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Semin Respir Crit Care Med 2023; 44(06): 746-761
DOI: 10.1055/s-0043-1770118
Review Article

Management of Pulmonary Arterial Hypertension

Jason Weatherald
1   Division of Pulmonary Medicine, Department of Medicine, University of Alberta, Edmonton, Canada
,
Rhea A. Varughese
1   Division of Pulmonary Medicine, Department of Medicine, University of Alberta, Edmonton, Canada
,
Jonathan Liu
2   Division of Respirology, Department of Medicine, University of Calgary, Calgary, Canada
,
Marc Humbert
3   Faculté de Médecine, Université Paris-Saclay, Le Kremlin-Bicêtre, France
4   Service de Pneumologie et Soins Intensifs Respiratoires, Assistance Publique Hôpitaux de Paris, Hôpital Bicêtre, Le Kremlin-Bicêtre, France
5   Hôpital Marie Lannelongue, Le Plessis Robinson, INSERM UMR_S 999, France
› Author Affiliations Funding J.W. is funded by the Canadian Institutes of Health Research and the Heart and Stroke Foundation of Canada.
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Abstract

Pulmonary arterial hypertension (PAH) is a rare pulmonary vascular disease characterized by progressive pulmonary arterial remodeling, increased pulmonary vascular resistance, right ventricular dysfunction, and reduced survival. Effective therapies have been developed that target three pathobiologic pathways in PAH: nitric oxide, endothelin-1, and prostacyclin. Approved therapies for PAH include phosphodiesterase type-5 inhibitors, soluble guanylate cyclase stimulators, endothelin receptor antagonists, prostacyclin analogs, and prostacyclin receptor agonists. Management of PAH in the modern era incorporates multidimensional risk assessment to guide the use of these medications. For patients with PAH and without significant comorbidities, current guidelines recommend two oral medications (phosphodiesterase type-5 inhibitor and endothelin receptor antagonist) for low- and intermediate-risk patients, with triple therapy including a parenteral prostacyclin to be considered in those at high or intermediate-high risk. Combination therapy may be poorly tolerated and less effective in patients with PAH and cardiopulmonary comorbidities. Thus, a single-agent approach with individualized decisions to add-on other PAH therapies is recommended in older patients and those with significant comorbid conditions. Management of PAH is best performed in multidisciplinary teams located in experienced centers. Other core pillars of PAH management include supportive and adjunctive treatments including oxygen, diuretics, rehabilitation, and anticoagulation in certain patients. Patients with PAH who progress despite optimal treatment or who are refractory to best medical care should be referred for lung transplantation, if eligible. Despite considerable progress, PAH is often fatal and new therapies that reverse the disease and improve outcomes are desperately needed.

Keywords

pulmonary arterial hypertension - management - treatment - risk assessment


Publication History

Article published online:
27 June 2023

© 2023. Thieme. All rights reserved.

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  • References

  • 1 Lau EMT, Giannoulatou E, Celermajer DS, Humbert M. Epidemiology and treatment of pulmonary arterial hypertension. Nat Rev Cardiol 2017; 14 (10) 603-614
    CrossrefPubMedSearch in Google Scholar
  • 2 Hassoun PM. Pulmonary arterial hypertension. N Engl J Med 2021; 385 (25) 2361-2376
    CrossrefPubMedSearch in Google Scholar
  • 3 Humbert M, Guignabert C, Bonnet S. et al. Pathology and pathobiology of pulmonary hypertension: state of the art and research perspectives. Eur Respir J 2019; 53 (01) 1801887
    CrossrefPubMedSearch in Google Scholar
  • 4 Hoeper MM, Kramer T, Pan Z. et al. Mortality in pulmonary arterial hypertension: prediction by the 2015 European pulmonary hypertension guidelines risk stratification model. Eur Respir J 2017; 50 (02) 1700740
    CrossrefPubMedSearch in Google Scholar
  • 5 Boucly A, Weatherald J, Savale L. et al. External validation of a refined 4-strata risk assessment score from the French Pulmonary Hypertension Registry. Eur Respir J 2021; 59 (06) 2102419
    CrossrefPubMedSearch in Google Scholar
  • 6 Galiè N, Humbert M, Vachiery J-L. 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). Eur Respir J 2015; 46 (04) 903-975
    CrossrefPubMedSearch in Google Scholar
  • 7 Humbert M, Kovacs G, Hoeper MM. et al; ESC/ERS Scientific Document Group. 2022 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Respir J 2023; 61 (01) 2200879
    Search in Google Scholar
  • 8 Humbert M, Kovacs G, Hoeper MM. et al; ESC/ERS Scientific Document Group. 2022 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Heart J 2022; 43 (38) 3618-3731
    CrossrefPubMedSearch in Google Scholar
