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Endothelin receptor antagonists for pulmonary arterial hypertension

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Referencias

AMBITION {published and unpublished data}

Galie N, Barbera JA, Frost AE, Ghofrani HA, Hoeper MM, McLaughlin VV, et al. Initial use of ambrisentan plus tadalafil in pulmonary arterial hypertension. New England Journal of Medicine 2015;373(9):834-44. CENTRAL [DOI: 10.1056/NEJMoa1413687]

ARIES‐1 {published data only}

Galiè N, Olschewski H, Oudiz RJ, Torres F, Frost A, Ghofrani HA, et al. Ambrisentan for the treatment of pulmonary arterial hypertension: results of the ambrisentan in pulmonary arterial hypertension, randomized, double-blind, placebo-controlled, multicenter, efficacy (ARIES) study 1 and 2. Circulation 2008;117(23):3010-9. CENTRAL
US Food and Drug Administration Center for Drug Evaluation and Research. Letairis (Ambrisentan) Tablets: Medical Review(s). www.accessdata.fda.gov/drugsatfda_docs/nda/2019/022081Orig1s039.pdf (accessed prior to 10 March 2020). CENTRAL

ARIES‐2 {published data only}

Galiè N, Olschewski H, Oudiz RJ, Torres F, Frost A, Ghofrani HA, et al. Ambrisentan for the treatment of pulmonary arterial hypertension: results of the ambrisentan in pulmonary arterial hypertension, randomized, double-blind, placebo-controlled, multicenter, efficacy (ARIES) study 1 and 2. Circulation 2008;117(23):3010-9. CENTRAL

BREATHE‐1 {published data only}

Rubin LJ, Badesch DB, Barst RJ, Galiè N, Black CM, Keogh A. Bosentan therapy for pulmonary arterial hypertension. New England Journal of Medicine 2002;346(12):896-903. CENTRAL
US Food and Drug Administration Center for Drug Evaluation and Research. Tracleer (Bosentan) Tablets: Medical Review(s). www.accessdata.fda.gov/drugsatfda_docs/nda/2001/21-290_Tracleer.cfm (accessed prior to 12 March 2020). CENTRAL

BREATHE‐2 {published data only}

Humbert M, Barst RJ, Robbins IM, Channick RN, Galiè N, Boonstra A, et al. Combination of bosentan with epoprostenol in pulmonary arterial hypertension: BREATHE-2. European Respiratory Journal 2004;24(3):353-9. CENTRAL
US Food and Drug Administration Center for Drug Evaluation and Research. Tracleer (Bosentan) Tablets: Medical Review(s). www.accessdata.fda.gov/drugsatfda_docs/nda/2001/21-290_Tracleer.cfm (accessed prior to 12 March 2020). CENTRAL

BREATHE‐5 {published data only}

Galiè N, Beghetti M, Gatzoulis MA, Granton J, Berger RM, Lauer A, et al. Bosentan therapy in patients with Eisenmenger syndrome: a multicenter, double-blind, randomized, placebo-controlled study. Circulation 2006;114(1):48-54. CENTRAL

Channick 2001 {published data only}

Badesch DB, Bodin F, Channick RN, Frost A, Rainisio M, Robbins IM, et al. Complete results of the first randomized, placebo-controlled study of bosentan, a dual endothelin receptor antagonist, in pulmonary arterial hypertension. Current Therapeutic Research, Clinical and Experimental 2002;63(4):227-46. CENTRAL
Channick RN, Simonneau G, Sitbon O, Robbins IM, Frost A, Tapson VF. Effects of the dual endothelin-receptor antagonist bosentan in patients with pulmonary hypertension: a randomised placebo-controlled study. Lancet 2001;358(9288):1119-23. CENTRAL

COMPASS‐2 {published data only}

McLaughlin V, Channick RN, Ghofrani HA, Lemarie JC, Naeije R, Packer M, et al. Bosentan added to sildenafil therapy in patients with pulmonary arterial hypertension. European Respiratory Journal 2015;46(2):405-13. CENTRAL [DOI: 10.1183/13993003.02044-2014]

EARLY {published and unpublished data}

Galiè N, Rubin L, Hoeper M, Jansa P, Al-Hiti H, Meyer G, 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):2093-100. CENTRAL

EDITA {published data only}

Pan Z, Marra AM, Benjamin N, Eichstaedt CA, Blank N, Bossone E, et al. Early treatment with ambrisentan of mildly elevated mean pulmonary arterial pressure associated with systemic sclerosis: a randomized, controlled, double-blind, parallel group study (EDITA study). Arthritis Research & Therapy 2019;21:217. CENTRAL

Galiè 2003 {published data only}

Galiè N, Hinderliter AL, Torbicki A, Fourme T, Simonneau G, Pulido T, et al. Effects of the oral endothelin-receptor antagonist bosentan on echocardiographic and doppler measures in patients with pulmonary arterial hypertension. Journal of the American College of Cardiology 2003;41(8):1380-6. CENTRAL

MAESTRO {published data only}

Gatzoulis MA, Landzberg M, Beghetti M, Berger RM, Efficace M, Gesang S, et al. Evaluation of macitentan in patients with Eisenmenger Syndrome. Circulation 2019;139(1):51-63. CENTRAL [DOI: 10.1161/CIRCULATIONAHA.118.033575]

