Efficacy, safety and clinical pharmacology of macitentan in comparison to other endothelin receptor antagonists in the treatment of pulmonary arterial hypertension

Expert Opinion on Drug Safety

Volumn 13, Issue 3, 2014, Pages 391-405

  Dingemanse, Jasper ^a   Sidharta, Patricia N ^a   Maddrey, Willis C ^b   Rubin, Lewis J ^c   Mickail, Hani ^a  

^a ACTELION PHARMACEUTICALS LTD   (Switzerland)

^b UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER   (United States)

^c UNIVERSITY OF CALIFORNIA   (United States)

Author keywords

Clinical pharmacology; Drug safety; Endothelin receptor antagonists; Macitentan; Pulmonary arterial hypertension

Indexed keywords

AMBRISENTAN; AMINOTRANSFERASE; BOSENTAN; DRUG METABOLITE; LIVER ENZYME; MACITENTAN;

AMINOTRANSFERASE BLOOD LEVEL; ANEMIA; ARTICLE; CARDIOVASCULAR MORTALITY; CLINICAL PHARMACOLOGY; COMPARATIVE STUDY; DRUG EFFICACY; DRUG MECHANISM; DRUG METABOLISM; DRUG SAFETY; DRUG SCREENING; EDEMA; FLUID RETENTION; HEMOGLOBIN DETERMINATION; HUMAN; LONG TERM CARE; MORBIDITY; OUTCOME ASSESSMENT; PHASE 1 CLINICAL TRIAL (TOPIC); PHASE 2 CLINICAL TRIAL (TOPIC); PULMONARY HYPERTENSION; SIDE EFFECT;

ANIMALS; HUMANS; HYPERTENSION, PULMONARY; PYRIMIDINES; RECEPTORS, ENDOTHELIN; SULFONAMIDES;

EID: 84896696727     PISSN: 14740338     EISSN: 1744764X     Source Type: Journal    
DOI: 10.1517/14740338.2014.859674     Document Type: Article

References (108)