  • 9 Weatherald J, Boucly A, Peters A. et al; Evolving Landscape of Pulmonary Arterial Hypertension and Redesigning Pulmonary Arterial Hypertension Clinical Trials Task Force of the 18th Global CardioVascular Clinical Trialists Forum. The evolving landscape of pulmonary arterial hypertension clinical trials. Lancet 2022; 400 (10366): 1884-1898
    CrossrefPubMedSearch in Google Scholar
  • 10 Corbin JD, Francis SH. Cyclic GMP phosphodiesterase-5: target of sildenafil. J Biol Chem 1999; 274 (20) 13729-13732
    CrossrefPubMedSearch in Google Scholar
  • 11 Tantini B, Manes A, Fiumana E. et al. Antiproliferative effect of sildenafil on human pulmonary artery smooth muscle cells. Basic Res Cardiol 2005; 100 (02) 131-138
    CrossrefPubMedSearch in Google Scholar
  • 12 Galiè N, Ghofrani HA, Torbicki A. et al; Sildenafil Use in Pulmonary Arterial Hypertension (SUPER) Study Group. Sildenafil citrate therapy for pulmonary arterial hypertension. N Engl J Med 2005; 353 (20) 2148-2157
    CrossrefPubMedSearch in Google Scholar
  • 13 Badesch DB, Hill NS, Burgess G. et al; SUPER Study Group. Sildenafil for pulmonary arterial hypertension associated with connective tissue disease. J Rheumatol 2007; 34 (12) 2417-2422
    PubMedSearch in Google Scholar
  • 14 Galiè N, Brundage BH, Ghofrani HA. et al; Pulmonary Arterial Hypertension and Response to Tadalafil (PHIRST) Study Group. Tadalafil therapy for pulmonary arterial hypertension. Circulation 2009; 119 (22) 2894-2903
    CrossrefPubMedSearch in Google Scholar
  • 15 Barnes H, Brown Z, Burns A, Williams T. Phosphodiesterase 5 inhibitors for pulmonary hypertension. Cochrane Database Syst Rev 2019; 1 (01) CD012621
    PubMedSearch in Google Scholar
  • 16 Hambly N, Granton J. Riociguat for the treatment of pulmonary hypertension. Expert Rev Respir Med 2015; 9 (06) 679-695
    CrossrefPubMedSearch in Google Scholar
  • 17 Schermuly RT, Stasch J-P, Pullamsetti SS. et al. Expression and function of soluble guanylate cyclase in pulmonary arterial hypertension. Eur Respir J 2008; 32 (04) 881-891
    CrossrefPubMedSearch in Google Scholar
  • 18 Ghofrani H-A, Galiè N, Grimminger F. et al; PATENT-1 Study Group. Riociguat for the treatment of pulmonary arterial hypertension. N Engl J Med 2013; 369 (04) 330-340
    CrossrefPubMedSearch in Google Scholar
  • 19 Rubin LJ, Galiè N, Grimminger F. et al. Riociguat for the treatment of pulmonary arterial hypertension: a long-term extension study (PATENT-2). Eur Respir J 2015; 45 (05) 1303-1313
    CrossrefPubMedSearch in Google Scholar
  • 20 Humbert M, Coghlan JG, Ghofrani H-A. et al. Riociguat for the treatment of pulmonary arterial hypertension associated with connective tissue disease: results from PATENT-1 and PATENT-2. Ann Rheum Dis 2017; 76 (02) 422-426
    CrossrefPubMedSearch in Google Scholar
  • 21 Rosenkranz S, Ghofrani H-A, Beghetti M. et al. Riociguat for pulmonary arterial hypertension associated with congenital heart disease. Heart 2015; 101 (22) 1792-1799
    CrossrefPubMedSearch in Google Scholar
  • 22 Hoeper MM, Gomez Sanchez M-A, Humbert M. et al; Collaborators List. Riociguat treatment in patients with pulmonary arterial hypertension: Final safety data from the EXPERT registry. Respir Med 2020; 177: 106241
    CrossrefPubMedSearch in Google Scholar
  • 23 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 (05) 1314-1322
    CrossrefPubMedSearch in Google Scholar
  • 24 Giaid A, Yanagisawa M, Langleben D. et al. Expression of endothelin-1 in the lungs of patients with pulmonary hypertension. N Engl J Med 1993; 328 (24) 1732-1739
    CrossrefPubMedSearch in Google Scholar
  • 25 Stewart DJ, Levy RD, Cernacek P, Langleben D. Increased plasma endothelin-1 in pulmonary hypertension: marker or mediator of disease?. Ann Intern Med 1991; 114 (06) 464-469
    CrossrefPubMedSearch in Google Scholar
  • 26 Davie N, Haleen SJ, Upton PD. et al. ET(A) and ET(B) receptors modulate the proliferation of human pulmonary artery smooth muscle cells. Am J Respir Crit Care Med 2002; 165 (03) 398-405
    CrossrefPubMedSearch in Google Scholar
  • 27 Rubin LJ, Badesch DB, Barst RJ. et al. Bosentan therapy for pulmonary arterial hypertension. N Engl J Med 2002; 346 (12) 896-903
    CrossrefPubMedSearch in Google Scholar
  • 28 Galiè N, Rubin Lj, Hoeper M. et al. Treatment of patients with mildly symptomatic pulmonary arterial hypertension with bosentan (EARLY study): a double-blind, randomised controlled trial. Lancet 2008; 371 (9630): 2093-2100
    CrossrefPubMedSearch in Google Scholar
  • 29 Humbert M, Segal ES, Kiely DG, Carlsen J, Schwierin B, Hoeper MM. Results of European post-marketing surveillance of bosentan in pulmonary hypertension. Eur Respir J 2007; 30 (02) 338-344
    CrossrefPubMedSearch in Google Scholar