PORTICO {published data only}

Krowka MJ, Cottreel E, De Groote P, Hoeper MM, Kim N, Martin N, et al. Efficacy and safety of macitentan in patients with portopulmonary hypertension: the randomized, placebo controlled portico trial. Hepatology. Conference 2018;Suppl 1:70A-71. CENTRAL [DOI: 10.1002/hep.30256]
Sitbon O, Bosch J, Cottreel E, Csonka D, de Groote P, Hoeper MM, et al. Macitentan for the treatment of portopulmonary hypertension (PORTICO): a multicentre, randomised, double-blind, placebo-controlled, phase 4 trial. Lancet Respiratory Medicine 2019;7:594-604. CENTRAL

SERAPH {published data only}

Wilkins MR, Paul GA, Strange JW, Tunariu N, Gin-Sing W, Banya WA, et al. Sildenafil versus endothelin receptor antagonist for pulmonary hypertension (SERAPH) study. American Journal of Respiratory and Critical Care Medicine 2005;171(11):1292-7. CENTRAL

SERAPHIN {published and unpublished data}

Pulido T, Adzerikho I, Channick RN, Delcroix M, Galie N, Ghofrani HA, et al. Macitentan and morbidity and mortality in pulmonary arterial hypertension. New England Journal of Medicine 2013;369(9):809-18. CENTRAL [DOI: 10.1056/NEJMoa1213917]

STRIDE‐1 {published and unpublished data}

Barst RJ, Langleben D, Frost E, Horn EM, Oudiz R, Shapiro S, et al. Sitaxsentan therapy for pulmonary arterial hypertension. American Journal of Respiratory and Critical Care Medicine 2004;169:441-7. CENTRAL
European Medicines Agency. EPARs for authorised medicinal products for human use: Thelin. European Public Assessment Report. www.emea.europa.eu/humandocs/PDFs/EPAR/thelin/H-679-en6.pdf (accessed 22 March 2008). CENTRAL
Therapeutic Goods Administration (TGA), Australia. Public summary documents by product: Thelin. www.health.gov.au/internet/main/publishing.nsf/Content/pbac-psd-sitaxentan-sodium-july07 (accessed 25 April 2008). CENTRAL

STRIDE‐2 {published data only}

Barst RJ, Langleben D, Badesch D, Frost A, Lawrence EC, Shapiro S, et al. Treatment of pulmonary arterial hypertension with the selective endothelin-A receptor antagonist sitaxsentan. Journal of the American College of Cardiology 2006;47(10):2049-56. CENTRAL
European Medicines Agency. EPARs for authorised medicinal products for human use: Thelin. European Public Assessment Report. www.ema.europa.eu/en/medicines/human/EPAR/thelin (accessed prior to 22 March 2020). CENTRAL
Therapeutic Goods Administration (TGA), Australia. Public summary documents by product: Thelin. www.health.gov.au/internet/main/publishing.nsf/Content/pbac-psd-sitaxentan-sodium-july07 (accessed 25 April 2008). CENTRAL

STRIDE‐4 {published data only}

European Medicines Agency. EPARs for authorised medicinal products for human use: Thelin. European Public Assessment Report. www.ema.europa.eu/en/medicines/human/EPAR/thelin (accessed 22 March 2008). CENTRAL

Ahn 2014 {published data only}

Ahn LY, Kim SE, Yi S, Dingemanse J, Lim KS, Jang IJ, et al. Pharmacokinetic-pharmacodynamic relationships of macitentan, a new endothelin receptor antagonist, after multiple dosing in healthy Korean subjects. American Journal of Cardiovascular Drugs 2014;14(5):377-85. CENTRAL

ASSET‐2 {published data only}

Barst RJ, Mubarak KK, Machado RF, Ataga KI, Benza RL, Castro O, et al. Exercise capacity and haemodynamics inpatients with sickle cell disease with pulmonary hypertension treated with bosentan: results of the ASSET studies. British Journal of Haematology 2010;149(3):426-35. CENTRAL

Atsmon 2013 {published data only}

Atsmon J, Dingemanse J, Shaikevich D, Volokhov I, Sidharta PN. Investigation of the effects of ketoconazole on the pharmacokinetics of macitentan, a novel dual endothelin receptor antagonist, in healthy subjects. Clinical Pharmacokinetics 2013;52(8):685-92. CENTRAL [DOI: 10.1007/s40262-013-0063-8]

Barst 2011 {published data only}

Barst RJ, Oudiz RJ, Beardsworth A, Brundage BH, Simonneau G, Ghofrani HA, et al. Tadalafil monotherapy and as add-on to background bosentan in patients with pulmonary arterial hypertension. Journal of Heart and Lung Transplantation 2011;30(6):632-43. CENTRAL

Baughman 2014 {published data only}

Baughman RP, Culver DA, Cordova FC, Padilla M, Gibson KF, Lower EE, et al. Bosentan for sarcoidosis-associated pulmonary hypertension: a double-blind placebo controlled randomized trial. Chest 2014;145(4):810-7. CENTRAL

Benza 2007 {published data only}

Benza RL, Mehta S, Keogh A, Lawrence EC, Oudiz RJ, Barst RJ. Sitaxsentan treatment for patients with pulmonary arterial hypertension discontinuing bosentan. Journal of Heart and Lung Transplantation 2007;26(1):63-9. CENTRAL

Bose 2011 {published data only}

Bose N, Bena J, Trunick C, Petrich J, Bork DJ, Krishnan G, et al. Evaluation of the effect of ambrisentan on digital microvascular flow in patients with systemic sclerosis using laser doppler perfusion imaging. Arthritis and Rheumatism 2011;63(10 Suppl 1):S276-7. CENTRAL