1. Galiè N, Hoeper MM, Humbert M, et al. Guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Respir J 2009;34:1219-63
2. Simonneau G, Robbins I, Beghetti M, et al. Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol 2009;54:S43-543
3. Channick RN, Simonneau G, Sitbon O, et al. Effects of the dual endothelinreceptor antagonist bosentan in patients with pulmonary hypertension: A randomised placebo-controlled study. Lancet 2001;358:1119-23
4. Rubin LJ, Badesch DB, Barst RJ, et al. Bosentan therapy for pulmonary arterial hypertension. N Engl J Med 2002;346:896-903
5. Galiè N, Badesch BD, Oudiz R, et al. Ambrisentan therapy for pulmonary arterial hypertension. J Am Coll Cardiol 2005;46:529-35
6. Galiè N, Olschewski H, Oudiz RJ, et al. Ambrisentan for the treatment of pulmonary arterial hypertension: Results of the ambrisentan in pulmonary arterial hypertension, randomized, double-blind, placebo-controlled, multicenter, efficacy (ARIES) study 1 and 2. Circulation 2008;117:3010-19
7. Galiè N, Ghofrani HA, Torbicki A, et al. Sildenafil citrate therapy for pulmonary arterial hypertension. N Engl J Med 2005;353:2148-57
8. Galiè N, Brundage B, Ghofrani HA, et al. Tadalafil therapy for pulmonary arterial hypertension. Circulation 2009;119:2894-903
9. Barst RJ, Oudiz RJ, Beardsworth A, et al. Tadalafil monotherapy and as addon to background bosentan in patients with pulmonary arterial hypertension. J Heart Lung Transplant 2011;30: 632-43
10. Rubin LJ, Mendoza Hood M, et al. Treatment of primary pulmonary hypertension with continuous intravenous prostacyclin (epoprostenol). Results of a randomized trial. Ann Intern Med 1990;112:485-91
11. Barst RJ, Rubin LJ, Long WA, et al. A comparison of continuous intravenous epoprostenol (prostacyclin) with conventional therapy for primary pulmonary hypertension. N Engl J Med 1996;334:296-301
12. Simonneau G, Barst RJ, Galiè N, et al. Continuous subcutaneous infusion of treprostinil, a prostacyclin analog, in patients with pulmonary arterial hypertension: A double-blind, randomized, placebo-controlled trial. Am J Respir Crit Care Med 2002; 165:800-4
13. Olschewski H, Simonneau G, Galiè N, et al. Inhaled iloprost for severe pulmonary hypertension. N Engl J Med 2002;347:322-9
14. Saji T, Ozawa Y, Ishikita T, et al. Short-term hemodynamic effect of a new oral PGI2 analogue, beraprost, in primary and secondary pulmonary hypertension. Am J Cardiol 1996;78:244-7
15. Barst RJ, Langleben D, Frost A, et al. Sitaxsentan therapy for pulmonary arterial hypertension. Am J Respir Crit Care Med 2004;169:441-7
16. European Medicines Agency. Thelin (sitaxentan) to be withdrawn due to cases of unpredictable serious liver injury [press release]. 2010
17. Galiè N, Hoeper MM, Humbert M, et al. ESC Committee for Practice Guidelines (CPG). Guidelines for the diagnosis and treatment of pulmonary hypertension: The Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS), endorsed by the International Society of Heart and Lung Transplantation (ISHLT). Eur Heart J 2009;30:2493-537
18. McLaughlin VV, Archer SL, Badesch DB, et al. ACCF/ AHA 2009 expert consensus document on pulmonary hypertension a report of the American College of Cardiology Foundation Task Force on Expert Consensus Documents and the American Heart Association developed in collaboration with the American College of Chest Physicians; American Thoracic Society, Inc.; and the Pulmonary Hypertension Association. J Am Coll Cardiol 2009;53:1573-619
19. Miyamoto S, Nagaya N, Satoh T, et al. 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;161:487-92
20. Provencher S, Chemla D, Hervé P, et al. Heart rate responses during the 6-minute walk test in pulmonary arterial hypertension. Eur Respir J 2006;27:114-20
21. Strange G, Keogh AM, Williams TJ, et al. Bosentan therapy in patients with pulmonary arterial hypertension: The relationship between improvements in 6 minute walk distance and quality of life. Respirology 2008;13:674-82
