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Current Respiratory Medicine Reviews

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ISSN (Print): 1573-398X
ISSN (Online): 1875-6387

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Review Article

Pulmonary Arterial Hypertension (PAH) Group 1: Overview, Workup, Risk Stratification, and Current (and Future) Treatment Approaches

Author(s): Maidah Yaqoob, Thomas W. DeCato* and Ronald Oudiz

Volume 20, Issue 2, 2024

Published on: 11 January, 2024

Page: [107 - 126] Pages: 20

DOI: 10.2174/011573398X268093231226043639

Price: $65

Abstract

Risk assessment (or risk stratification) and both current and future therapies for pulmonary arterial hypertension (PAH) will be discussed in part B. Risk assessment is key in the initial evaluation and follow-up of persons with PAH. Risk assessment provides information on disease severity and mortality, which, over time, have been incorporated into the application of PAH therapies. After the initial risk assessment, a 4-strata approach is recommended at subsequent follow- up evaluations by the 2022 ERS/ESC pulmonary hypertension (PH) guidelines as described initially in COMPERA 2.0. This method appears to have increased sensitivity to changes in risk from baseline to follow-up and to changes in long-term mortality risk. Current PAH therapies target the prostacyclin, endothelin, and nitric oxide pathways. A sequential approach to therapy has been recommended since publication of the 2009 guidelines and, in the most recent iteration incorporates the 4-strata approach at follow-up. Additional therapy is recommended when intermediate- high or high-risk status is present. New therapies are under active investigation that include targeting novel pathways. Sotatercept, a fusion protein that binds to and sequesters select transforming growth factor β superfamily ligands, is the most promising novel therapy at this time. A recent phase 3, randomized, double-blind, placebo-controlled study in group 1 PAH patients showed a statistically significant improvement in 6-minute walk distance and additional studies of this drug in PH populations are ongoing. Progress in phenotyping this heterogeneous disease is being made, and as PAH therapies continue to evolve, the use of personalized treatment regimens may be possible in the care of this complex, and highly morbid and mortal disease.

Keywords: Group 1 pulmonary hypertension, pulmonary arterial hypertension, risk stratification, treatment.

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[1]
Humbert, M.; Kovacs, G.; Hoeper, M.M.; Badagliacca, R.; Berger, R.M.F.; Brida, M.; Carlsen, J.; Coats, A.J.S.; Escribano-Subias, P.; Ferrari, P.; Ferreira, D.S.; Ghofrani, H.A.; Giannakoulas, G.; Kiely, D.G.; Mayer, E.; Meszaros, G.; Nagavci, B.; Olsson, K.M.; Pepke-Zaba, J.; Quint, J.K.; Rådegran, G.; Simonneau, G.; Sitbon, O.; Tonia, T.; Toshner, M.; Vachiery, J.L.; Vonk Noordegraaf, A.; Delcroix, M.; Rosenkranz, S. 2022 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension. Eur. Respir. J., 2023, 61(1), 2200879.
[http://dx.doi.org/10.1183/13993003.00879-2022] [PMID: 36028254]
[2]
Barst, R.J.; Chung, L.; Zamanian, R.T.; Turner, M.; McGoon, M.D. Functional class improvement and 3-year survival outcomes in patients with pulmonary arterial hypertension in the REVEAL Registry. Chest, 2013, 144(1), 160-168.
[http://dx.doi.org/10.1378/chest.12-2417] [PMID: 23429998]
[3]
Galiè, N.; Humbert, M.; Vachiery, J.L.; Gibbs, S.; Lang, I.; Torbicki, A.; Simonneau, G.; Peacock, A.; Vonk Noordegraaf, A.; Beghetti, M.; Ghofrani, A.; Gomez Sanchez, M.A.; Hansmann, G.; Klepetko, W.; Lancellotti, P.; Matucci, M.; McDonagh, T.; Pierard, L.A.; Trindade, P.T.; Zompatori, M.; Hoeper, M. 2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension. Eur. Heart J., 2016, 37(1), 67-119.
[http://dx.doi.org/10.1093/eurheartj/ehv317] [PMID: 26320113]
[4]
Galiè, N.; Channick, R.N.; Frantz, R.P.; Grünig, E.; Jing, Z.C.; Moiseeva, O.; Preston, I.R.; Pulido, T.; Safdar, Z.; Tamura, Y.; McLaughlin, V.V. Risk stratification and medical therapy of pulmonary arterial hypertension. Eur. Respir. J., 2019, 53(1), 1801889.
[http://dx.doi.org/10.1183/13993003.01889-2018] [PMID: 30545971]
[5]
D’Alonzo, G.E.; Barst, R.J.; Ayres, S.M.; Bergofsky, E.H.; Brundage, B.H.; Detre, K.M.; Fishman, A.P.; Goldring, R.M.; Groves, B.M.; Kernis, J.T.; Levy, P.S.; Pietra, G.G.; Reid, L.M.; Reeves, J.T.; Rich, S.; Vreim, C.E.; Williams, G.W.; Wu, M. Survival in patients with primary pulmonary hypertension. Results from a national prospective registry. Ann. Intern. Med., 1991, 115(5), 343-349.
[http://dx.doi.org/10.7326/0003-4819-115-5-343] [PMID: 1863023]
[6]
Miyamoto, S.; Nagaya, N.; Satoh, T.; Kyotani, S.; Sakamaki, F.; Fujita, M.; Nakanishi, N.; Miyatake, K. Clinical correlates and prognostic significance of six-minute walk test in patients with primary pulmonary hypertension. Comparison with cardiopulmonary exercise testing. Am. J. Respir. Crit. Care Med., 2000, 161(2), 487-492.
[http://dx.doi.org/10.1164/ajrccm.161.2.9906015] [PMID: 10673190]
[7]
Wensel, R.; Opitz, C.F.; Anker, S.D.; Winkler, J.; Höffken, G.; Kleber, F.X.; Sharma, R.; Hummel, M.; Hetzer, R.; Ewert, R. Assessment of survival in patients with primary pulmonary hypertension: importance of cardiopulmonary exercise testing. Circulation, 2002, 106(3), 319-324.
[http://dx.doi.org/10.1161/01.CIR.0000022687.18568.2A] [PMID: 12119247]
[8]
Mancini, D.M.; Eisen, H.; Kussmaul, W.; Mull, R.; Edmunds, L.H., Jr; Wilson, J.R. Value of peak exercise oxygen consumption for optimal timing of cardiac transplantation in ambulatory patients with heart failure. Circulation, 1991, 83(3), 778-786.
[http://dx.doi.org/10.1161/01.CIR.83.3.778] [PMID: 1999029]
[9]
Chua, T.P.; Ponikowski, P.; Harrington, D.; Anker, S.D.; Webb-Peploe, K.; Clark, A.L.; Poole-Wilson, P.A.; Coats, A.J.S. Clinical correlates and prognostic significance of the ventilatory response to exercise in chronic heart failure. J. Am. Coll. Cardiol., 1997, 29(7), 1585-1590.
[http://dx.doi.org/10.1016/S0735-1097(97)00078-8] [PMID: 9180123]
[10]
Oudiz, R.J.; Midde, R.; Hovanesyan, A.; Sun, X.G.; Roveran, G.; Hansen, J.E.; Wasserman, K. Usefulness of right-to-left shunting and poor exercise gas exchange for predicting prognosis in patients with pulmonary arterial hypertension. Am. J. Cardiol., 2010, 105(8), 1186-1191.
[http://dx.doi.org/10.1016/j.amjcard.2009.12.024] [PMID: 20381675]
[11]
Schwaiblmair, M.; Faul, C.; von Scheidt, W.; Berghaus, T.M. Ventilatory efficiency testing as prognostic value in patients with pulmonary hypertension. BMC Pulm. Med., 2012, 12(1), 23.
[http://dx.doi.org/10.1186/1471-2466-12-23] [PMID: 22676304]
[12]
Ferreira, E.V.M.; Ota-Arakaki, J.S.; Ramos, R.P.; Barbosa, P.B.; Almeida, M.; Treptow, E.C.; Valois, F.M.; Nery, L.E.; Neder, J.A. Optimizing the evaluation of excess exercise ventilation for prognosis assessment in pulmonary arterial hypertension. Eur. J. Prev. Cardiol., 2014, 21(11), 1409-1419.
[http://dx.doi.org/10.1177/2047487313494293] [PMID: 23787797]
[13]
Thenappan, T.; Shah, S.J.; Rich, S.; Tian, L.; Archer, S.L.; Gomberg-Maitland, M. Survival in pulmonary arterial hypertension: A reappraisal of the NIH risk stratification equation. Eur. Respir. J., 2010, 35(5), 1079-1087.
[http://dx.doi.org/10.1183/09031936.00072709] [PMID: 20032020]
[14]
Humbert, M.; Sitbon, O.; Chaouat, A.; Bertocchi, M.; Habib, G.; Gressin, V.; Yaïci, A.; Weitzenblum, E.; Cordier, J.F.; Chabot, F.; Dromer, C.; Pison, C.; Reynaud-Gaubert, M.; Haloun, A.; Laurent, M.; Hachulla, E.; Cottin, V.; Degano, B.; Jaïs, X.; Montani, D.; Souza, R.; Simonneau, G. Survival in patients with idiopathic, familial, and anorexigen-associated pulmonary arterial hypertension in the modern management era. Circulation, 2010, 122(2), 156-163.
[http://dx.doi.org/10.1161/CIRCULATIONAHA.109.911818] [PMID: 20585011]
[15]
Benza, R.L.; Miller, D.P.; Gomberg-Maitland, M.; Frantz, R.P.; Foreman, A.J.; Coffey, C.S.; Frost, A.; Barst, R.J.; Badesch, D.B.; Elliott, C.G.; Liou, T.G.; McGoon, M.D. Predicting survival in pulmonary arterial hypertension. Circulation, 2010, 122(2), 164-172.
[http://dx.doi.org/10.1161/CIRCULATIONAHA.109.898122] [PMID: 20585012]
[16]
Benza, R.L.; Gomberg-Maitland, M.; Miller, D.P.; Frost, A.; Frantz, R.P.; Foreman, A.J.; Badesch, D.B.; McGoon, M.D. The REVEAL Registry risk score calculator in patients newly diagnosed with pulmonary arterial hypertension. Chest, 2012, 141(2), 354-362.
[http://dx.doi.org/10.1378/chest.11-0676] [PMID: 21680644]
[17]
Farber, H.W.; Miller, D.P.; Poms, A.D.; Badesch, D.B.; Frost, A.E.; Rouzic, E.M-L.; Romero, A.J.; Benton, W.W.; Elliott, C.G.; McGoon, M.D.; Benza, R.L. Five-Year outcomes of patients enrolled in the REVEAL Registry. Chest, 2015, 148(4), 1043-1054.
[http://dx.doi.org/10.1378/chest.15-0300] [PMID: 26066077]
[18]
Humbert, M.; Sitbon, O.; Yaïci, A.; Montani, D.; O’Callaghan, D.S.; Jaïs, X.; Parent, F.; Savale, L.; Natali, D.; Günther, S.; Chaouat, A.; Chabot, F.; Cordier, J.F.; Habib, G.; Gressin, V.; Jing, Z.C.; Souza, R.; Simonneau, G. Survival in incident and prevalent cohorts of patients with pulmonary arterial hypertension. Eur. Respir. J., 2010, 36(3), 549-555.
[http://dx.doi.org/10.1183/09031936.00057010] [PMID: 20562126]
[19]
Barst, R.J.; Gibbs, J.S.R.; Ghofrani, H.A.; Hoeper, M.M.; McLaughlin, V.V.; Rubin, L.J.; Sitbon, O.; Tapson, V.F.; Galiè, N. Updated evidence-based treatment algorithm in pulmonary arterial hypertension. J. Am. Coll. Cardiol., 2009, 54(S1), S78-S84.
[http://dx.doi.org/10.1016/j.jacc.2009.04.017] [PMID: 19555861]
[20]
McLaughlin, V.V.; Archer, S.L.; Badesch, D.B.; Barst, R.J.; Farber, H.W.; Lindner, J.R.; Mathier, M.A.; McGoon, M.D.; Park, M.H.; Rosenson, R.S.; Rubin, L.J.; Tapson, V.F.; Varga, J. ACCF/AHA 2009 expert consensus document on pulmonary hypertension. J. Am. Coll. Cardiol., 2009, 53(17), 1573-1619.
[http://dx.doi.org/10.1016/j.jacc.2009.01.004] [PMID: 19389575]
[21]
Kane, G.C.; Maradit-Kremers, H.; Slusser, J.P.; Scott, C.G.; Frantz, R.P.; McGoon, M.D. Integration of clinical and hemodynamic parameters in the prediction of long-term survival in patients with pulmonary arterial hypertension. Chest, 2011, 139(6), 1285-1293.
[http://dx.doi.org/10.1378/chest.10-1293] [PMID: 21071530]
[22]
Lee, W.T.N.; Ling, Y.; Sheares, K.K.; Pepke-Zaba, J.; Peacock, A.J.; Johnson, M.K. Predicting survival in pulmonary arterial hypertension in the UK. Eur. Respir. J., 2012, 40(3), 604-611.
[http://dx.doi.org/10.1183/09031936.00196611] [PMID: 22556026]
[23]
Sitbon, O.; Benza, R.L.; Badesch, D.B.; Barst, R.J.; Elliott, C.G.; Gressin, V.; Lemarié, J.C.; Miller, D.P.; Muros-Le Rouzic, E.; Simonneau, G.; Frost, A.E.; Farber, H.W.; Humbert, M.; McGoon, M.D. Validation of two predictive models for survival in pulmonary arterial hypertension. Eur. Respir. J., 2015, 46(1), 152-164.
[http://dx.doi.org/10.1183/09031936.00004414] [PMID: 25837032]
[24]
Nickel, N.; Golpon, H.; Greer, M.; Knudsen, L.; Olsson, K.; Westerkamp, V.; Welte, T.; Hoeper, M.M. The prognostic impact of follow-up assessments in patients with idiopathic pulmonary arterial hypertension. Eur. Respir. J., 2012, 39(3), 589-596.
[http://dx.doi.org/10.1183/09031936.00092311] [PMID: 21885392]
[25]
Benza, R.L.; Miller, D.P.; Foreman, A.J.; Frost, A.E.; Badesch, D.B.; Benton, W.W.; McGoon, M.D. 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), 356-361.
[http://dx.doi.org/10.1016/j.healun.2014.09.016] [PMID: 25447572]
[26]
Hoeper, M.M.; Kramer, T.; Pan, Z.; Eichstaedt, C.A.; Spiesshoefer, J.; Benjamin, N.; Olsson, K.M.; Meyer, K.; Vizza, C.D.; Vonk-Noordegraaf, A.; Distler, O.; Opitz, C.; Gibbs, J.S.R.; Delcroix, M.; Ghofrani, H.A.; Huscher, D.; Pittrow, D.; Rosenkranz, S.; Grünig, E. Mortality in pulmonary arterial hypertension: Prediction by the 2015 European pulmonary hypertension guidelines risk stratification model. Eur. Respir. J., 2017, 50(2), 1700740.
[http://dx.doi.org/10.1183/13993003.00740-2017] [PMID: 28775047]
[27]
Boucly, A.; Weatherald, J.; Savale, L.; Jaïs, X.; Cottin, V.; Prevot, G.; Picard, F.; de Groote, P.; Jevnikar, M.; Bergot, E.; Chaouat, A.; Chabanne, C.; Bourdin, A.; Parent, F.; Montani, D.; Simonneau, G.; Humbert, M.; Sitbon, O. Risk assessment, prognosis and guideline implementation in pulmonary arterial hypertension. Eur. Respir. J., 2017, 50(2), 1700889.
[http://dx.doi.org/10.1183/13993003.00889-2017] [PMID: 28775050]
[28]
Kylhammar, D.; Kjellström, B.; Hjalmarsson, C.; Jansson, K.; Nisell, M.; Söderberg, S.; Wikström, G.; Rådegran, G. A comprehensive risk stratification at early follow-up determines prognosis in pulmonary arterial hypertension. Eur. Heart J., 2018, 39(47), 4175-4181.
[http://dx.doi.org/10.1093/eurheartj/ehx257] [PMID: 28575277]
[29]
Weatherald, J.; Sitbon, O.; Humbert, M. Validation of a risk assessment instrument for pulmonary arterial hypertension. Eur. Heart J., 2018, 39(47), 4182-4185.
[http://dx.doi.org/10.1093/eurheartj/ehx301] [PMID: 28637288]
[30]
Benza, R.L.; Gomberg-Maitland, M.; Elliott, C.G.; Farber, H.W.; Foreman, A.J.; Frost, A.E.; McGoon, M.D.; Pasta, D.J.; Selej, M.; Burger, C.D.; Frantz, R.P. Predicting survival in patients with pulmonary arterial hypertension. Chest, 2019, 156(2), 323-337.
[http://dx.doi.org/10.1016/j.chest.2019.02.004] [PMID: 30772387]
[31]
Benza, R.L.; Kanwar, M.K.; Raina, A.; Scott, J.V.; Zhao, C.L.; Selej, M.; Elliott, C.G.; Farber, H.W. Development and validation of an abridged version of the REVEAL 2.0 risk score calculator, REVEAL Lite 2, for use in patients with pulmonary arterial hypertension. Chest, 2021, 159(1), 337-346.