Bruderer 2014 {published data only}

Bruderer S, Hurst N, Kaufmann P, Dingemanse J. Multiple-dose up-titration study to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of selexipag, an orally available selective prostacyclin receptor agonist, in healthy subjects. Pharmacology 2014;94(3-4):148-56. CENTRAL

BUILD‐2 {unpublished data only}NCT00070590

NCT00070590. Efficacy and safety of oral bosentan in pulmonary fibrosis associated with scleroderma. clinicaltrials.gov/ct2/show/NCT00070590 (first received 8 October 2003). CENTRAL

Burgess 2008 {published data only}

Burgess G, Hoogkamer H, Collings L, Dingemanse J. Mutual pharmacokinetic interactions between steady-state bosentan and sildenafil. European Journal of Clinical Pharmacology 2008;64(1):43-50. CENTRAL

Cardenas 2020 {published data only}

Cardenas KPC, Velazquez JER, Escobar JJO, Chirinos J, Pendela M. Bioequivalence and tolerability of ambrisentan: a pharmacokinetic study in Mexican healthy male subjects. European Journal of Drug Metabolism and Pharmacokinetics 2020;45:611-8. CENTRAL

Chin 2020 {published data only}

Chin KM, Sitbon O, Doelberg M, Gibbs JSR, Hoeper MM, Martin N, et al. Efficacy and safety of initial triple oral versus initial double oral combination therapy in patients with newly diagnosed pulmonary arterial hypertension (PAH): results of the randomized controlled triton study. American Journal of Respiratory and Critical Care Medicine 2020;201:A2928. CENTRAL

Coyne 2005 {published data only}

Coyne TC, Garces PC, Kramer W. No clinical interaction between sitaxsentan and sildenafil. In: American Thoracic Society 2005 International Conference, 2005 May 20-25; San Diego (CA). 2005. CENTRAL [[A57] [Poster: K70]]

Danaietash 2019 {published data only}

Danaietash P, Verweij P, Flamion B, Menard J, Bellet M. Efficacy and safety of various doses of the new dual endothelin receptor antagonist aprocitentan in the treatment of hypertension. European Heart Journal 2019;40(Suppl 1):ehz747.0004. CENTRAL

Denault 2013 {published data only}

Denault AY, Pearl RG, Michler RE, Rao V, Tsui SS, Seitelberger R, et al. Tezosentan and right ventricular failure in patients with pulmonary hypertension undergoing cardiac surgery: the TACTICS trial. Journal of Cardiothoracic and Vascular Anesthesia 2013;27(6):1212-7. CENTRAL

Dhaun 2011 {published data only}

Dhaun N, Johnston NR, Goddard J, Webb DJ. Chronic selective endothelin a receptor antagonism reduces serum uric acid in hypertensive chronic kidney disease. Hypertension 2011;58(2):e11-2. CENTRAL

Escribano‐Subias 2019 {published data only}

Escribano-Subias P, Bendjenana H, Curtis PS, Lang I, Vonk Noordegraaf A. Ambrisentan for treatment of inoperable chronic thromboembolic pulmonary hypertension (CTEPH). Pulmonary Circulation 2019;9(2):2045894019846433. CENTRAL [DOI: 10.1177/2045894019846433]

Faoro 2009 {published data only}

Faoro V, Boldingh S, Moreels M, Martinez S, Lamotte M, Unger P, et al. Bosentan decreases pulmonary vascular resistance and improves exercise capacity in acute hypoxia. Chest 2009;135(5):1215-22. CENTRAL

Fatima 2018 {published data only}

Fatima N, Arshad S, Quddusi AI, Rehman A, Nadeem A, Iqbal I. Comparison of the efficacy of sildenafil alone versus sildenafil plus bosentan in newborns with persistent pulmonary hypertension. Journal of Ayub Medical College, Abbottabad 2018;30(3):333-6. CENTRAL

Frey 2008 {published data only}

Frey R, Muck W, Unger S, Artmeier-Brandt U, Weimann G, Wensing G. Single-dose pharmacokinetics, pharmacodynamics, tolerability, and safety of the soluble guanylate cyclase stimulator BAY 63-2521: an ascending-dose study in healthy male volunteers. Journal of Clinical Pharmacology 2008;48(8):926-34. CENTRAL

Galiè 2005 {published data only}

Galiè N, Badesch D, Oudiz R, Simonneau G, McGoon MD, Keogh AM, et al. Ambrisentan therapy for pulmonary arterial hypertension. Journal of the American College of Cardiology 2005;46(3):529-35. CENTRAL

Galiè 2009a {published data only}

Galiè N, Brundage BH, Ghofrani HA, Oudiz RJ, Simonneau G, Safdar Z, et al. Tadalafil therapy for pulmonary arterial hypertension. Circulation 2009;119(22):2894-903. CENTRAL

Galiè 2009b {published data only}

Galiè N, Naeije R, Burgess G, Dilleen M. 3-year survival of patients treated with sitaxentan sodium (Thelin) for pulmonary arterial hypertension. European Heart Journal 2009;Abstract Supplement:262. CENTRAL

Galiè 2010 {published data only}

Galiè N, Badesch D, Fleming T, Simonneau G, Rubin L, Ewert R, et al. Effects of inhaled aviptadil (vasoactive intestinal peptide) in patients with pulmonary arterial hypertension (PAH): results from a phase II study. European Heart Journal 2010;3122(Suppl 1):22, 347. CENTRAL