22. Humbert M, Sitbon O, Chaouat A, et al. Pulmonary arterial hypertension in France: Results from a national registry. Am J Respir Crit Care Med 2006; 173:1023-30
23. Macchia A, Marchioli R, Tognoni G, et al. Systematic review of trials using vasodilators in pulmonary arterial hypertension: Why a new approach is needed. Am Heart J 2010;159:245-57
24. Provencher S, Sitbon O, Humbert M, et al. Long-term outcome with first-line bosentan therapy in idiopathic pulmonary arterial hypertension. Eur Heart J 2006;27:589-95
25. Fritz JS, Blair C, Oudiz RJ, et al. Baseline and Follow-up 6-Min Walk Distance and Brain Natriuretic Peptide Predict 2-Year Mortality in Pulmonary Arterial Hypertension. Chest 2013;143: 315-23
26. Nickel N, Golpon H, Greer M, et al. The prognostic impact of follow-up assessments in patients with idiopathic pulmonary arterial hypertension. Eur Respir J 2012;39:589-96
27. Gabler NB, French B, Strom BL, et al. Validation of Six-Minute-Walk Distance as a surrogate endpoint in pulmonary arterial hypertension trials. Circulation 2012;126:349-56
28. Savarese G, Paolillo S, Constanso P, et al. Do changes of 6-minute walk distance predict clinical events in patients with pulmonary arterial hypertension? A meta-analysis of 22 randomized trials. J Am Coll Cardiol 2012;60:1192-201
29. Rubin LJ. The 6-minute walk test in pulmonary arterial hypertension: How far is enough? Am J Respir Crit Care Med 2012;186:396-7
30. Peacock AJ, Naeije R, Galiè N, et al. End-points and clinical trial design in pulmonary arterial hypertension: Have we made progress? Eur Respir J 2009;34: 231-42
31. Guideline on the clinical investigations on medicinal products for the treatment of pulmonary arterial hypertension. Committee for Medicinal Products for Human Use. European Medicines Agency (EMEA). 2009.Available from: Http://www.emea. europa.eu/docs/en GB/document library/ Scientific guideline/2009/12/ WC500016686.pdf [Accessed 17 July 2012]
32. Galiè N, Simonneau G, Barst RJ, et al. Clinical worsening in trials of pulmonary arterial hypertension: Results and implications. Curr Opin Pulm Med 2010;16 Suppl 1:S11-19
33. McLaughlin VV, Badesch DB, Delcroix M, et al. End points and clinical trial design in pulmonary arterial hypertension. J Am Coll Cardiol 2009;54(1 Suppl):S97-107
34. Bolli MH, Boss C, Binkert C, et al. The discovery of N-[5-(4-bromophenyl) -6-[2- [(5-bromo-2-pyrimidinyl)oxy]ethoxy]-4- pyrimidinyl]-N'-propylsulfamide (Macitentan), an orally active, potent, dual endothelin receptor antagonist. J Med Chem 2012;55:7849-61
35. Cardillo C, Kilcoyne CM, Waclawiw M, et al. Role of endothelin in the increased vascular tone of patients with essential hypertension. Hypertension 1999;33: 753-8
36. Sauvageau S, Thorin E, Caron A, Dupuis J. Evaluation of endothelin-1-induced pulmonary vasoconstriction following myocardial infarction. Exp Biol Med 2006;231: 840-6
37. Dupuis J. Endothelin: Setting the scene in PAH. Eur Respir Rev 2007;16:3-7
38. Iglarz M, Clozel M. Mechanisms of ET-1-induced endothelial dysfunction. J Cardiovasc Pharmacol 2007;50:621-8
39. 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;327:736-45
40. Iglarz M, Clozel M. At the heart of tissue: Endothelin system and end-organ damage. Clin Sci 2010;119:453-63
41. Gatfield J, Grandjean CM, Sasse T, et al. Slow receptor dissociation kinetics differentiate macitentan from other endothelin receptor antagonists in pulmonary arterial smooth muscle cells. PLoS One 2012;7(10):e47662
42. Raja SG. Macitentan, a tissue-targeting endothelin receptor antagonist for the potential oral treatment of pulmonary arterial hypertension and idiopathic pulmonary fibrosis. Curr Opin Investig Drugs 2010;11:1066-73
43. Iglarz M, Rey M, Hess P, et al. Superior in vivo efficacy of macitentan: Comparison to other endothelin receptor antagonists. Eur Respir J 2012; 40(Suppl 56):717s 44. Available from: Http://trials.actelion.com/ asp/Trial-Registry/ RStudyInfo.asp? ST=AC-055-201
44. Barst RJ. Is it possible to reverse the endothelial dysfunction in pulmonary arterial hypertension? J Am Coll Cardiol 2007;49:1572-4
45. Pulido T, Adzerikho I, Channick R, et al. Macitentan and morbidity and mortality in pulmonary arterial hypertension. New Engl J Med 2013;369:809-18
46. Channick RN, Delcroix M, Galiè N, et al. Macitentan reduces PAH-related hospitalizations: Results from the randomized controlled SERAPHIN trial. Am J Respir Crit Care Med 2013;187: A3527
47. Mehta S, Channick RN, Delcroix M, et al. Macitentan improves health-related quality of life in pulmonary arterial hypertension: Results from the randomized controlled SERAPHIN trial. Am J Respir Crit Care Med 2013;187:A3269
48. Galiè N, Channick RN, Delcroix M, et al. Sustained effect of macitentan, a novel oral endothelin receptor antagonist, on exercise capacity and the association of its measure with long-term outcomes in pulmonary arterial hypertension. Eur Heart J 2013;34(Suppl):186
49. Abman SH. Role of endothelin receptor antagonists in the treatment of pulmonary arterial hypertension. Annu Rev Med 2009;60:13-23
50. O'Callaghan DS, Savale L, Yaici A, et al. Endothelin receptor antagonists for the treatment of pulmonary arterial hypertension. Exp Opin Pharmacother 2011;12:1585-96
51. Fattinger K, Funk C, Pantze M, et al. The endothelin antagonist bosentan inhibits the canalicular bile salt export pump: A potential mechanism for hepatic adverse reactions. Clin Pharmcol Ther 2001;69:223-31
52. Hartman JC, Brouwer K, Mandagere A, et al. Evaluation of the endothelin receptor antagonists ambrisentan, darusentan, bosentan, and sitaxsentan as substrates and inhibitors of hepatobiliary transporters in sandwich-cultured human hepatocytes. Can J Physiol Pharmacol 2010;88:682-91
53. Raghu G, Million-Rousseau R, Morganti A, et al. Macitentan for the treatment of idiopathic pulmonary fibrosis: The randomised controlled MUSIC trial. Eur Respir J 2013;doi:10.1183/09031936.00104612
54. Pratt DS, Kaplan M. Cirrhosis and its complications: Cardiac cirrhosis. In: Fauci AS, Braunwald E, Kasper DL, Hauser SL, Longo DL, Jameson JL, Loscaizo J, editors. Harrison's principles of internal medicine, 17e. Part 14: Disorders of the gastrointestinal system; section 2: Liver and biliary tract disease; Chapter 302. McGraw-Hill, New York, 2011. Available from: Http://www. accessmedicine.com/ [Accessed 13 September 2012]
55. Weisberg IS, Jacobson IM. Cardiovascular diseases and the liver. Clin Liver Dis 2011;15:1-20
56. Myers RP, Cerini R, Sayegh R, et al. Cardiac hepatopathy: Clinical, hemodynamic, and histologic characteristics and correlations. Hepatology 2003;37:393-400
57. Catez E, Ngoc ET, Decoodt P. Fulminant hepatic necrosis resulting from heart failure. Acta Cardiol 2009;64:95-7
58. Dumitru I, Baker M. Heart Failure. eMedicine Specialties. Updated. 2010.Available from: Http://emedicine. medscape.com/article/163062-overview [Accessed 13 September 2012]
59. Takeda Y, Takeda Y, Tomimoto S, et al. Bilirubin as a prognostic marker in patients with pulmonary arterial hypertension. BMC Pulm Med 2010;10:22
60. Abbott S, Fagan-Smith E, Coyne T. Background incidence of elevated aminotransferases in Pulmonary Arterial Hypertension: Results from 4 placebo controlled clinical trials. ATS International Conference abstract; San Diego, CA; 2006
61. Humbert M, Segal ES, Kiely DG, et al. Results of European postmarketing surveillance of bosentan in pulmonary hypertension. Eur Respir J 2007;30:338-44
62. Abraham S, Begum S, Isenberg D. Hepatic manifestations of autoimmune rheumatic diseases. Ann Rheum Dis 2004;63:123-9
63. Aoki S, Tada Y, Ohta A, et al. Autoimmune hepatitis associated with mixed connective tissue disease: Report of a case and a review of the literature. Nihon Rinsho Meneki Gakkai Kaishi 2001;24:75-80
64. Marie I, Levesque H, Tranvouez JL, et al. Autoimmune hepatitis and systemic sclerosis: A new overlap syndrome? Rheumatology (Oxford) 2001;40:102-6
65. Min JK, Han NI, Kim JA, et al. A case of cholestatic autoimmune hepatitis and acute hepatic failure: An unusual hepatic manifestation of mixed connective tissue disease and Sj€ogren's syndrome. J Korean Med Sci 2001;16:512-15
66. Tomsic M, Ferlan-Marolt V, Kveder T, et al. Mixed connective tissue disease associated with autoimmune hepatitis and thyroiditis. Ann Rheum Dis 1992; 51:544
67. Matsumoto T, Kobayashi S, Shimizu H, et al. The liver in collagen diseases: Pathologic study of 160 cases with particular reference to hepatic arteritis, primary biliary cirrhosis, autoimmune hepatitis and nodular regenerative hyperplasia of the liver. Liver 2000;20:366-73
68. Youssef WI, Tavill AS. Connective tissue diseases and the liver. J Clin Gastroenterol 2002;35:345-9
69. Krawitt EL. Autoimmune hepatitis. N Engl J Med 2006;354:54-66
70. [Ambrisentan Med Rev Part 2] U.S. Food and Drug Administration, CDER, Division of Cardio-Renal Products. Medical Review of Ambrisentan (Letairis), NDA 22-081. 2007.Available from: Http://www. accessdata.fda.gov/drugsatfda-docs/ nda/ 2007/022081s000TOC.cfm [Accessed 28 August 2013]
71. Letairis, USPI. Available from: Www. accessdata.fda.gov/drugsatfdadocs/ label/ ./022081s008ubl.pdf 73. Tracleer, USPI. Available from: Www. accessdata.fda.gov/drugsatfdadocs/label/ ./021290s012ubl.pdf
72. Vercauteren M, Strasser D, Vezzali E, et al. Vasopressin is involved in endothelin receptor antagonist-induced fluid retention in rat. Differential effect of selective ETA and dual ETA/ETB receptor antagonists. Eur Respir J 2012; 40(Suppl 56):716s
73. Shapiro S, Pollock DM, Gillies H, et al. Frequency of edema in patients with pulmonary arterial hypertension receiving ambrisentan. Am J Cardiol 2012. Available from: Http://dx.doi.org/10.1016/j. amjcard.2012.06.040
74. Available from: Http://www.medicines. org.uk/emc/history/20848/SPC/ Volibris
75. Hu L, Wang W, Dinkins A, et al. Effects of endothelin receptor antagonists and tadalafil on plasma volume expansion in normal salt fed Dahl S rats. Am Thorac Soc 2012;A1904
76. Sidharta PN, van Giersbergen PL, Halabi A, et al. Macitentan: Entry-into-humans study with a new endothelin receptor antagonist. Eur J Clin Pharmacol 2011;67:977-84
77. Sidharta PN, van Giersbergen PL, Dingemanse J. Safety, tolerability, pharmacokinetics, and pharmacodynamics of macitentan, an endothelin receptor antagonist, in an ascending multiple-dose study in healthy subjects. J Clin Pharmacol 2013;published online 30 July 2013; doi:10.1002/jcph.152
78. Bruderer S, Marjason J, Sidharta P, Dingemanse J. Pharmacokinetics of macitentan in Caucasian and Japanese subjects: The influence of ethnicity and sex. Pharmacology 2013;91:331-8
79. Dingemanse J, van Giersbergen PLM. Clinical pharmacology of bosentan, a dual endothelin receptor antagonist. Clin Pharmacokinet 2004;43:1089-115
80. Bruderer S, Hopfgartner G, Seiberling M, et al. Absorption, distribution, metabolism, and excretion of macitentan, a dual endothelin receptor antagonist, in humans. Xenobiotica 2012;42:901-10
81. Sidharta P, Lindegger N, van Giersbergen P, et al. Single-dose pharmacokinetics, safety, and tolerability of macitentan, a new dual endothelin receptor antagonist, in subjects with mild, moderate, or severe hepatic impairment. Chest 2012;142:826A
82. Sidharta P, Lindegger N, Ulc I, et al. Single-dose pharmacokinetics, safety, and tolerability of macitentan, a new dual endothelin receptor antagonist, in subjects with severe renal function impairment. Chest 2012;142:830A
83. Bruderer S, Aanismaa P, Homery MC, et al. Effect of cyclosporine and rifampin on the pharmacokinetics of macitentan, a tissue-targeting dual endothelin receptor antagonist. AAPS J 2012;14: 68-78
84. Weiss J, Theile D, Ru?ppell MA, et al. Interaction profile of macitentan, a new non-selective endothelin-1 receptor antagonist, in vitro. Eur J Pharmacol 2013;15:168-75
85. Sidharta PN, Dietrich H, Dingemanse J. Investigation of the effect of macitentan on the pharmacokinetics and pharmacodynamics of warfarin in healthy male subjects. Br J Clin Pharmacol 2009;68:788-9