  • 30 Galiè N, Olschewski H, Oudiz RJ. et al; Ambrisentan in Pulmonary Arterial Hypertension, Randomized, Double-Blind, Placebo-Controlled, Multicenter, Efficacy Studies (ARIES) Group. 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
    CrossrefPubMedSearch in Google Scholar
  • 31 Oudiz RJ, Galiè N, Olschewski H. et al; ARIES Study Group. Long-term ambrisentan therapy for the treatment of pulmonary arterial hypertension. J Am Coll Cardiol 2009; 54 (21) 1971-1981
    CrossrefPubMedSearch in Google Scholar
  • 32 Iglarz M, Binkert C, Morrison K. et al. Pharmacology of macitentan, an orally active tissue-targeting dual endothelin receptor antagonist. J Pharmacol Exp Ther 2008; 327 (03) 736-745
    CrossrefPubMedSearch in Google Scholar
  • 33 Pulido T, Adzerikho I, Channick RN. et al; SERAPHIN Investigators. Macitentan and morbidity and mortality in pulmonary arterial hypertension. N Engl J Med 2013; 369 (09) 809-818
    CrossrefPubMedSearch in Google Scholar
  • 34 O'Connell C, Amar D, Boucly A. et al. Comparative safety and tolerability of prostacyclins in pulmonary hypertension. Drug Saf 2016; 39 (04) 287-294
    CrossrefPubMedSearch in Google Scholar
  • 35 Barst RJ, Rubin LJ, Long WA. et al; Primary Pulmonary Hypertension Study Group. A comparison of continuous intravenous epoprostenol (prostacyclin) with conventional therapy for primary pulmonary hypertension. N Engl J Med 1996; 334 (05) 296-301
    CrossrefPubMedSearch in Google Scholar
  • 36 Chin KM, Badesch DB, Robbins IM. et al. Two formulations of epoprostenol sodium in the treatment of pulmonary arterial hypertension: EPITOME-1 (epoprostenol for injection in pulmonary arterial hypertension), a phase IV, open-label, randomized study. Am Heart J 2014; 167 (02) 218-225.e1
    CrossrefPubMedSearch in Google Scholar
  • 37 Simonneau G, Barst RJ, Galie N. et al; Treprostinil Study Group. 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 (06) 800-804
    CrossrefPubMedSearch in Google Scholar
  • 38 Hiremath J, Thanikachalam S, Parikh K. et al; TRUST Study Group. Exercise improvement and plasma biomarker changes with intravenous treprostinil therapy for pulmonary arterial hypertension: a placebo-controlled trial. J Heart Lung Transplant 2010; 29 (02) 137-149
    CrossrefPubMedSearch in Google Scholar
  • 39 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 (03) 683-688
    CrossrefPubMedSearch in Google Scholar
  • 40 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 (18) 1915-1922
    CrossrefPubMedSearch in Google Scholar
  • 41 Hill NS, Feldman JP, Sahay S. et al; INSPIRE Study Investigators. INSPIRE: Safety and tolerability of inhaled Yutrepia (treprostinil) in pulmonary arterial hypertension (PAH). Pulm Circ 2022; 12 (03) e12119
    CrossrefPubMedSearch in Google Scholar
  • 42 Tapson VF, Torres F, Kermeen F. 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 (06) 1383-1390
    CrossrefPubMedSearch in Google Scholar
  • 43 Tapson VF, Jing Z-C, Xu K-F. et al; FREEDOM-C2 Study Team. 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 (03) 952-958
    CrossrefPubMedSearch in Google Scholar
  • 44 Jing Z-C, Parikh K, Pulido T. et al. Efficacy and safety of oral treprostinil monotherapy for the treatment of pulmonary arterial hypertension: a randomized, controlled trial. Circulation 2013; 127 (05) 624-633
    CrossrefPubMedSearch in Google Scholar
  • 45 White RJ, Jerjes-Sanchez C, Bohns Meyer GM. et al; FREEDOM-EV Investigators. Combination therapy with oral treprostinil for pulmonary arterial hypertension. A double-blind placebo-controlled clinical trial. Am J Respir Crit Care Med 2020; 201 (06) 707-717
    CrossrefPubMedSearch in Google Scholar
  • 46 Olschewski H, Simonneau G, Galiè N. et al; Aerosolized Iloprost Randomized Study Group. Inhaled iloprost for severe pulmonary hypertension. N Engl J Med 2002; 347 (05) 322-329
    CrossrefPubMedSearch in Google Scholar
  • 47 McLaughlin VV, Oudiz RJ, Frost A. et al. Randomized study of adding inhaled iloprost to existing bosentan in pulmonary arterial hypertension. Am J Respir Crit Care Med 2006; 174 (11) 1257-1263
    CrossrefPubMedSearch in Google Scholar
  • 48 Hoeper MM, Leuchte H, Halank M. et al. Combining inhaled iloprost with bosentan in patients with idiopathic pulmonary arterial hypertension. Eur Respir J 2006; 28 (04) 691-694
    CrossrefPubMedSearch in Google Scholar
  • 49 Kaufmann P, Okubo K, Bruderer S. et al. Pharmacokinetics and tolerability of the novel oral prostacyclin IP receptor agonist selexipag. Am J Cardiovasc Drugs 2015; 15 (03) 195-203
    CrossrefPubMedSearch in Google Scholar
  • 50 Kaufmann P, Cruz HG, Krause A, Ulč I, Halabi A, Dingemanse J. Pharmacokinetics of the novel oral prostacyclin receptor agonist selexipag in subjects with hepatic or renal impairment. Br J Clin Pharmacol 2016; 82 (02) 369-379
    CrossrefPubMedSearch in Google Scholar
  • 51 Sitbon O, Channick R, Chin KM. et al; GRIPHON Investigators. Selexipag for the treatment of pulmonary arterial hypertension. N Engl J Med 2015; 373 (26) 2522-2533
    CrossrefPubMedSearch in Google Scholar
  • 52 Sargent T, Hansen L, Hohsfield R. Transitions between infused and oral prostacyclin pathway agents in pulmonary arterial hypertension: key considerations. Pulm Circ 2020; 10 (03) 2045894020931324
    Search in Google Scholar
  • 53 Holthaus N, Prins K, Rose L, Prisco S, Pritzker M, Thenappan T. EXPRESS: transition from parental prostacyclin to selexipag: a case series of five pulmonary arterial hypertension patients. Pulm Circ 2019; 9 (03) 2045894019862167
    CrossrefPubMedSearch in Google Scholar
  • 54 Fanous SM, Janmohamed M. Transition from treprostinil to selexipag in patients with pulmonary arterial hypertension: case series. Am J Health Syst Pharm 2018; 75 (23) 1877-1881
    CrossrefPubMedSearch in Google Scholar
  • 55 Parikh KS, Doerfler S, Shelburne N. et al. Experience in transitioning from parenteral prostacyclins to selexipag in pulmonary arterial hypertension. J Cardiovasc Pharmacol 2020; 75 (04) 299-304
    CrossrefPubMedSearch in Google Scholar
  • 56 Frost A, Janmohamed M, Fritz JS. et al. Safety and tolerability of transition from inhaled treprostinil to oral selexipag in pulmonary arterial hypertension: Results from the TRANSIT-1 study. J Heart Lung Transplant 2019; 38 (01) 43-50
    CrossrefPubMedSearch in Google Scholar
  • 57 Yanaka K, Guillien A, Soumagne T. et al. Transition from intravenous epoprostenol to selexipag in pulmonary arterial hypertension: a word of caution. Eur Respir J 2020; 55 (06) 1902418
    CrossrefPubMedSearch in Google Scholar
  • 58 Simonneau G, Montani D, Celermajer DS. et al. Haemodynamic definitions and updated clinical classification of pulmonary hypertension. Eur Respir J 2019; 53 (01) 1801913
    CrossrefPubMedSearch in Google Scholar
  • 59 Sitbon O, Humbert M, Jaïs X. et al. Long-term response to calcium channel blockers in idiopathic pulmonary arterial hypertension. Circulation 2005; 111 (23) 3105-3111
    CrossrefPubMedSearch in Google Scholar
  • 60 Hemnes AR, Zhao M, West J. et al. Critical genomic networks and vasoreactive variants in idiopathic pulmonary arterial hypertension. Am J Respir Crit Care Med 2016; 194 (04) 464-475
    CrossrefPubMedSearch in Google Scholar
  • 61 Hemnes AR, Trammell AW, Archer SL. et al. Peripheral blood signature of vasodilator-responsive pulmonary arterial hypertension. Circulation 2015; 131 (04) 401-409 , discussion 409
    CrossrefPubMedSearch in Google Scholar
  • 62 Rich S, Kaufmann E, Levy PS. The effect of high doses of calcium-channel blockers on survival in primary pulmonary hypertension. N Engl J Med 1992; 327 (02) 76-81
    CrossrefPubMedSearch in Google Scholar
  • 63 Montani D, Savale L, Natali D. et al. Long-term response to calcium-channel blockers in non-idiopathic pulmonary arterial hypertension. Eur Heart J 2010; 31 (15) 1898-1907
    CrossrefPubMedSearch in Google Scholar
  • 64 Humbert M, McLaughlin V, Gibbs JSR. et al; PULSAR Trial Investigators. Sotatercept for the treatment of pulmonary arterial hypertension. N Engl J Med 2021; 384 (13) 1204-1215
    CrossrefPubMedSearch in Google Scholar
  • 65 Humbert M, McLaughlin V, Gibbs JSR. et al. Sotatercept for the treatment of pulmonary arterial hypertension: PULSAR open-label extension. Eur Respir J 2023; 61 (01) 2201347
    CrossrefPubMedSearch in Google Scholar
  • 66 Hoeper MM, Badesch DB, Ghofrani HA. et al; STELLAR Trial Investigators. Phase 3 trial of sotatercept for treatment of pulmonary arterial hypertension. N Engl J Med 2023; 388 (16) 1478-1490
    CrossrefPubMedSearch in Google Scholar
  • 67 Benza RL, Gomberg-Maitland M, Elliott CG. 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 (02) 323-337
    Search in Google Scholar
  • 68 Benza RL, Kanwar MK, Raina A. et al. 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 (01) 337-346
    CrossrefPubMedSearch in Google Scholar
  • 69 Kylhammar D, Kjellström B, Hjalmarsson C. et al. A comprehensive risk stratification at early follow-up determines prognosis in pulmonary arterial hypertension. Eur Heart J 2018; 39 (47) 4175-4181
    CrossrefPubMedSearch in Google Scholar
  • 70 Hoeper MM, Pausch C, Olsson KM. et al. COMPERA 2.0: a refined 4-strata risk assessment model for pulmonary arterial hypertension. Eur Respir J 2021; 60 (01) 2102311
    CrossrefPubMedSearch in Google Scholar
  • 71 Boucly A, Weatherald J, Savale L. et al. Risk assessment, prognosis and guideline implementation in pulmonary arterial hypertension. Eur Respir J 2017; 50 (02) 1700889
    CrossrefPubMedSearch in Google Scholar
  • 72 Weatherald J, Boucly A, Launay D. et al. Haemodynamics and serial risk assessment in systemic sclerosis associated pulmonary arterial hypertension. Eur Respir J 2018; 52 (04) 1800678
    CrossrefPubMedSearch in Google Scholar
  • 73 Galiè N, Channick RN, Frantz RP. et al. Risk stratification and medical therapy of pulmonary arterial hypertension. Eur Respir J 2019; 53 (01) 1801889
    CrossrefPubMedSearch in Google Scholar
  • 74 Galiè N, Barberà JA, Frost AE. et al; AMBITION Investigators. Initial use of ambrisentan plus tadalafil in pulmonary arterial hypertension. N Engl J Med 2015; 373 (09) 834-844
    CrossrefPubMedSearch in Google Scholar
  • 75 Sitbon O, Cottin V, Canuet M. et al. Initial combination therapy of macitentan and tadalafil in pulmonary arterial hypertension. Eur Respir J 2020; 56 (03) 2000673
    CrossrefPubMedSearch in Google Scholar
  • 76 Sitbon O, Sattler C, Bertoletti L. et al. Initial dual oral combination therapy in pulmonary arterial hypertension. Eur Respir J 2016; 47 (06) 1727-1736
    CrossrefPubMedSearch in Google Scholar
  • 77 van de Veerdonk MC, Huis In T Veld AE, Marcus JT. et al. Upfront combination therapy reduces right ventricular volumes in pulmonary arterial hypertension. Eur Respir J 2017; 49 (06) 1700007
    CrossrefPubMedSearch in Google Scholar
  • 78 Palazzini M, Hirani N, Dardi F. et al. Initial combination with bosentan and sildenafil as compared with initial monotherapy with the same drugs in patients with pulmonary arterial hypertension: a case-control, multicenter study [Internet]. In: C106. Wrecking Ball: New Paradigms in Understanding and Treatment of PH. American Thoracic Society; 2016:A6317–A6317 [cited August 20, 2018]. Accessed May 24, 2023 at: https://www.atsjournals.org/doi/abs/10.1164/ajrccm-conference.2016.193.1_MeetingAbstracts.A6317
    PubMed
  • 79 Hassoun PM, Zamanian RT, Damico R. et al. Ambrisentan and tadalafil up-front combination therapy in scleroderma-associated pulmonary arterial hypertension. Am J Respir Crit Care Med 2015; 192 (09) 1102-1110
    CrossrefPubMedSearch in Google Scholar
  • 80 Weatherald J, Thakrar MV, Varughese RA. et al. Upfront riociguat and ambrisentan combination therapy for newly diagnosed pulmonary arterial hypertension: a prospective open-label trial. J Heart Lung Transplant 2022; 41 (05) 563-567
    CrossrefPubMedSearch in Google Scholar
  • 81 Sulica R, Sangli S, Chakravarti A, Steiger D. Clinical and hemodynamic benefit of macitentan and riociguat upfront combination in patients with pulmonary arterial hypertension. Pulm Circ 2019; 9 (01) 2045894019826944
    CrossrefPubMedSearch in Google Scholar
  • 82 Sitbon O, Jaïs X, Savale L. et al. Upfront triple combination therapy in pulmonary arterial hypertension: a pilot study. Eur Respir J 2014; 43 (06) 1691-1697
    CrossrefPubMedSearch in Google Scholar
  • 83 D'Alto M, Badagliacca R, Argiento P. et al. Risk reduction and right heart reverse remodeling by upfront triple combination therapy in pulmonary arterial hypertension. Chest 2020; 157 (02) 376-383
    CrossrefPubMedSearch in Google Scholar
  • 84 Boucly A, Savale L, Jaïs X. et al. Association between initial treatment strategy and long-term survival in pulmonary arterial hypertension. Am J Respir Crit Care Med 2021; 204 (07) 842-854
    CrossrefPubMedSearch in Google Scholar
  • 85 Chin KM, Sitbon O, Doelberg M, Feldman J, Grünig E, Hoeper MM, Martin N, Mathai SC, McLaughlin VV, 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
    CrossrefPubMedSearch in Google Scholar
  • 86 Hoeper MM, Al-Hiti H, Benza RL. et al; REPLACE Investigators. 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 (06) 573-584
    CrossrefPubMedSearch in Google Scholar
  • 87 Coghlan JG, Channick R, Chin K. et al. Targeting the prostacyclin pathway with selexipag in patients with pulmonary arterial hypertension receiving double combination therapy: insights from the randomized controlled GRIPHON study. Am J Cardiovasc Drugs 2018; 18 (01) 37-47
    CrossrefPubMedSearch in Google Scholar
  • 88 Hoeper MM, Boucly A, Sitbon O. Age, risk and outcomes in idiopathic pulmonary arterial hypertension. Eur Respir J 2018; 51 (05) 1800629
    CrossrefPubMedSearch in Google Scholar
  • 89 McLaughlin VV, Vachiery J-L, Oudiz RJ. et al; AMBITION Study Group. Patients with pulmonary arterial hypertension with and without cardiovascular risk factors: Results from the AMBITION trial. J Heart Lung Transplant 2019; 38 (12) 1286-1295
    CrossrefPubMedSearch in Google Scholar
  • 90 Hoeper MM, Pausch C, Grünig E. et al. Idiopathic pulmonary arterial hypertension phenotypes determined by cluster analysis from the COMPERA registry. J Heart Lung Transplant 2020; 39 (12) 1435-1444
    CrossrefPubMedSearch in Google Scholar
  • 91 Hoeper MM, Dwivedi K, Pausch C. et al. Phenotyping of idiopathic pulmonary arterial hypertension: a registry analysis. Lancet Respir Med 2022; 10 (10) 937-948
    CrossrefPubMedSearch in Google Scholar
  • 92 Hjalmarsson C, Rådegran G, Kylhammar D. et al; SveFPH and SPAHR. Impact of age and comorbidity on risk stratification in idiopathic pulmonary arterial hypertension. Eur Respir J 2018; 51 (05) 1702310
    CrossrefPubMedSearch in Google Scholar
  • 93 Leard LE, Holm AM, Valapour M. et al. 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
    CrossrefPubMedSearch in Google Scholar
  • 94 Kolaitis NA, Chen H, Calabrese DR. et al. The lung allocation score remains inequitable for patients with PAH, even after the 2015 revision. Am J Respir Crit Care Med 2022; 207 (03) 300-311
    CrossrefPubMedSearch in Google Scholar
  • 95 Khush KK, Cherikh WS, Chambers DC. et al; International Society for Heart and Lung Transplantation. The International Thoracic Organ Transplant Registry of the International Society for Heart and Lung Transplantation: Thirty-sixth adult heart transplantation report - 2019; focus theme: donor and recipient size match. J Heart Lung Transplant 2019; 38 (10) 1056-1066
    CrossrefPubMedSearch in Google Scholar
  • 96 Diamond JM, Lee JC, Kawut SM. et al; Lung Transplant Outcomes Group. Clinical risk factors for primary graft dysfunction after lung transplantation. Am J Respir Crit Care Med 2013; 187 (05) 527-534
    CrossrefPubMedSearch in Google Scholar
  • 97 Porteous MK, Lee JC, Lederer DJ. et al; Lung Transplant Outcomes Group. Clinical risk factors and prognostic model for primary graft dysfunction after lung transplantation in patients with pulmonary hypertension. Ann Am Thorac Soc 2017; 14 (10) 1514-1522
    CrossrefPubMedSearch in Google Scholar
  • 98 Christie JD, Carby M, Bag R, Corris P, Hertz M, Weill D. ISHLT Working Group on Primary Lung Graft Dysfunction. Report of the ISHLT Working Group on Primary Lung Graft Dysfunction part II: definition. A consensus statement of the International Society for Heart and Lung Transplantation. J Heart Lung Transplant 2005; 24 (10) 1454-1459
    CrossrefPubMedSearch in Google Scholar
  • 99 Hoetzenecker K, Donahoe L, Yeung JC. et al. Extracorporeal life support as a bridge to lung transplantation-experience of a high-volume transplant center. J Thorac Cardiovasc Surg 2018; 155 (03) 1316-1328.e1
    CrossrefPubMedSearch in Google Scholar
  • 100 Rosenzweig EB, Gannon WD, Madahar P. et al. Extracorporeal life support bridge for pulmonary hypertension: a high-volume single-center experience. J Heart Lung Transplant 2019; 38 (12) 1275-1285
    CrossrefPubMedSearch in Google Scholar
  • 101 Hoeper MM, Benza RL, Corris P. et al. Intensive care, right ventricular support and lung transplantation in patients with pulmonary hypertension. Eur Respir J 2019; 53 (01) 1801906
    CrossrefPubMedSearch in Google Scholar
  • 102 Ulrich S, Hasler ED, Saxer S. et al. Effect of breathing oxygen-enriched air on exercise performance in patients with precapillary pulmonary hypertension: randomized, sham-controlled cross-over trial. Eur Heart J 2017; 38 (15) 1159-1168
    CrossrefPubMedSearch in Google Scholar
  • 103 Ulrich S, Saxer S, Hasler ED. et al. Effect of domiciliary oxygen therapy on exercise capacity and quality of life in patients with pulmonary arterial or chronic thromboembolic pulmonary hypertension: a randomised, placebo-controlled trial. Eur Respir J 2019; 54 (02) 1900276
    CrossrefPubMedSearch in Google Scholar
  • 104 Fuster V, Steele PM, Edwards WD, Gersh BJ, McGoon MD, Frye RL. Primary pulmonary hypertension: natural history and the importance of thrombosis. Circulation 1984; 70 (04) 580-587
    CrossrefPubMedSearch in Google Scholar
  • 105 Khan MS, Usman MS, Siddiqi TJ. et al. Is anticoagulation beneficial in pulmonary arterial hypertension?. Circ Cardiovasc Qual Outcomes 2018; 11 (09) e004757
    CrossrefPubMedSearch in Google Scholar
  • 106 Caldeira D, Loureiro MJ, Costa J, Pinto FJ, Ferreira JJ. Oral anticoagulation for pulmonary arterial hypertension: systematic review and meta-analysis. Can J Cardiol 2014; 30 (08) 879-887
    CrossrefPubMedSearch in Google Scholar
  • 107 Wang P, Hu L, Yin Y. et al. Can anticoagulants improve the survival rate for patients with idiopathic pulmonary arterial hypertension? A systematic review and meta-analysis. Thromb Res 2020; 196: 251-256
    CrossrefPubMedSearch in Google Scholar
  • 108 Johnson SR, Granton JT, Tomlinson GA. et al. Warfarin in systemic sclerosis-associated and idiopathic pulmonary arterial hypertension. A Bayesian approach to evaluating treatment for uncommon disease. J Rheumatol 2012; 39 (02) 276-285
    CrossrefPubMedSearch in Google Scholar
  • 109 Olsson KM, Delcroix M, Ghofrani HA. et al. Anticoagulation and survival in pulmonary arterial hypertension: results from the Comparative, Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension (COMPERA). Circulation 2014; 129 (01) 57-65
    CrossrefPubMedSearch in Google Scholar
  • 110 Preston IR, Roberts KE, Miller DP. et al. Effect of warfarin treatment on survival of patients with pulmonary arterial hypertension (PAH) in the Registry to Evaluate Early and Long-Term PAH Disease Management (REVEAL). Circulation 2015; 132 (25) 2403-2411
    CrossrefPubMedSearch in Google Scholar
  • 111 Margelidon-Cozzolino V, Delavenne X, Catella-Chatron J. et al. Indications and potential pitfalls of anticoagulants in pulmonary hypertension: Would DOACs become a better option than VKAs?. Blood Rev 2019; 37: 100579
    CrossrefPubMedSearch in Google Scholar
  • 112 Jackson ML, Nelson JC, Jackson LA. Risk factors for community-acquired pneumonia in immunocompetent seniors. J Am Geriatr Soc 2009; 57 (05) 882-888
    CrossrefPubMedSearch in Google Scholar
  • 113 Torres A, Blasi F, Dartois N, Akova M. Which individuals are at increased risk of pneumococcal disease and why? Impact of COPD, asthma, smoking, diabetes, and/or chronic heart disease on community-acquired pneumonia and invasive pneumococcal disease. Thorax 2015; 70 (10) 984-989
    CrossrefPubMedSearch in Google Scholar
  • 114 Ciszewski A. Cardioprotective effect of influenza and pneumococcal vaccination in patients with cardiovascular diseases. Vaccine 2018; 36 (02) 202-206
    CrossrefPubMedSearch in Google Scholar
  • 115 Badagliacca R, Papa S, D'Alto M. et al; Italian Pulmonary Hypertension NETwork (iPHNET). The paradox of pulmonary arterial hypertension in Italy in the COVID-19 era: is risk of disease progression around the corner?. Eur Respir J 2022; 60 (04) 2102276
    CrossrefPubMedSearch in Google Scholar
  • 116 Montani D, Certain M-C, Weatherald J. et al; French PH Network PULMOTENSION Investigators. COVID-19 in patients with pulmonary hypertension: a national prospective cohort study. Am J Respir Crit Care Med 2022; 206 (05) 573-583
    CrossrefPubMedSearch in Google Scholar
  • 117 Wieteska-Miłek M, Szmit S, Florczyk M, Kuśmierczyk-Droszcz B, Ryczek R, Kurzyna M. COVID-19 vaccination in patients with pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension: safety profile and reasons for opting against vaccination. Vaccines (Basel) 2021; 9 (12) 1395
    CrossrefPubMedSearch in Google Scholar
  • 118 MM Vanhoof J, Delcroix M, Vandevelde E. et al. Emotional symptoms and quality of life in patients with pulmonary arterial hypertension. J Heart Lung Transplant 2014; 33 (08) 800-808
    CrossrefPubMedSearch in Google Scholar
  • 119 Bussotti M, Sommaruga M. Anxiety and depression in patients with pulmonary hypertension: impact and management challenges. Vasc Health Risk Manag 2018; 14: 349-360
    CrossrefPubMedSearch in Google Scholar
  • 120 Guillevin L, Armstrong I, Aldrighetti R. et al. Understanding the impact of pulmonary arterial hypertension on patients' and carers' lives. Eur Respir Rev 2013; 22 (130) 535-542
    CrossrefPubMedSearch in Google Scholar
  • 121 Takita Y, Takeda Y, Fujisawa D, Kataoka M, Kawakami T, Doorenbos AZ. Depression, anxiety and psychological distress in patients with pulmonary hypertension: a mixed-methods study. BMJ Open Respir Res 2021; 8 (01) e000876
    CrossrefPubMedSearch in Google Scholar
  • 122 Halimi L, Marin G, Molinari N. et al. Impact of psychological factors on the health-related quality of life of patients treated for pulmonary arterial hypertension. J Psychosom Res 2018; 105: 45-51
    CrossrefPubMedSearch in Google Scholar
  • 123 Harzheim D, Klose H, Pinado FP. et al. Anxiety and depression disorders in patients with pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension. Respir Res 2013; 14 (01) 104
    CrossrefPubMedSearch in Google Scholar
  • 124 Löwe B, Gräfe K, Ufer C. et al. Anxiety and depression in patients with pulmonary hypertension. Psychosom Med 2004; 66 (06) 831-836
    CrossrefPubMedSearch in Google Scholar
  • 125 Olsson KM, Meltendorf T, Fuge J. et al. Prevalence of mental disorders and impact on quality of life in patients with pulmonary arterial hypertension. Front Psychiatry 2021; 12: 667602
    CrossrefPubMedSearch in Google Scholar
  • 126 Saleh D, Fisher JH, Provencher S, Liang Z, Ryerson CJ, Weatherald J. A systematic evaluation of the quality, accuracy, and reliability of internet websites about pulmonary arterial hypertension. Ann Am Thorac Soc 2022; 19 (08) 1404-1413
    CrossrefPubMedSearch in Google Scholar
  • 127 Morrell NW, Aldred MA, Chung WK. et al. Genetics and genomics of pulmonary arterial hypertension. Eur Respir J 2019; 53 (01) 1801899
    CrossrefPubMedSearch in Google Scholar
  • 128 Montani D, Girerd B, Jaïs X. et al. Screening for pulmonary arterial hypertension in adults carrying a BMPR2 mutation. Eur Respir J 2021; 58 (01) 2004229
    CrossrefPubMedSearch in Google Scholar
  • 129 Ehlken N, Lichtblau M, Klose H. et al. Exercise training improves peak oxygen consumption and haemodynamics in patients with severe pulmonary arterial hypertension and inoperable chronic thrombo-embolic pulmonary hypertension: a prospective, randomized, controlled trial. Eur Heart J 2016; 37 (01) 35-44
    CrossrefPubMedSearch in Google Scholar
  • 130 Grünig E, MacKenzie A, Peacock AJ. et al. 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
    CrossrefPubMedSearch in Google Scholar
  • 131 Chia KSW, Brown K, Kotlyar E, Wong PKK, Faux SG, Shiner CT. ‘Tired, afraid, breathless…. ’ An international survey of the exercise experience for people living with pulmonary hypertension. Pulm Circ 2020; 10 (04) 2045894020968023
    Search in Google Scholar
  • 132 Weiss BM, Zemp L, Seifert B, Hess OM. Outcome of pulmonary vascular disease in pregnancy: a systematic overview from 1978 through 1996. J Am Coll Cardiol 1998; 31 (07) 1650-1657
    CrossrefPubMedSearch in Google Scholar
  • 133 Jha N, Jha AK, Mishra SK, Sagili H. Pulmonary hypertension and pregnancy outcomes: systematic review and meta-analysis. Eur J Obstet Gynecol Reprod Biol 2020; 253: 108-116
    CrossrefPubMedSearch in Google Scholar
  • 134 Sliwa K, van Hagen IM, Budts W. et al; ROPAC Investigators. Pulmonary hypertension and pregnancy outcomes: data from the Registry Of Pregnancy and Cardiac Disease (ROPAC) of the European Society of Cardiology. Eur J Heart Fail 2016; 18 (09) 1119-1128
    CrossrefPubMedSearch in Google Scholar
  • 135 Duarte AG, Thomas S, Safdar Z. et al. Management of pulmonary arterial hypertension during pregnancy: a retrospective, multicenter experience. Chest 2013; 143 (05) 1330-1336
    CrossrefPubMedSearch in Google Scholar
  • 136 Jaïs X, Olsson KM, Barbera JA. et al. Pregnancy outcomes in pulmonary arterial hypertension in the modern management era. Eur Respir J 2012; 40 (04) 881-885
    CrossrefPubMedSearch in Google Scholar
  • 137 Kiely DG, Condliffe R, Webster V. et al. Improved survival in pregnancy and pulmonary hypertension using a multiprofessional approach. BJOG 2010; 117 (05) 565-574
    CrossrefPubMedSearch in Google Scholar
  • 138 Luo J, Shi H, Xu L, Su W, Li J. Pregnancy outcomes in patients with pulmonary arterial hypertension: a retrospective study. Medicine (Baltimore) 2020; 99 (23) e20285
    CrossrefPubMedSearch in Google Scholar
  • 139 Bédard E, Dimopoulos K, Gatzoulis MA. Has there been any progress made on pregnancy outcomes among women with pulmonary arterial hypertension?. Eur Heart J 2009; 30 (03) 256-265
    CrossrefPubMedSearch in Google Scholar
  • 140 Hemnes AR, Kiely DG, Cockrill BA. et al. Statement on pregnancy in pulmonary hypertension from the Pulmonary Vascular Research Institute. Pulm Circ 2015; 5 (03) 435-465
    CrossrefPubMedSearch in Google Scholar
  • 141 Hill CC, Pickinpaugh J. Physiologic changes in pregnancy. Surg Clin North Am 2008; 88 (02) 391-401, vii
    CrossrefPubMedSearch in Google Scholar
  • 142 Muller BA, Diab KA. Pulmonary hypertension in pregnancy and its effects on the fetus. Semin Fetal Neonatal Med 2022; 27 (04) 101348
    CrossrefPubMedSearch in Google Scholar
  • 143 Corbach N, Berlier C, Lichtblau M. et al. Favorable pregnancy outcomes in women with well-controlled pulmonary arterial hypertension. Front Med (Lausanne) 2021; 8: 689764
    CrossrefPubMedSearch in Google Scholar
  • 144 Bostock S, Sheares K, Cannon J, Taboada D, Pepke-Zaba J, Toshner M. The potential effects of pregnancy in a patient with idiopathic pulmonary arterial hypertension responding to calcium channel blockade. Eur Respir J 2017; 50 (06) 1701141
    CrossrefPubMedSearch in Google Scholar
  • 145 Cheron C, McBride SA, Antigny F. et al. Sex and gender in pulmonary arterial hypertension. Eur Respir Rev 2021; 30 (162) 200330
    CrossrefPubMedSearch in Google Scholar
  • 146 Kamp JC, von Kaisenberg C, Greve S. et al. Pregnancy in pulmonary arterial hypertension: Midterm outcomes of mothers and offspring. J Heart Lung Transplant 2021; 40 (03) 229-233
    CrossrefPubMedSearch in Google Scholar
  • 147 Dunn L, Greer R, Flenady V, Kumar S. Sildenafil in pregnancy: a systematic review of maternal tolerance and obstetric and perinatal outcomes. Fetal Diagn Ther 2017; 41 (02) 81-88
    CrossrefPubMedSearch in Google Scholar
  • 148 Olsson KM, Channick R. Pregnancy in pulmonary arterial hypertension. Eur Respir Rev 2016; 25 (142) 431-437
    CrossrefPubMedSearch in Google Scholar
  • 149 Keepanasseril A, Pillai AA, Yavanasuriya J, Raj A, Satheesh S, Kundra P. Outcome of pregnancies in women with pulmonary hypertension: a single-centre experience from South India. BJOG 2019; 126 (suppl 4): 43-49
    CrossrefPubMedSearch in Google Scholar