Ghofrani 2010 {published data only}

Ghofrani HA, Morrell NW, Hoeper MM, Olschewski H, Peacock A, Barst RJ, et al. Long term use of imatinib In patients with severe pulmonary arterial hypertension [Abstract]. American Journal of Respiratory and Critical Care Medicine 2010;181:A2513. CENTRAL

Ghofrani 2017 {published data only}

Ghofrani HA, Simonneau G, D'Armini AM, Fedullo P, Howard LS, Jais X, et al. Macitentan for the treatment of inoperable chronic thromboembolic pulmonary hypertension (MERIT-1): results from the multicentre, phase 2, randomised, double-blind, placebo-controlled study. Lancet Respiratory Medicine 2017;5(10):785-94. CENTRAL

Gillies 2011 {published data only}

Gillies HC, Wang X, Staehr P, Zack J. PAH therapy in HIV: lack of drug-drug interaction between ambrisentan and ritonavir. American Journal of Respiratory and Critical Care Medicine 2011;183:A5913. CENTRAL

Gillies 2013 {published data only}

Gillies H, Henig N, Pederson P, Shao L, Chien J, O'Riordan T, et al. A placebo-controlled study of ambrisentan in subjects with idiopathic pulmonary fibrosis (ARTEMIS-IPF). Life Sciences 2013;93(25-6):e59. CENTRAL

Givertz 2000 {published data only}

Givertz MM, Colucci WS, LeJemtel TH, Gottlieb SS, Hare JM, Slawsky MT, et al. Acute endothelin A receptor blockade causes selective pulmonary vasodilation in patients with chronic heart failure. Circulation 2000;101(25):2922-7. CENTRAL

Gomberg‐Maitland 2005 {published data only}

Gomberg-Maitland M, McLaughlin V, Gulati M, Rich S, Arbor A. Efficacy and safety of sildenafil and atorvastatin added to bosentan as therapy for pulmonary arterial hypertension. In: American Thoracic Society 2005 International Conference; 2005 May 20-25; San Diego (CA). 2005. CENTRAL [[A57] [Poster: K18]]

Gotti 2014 {published data only}

Gotti E, Manes A, Palazzini M, Bernabe C, Bachetti C, Conficoni E, et al. A randomized open label study comparing first-line treatment with bosentan or sildenafil in chronic thromboembolic pulmonary hypertension (CTEPH). European Heart Journal 2014;35:208. CENTRAL

Gotzkowsky 2010 {published data only}

Gotzkowsky SK, Dingemanse J, Lai A, Mottola D, Laliberte K. Lack of a pharmacokinetic interaction between oral treprostinil and bosentan in healthy adult volunteers. Journal of Clinical Pharmacology 2010;50(7):829-34. CENTRAL

Grander 2014 {published data only}

Grander W, Koller K, Steringer-Mascherbauer R, Ebner CH. Endothelin receptor blockade in heart failure with diastolic dysfunction and pulmonary hypertension. European Heart Journal 2014;35:692. CENTRAL

Grill 2020 {published data only}

Grill S, Bruderer S, Sidharta PN, Antonova M, Globig S, Carlson J, et al. Bioequivalence of macitentan and tadalafil given as fixed-dose combination or single-component tablets in healthy subjects. British Journal of Clinical Pharmacology 2020;86(12):2424-34. CENTRAL

Gutierrez 2013 {published data only}

Gutierrez MM, Nicolas LB, Donazzolo Y, Dingemanse J. Relative bioavailability of a newly developed pediatric formulation of bosentan vs. the adult formulation. International Journal of Clinical Pharmacology and Therapeutics 2013;51(6):529-36. CENTRAL

Han 2017 {published data only}

Han X, Zhang Y, Dong L, Fang L, Chai Y, Niu M, et al. Treatment of pulmonary arterial hypertension using initial combination therapy of bosentan and iloprost. Respiratory Care 2017;62(4):489-96. CENTRAL [DOI: 10.4187/respcare.05280]

Hill 2018 {published data only}

Hill KD, Maharaj A, Thompson E, Li JS, Pearson E, Hornik C. A double blind, randomized, controlled pharmacokinetic and pharmacodynamics trial of ambrisentan after Fontan surgery. Circulation 2018;138:A14968. CENTRAL

Hoeper 2006 {published data only}

Hoeper MM, Leuchte H, Halank M, Wilkens H, Meyer FJ, Seyfarth HJ, et al. Combining inhaled iloprost with bosentan in patients with idiopathic pulmonary arterial hypertension. European Respiratory Journal 2006;28(4):691-4. CENTRAL

Howard 2019 {published data only}

Howard LS, Ghofrani HA, D'Armini AM, Fedullo P, Gesang S, Jais X, et al. Long-term safety, tolerability and efficacy of macitentan in patients with inoperable chronic thromboembolic pulmonary hypertension: the merit-1 study and its open-label extension merit-2. In: American Journal of Respiratory and Critical Care Medicine. Vol. 201. 2019:A6068. CENTRAL

Huez 2009 {published data only}

Huez S, Faoro V, Moreels M, Bastin R, Retailleau K, Lamotte M, et al. Role of pulmonary hypertension and right ventricular dysfunction in aerobic exercise capacity limitation in normal volunteers at high altitude. Acta Cardiologica 2009;64(1):114. CENTRAL