86. Walker G, Mandagere A, Dufton C, Venitz J. The pharmacokinetics and pharmacodynamics of warfarin in combination with ambrisentan in healthy volunteers. Br J Clin Pharmacol 2009;67:527-34
87. Weber C, Banken L, Birnboeck H, Schulz R. Effect of the endothelinreceptor antagonist bosentan on the pharmacokinetics and pharmacodynamics of warfarin. J Clin Pharmacol 1999;39: 847-54
88. Binet I, Wallnofer A, Weber C, et al. Renal hemodynamics and pharmacokinetics of bosentan with and without cyclosporine A. Kidney Int 2000;57:224-31
89. Spence R, Mandagere A, Richards DB, et al. Potential for pharmacokinetic interactions between ambrisentan and cyclosporine. Clin Pharmacol Ther 2010;88:513-20
90. Treiber A, Schneiter R, Hausler S, et al. Bosentan is a substrate of human OATP1B1 and OATP1B3: Inhibition of hepatic uptake as the common mechanism of its interactions with cyclosporin A, rifampicin, and sildenafil. Drug Metab Dispos 2007;35:1400-7
91. Sidharta PN, van Giersbergen PL, Wolzt M, et al. Lack of clinically relevant pharmacokinetic interactions between the dual endothelin receptor antagonist macitentan and sildenafil in healthy subjects. Am J Respir Crit Care Med 2012;185:A4802
92. Barst RJ, Gibbs JS, Ghofrani HA, et al. Updated evidence-based treatment algorithm in pulmonary arterial hypertension. J Am Coll Cardiol 2009;54(1 Suppl):S78-84
93. Galiè N, Negro L, Simonneau G. The use of combination therapy in pulmonary arterial hypertension: New developments. Eur Respir Rev 2009;18(113):148-53
94. Burgess G, Hoogkamer H, Collings L, Dingemanse J. Mutual pharmacokinetic interactions between steady-state bosentan and sildenafil. Eur J Clin Pharmacol 2008;64:43-50
95. Gruenig E, Michelakis E, Vachiery J-L, et al. Acute hemodynamic effects of single-dose sildenafil when added to established bosentan therapy in patients with pulmonary hypertension: Results of the COMPASS-1 study. J Clin Pharmacol 2009;49:1343-52
96. Spence R, Mandagere A, Dufton C, Venitz J. Pharmacokinetics and safety of ambrisentan in combination with sildenafil in healthy volunteers. J Clin Pharmacol 2008;48:1451-9
97. Atsmon J, Dingemanse J, Shaikevich D, et al. Investigation of the effects of ketoconazole on the pharmacokinetics of macitentan, a novel dual endothelin receptor antagonist, in healthy subjects. Clin Pharmacokinet 2013;52:685-92
98. van Giersbergen PLM, Halabi A, Dingemanse J. Single- and multiple-dose pharmacokinetics of bosentan and its interaction with ketoconazole. Br J Clin Pharmacol 2002;53: 589-95
99. Richards DB, Walker GA, Mandagere A, et al. Effect of ketoconazole on the pharmacokinetic profile of ambrisentan. J Clin Pharmacol 2009;49:719-24
100. Venitz J, Zack J, Gillies H, et al. Clinical pharmacokinetics and drug-drug interactions of endothelin receptor antagonists in pulmonary arterial hypertension. J Clin Pharmacol 2012;52:1784-805
101. 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;371:2093-100
102. Schermuly RT, Janssen W, Weissmann N, et al. Riociguat for the treatment of pulmonary hypertension. Expert Opin Investig Drugs 2011;20:567-76
103. Sitbon O, Morrell N. Pathways in pulmonary arterial hypertension: The future is here. Eur Respir Rev 2012;21(126):321-7
104. Yao A. Recent advances and future perpectives in therapeutic strategies for pulmonary arterial hypertension. J Cardiol 2012. Available from: Http://dx.doi.org/ 10.1016/j.jjcc.2012.08.009
105. Simonneau G, Rubin LJ, Galiè N, et al. Addition of sildenafil to long-term intravenous epoprostenol therapy in patients with pulmonary arterial hypertension: A randomized trial. Ann Intern Med 2008;149:521-30
106. 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;174:1257-63
107. McLaughlin VV, Benza RL, Rubin LJ, et al. Addition of inhaled treprostinil to oral therapy for pulmonary arterial hypertension: A randomized controlled clinical trial. J Am Coll Cardiol 2010;55:1915-22
108. Humbert M, Barst RJ, Robbins IM, et al. Combination of bosentan with epoprostenol in pulmonary arterial hypertension: BREATHE-2. Eur Respir J 2004;24:353-9