[http://dx.doi.org/10.1016/j.chest.2020.08.2069] [PMID: 32882243]
[32]
Hoeper, M.M.; Pausch, C.; Olsson, K.M.; Huscher, D.; Pittrow, D.; Grünig, E.; Staehler, G.; Vizza, C.D.; Gall, H.; Distler, O.; Opitz, C.; Gibbs, J.S.R.; Delcroix, M.; Ghofrani, H.A.; Park, D.H.; Ewert, R.; Kaemmerer, H.; Kabitz, H.J.; Skowasch, D.; Behr, J.; Milger, K.; Halank, M.; Wilkens, H.; Seyfarth, H.J.; Held, M.; Dumitrescu, D.; Tsangaris, I.; Vonk-Noordegraaf, A.; Ulrich, S.; Klose, H.; Claussen, M.; Lange, T.J.; Rosenkranz, S. COMPERA 2.0: A refined four-stratum risk assessment model for pulmonary arterial hypertension. Eur. Respir. J., 2022, 60(1), 2102311.
[http://dx.doi.org/10.1183/13993003.02311-2021] [PMID: 34737226]
[33]
Kylhammar, D.; Hjalmarsson, C.; Hesselstrand, R.; Jansson, K.; Kavianipour, M.; Kjellström, B.; Nisell, M.; Söderberg, S.; Rådegran, G. Predicting mortality during long-term follow-up in pulmonary arterial hypertension. ERJ Open Res., 2021, 7(2), 00837-2020.
[http://dx.doi.org/10.1183/23120541.00837-2020] [PMID: 34084789]
[34]
Boucly, A.; Weatherald, J.; Savale, L.; de Groote, P.; Cottin, V.; Prévot, G.; Chaouat, A.; Picard, F.; Horeau-Langlard, D.; Bourdin, A.; Jutant, E.M.; Beurnier, A.; Jevnikar, M.; Jaïs, X.; Simonneau, G.; Montani, D.; Sitbon, O.; Humbert, M. External validation of a refined four-stratum risk assessment score from the French pulmonary hypertension registry. Eur. Respir. J., 2022, 59(6), 2102419.
[http://dx.doi.org/10.1183/13993003.02419-2021] [PMID: 34737227]
[35]
Leard, L.E.; Holm, A.M.; Valapour, M.; Glanville, A.R.; Attawar, S.; Aversa, M.; Campos, S.V.; Christon, L.M.; Cypel, M.; Dellgren, G.; Hartwig, M.G.; Kapnadak, S.G.; Kolaitis, N.A.; Kotloff, R.M.; Patterson, C.M.; Shlobin, O.A.; Smith, P.J.; Solé, A.; Solomon, M.; Weill, D.; Wijsenbeek, M.S.; Willemse, B.W.M.; Arcasoy, S.M.; Ramos, K.J. Consensus document for the selection of lung transplant candidates: An update from the International Society for Heart and Lung Transplantation. J. Heart Lung Transplant., 2021, 40(11), 1349-1379.
[http://dx.doi.org/10.1016/j.healun.2021.07.005] [PMID: 34419372]
[36]
McLaughlin, V.V.; Sitbon, O.; Badesch, D.B.; Barst, R.J.; Black, C.; Galiè, N.; Rainisio, M.; Simonneau, G.; Rubin, L.J. Survival with first-line bosentan in patients with primary pulmonary hypertension. Eur. Respir. J., 2005, 25(2), 244-249.
[http://dx.doi.org/10.1183/09031936.05.00054804] [PMID: 15684287]
[37]
Raymond, R.J.; Hinderliter, A.L.; Willis, P.W., IV; Ralph, D.; Caldwell, E.J.; Williams, W.; Ettinger, N.A.; Hill, N.S.; Summer, W.R.; de Boisblanc, B.; Schwartz, T.; Koch, G.; Clayton, L.M.; Jöbsis, M.M.; Crow, J.W.; Long, W. Echocardiographic predictors of adverse outcomes in primary pulmonary hypertension. J. Am. Coll. Cardiol., 2002, 39(7), 1214-1219.
[http://dx.doi.org/10.1016/S0735-1097(02)01744-8] [PMID: 11923049]
[38]
Ernande, L.; Cottin, V.; Leroux, P.Y.; Girerd, N.; Huez, S.; Mulliez, A.; Bergerot, C.; Ovize, M.; Mornex, J.F.; Cordier, J.F.; Naeije, R.; Derumeaux, G. Right isovolumic contraction velocity predicts survival in pulmonary hypertension. J. Am. Soc. Echocardiogr., 2013, 26(3), 297-306.
[http://dx.doi.org/10.1016/j.echo.2012.11.011] [PMID: 23265440]
[39]
Forfia, P.R.; Fisher, M.R.; Mathai, S.C.; Housten-Harris, T.; Hemnes, A.R.; Borlaug, B.A.; Chamera, E.; Corretti, M.C.; Champion, H.C.; Abraham, T.P.; Girgis, R.E.; Hassoun, P.M. Tricuspid annular displacement predicts survival in pulmonary hypertension. Am. J. Respir. Crit. Care Med., 2006, 174(9), 1034-1041.
[http://dx.doi.org/10.1164/rccm.200604-547OC] [PMID: 16888289]
[40]
Badagliacca, R.; Papa, S.; Valli, G.; Pezzuto, B.; Poscia, R.; Manzi, G.; Giannetta, E.; Sciomer, S.; Palange, P.; Naeije, R.; Fedele, F.; Vizza, C.D. Echocardiography combined with cardiopulmonary exercise testing for the prediction of outcome in idiopathic pulmonary arterial hypertension. Chest, 2016, 150(6), 1313-1322.
[http://dx.doi.org/10.1016/j.chest.2016.07.036] [PMID: 27554298]
[41]
Tello, K.; Axmann, J.; Ghofrani, H.A.; Naeije, R.; Narcin, N.; Rieth, A.; Seeger, W.; Gall, H.; Richter, M.J. Relevance of the TAPSE/PASP ratio in pulmonary arterial hypertension. Int. J. Cardiol., 2018, 266, 229-235.
[http://dx.doi.org/10.1016/j.ijcard.2018.01.053] [PMID: 29887454]
[42]
Ghio, S.; Mercurio, V.; Fortuni, F.; Forfia, P.R.; Gall, H.; Ghofrani, A.; Mathai, S.C.; Mazurek, J.A.; Mukherjee, M.; Richter, M.; Scelsi, L.; Hassoun, P.M.; Tello, K. A comprehensive echocardiographic method for risk stratification in pulmonary arterial hypertension. Eur. Respir. J., 2020, 56(3), 2000513.
[http://dx.doi.org/10.1183/13993003.00513-2020] [PMID: 32430422]
[43]
Badano, L.P.; Addetia, K.; Pontone, G.; Torlasco, C.; Lang, R.M.; Parati, G.; Muraru, D. Advanced imaging of right ventricular anatomy and function. Heart, 2020, 106(19), 1469-1476.
[http://dx.doi.org/10.1136/heartjnl-2019-315178] [PMID: 32620556]
[44]
Lewis, R.A.; Johns, C.S.; Cogliano, M.; Capener, D.; Tubman, E.; Elliot, C.A.; Charalampopoulos, A.; Sabroe, I.; Thompson, A.A.R.; Billings, C.G.; Hamilton, N.; Baster, K.; Laud, P.J.; Hickey, P.M.; Middleton, J.; Armstrong, I.J.; Hurdman, J.A.; Lawrie, A.; Rothman, A.M.K.; Wild, J.M.; Condliffe, R.; Swift, A.J.; Kiely, D.G. Identification of cardiac magnetic resonance imaging thresholds for risk stratification in pulmonary arterial hypertension. Am. J. Respir. Crit. Care Med., 2020, 201(4), 458-468.
[http://dx.doi.org/10.1164/rccm.201909-1771OC] [PMID: 31647310]
[45]
Swift, A.J.; Capener, D.; Johns, C.; Hamilton, N.; Rothman, A.; Elliot, C.; Condliffe, R.; Charalampopoulos, A.; Rajaram, S.; Lawrie, A.; Campbell, M.J.; Wild, J.M.; Kiely, D.G. Magnetic resonance imaging in the prognostic evaluation of patients with pulmonary arterial hypertension. Am. J. Respir. Crit. Care Med., 2017, 196(2), 228-239.
[http://dx.doi.org/10.1164/rccm.201611-2365OC] [PMID: 28328237]
[46]
van der Bruggen, C.E.; Handoko, M.L.; Bogaard, H.J.; Marcus, J.T.; Oosterveer, F.P.T.; Meijboom, L.J.; Westerhof, B.E.; Vonk, N.A.; de Man, F.S. The value of hemodynamic measurements or cardiac mri in the follow-up of patients with idiopathic pulmonary arterial hypertension. Chest, 2021, 159(4), 1575-1585.
[http://dx.doi.org/10.1016/j.chest.2020.10.077] [PMID: 33197401]
[47]
Huis In ’t Veld, A.E.; Van de Veerdonk, M.C.; Spruijt, O.; Groeneveldt, J.A.; Marcus, J.T.; Westerhof, N.; Bogaard, H.J.; Vonk-Noordegraaf, A. EXPRESS: Preserving right ventricular function in patients with pulmonary arterial hypertension: Single centre experience with a cardiac magnetic resonance imaging-guided treatment strategy. Pulm. Circ., 2019, 2045894018824553.
[PMID: 30632454]
[48]
van de Veerdonk, M.C.; Marcus, J.T.; Westerhof, N.; de Man, F.S.; Boonstra, A.; Heymans, M.W.; Bogaard, H.J.; Vonk Noordegraaf, A. Signs of right ventricular deterioration in clinically stable patients with pulmonary arterial hypertension. Chest, 2015, 147(4), 1063-1071.
[http://dx.doi.org/10.1378/chest.14-0701] [PMID: 25376008]
[49]
Simons, J.E.; Mann, E.B.; Pierozynski, A. Assessment of risk of disease progression in pulmonary arterial hypertension: Insights from an international survey of clinical practice. Adv. Ther., 2019, 36(9), 2351-2363.
[http://dx.doi.org/10.1007/s12325-019-01030-4] [PMID: 31313097]
[50]
Sahay, S.; Tonelli, A.R.; Selej, M.; Watson, Z.; Benza, R.L. Risk assessment in patients with functional class II pulmonary arterial hypertension: Comparison of physician gestalt with ESC/ERS and the REVEAL 2.0 risk score. PLoS One, 2020, 15(11), e0241504.
[http://dx.doi.org/10.1371/journal.pone.0241504] [PMID: 33175857]
[51]
Hoeper, M.M.; Pausch, C.; Olsson, K.M.; Huscher, D.; Pittrow, D.; Grünig, E.; Staehler, G.; Vizza, C.D.; Gall, H.; Distler, O.; Opitz, C.; Gibbs, J.S.R.; Delcroix, M.; Ghofrani, H.A.; Ewert, R.; Kaemmerer, H.; Kabitz, H.J.; Skowasch, D.; Behr, J.; Milger, K.; Halank, M.; Wilkens, H.; Seyfarth, H.J.; Held, M.; Dumitrescu, D.; Tsangaris, I.; Vonk-Noordegraaf, A.; Ulrich, S.; Klose, H.; Claussen, M.; Eisenmann, S.; Schmidt, K.H.; Rosenkranz, S.; Lange, T.J. Prognostic value of improvement endpoints in pulmonary arterial hypertension trials: A COMPERA analysis. J. Heart Lung Transplant., 2022, 41(7), 971-981.
[http://dx.doi.org/10.1016/j.healun.2022.03.011] [PMID: 35430147]
[52]
Hoeper, M.M.; Al-Hiti, H.; Benza, R.L.; Chang, S.A.; Corris, P.A.; Gibbs, J.S.R.; Grünig, E.; Jansa, P.; Klinger, J.R.; Langleben, D.; McLaughlin, V.V.; Meyer, G.M.B.; Ota-Arakaki, J.; Peacock, A.J.; Pulido, T.; Rosenkranz, S.; Vizza, C.D.; Vonk-Noordegraaf, A.; White, R.J.; Chang, M.; Kleinjung, F.; Meier, C.; Paraschin, K.; Ghofrani, H.A.; Simonneau, G.; Olschewski, H.; Delcroix, M.; Andrade-Lima, M.; de Amorim Corrêac, R.; Figueiredo Campos, F.; Ota Arakaki, J.; Meyer, G.; De Souza, R.; Langleben, D.; Al-Hiti, H.; Jansa, P.; Mellemkjær, S.; Bauer, F.; Montani, D.; Simonneau, G.; Drömann, D.; Ghofrani, H-A.; Grünig, E.; Halank, M.; Held, M.; Hoeper, M.M.; Klose, H.; Kneidinger, N.; Leuchte, H.; Opitz, C.; Rosenkranz, S.; Wilkens, H.; Wirtz, H.; Karvounis, H.; Pitsiou, G.; Orfanos, S.; D’Alto, M.; Ghio, S.; Vizza, C.D.; Vitulo, P.; Nakayama, T.; Maki, H.; Tatebe, S.; de los Rios Ibarra, M.; Pulido, T.; Van Dijk, A.; Vonk-Noordegraaf, A.; Roleder, T.; Castro, G.; Loureiro, M.J.; Robalo-Martins, S.; Barberá, J.A.; Lázaro, M.; Perez-Penate, G.M.; Román, A.; Cheng, C-C.; Hsu, C-H.; Hsu, H-H.; Atahan, E.; Mogulkoc Bishop, N.; Okumus, N.G.; Onen, Z.; Chang, H-J.; Chang, S-A.; Lee, J-S.; Kim, H-K.; Coghlan, J.G.; Corris, P.A.; Church, A.C.; Condliffe, R.; Gibbs, J.S.R.; Peacock, A.J.; Wort, S.; Allen, R.; Allen, S.; Awdish, R.; Benza, R.L.; DeSouza, S.; Feldman, J.; Johri, S.; Klinger, J.R.; Layish, D.; McConnell, J.; McLaughlin, V.V.; Migliore, C.; Rahaghi, F.; Rischard, F.; Robbins, I.; Satterwhite, L.; Shah, T.; Sulica, R.; White, R.J. Switching to riociguat versus maintenance therapy with phosphodiesterase-5 inhibitors in patients with pulmonary arterial hypertension (REPLACE): A multicentre, open-label, randomised controlled trial. Lancet Respir. Med., 2021, 9(6), 573-584.
[http://dx.doi.org/10.1016/S2213-2600(20)30532-4] [PMID: 33773120]
[53]
Humbert, M.; McLaughlin, V.; Gibbs, J.S.R.; Gomberg-Maitland, M.; Hoeper, M.M.; Preston, I.R.; Souza, R.; Waxman, A.; Escribano, S.P.; Feldman, J.; Meyer, G.; Montani, D.; Olsson, K.M.; Manimaran, S.; Barnes, J.; Linde, P.G.; de Oliveira Pena, J.; Badesch, D.B. Sotatercept for the treatment of pulmonary arterial hypertension. N. Engl. J. Med., 2021, 384(13), 1204-1215.
[http://dx.doi.org/10.1056/NEJMoa2024277] [PMID: 33789009]
[54]
Barst, R.J.; Rubin, L.J.; Long, W.A.; McGoon, M.D.; Rich, S.; Badesch, D.B.; Groves, B.M.; Tapson, V.F.; Bourge, R.C.; Brundage, B.H.; Koerner, S.K.; Langleben, D.; Keller, C.A.; Murali, S.; Uretsky, B.F.; Clayton, L.M.; Jöbsis, M.M.; Blackburn, S.D., Jr; Shortino, D.; Crow, J.W. A comparison of continuous intravenous epoprostenol (prostacyclin) with conventional therapy for primary pulmonary hypertension. N. Engl. J. Med., 1996, 334(5), 296-301.
[http://dx.doi.org/10.1056/NEJM199602013340504] [PMID: 8532025]
[55]
Delcroix, M.; Howard, L. Pulmonary arterial hypertension: The burden of disease and impact on quality of life. Eur. Respir. Rev., 2015, 24(138), 621-629.
[http://dx.doi.org/10.1183/16000617.0063-2015] [PMID: 26621976]
[56]
Olsson, K.M.; Meltendorf, T.; Fuge, J.; Kamp, J.C.; Park, D.H.; Richter, M.J.; Gall, H.; Ghofrani, H.A.; Ferrari, P.; Schmiedel, R.; Kulla, H.D.; Heitland, I.; Lepsy, N.; Dering, M.R.; Hoeper, M.M.; Kahl, K.G. Prevalence of mental disorders and impact on quality of life in patients with pulmonary arterial hypertension. Front. Psychiatry, 2021, 12, 667602.
[http://dx.doi.org/10.3389/fpsyt.2021.667602] [PMID: 34135787]
[57]
Grünig, E.; MacKenzie, A.; Peacock, A.J.; Eichstaedt, C.A.; Benjamin, N.; Nechwatal, R.; Ulrich, S.; Saxer, S.; Bussotti, M.; Sommaruga, M.; Ghio, S.; Gumbiene, L.; Palevičiūtė, E.; Jurevičienė, E.; Cittadini, A.; Stanziola, A.A.; Marra, A.M.; Kovacs, G.; Olschewski, H.; Barberà, J.A.; Blanco, I.; Spruit, M.A.; Franssen, F.M.E.; Vonk Noordegraaf, A.; Reis, A.; Santos, M.; Viamonte, S.G.; Demeyer, H.; Delcroix, M.; Bossone, E.; Johnson, M. Standardized exercise training is feasible, safe, and effective in pulmonary arterial and chronic thromboembolic pulmonary hypertension: Results from a large European multicentre randomized controlled trial. Eur. Heart J., 2021, 42(23), 2284-2295.
[http://dx.doi.org/10.1093/eurheartj/ehaa696] [PMID: 33232470]
[58]
Rich, S.; Kaufmann, E.; Levy, P.S. The effect of high doses of calcium-channel blockers on survival in primary pulmonary hypertension. N. Engl. J. Med., 1992, 327(2), 76-81.
[http://dx.doi.org/10.1056/NEJM199207093270203] [PMID: 1603139]
[59]
Sitbon, O.; Humbert, M.; Jaïs, X.; Ioos, V.; Hamid, A.M.; Provencher, S.; Garcia, G.; Parent, F.; Hervé, P.; Simonneau, G. Long-term response to calcium channel blockers in idiopathic pulmonary arterial hypertension. Circulation, 2005, 111(23), 3105-3111.
[http://dx.doi.org/10.1161/CIRCULATIONAHA.104.488486] [PMID: 15939821]
[60]
Jones, D.A.; Benjamin, C.W.; Linseman, D.A. Activation of thromboxane and prostacyclin receptors elicits opposing effects on vascular smooth muscle cell growth and mitogen-activated protein kinase signaling cascades. Mol. Pharmacol., 1995, 48(5), 890-896.
[PMID: 7476920]
[61]
Krowka, M.J.; Frantz, R.P.; McGoon, M.D.; Severson, C.; Plevak, D.J.; Wiesner, R.H. Improvement in pulmonary hemodynamics during intravenous epoprostenol (prostacyclin): A study of 15 patients with moderate to severe portopulmonary hypertension. Hepatology, 1999, 30(3), 641-648.
[http://dx.doi.org/10.1002/hep.510300307] [PMID: 10462369]
[62]
McLaughlin, V.V.; Shillington, A.; Rich, S. Survival in primary pulmonary hypertension: The impact of epoprostenol therapy. Circulation, 2002, 106(12), 1477-1482.
[http://dx.doi.org/10.1161/01.CIR.0000029100.82385.58] [PMID: 12234951]
[63]
Nunes, H.; Humbert, M.; Sitbon, O.; Morse, J.H.; Deng, Z.; Knowles, J.A.; Le Gall, C.; Parent, F.; Garcia, G.; Hervé, P.; Barst, R.J.; Simonneau, G. Prognostic factors for survival in human immunodeficiency virus-associated pulmonary arterial hypertension. Am. J. Respir. Crit. Care Med., 2003, 167(10), 1433-1439.
[http://dx.doi.org/10.1164/rccm.200204-330OC] [PMID: 12615632]
[64]
Rosenzweig, E.B.; Kerstein, D.; Barst, R.J. Long-term prostacyclin for pulmonary hypertension with associated congenital heart defects. Circulation, 1999, 99(14), 1858-1865.
[http://dx.doi.org/10.1161/01.CIR.99.14.1858] [PMID: 10199883]
[65]
Simonneau, G.; Barst, R.J.; Galie, N.; Naeije, R.; Rich, S.; Bourge, R.C.; Keogh, A.; Oudiz, R.; Frost, A.; Blackburn, S.D.; Crow, J.W.; Rubin, L.J. 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), 800-804.
[http://dx.doi.org/10.1164/ajrccm.165.6.2106079] [PMID: 11897647]
[66]
Bourge, R.C.; Waxman, A.B.; Gomberg-Maitland, M.; Shapiro, S.M.; Tarver, J.H., III; Zwicke, D.L.; Feldman, J.P.; Chakinala, M.M.; Frantz, R.P.; Torres, F.; Cerkvenik, J.; Morris, M.; Thalin, M.; Peterson, L.; Rubin, L.J. Treprostinil administered to treat pulmonary arterial hypertension using a fully implantable programmable intravascular delivery system. Chest, 2016, 150(1), 27-34.
[http://dx.doi.org/10.1016/j.chest.2015.11.005] [PMID: 27396777]
[67]
McLaughlin, V.V.; Benza, R.L.; Rubin, L.J.; Channick, R.N.; Voswinckel, R.; Tapson, V.F.; Robbins, I.M.; Olschewski, H.; Rubenfire, M.; Seeger, W. Addition of inhaled treprostinil to oral therapy for pulmonary arterial hypertension: A randomized controlled clinical trial. J. Am. Coll. Cardiol., 2010, 55(18), 1915-1922.
[http://dx.doi.org/10.1016/j.jacc.2010.01.027] [PMID: 20430262]
[68]
Spikes, L.A.; Bajwa, A.A.; Burger, C.D.; Desai, S.V.; Eggert, M.S.; El-Kersh, K.A.; Fisher, M.R.; Johri, S.; Joly, J.M.; Mehta, J.; Palevsky, H.I.; Ramani, G.V.; Restrepo-Jaramillo, R.; Sahay, S.; Shah, T.G.; Deng, C.; Miceli, M.; Smith, P.; Shapiro, S.M. BREEZE: Open-label clinical study to evaluate the safety and tolerability of treprostinil inhalation powder as Tyvaso DPI™ in patients with pulmonary arterial hypertension. Pulm. Circ., 2022, 12(2), e12063.
[http://dx.doi.org/10.1002/pul2.12063] [PMID: 35514770]
[69]
Tapson, V.F.; Torres, F.; Kermeen, F.; Keogh, A.M.; Allen, R.P.; Frantz, R.P.; Badesch, D.B.; Frost, A.E.; Shapiro, S.M.; Laliberte, K.; Sigman, J.; Arneson, C.; Galiè, N. 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), 1383-1390.
[http://dx.doi.org/10.1378/chest.11-2212] [PMID: 22628490]
[70]
Tapson, V.F.; Jing, Z.C.; Xu, K.F.; Pan, L.; Feldman, J.; Kiely, D.G.; Kotlyar, E.; McSwain, C.S.; Laliberte, K.; Arneson, C.; Rubin, L.J. 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), 952-958.
[http://dx.doi.org/10.1378/chest.12-2875] [PMID: 23669822]
[71]
Jing, Z.C.; Parikh, K.; Pulido, T.; Jerjes-Sanchez, C.; White, R.J.; Allen, R.; Torbicki, A.; Xu, K.F.; Yehle, D.; Laliberte, K.; Arneson, C.; Rubin, L.J. Efficacy and safety of oral treprostinil monotherapy for the treatment of pulmonary arterial hypertension: A randomized, controlled trial. Circulation, 2013, 127(5), 624-633.
[http://dx.doi.org/10.1161/CIRCULATIONAHA.112.124388] [PMID: 23307827]
[72]
White, R.J.; Jerjes-Sanchez, C.; Bohns Meyer, G.M.; Pulido, T.; Sepulveda, P.; Wang, K.Y.; Grünig, E.; Hiremath, S.; Yu, Z.; Gangcheng, Z.; Yip, W.L.J.; Zhang, S.; Khan, A.; Deng, C.Q.; Grover, R.; Tapson, V.F.; Svetliza, G.N.; Lescano, A.J.; Bortman, G.R.; Diez, F.A.; Botta, C.E.; Fitzgerald, J.; Feenstra, E.; Kermeen, F.D.; Keogh, A.M.; Williams, T.J.; Yousseff, P.P.; Ng, B.J-H.; Smallwood, D.M.N.; Dwyer, N.B.; Brown, M.R.; Lang, I.M.; Steringer-Mascherbauer, R.; Arakaki, J.S.O.; Campos, F.T.A.F.; de Amorim, C.R.; de Souza, R.; Bohns, M.G.M.; Moreira, M.A.C.; Yoo, H.H.B.; Lapa, M.S.; Swiston, J.; Hirani, N.; Mehta, S.; Michelakis, E.; Sepulveda, P.A.; Blancaire, M.M.Z.; Liu, J.; Shuyang, Z.; Pan, L.; Chunde, B.; Qun, Y.; Xiaoshu, C.; Zaixin, Y.; Li, X.; Hua, Y.; Gangcheng, Z.; Zhu, X.; Chen, Y.; Zhaozhong, C.; Yang, Y.; Daxin, Z.; Jieyan, S.; Nielsen-Kudsk, J.E.; Carlsen, J.; Bourdin, A.; Hachulla, E.; Dromer, C.; Chaouat, A.; Reynaud-Gauber, M.; Seronde, M-F.; Klose, H.; Halank, M.; Hoffken, G.; Ewert, R.; Rosenkranz, S.; Grunig, E.; Kruger, U.; Kronsbein, J.; Hauptmeier, B.M.; Koch, A.; Held, M.; Lange, T.J.; Neurohr, C.; Wilkens, H.; Wilhelm Wirtz, H.R.; Konstantinides, S.; Argyropoulou-Pataka, P.; Orfanos, S.; Hiremath, S.; Kerkar, P.G.; Suresh, P.V.; Baxi, H.A.; Oomman, A.; Abhaichand, R.K.; Arjun, P.K.E.; Chopra, V.; Mehrotra, R.; Rajput, R.K.; Sawhney, J.P.S.; Bimalendu, S.; Sharma, K.H.; Sastry, B.K.S.; Kramer, M.R.; Segel, M.J.; Ben-Dov, I.; Berkman, N.; Yigla, M.; Adir, Y.; D’Alto, M.; Vizza, C.D.; Scelsi, L.; Vitulo, P.; Pulido, T.R.; Jerjes-Sanchez, C.; Boonstra, A.; Vonk, M.C.; Sobkowicz, B.; Mularek-Kubzdela, T.; Torbicki, A.; Podolec, P.; Teik, L.S.; Yip, W.L.J.; Chang, H-J.; Kim, H-K.; Park, J-B.; Chang, S-A.; Kim, D-K.; Chang, S-A.; Chung, W-J.; Song, J-M.; Nissell, M.; Hjalmarsson, C.; Rundqvist, B.; Huang, W-C.; Cheng, C-C.; Hsu, C-H.; Hsu, H-H.; Wang, K-Y.; Coghlan, J.G.; Kiely, D.G.; Pepke-Zaba, J.W.; Lordan, J.L.; Corris, P.A.; Cadaret, L.; Hansdottir, S.; Oudiz, R.J.; Badesch, D.B.; Mathier, M.; Schilz, R.; Hill, N.; Waxman, A.; Markin, C.J.; Zwicke, D.L.; Fisher, M.; Franco, V.; Sood, N.; Park, M.H.; Allen, R.; Feldman, J.P.; Balasubramanian, V.; Seeram, V.K.; Bajwa, A.; Thompson, A.B., III; Migliore, C.; Elwing, J.; McConnell, J.W.; Mehta, J.P.; Rahaghi, F.F.; Rame, J.E.; Khan, A.; Patel, B.; Oren, R.M.; Klinger, J.R.; Alnuaimat, H.; Allen, S.; Harvey, W.; Eggert, M.S.; Hage, A.; Miller, C.E.; Awdish, R.L.A.; Cajigas, H.; Grinnan, D.; Trichon, B.H.; McDonough, C.; White, R.J.; Rischard, F. Combination therapy with oral treprostinil for pulmonary arterial hypertension. A double-blind placebo-controlled clinical trial. Am. J. Respir. Crit. Care Med., 2020, 201(6), 707-717.
[http://dx.doi.org/10.1164/rccm.201908-1640OC] [PMID: 31765604]
[73]
White, R.J.; Parikh, K.; Allen, R.; Feldman, J.; Jerjez-Sanchez, C.; Pan, L.; Keogh, A.M.; Vizza, C.D.; Shapiro, S.M.; Gordon, K.; Broderick, M.; Bartolome, S. EXPRESS: Long term study of oral treprostinil to treat pulmonary arterial hypertension: Dosing, tolerability, and pharmacokinetics. Pulm. Circ., 2019, 10(4), 2045894019866335.
[PMID: 31290359]
[74]
Fares, W.H. Reply: Oral treprostinil combination trials post hoc secondary analyses: A step toward verifying its efficacy. Am. J. Respir. Crit. Care Med., 2016, 193(12), 1437-1438.
[http://dx.doi.org/10.1164/rccm.201604-0689LE] [PMID: 27304246]
[75]
Olschewski, H.; Simonneau, G.; Galiè, N.; Higenbottam, T.; Naeije, R.; Rubin, L.J.; Nikkho, S.; Speich, R.; Hoeper, M.M.; Behr, J.; Winkler, J.; Sitbon, O.; Popov, W.; Ghofrani, H.A.; Manes, A.; Kiely, D.G.; Ewert, R.; Meyer, A.; Corris, P.A.; Delcroix, M.; Gomez-Sanchez, M.; Siedentop, H.; Seeger, W. Inhaled iloprost for severe pulmonary hypertension. N. Engl. J. Med., 2002, 347(5), 322-329.
[http://dx.doi.org/10.1056/NEJMoa020204] [PMID: 12151469]
[76]
Galiè, N.; Humbert, M.; Vachiéry, J.L.; Vizza, C.; Kneussl, M.; Manes, A.; Sitbon, O.; Torbicki, A.; Delcroix, M.; Naeije, R.; Hoeper, M.; Chaouat, A.; Morand, S.; Besse, B.; Simonneau, G. 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(9), 1496-1502.
[http://dx.doi.org/10.1016/S0735-1097(02)01786-2] [PMID: 11985913]
[77]
Barst, R.J.; McGoon, M.; McLaughlin, V.; Tapson, V.; Oudiz, R.; Shapiro, S.; Robbins, I.M.; Channick, R.; Badesch, D.; Rayburn, B.K.; Flinchbaugh, R.; Sigman, J.; Arneson, C.; Jeffs, R.; Sigman, J.; Arneson, C.; Jeffs, R. Beraprost therapy for pulmonary arterial hypertension. J. Am. Coll. Cardiol., 2003, 41(12), 2119-2125.
[http://dx.doi.org/10.1016/S0735-1097(03)00463-7] [PMID: 12821234]
[78]
Simonneau, G.; Torbicki, A.; Hoeper, M.M.; Delcroix, M.; Karlócai, K.; Galiè, N.; Degano, B.; Bonderman, D.; Kurzyna, M.; Efficace, M.; Giorgino, R.; Lang, I.M. Selexipag: An oral, selective prostacyclin receptor agonist for the treatment of pulmonary arterial hypertension. Eur. Respir. J., 2012, 40(4), 874-880.
[http://dx.doi.org/10.1183/09031936.00137511] [PMID: 22362844]
[79]
Sitbon, O.; Channick, R.; Chin, K.M.; Frey, A.; Gaine, S.; Galiè, N.; Ghofrani, H.A.; Hoeper, M.M.; Lang, I.M.; Preiss, R.; Rubin, L.J.; Di Scala, L.; Tapson, V.; Adzerikho, I.; Liu, J.; Moiseeva, O.; Zeng, X.; Simonneau, G.; McLaughlin, V.V. Selexipag for the treatment of pulmonary arterial hypertension. N. Engl. J. Med., 2015, 373(26), 2522-2533.
[http://dx.doi.org/10.1056/NEJMoa1503184] [PMID: 26699168]
[80]
Oudiz, R.J.; Farber, H.W. Dosing considerations in the use of intravenous prostanoids in pulmonary arterial hypertension: An experience-based review. Am. Heart J., 2009, 157(4), 625-635.
[http://dx.doi.org/10.1016/j.ahj.2008.10.029] [PMID: 19332188]
[81]
Clozel, M.; Maresta, A.; Humbert, M. Endothelin receptor antagonists. Handb. Exp. Pharmacol., 2013, 218, 199-227.
[http://dx.doi.org/10.1007/978-3-642-38664-0_9] [PMID: 24092342]
[82]
Rubin, L.J.; Badesch, D.B.; Barst, R.J.; Galiè, N.; Black, C.M.; 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(12), 896-903.
[http://dx.doi.org/10.1056/NEJMoa012212] [PMID: 11907289]
[83]
Humbert, M.; Segal, E.S.; Kiely, D.G.; Carlsen, J.; Schwierin, B.; Hoeper, M.M. Results of European post-marketing surveillance of bosentan in pulmonary hypertension. Eur. Respir. J., 2007, 30(2), 338-344.
[http://dx.doi.org/10.1183/09031936.00138706] [PMID: 17504794]
[84]
Giersbergen, P.L.M.; Halabi, A.; Dingemanse, J. Pharmacokinetic interaction between bosentan and the oral contraceptives norethisterone and ethinyl estradiol. Int. J. Clin. Pharmacol. Ther., 2006, 44(3), 113-118.
[http://dx.doi.org/10.5414/CPP44113] [PMID: 16550733]
[85]
Paul, G.A.; Gibbs, J.S.R.; Boobis, A.R.; Abbas, A.; Wilkins, M.R. Bosentan decreases the plasma concentration of sildenafil when coprescribed in pulmonary hypertension. Br. J. Clin. Pharmacol., 2005, 60(1), 107-112.
[http://dx.doi.org/10.1111/j.1365-2125.2005.02383.x] [PMID: 15963102]
[86]
Weber, C.; Banken, L.; Birnboeck, H.; Schulz, R. Effect of the endothelin-receptor antagonist bosentan on the pharmacokinetics and pharmacodynamics of warfarin. J. Clin. Pharmacol., 1999, 39(8), 847-854.
[http://dx.doi.org/10.1177/00912709922008380] [PMID: 10434238]
[87]
Wrishko, R.E.; Dingemanse, J.; Yu, A.; Darstein, C.; Phillips, D.L.; Mitchell, M.I. Pharmacokinetic interaction between tadalafil and bosentan in healthy male subjects. J. Clin. Pharmacol., 2008, 48(5), 610-618.
[http://dx.doi.org/10.1177/0091270008315315] [PMID: 18305126]
[88]
Galiè, N.; Olschewski, H.; Oudiz, R.J.; Torres, F.; Frost, A.; Ghofrani, H.A.; Badesch, D.B.; McGoon, M.D.; McLaughlin, V.V.; Roecker, E.B.; Gerber, M.J.; Dufton, C.; Wiens, B.L.; Rubin, L.J. 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), 3010-3019.
[http://dx.doi.org/10.1161/CIRCULATIONAHA.107.742510] [PMID: 18506008]
[89]
Pulido, T.; Adzerikho, I.; Channick, R.N.; Delcroix, M.; Galiè, N.; Ghofrani, H.A.; Jansa, P.; Jing, Z.C.; Le Brun, F.O.; Mehta, S.; Mittelholzer, C.M.; Perchenet, L.; Sastry, B.K.S.; Sitbon, O.; Souza, R.; Torbicki, A.; Zeng, X.; Rubin, L.J.; Simonneau, G. Macitentan and morbidity and mortality in pulmonary arterial hypertension. N. Engl. J. Med., 2013, 369(9), 809-818.
[http://dx.doi.org/10.1056/NEJMoa1213917] [PMID: 23984728]
[90]
Schermuly, R.T.; Janssen, W.; Weissmann, N.; Stasch, J.P.; Grimminger, F.; Ghofrani, H.A. Riociguat for the treatment of pulmonary hypertension. Expert Opin. Investig. Drugs, 2011, 20(4), 567-576.
[http://dx.doi.org/10.1517/13543784.2011.565048] [PMID: 21391889]
[91]
Galiè, N.; Müller, K.; Scalise, A.V.; Grünig, E. PATENT PLUS: A blinded, randomised and extension study of riociguat plus sildenafil in pulmonary arterial hypertension. Eur. Respir. J., 2015, 45(5), 1314-1322.
[http://dx.doi.org/10.1183/09031936.00105914] [PMID: 25657022]
[92]
Sastry, B.K.S.; Narasimhan, C.; Reddy, N.K.; Raju, B.S. Clinical efficacy of sildenafil in primary pulmonary hypertension. J. Am. Coll. Cardiol., 2004, 43(7), 1149-1153.
[http://dx.doi.org/10.1016/j.jacc.2003.10.056] [PMID: 15063421]
[93]
Galiè, N.; Ghofrani, H.A.; Torbicki, A.; Barst, R.J.; Rubin, L.J.; Badesch, D.; Fleming, T.; Parpia, T.; Burgess, G.; Branzi, A.; Grimminger, F.; Kurzyna, M.; Simonneau, G. Sildenafil citrate therapy for pulmonary arterial hypertension. N. Engl. J. Med., 2005, 353(20), 2148-2157.
[http://dx.doi.org/10.1056/NEJMoa050010] [PMID: 16291984]
[94]
Galiè, N.; Brundage, B.H.; Ghofrani, H.A.; Oudiz, R.J.; Simonneau, G.; Safdar, Z.; Shapiro, S.; White, R.J.; Chan, M.; Beardsworth, A.; Frumkin, L.; Barst, R.J. Tadalafil therapy for pulmonary arterial hypertension. Circulation, 2009, 119(22), 2894-2903.
[http://dx.doi.org/10.1161/CIRCULATIONAHA.108.839274] [PMID: 19470885]
[95]
Klinger, J.R.; Elliott, C.G.; Levine, D.J.; Bossone, E.; Duvall, L.; Fagan, K.; Frantsve-Hawley, J.; Kawut, S.M.; Ryan, J.J.; Rosenzweig, E.B.; Sederstrom, N.; Steen, V.D.; Badesch, D.B. Therapy for pulmonary arterial hypertension in adults. Chest, 2019, 155(3), 565-586.
[http://dx.doi.org/10.1016/j.chest.2018.11.030] [PMID: 30660783]
[96]
Ghofrani, H.A.; Galiè, N.; Grimminger, F.; Grünig, E.; Humbert, M.; Jing, Z.C.; Keogh, A.M.; Langleben, D.; Kilama, M.O.; Fritsch, A.; Neuser, D.; Rubin, L.J. Riociguat for the treatment of pulmonary arterial hypertension. N. Engl. J. Med., 2013, 369(4), 330-340.
[http://dx.doi.org/10.1056/NEJMoa1209655] [PMID: 23883378]
[97]
Hoeper, M.M.; Markevych, I.; Spiekerkoetter, E.; Welte, T.; Niedermeyer, J. Goal-oriented treatment and combination therapy for pulmonary arterial hypertension. Eur. Respir. J., 2005, 26(5), 858-863.
[http://dx.doi.org/10.1183/09031936.05.00075305] [PMID: 16264047]
[98]
Simonneau, G.; Rubin, L.J.; Galiè, N.; Barst, R.J.; Fleming, T.R.; Frost, A.E.; Engel, P.J.; Kramer, M.R.; Burgess, G.; Collings, L.; Cossons, N.; Sitbon, O.; Badesch, D.B. Addition of sildenafil to long-term intravenous epoprostenol therapy in patients with pulmonary arterial hypertension: A randomized trial. Ann. Intern. Med., 2008, 149(8), 521-530.
[http://dx.doi.org/10.7326/0003-4819-149-8-200810210-00004] [PMID: 18936500]
[99]
Galiè, N.; Hoeper, M.M.; Humbert, M.; Torbicki, A.; Vachiery, J.L.; Barbera, J.A.; Beghetti, M.; Corris, P.; Gaine, S.; Gibbs, J.S.; Gomez-Sanchez, M.A.; Jondeau, G.; Klepetko, W.; Opitz, C.; Peacock, A.; Rubin, L.; Zellweger, M.; Simonneau, G.; Vahanian, A.; Auricchio, A.; Bax, J.; Ceconi, C.; Dean, V.; Filippatos, G.; Funck-Brentano, C.; Hobbs, R.; Kearney, P.; McDonagh, T.; McGregor, K.; Popescu, B.A.; Reiner, Z.; Sechtem, U.; Sirnes, P.A.; Tendera, M.; Vardas, P.; Widimsky, P.; Sechtem, U.; Al Attar, N.; Andreotti, F.; Aschermann, M.; Asteggiano, R.; Benza, R.; Berger, R.; Bonnet, D.; Delcroix, M.; Howard, L.; Kitsiou, A.N.; Lang, I.; Maggioni, A.; Nielsen-Kudsk, J.E.; Park, M.; Perrone-Filardi, P.; Price, S.; Domenech, M.T.S.; Vonk-Noordegraaf, A.; Zamorano, J.L. 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(20), 2493-2537.
[http://dx.doi.org/10.1093/eurheartj/ehp297] [PMID: 19713419]
[100]
Ghofrani, H.A.; Humbert, M. The role of combination therapy in managing pulmonary arterial hypertension. Eur. Respir. Rev., 2014, 23(134), 469-475.
[http://dx.doi.org/10.1183/09059180.00007314] [PMID: 25445945]
[101]
McLaughlin, V.V.; Shah, S.J.; Souza, R.; Humbert, M. Management of pulmonary arterial hypertension. J. Am. Coll. Cardiol., 2015, 65(18), 1976-1997.
[http://dx.doi.org/10.1016/j.jacc.2015.03.540] [PMID: 25953750]
[102]
Humbert, M.; Barst, R.J.; Robbins, I.M.; Channick, R.N.; Galiè, N.; Boonstra, A.; Rubin, L.J.; Horn, E.M.; Manes, A.; Simonneau, G. Combination of bosentan with epoprostenol in pulmonary arterial hypertension: BREATHE-2. Eur. Respir. J., 2004, 24(3), 353-359.
[http://dx.doi.org/10.1183/09031936.04.00028404] [PMID: 15358690]
[103]
Sitbon, O.; Sattler, C.; Bertoletti, L.; Savale, L.; Cottin, V.; Jaïs, X.; De 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(6), 1727-1736.
[http://dx.doi.org/10.1183/13993003.02043-2015] [PMID: 26989105]
[104]
Chin, K.M.; Sitbon, O.; Doelberg, M.; Feldman, J.; Gibbs, J.S.R.; Grünig, E.; Hoeper, M.M.; Martin, N.; Mathai, S.C.; McLaughlin, V.V.; Perchenet, L.; Poch, D.; Saggar, R.; Simonneau, G.; Galiè, N. Three- versus two-drug therapy for patients with newly diagnosed pulmonary arterial hypertension. J. Am. Coll. Cardiol., 2021, 78(14), 1393-1403.
[http://dx.doi.org/10.1016/j.jacc.2021.07.057] [PMID: 34593120]
[105]
Sitbon, O.; Jaïs, X.; Savale, L.; Cottin, V.; Bergot, E.; Macari, E.A.; 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), 1691-1697.
[http://dx.doi.org/10.1183/09031936.00116313] [PMID: 24627535]
[106]
D’Alto, M.; Badagliacca, R.; Argiento, P.; Romeo, E.; Farro, A.; Papa, S.; Sarubbi, B.; Russo, M.G.; Vizza, C.D.; Golino, P.; Naeije, R. Risk reduction and right heart reverse remodeling by upfront triple combination therapy in pulmonary arterial hypertension. Chest, 2020, 157(2), 376-383.
[http://dx.doi.org/10.1016/j.chest.2019.09.009] [PMID: 31563498]
[107]
Boucly, A.; Savale, L.; Jaïs, X.; Bauer, F.; Bergot, E.; Bertoletti, L.; Beurnier, A.; Bourdin, A.; Bouvaist, H.; Bulifon, S.; Chabanne, C.; Chaouat, A.; Cottin, V.; Dauphin, C.; Degano, B.; De Groote, P.; Favrolt, N.; Feng, Y.; Horeau-Langlard, D.; Jevnikar, M.; Jutant, E.M.; Liang, Z.; Magro, P.; Mauran, P.; Moceri, P.; Mornex, J.F.; Palat, S.; Parent, F.; Picard, F.; Pichon, J.; Poubeau, P.; Prévot, G.; Renard, S.; Reynaud-Gaubert, M.; Riou, M.; Roblot, P.; Sanchez, O.; Seferian, A.; Tromeur, C.; Weatherald, J.; Simonneau, G.; Montani, D.; Humbert, M.; Sitbon, O. Association between initial treatment strategy and long-term survival in pulmonary arterial hypertension. Am. J. Respir. Crit. Care Med., 2021, 204(7), 842-854.
[http://dx.doi.org/10.1164/rccm.202009-3698OC] [PMID: 34185620]
[108]
Morrell, N.W.; Aldred, M.A.; Chung, W.K.; Elliott, C.G.; Nichols, W.C.; Soubrier, F.; Trembath, R.C.; Loyd, J.E. Genetics and genomics of pulmonary arterial hypertension. Eur. Respir. J., 2019, 53(1), 1801899.
[http://dx.doi.org/10.1183/13993003.01899-2018] [PMID: 30545973]
[109]
Yung, L.M.; Yang, P.; Joshi, S.; Augur, Z.M.; Kim, S.S.J.; Bocobo, G.A.; Dinter, T.; Troncone, L.; Chen, P.S.; McNeil, M.E.; Southwood, M.; Poli de Frias, S.; Knopf, J.; Rosas, I.O.; Sako, D.; Pearsall, R.S.; Quisel, J.D.; Li, G.; Kumar, R.; Yu, P.B. ACTRIIA-Fc rebalances activin/GDF versus BMP signaling in pulmonary hypertension. Sci. Transl. Med., 2020, 12(543), eaaz5660.
[http://dx.doi.org/10.1126/scitranslmed.aaz5660] [PMID: 32404506]
[110]
A study of sotatercept for the treatment of pulmonary arterial hypertension (SPECTRA). Patent NCT03738150, 2021.
[111]
A long-term follow-up study of sotatercept for PAH treatment (SOTERIA). Patent NCT04796337, NCT04796337.
[112]
Study of sotatercept in newly diagnosed intermediate- and high-risk PAH participants (MK-7962-005/​A011-13) (HYPERION). Patent NCT04811092, 2023.
[113]
A study of sotatercept in participants with PAH WHO FC III or FC IV at high risk of mortality (MK-7962-006/​ZENITH) (ZENITH). Patent NCT04896008, 2023.
[114]
Humbert, M.; McLaughlin, V.; Gibbs, J.S.R.; Gomberg-Maitland, M.; Hoeper, M.M.; Preston, I.R.; Souza, R.; Waxman, A.B.; Ghofrani, H.A.; Escribano Subias, P.; Feldman, J.; Meyer, G.; Montani, D.; Olsson, K.M.; Manimaran, S.; de Oliveira, P.J.; Badesch, D.B. Sotatercept for the treatment of pulmonary arterial hypertension: PULSAR open-label extension. Eur. Respir. J., 2023, 61(1), 2201347.
[http://dx.doi.org/10.1183/13993003.01347-2022] [PMID: 36041750]
[115]
Hoeper, M.M.; Badesch, D.B.; Ghofrani, H.A.; Gibbs, J.S.R.; Gomberg-Maitland, M.; McLaughlin, V.V.; Preston, I.R.; Souza, R.; Waxman, A.B.; Grünig, E.; Kopeć, G.; Meyer, G.; Olsson, K.M.; Rosenkranz, S.; Xu, Y.; Miller, B.; Fowler, M.; Butler, J.; Koglin, J.; de Oliveira Pena, J.; Humbert, M. Phase 3 trial of sotatercept for treatment of pulmonary arterial hypertension. N. Engl. J. Med., 2023, 388(16), 1478-1490.
[http://dx.doi.org/10.1056/NEJMoa2213558] [PMID: 36877098]
[116]
Long, L.; MacLean, M.R.; Jeffery, T.K.; Morecroft, I.; Yang, X.; Rudarakanchana, N.; Southwood, M.; James, V.; Trembath, R.C.; Morrell, N.W. Serotonin increases susceptibility to pulmonary hypertension in BMPR2-deficient mice. Circ. Res., 2006, 98(6), 818-827.
[http://dx.doi.org/10.1161/01.RES.0000215809.47923.fd] [PMID: 16497988]
[117]
Lazarus, H.M.; Denning, J.; Wring, S.; Palacios, M.; Hoffman, S.; Crizer, K.; Kamau-Kelley, W.; Symonds, W.; Feldman, J. A trial design to maximize knowledge of the effects of rodatristat ethyl in the treatment of pulmonary arterial hypertension (ELEVATE 2). Pulm. Circ., 2022, 12(2), e12088.
[http://dx.doi.org/10.1002/pul2.12088] [PMID: 35795492]
[118]
Imatinib (QTI571) in pulmonary arterial hypertension (IMPRES). Patent NCT00902174, 2016.
[119]
Bardoxolone methyl evaluation in patients with pulmonary hypertension (PH) - LARIAT. Patent NCT02036970, 2023.
[120]
Bardoxolone methyl in patients with connective tissue disease-associated pulmonary arterial hypertension - CATALYST. Patent NCT02657356, 2023.
[121]
Extended access program to assess long-term safety of bardoxolone methyl in patients with pulmonary hypertension (RANGER). Patent NCT030681301, 2017.
[122]
Interventions against insulin resistance in pulmonary arterial hypertension. Patent NCT0361745,
[123]
Effects of inhaled aviptadil (Vasoactive Intestinal Peptide) in patients with pulmonary arterial hypertension. Am. J. Respir. Crit. Care Med., 2010, 181, A2516.
[124]
Phase 2 study to assess safety, tolerability and efficacy of once weekly SC pemziviptadil (PB1046) in subjects with symptomatic PAH (VIP). Patent NCT03556020, 2022.
[125]
Drake, K.M.; Dunmore, B.J.; McNelly, L.N.; Morrell, N.W.; Aldred, M.A. Correction of nonsense BMPR2 and SMAD9 mutations by ataluren in pulmonary arterial hypertension. Am. J. Respir. Cell Mol. Biol., 2013, 49(3), 403-409.
[http://dx.doi.org/10.1165/rcmb.2013-0100OC] [PMID: 23590310]
[126]
Granton, J.; Langleben, D.; Kutryk, M.B.; Camack, N.; Galipeau, J.; Courtman, D.W.; Stewart, D.J. Endothelial NO-synthase gene-enhanced progenitor cell therapy for pulmonary arterial hypertension. Circ. Res., 2015, 117(7), 645-654.
[http://dx.doi.org/10.1161/CIRCRESAHA.114.305951] [PMID: 26195220]
[127]
ALlogeneic cardiosphere-derived stem cells (CDCs) for pulmonary hypertension therapy (ALPHA). Patent NCT03145298, 2023.
[128]
Khural, J.S.; Houston, B.A.; Leary, P.J.; Mathai, S.C.; Kolb, T.M.; Damico, R.; Hassoun, P.M.; Kass, D.A.; Hsu, S.; Tedford, R.J. Right atrial pacing to improve acute hemodynamics in pulmonary arterial hypertension. Am. J. Respir. Crit. Care Med., 2021, 203(4), 508-511.
[http://dx.doi.org/10.1164/rccm.202006-2278LE] [PMID: 33026819]
[129]
Torres, F.; Farber, H.; Ristic, A.; McLaughlin, V.; Adams, J.; Zhang, J.; Klassen, P.; Shanahan, W.; Grundy, J.; Hoffmann, I.; Cabell, C.; Escribano Subías, P.; Sood, N.; Keogh, A.; D’Souza, G.; Rubin, L. Efficacy and safety of ralinepag, a novel oral IP agonist, in PAH patients on mono or dual background therapy: Results from a phase 2 randomised, parallel group, placebo-controlled trial. Eur. Respir. J., 2019, 54(4), 1901030.
[http://dx.doi.org/10.1183/13993003.01030-2019] [PMID: 31391223]
[130]
Chapman, R.W.; Corboz, M.R.; Fernandez, C.; Sullivan, E.; Stautberg, A.; Plaunt, A.J.; Konicek, D.M.; Malinin, V.; Li, Z.; Cipolla, D.; Perkins, W. Characterisation of cough evoked by inhaled treprostinil and treprostinil palmitil. ERJ Open Res., 2021, 7(1), 00592-2020.
[http://dx.doi.org/10.1183/23120541.00592-2020] [PMID: 33614774]

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