Hurst 2016 {published data only}

Hurst N, Pellek M, Dingemanse J, Sidharta PN. Lack of pharmacokinetic interactions between macitentan and a combined oral contraceptive in healthy female subjects. American College of Clinical Pharmacology 2016;56(6):669-74. CENTRAL

Iversen 2010 {published data only}

Iversen K, Jensen AS, Jensen TV, Vejlstrup NG, Sondergaard L. Combination therapy with bosentan and sildenafil in Eisenmenger syndrome: a randomized, placebo-controlled, double-blinded trial. European Heart Journal 2010;31(9):1124-31. CENTRAL

Jais 2008 {published data only}

Jais X, D'Armini AM, Jansa P, Torbicki A, Delcroix M, Ghofrani HA, et al. Bosentan for treatment of inoperable chronic thromboembolic pulmonary hypertension: BENEFiT (Bosentan Effects in iNopErable Forms of chronIc Thromboembolic pulmonary hypertension), a randomized, placebo-controlled trial. Journal of the American College of Cardiology 2008;52(25):2127-34. CENTRAL

Kalra 2002 {published data only}

Kalra PR, Moon JC, Coats AJ. Do results of the ENABLE (Endothelin Antagonist Bosentan for Lowering Cardiac Events in Heart Failure) study spell the end for non-selective endothelin antagonism in heart failure? International Journal of Cardiology 2002;85(2-3):195-7. CENTRAL

Kaluski 2008 {published data only}

Kaluski E, Cotter G, Leitman M, Milo-Cotter O, Krakover R, Kobrin I, et al. Clinical and hemodynamic effects of bosentan dose optimization in symptomatic heart failure patients with severe systolic dysfunction, associated with secondary pulmonary hypertension - a multi-center randomized study. Cardiology 2008;109(4):273-80. CENTRAL

Kefford 2010 {published data only}

Kefford RF, Clingan PR, Brady B, Ballmer A, Morganti A, Hersey P. A randomized, double-blind, placebo-controlled study of high-dose bosentan in patients with stage IV metastatic melanoma receiving first-line dacarbazine chemotherapy. Molecular Cancer 2010;9:69. CENTRAL

Keir 2013 {published data only}

Keir G, Corte T, Parfitt L, Maher T, Marino P, Renzoni E, et al. Bosentan in pulmonary hypertension associated with fibrotic idiopathic interstitial pneumonia: a randomized, double-blind, placebo-controlled study. European Respiratory Journal 2013;42:1179. CENTRAL

Keir 2014 {published data only}

Keir G, Corte T, Dimopoulos K, Gatzoulis M, Marino P, Renzoni E, et al. Non-invasive haemodynamic measurement to detect treatment response in pulmonary hypertension associated with fibrotic idiopathic interstitial pneumonia [Abstract]. European Respiratory Journal 2014;44(Suppl 58):P2335. CENTRAL

King 2008 {published data only}

King TE Jr, Behr J, Brown KK, du Bois RM, Lancaster L, de Andrade JA, et al. BUILD-1: a randomized placebo-controlled trial of bosentan in idiopathic pulmonary fibrosis. American Journal of Respiratory and Critical Care Medicine 2008;177(1):75-81. CENTRAL

Kiowski 1995 {published data only}

Kiowski W, Sutsch G, Hunziker P, Muller P, Kim J, Oechslin E, et al. Evidence for endothelin-1-mediated vasoconstriction in severe chronic heart failure. Lancet 1995;346(8977):732-6. CENTRAL

Koller 2017 {published data only}

Koller B, Steringer-Mascherbauer R, Ebner CH, Weber T, Ammer M, Eichinger J, et al. Pilot study of endothelin receptor blockade in heart failure with diastolic dysfunction and pulmonary hypertension (BADDHY-Trial). Heart, Lung and Circulation 2017;26(5):433-41. CENTRAL

Korn 2004 {published data only}

Korn JH, Mayes M, Matucci CM, Rainisio M, Pope J, Hachulla E, et al. Digital ulcers in systemic sclerosis: prevention by treatment with bosentan, an oral endothelin receptor antagonist. Arthritis and Rheumatism 2004;50(12):3985-93. CENTRAL

Lee 2009 {published data only}

Lee TM, Chen CC, Shen HN, Chang NC. Effects of pravastatin on functional capacity in patients with chronic obstructive pulmonary disease and pulmonary hypertension. Clinical Science 2009;116(6):497-505. CENTRAL

Lindegger 2014 {published data only}

Lindegger N, Sidharta PN, Reseski K, Dingemanse J. Macitentan, a dual endothelin receptor antagonist for the treatment of pulmonary arterial hypertension, does not affect cardiac repolarization in healthy subjects. Pulmonary Pharmacology and Therapeutics 2014;29(1):41-8. CENTRAL

Mazzanti 2013 {published data only}

Mazzanti G, Palazzini M, Leci E, Dardi F, Rinaldi A, D'Adamo A, et al. A randomized open label study comparing first-line treatment with bosentan or sildenafil in pulmonary arterial hypertension (PAH): long-term results. American Journal of Respiratory and Critical Care Medicine 2013;187:A3535. CENTRAL

McLaughlin 2003 {published data only}

McLaughlin VV, Gaine SP, Barst RJ, Oudiz RJ, Bourge RC, Frost A, et al. Efficacy and safety of treprostinil: an epoprostenol analog for primary pulmonary hypertension. Journal of Cardiovascular Pharmacology 2003;41(2):293-9. CENTRAL

McLaughlin 2006 {published data only}

McLaughlin VV, Oudiz RJ, Frost A, Tapson VF, Murali S, Channick RN, et al. Randomized study of adding inhaled iloprost to existing bosentan in pulmonary arterial hypertension. American Journal of Respiratory and Critical Care Medicine 2006;174(11):1257-63. CENTRAL

McLaughlin 2010 {published data only}

McLaughlin VV, Benza RL, Rubin LJ, Channick RN, Voswinckel R, Tapson VF, et al. Addition of inhaled treprostinil to oral therapy for pulmonary arterial hypertension: a randomized controlled clinical trial. Journal of the American College of Cardiology 2010;55(18):1915-22. CENTRAL

Mereles 2006 {published data only}

Mereles D, Ehlken N, Kreuscher S, Ghofrani S, Hoeper MM, Halank M, et al. Exercise and respiratory training improve exercise capacity and quality of life in patients with severe chronic pulmonary hypertension. Circulation 2006;114(14):1482-9. CENTRAL

Metersky 2011 {published data only}

Metersky M, Coyle T. The effect of the ET-1 receptor antagonist, bosentan, on patients with poorly controlled asthma: a 17 week, double-blind, placebo-controlled crossover pilot study. Chest 2011;140(4):919A. CENTRAL

Modesti 2006 {published data only}

Modesti PA, Vanni S, Morabito M, Modesti A, Marchetta M, Gamberi T, et al. Role of endothelin-1 in exposure to high altitude: Acute Mountain Sickness and Endothelin-1 (ACME-1) study. Circulation 2006;114(13):1410-6. CENTRAL

Naeije 2010 {published data only}

Naeije R, Huez S, Lamotte M, Retailleau K, Neupane S, Abramowicz D, et al. Pulmonary artery pressure limits exercise capacity at high altitude. European Respiratory Journal 2010;36(5):1049-55. CENTRAL

Nakahara 2010 {published data only}

Nakahara N, Wakamatsu A, Shimamura R, Nohda S, Miki S, Hirama T. Pharmacokinetics of ambrisentan, a novel drug for treatment of Pulmonary Arterial Hypertension (PAH), in Japanese subjects. Japanese Journal of Clinical Pharmacology and Therapeutics 2010;41(6):301-8. CENTRAL

NCT00077584 {unpublished data only}NCT00077584

NCT00077584. Efficacy and safety of oral bosentan on healing/prevention of digital (finger) ulcers in patients with scleroderma patients (RAPIDS-2) [A randomized, double-blind, placebo-controlled, multi-center study to assess the effect of bosentan on healing and prevention of ischemic digital ulcers in patients with systemic sclerosis]. clinicaltrials.gov/ct2/show/NCT00077584 (first received 11 February 2004). CENTRAL

Okour 2019 {published data only}

Okour M, Puri A, Chen G, Port K, Berni A, Khindri S, et al. A phase I study to show the relative bioavailability and bioequivalence of fixed-dose combinations of ambrisentan and tadalafil in healthy subjects. Clinical Therapeutics 2019;41:1110-27. CENTRAL

Oudiz 2007 {published data only}

Oudiz RJ. Long-term ambrisentan therapy provides sustained benefit in patients with pulmonary arterial hypertension. Chest 2007;132(4):474a. CENTRAL

Oudiz 2009 {published data only}

Oudiz RJ, Galiè N, Olschewski H, Torres F, Frost A, Ghofrani HA, et al. Long-term ambrisentan therapy for the treatment of pulmonary arterial hypertension. Journal of the American College of Cardiology 2009;54(21):1971-81. CENTRAL

Palazzini 2010 {published data only}

Palazzini M, Mazzanti G, Gotti E, Bulatovic I, Manes A, Marinelli A, et al. A randomized open label study comparing bosentan to sildenafil first-line treatment in pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension [Abstract]. American Journal of Respiratory and Critical Care Medicine 2010;181(Meeting Abstracts):A3357. CENTRAL

Raghu 2013 {published data only}

Raghu G, Behr J, Brown KK, Egan JJ, Kawut SM, Flaherty KR, et al. Treatment of idiopathic pulmonary fibrosis with ambrisentan: a parallel, randomized trial. Annals of Internal Medicine 2013;158(9):641-9. CENTRAL

Raghu 2015 {published data only}

Raghu G, Nathan SD, Behr J, Brown KK, Egan JJ, Kawut SM, et al. Pulmonary hypertension in idiopathic pulmonary fibrosis with mild-to-moderate restriction. European Respiratory Journal 2015;46(5):1370-7. CENTRAL

Reesink 2010 {published data only}

Reesink HJ, Surie S, Kloek JJ, Tan HL, Tepaske R, Fedullo PF, et al. Bosentan as a bridge to pulmonary endarterectomy for chronic thromboembolic pulmonary hypertension. Journal of Thoracic and Cardiovascular Surgery 2010;139(1):85-91. CENTRAL

Robbins 2006 {published data only}

Robbins IM, Kawut SM, Yung D, Reilly MP, Lloyd W, Cunningham G, et al. A study of aspirin and clopidogrel in idiopathic pulmonary arterial hypertension. European Respiratory Journal 2006;27(3):578-84. CENTRAL

Schmetterer 1998 {published data only}

Schmetterer L, Dallinger S, Bobr B, Selenko N, Eichler H-G, Wolzt M. Systemic and renal effects of an ET(A) receptor subtype-specific antagonist in healthy subjects. British Journal of Pharmacology 1998;124(5):930-4. CENTRAL

Schmidt 2001 {published data only}

Schmidt A, Bayerle-Eder M, Pleiner H, Zeisner C, Wolzt M, Mayer G, et al. The renal and systemic hemodynamic effects of a nitric oxide-synthase inhibitor are reversed by a selective endothelin A receptor antagonist in men. Nitric Oxide 2001;5(4):370-6. CENTRAL

Schuuring 2013 {published data only}

Schuuring MJ, Vis JC, van Dijk AP, van Melle JP, Vliegen HW, Pieper PG, et al. Impact of bosentan on exercise capacity in adults after the Fontan procedure: a randomized controlled trial. European Journal of Heart Failure 2013;15(6):690-8. CENTRAL

Seheult 2009 {published data only}

Seheult RD, Ruh K, Foster GP, Anholm JD. Prophylactic bosentan does not improve exercise capacity or lower pulmonary artery systolic pressure at high altitude. Respiratory Physiology and Neurobiology 2009;165(2-3):123-30. CENTRAL

Seibold 2010 {published data only}

Seibold JR, Denton CP, Furst DE, Guillevin L, Rubin LJ, Wells A, et al. Randomized, prospective, placebo-controlled trial of bosentan in interstitial lung disease secondary to systemic sclerosis. Arthritis and Rheumatism 2010;62(7):2101-8. CENTRAL

Sfikakis 2007 {published data only}

Sfikakis PP, Papamichael C, Stamatelopoulos KS, Tousoulis D, Fragiadaki KG, Katsichti P, et al. Improvement of vascular endothelial function using the oral endothelin receptor antagonist bosentan in patients with systemic sclerosis. Arthritis and Rheumatism 2007;56(6):1985-93. CENTRAL

Shang 2013 {published data only}

Shang XK, Li YP, Liu M, Zhou HM, Peng T, Deng XX, et al. Efficacy of endothelin receptor antagonist bosentan on the long-term prognosis in patients after Fontan operation. Zhonghua Xin Xue Guan Bing Za Zhi 2013;41(12):1025-8. CENTRAL

Shang 2016 {published data only}

Shang XK, Lu R, Zhang X, Zhang CD, Xiao SN, Liu M, et al. Efficacy of bosentan in patients after fontan procedures: a double-blind, randomized controlled trial. Journal of Huazhong University of Science and Technology [Medical Sciences] 2016;36(4):534-40. CENTRAL

Sharma 2014 {published data only}

Sharma SK, Ajmani S, Sharma A, Singh S, Sinha S, Vishnubhatla S, et al. Comparison of efficacy of different treatment regimens in pulmonary hypertension secondary to lung disease and/or hypoxia [Abstract]. American Journal of Respiratory and Critical Care Medicine 2014;189:A1892. CENTRAL

Shenoy 2011 {published data only}

Shenoy PD, Agarwal V. Tadalafil: a new role in Raynaud's phenomenon? International Journal of Clinical Rheumatology 2011;6(2):115-7. CENTRAL

Sidharta 2010 {published data only}

Sidharta PN, Atsmon J, Dingemanse J. Investigation of the effect of ketoconazole on the pharmacokinetics of macitentan in healthy male subjects. British Journal of Clinical Pharmacology 2010;70(6):930-1. CENTRAL

Sidharta 2013a {published data only}

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. Journal of Clinical Pharmacology 2013;53(11):1131-8. CENTRAL

Sidharta 2013b {published data only}

Sidharta PN, Lindegger N, Reseski K, Dingemanse J. Macitentan, a novel dual endothelin receptor antagonist, does not prolong the QT/QTC interval in a thorough QTC study in healthy subjects. Clinical Pharmacology and Therapeutics 2013;93(Suppl 1):S108-9. CENTRAL

Sidharta 2014 {published data only}

Sidharta PN, Dietrich H, Dingemanse J. Investigation of the effect of macitentan on the pharmacokinetics and pharmacodynamics of warfarin in healthy male subjects. Clinical Drug Investigation 2014;34(8):545-52. CENTRAL

Simonneau 2010 {published data only}

Simonneau G, Lang I, Torbicki A, Hoeper MM, Delcroix M, Karlocai K, et al. Efficacy, safety and tolerability of ACT-293987, a novel oral, non-prostanoid, prostaglandin I2 (IP) receptor agonist: results from a phase IIa study in pulmonary arterial hypertension (PAH). American Journal of Respiratory and Critical Care Medicine 2010;181(Meeting Abstracts):A2515. CENTRAL

Simonneau 2017 {published data only}

Simonneau G, Jing ZC, D'Armini AM, Fedullo P, Howard L, Jais X, et al. Macitentan for inoperable chronic thromboembolic pulmonary hypertension (CTEPH): results from the randomised controlled MERIT study. European Respiratory Journal 2017;50(Suppl 61):OA1984. CENTRAL

Spence 2008 {published data only}

Spence R, Mandagere A, Dufton C, Venitz J. Pharmacokinetics and safety of ambrisentan in combination with sildenafil in healthy volunteers. Journal of Clinical Pharmacology 2008;48(12):1451-9. CENTRAL

Spence 2009 {published data only}

Spence R, Mandagere A, Harrison B, Dufton C, Boinpally R. No clinically relevant pharmacokinetic and safety interactions of ambrisentan in combination with tadalafil in healthy volunteers. Journal of Pharmaceutical Sciences 2009;98(12):4962-74. CENTRAL

Stavros 2010 {published data only}

Stavros F, Kramer WG, Wilkins MR. The effects of sitaxentan on sildenafil pharmacokinetics and pharmacodynamics in healthy subjects. British Journal of Clinical Pharmacology 2010;69(1):23-6. CENTRAL

Stolz 2008 {published data only}

Stolz D, Rasch H, Linka A, Di Valentino M, Meyer A, Brutsche M, et al. A randomised, controlled trial of bosentan in severe COPD. European Respiratory Journal 2008;32(3):619-28. CENTRAL

Surie 2013 {published data only}

Surie S, Reesink HJ, Marcus JT, van der Plas MN, Kloek JJ, Vonk-Noordegraaf A, et al. Bosentan treatment is associated with improvement of right ventricular function and remodeling in chronic thromboembolic pulmonary hypertension. Clinical Cardiology 2013;36(11):698-703. CENTRAL

Tanaka 2017 {published data only}

Tanaka Y, Hino M, Gemma A. Potential benefit of bosentan therapy in borderline or less severe pulmonary hypertension secondary to idiopathic pulmonary fibrosis - an interim analysis of results from a prospective, single-center, randomized, parallel-group study. BMC Pulmonary Medicine 2017;17(1):200. CENTRAL [DOI: 10.1186/s12890-017-0523-2]

Tanaka 2019 {published data only}

Tanaka Y, Hino M, Aoyama J, Kosaihira S, Okano T, Seike M, et al. Interim report: long-term influence of bosentan on prognosis, activities of daily living (ADL), cardiac function and pulmonary function in patients with pulmonary hypertension secondary to COPD. In: Respirology. Vol. 24. 2019:239. CENTRAL

Vachiery 2018 {published data only}

Vachiery J-L, Delcroix M, Al-Hiti H, Efficace M, Hutyra M, Lack G, et al. Macitentan in pulmonary hypertension due to left ventricular dysfunction. European Respiratory Journal 2018;51(2):1880. CENTRAL

Van Der Zander 2006 {published data only}

Van Der Zander K, Houben AJHM, Webb DJ, Udo E, Kietselaer B, Hofstra L, et al. Selective endothelin B receptor blockade does not influence BNP-induced natriuresis in man. Kidney International 2006;69(5):864-8. CENTRAL

Van Giersbergen 2005 {published data only}

Van Giersbergen PLM, Dingemanse J. Comparative investigation of the pharmacokinetics of bosentan in Caucasian and Japanese healthy subjects. American College of Clinical Pharmacology 2005;45(1):42-7. CENTRAL

Webb 2017 {published data only}

Webb DJ, Coll B, Heerspink HJL, Andress D, Pritchett Y, Brennan JJ, et al. Longitudinal assessment of the effect of atrasentan on thoracic bioimpedance in diabetic nephropathy: a randomized, double-blind, placebo-controlled trial. Drugs in R&D 2017;17(3):441-8. CENTRAL

Worthington 2010 {published data only}

Worthington A, Collins N, Haddad R. Safety and feasibility of inhaled iloprost on exercise capacity in patients with pulmonary arterial hypertension. Heart Lung and Circulation 2010;19(2):1. CENTRAL

Wrishko 2008 {published data only}

Wrishko RE, Dingemanse J, Yu A, Darstein C, Phillips DL, Mitchell MI. Pharmacokinetic interaction between tadalafil and bosentan in healthy male subjects. Journal of Clinical Pharmacology 2008;48(5):610-8. CENTRAL

References to studies awaiting assessment

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Dwivedi 2018 {published data only}

Dwivedi P, Sharma SK, Dhir V, Rohit MK, Behera D, Jain S. AB0797 A randomised double blind placebo controlled trial to compare the efficacy of initial combination therapy vs monotherapy for pulmonary arterial hypertension in systemic sclerosis. Annals of the Rheumatic Diseases 2018;77(Suppl 2):1531. CENTRAL

Rinaldi 2018 {published data only}

Rinaldi A, Dardi F, Albini A, Gotti E, Monti E, Palazzini M, et al. Haemodynamic and exercise effects of different types of initial oral combination therapy in pulmonary arterial hypertension. In: European Heart Journal. Vol. 39. 2018:P6341. CENTRAL

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Altman DG, Bland JM. Statistics notes: interaction revisited: the difference between two estimates. BMJ 2003;326(7382):219.

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Badesch DB, the Aries Study Group. Ambrisentan therapy for pulmonary arterial hypertension: a comparison by PAH etiology. Chest 2007;132(4):488-9.

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Barst RJ, Rubin LJ, Long WA, McGoon MD, Rich S, Badesch DB. A comparison of continuous intravenous epoprostenol (prostacyclin) with conventional therapy for primary pulmonary hypertension. The Primary Pulmonary Hypertension Study Group. New England Journal of Medicine 1996;334(5):296-302.

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Chester AH, Yacoub MH. The role of endothelin-1 in pulmonary arterial hypertension. Global Cardiology Science and Practice 2014;2014(2):62-78.

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Denton CP, Humbert M, Rubin L, Black CM. Bosentan treatment for pulmonary arterial hypertension related to connective tissue disease: a subgroup analysis of the pivotal clinical trials and their open-label extensions. Annals of the Rheumatic Diseases 2006;65(10):1336-40.

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Duo-Ji MM, Long ZW. Comparative efficacy and acceptability of endothelin receptor antagonists for pulmonary arterial hypertension: a network meta-analysis. International Journal of Cardiology 2017;234:90-8.

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Galiè N, Humbert M, Vachiery JL, Gibbs S, Lang I, