1235-4
Published:
DOI: https://doi.org/10.1007/s11886-019-1235-4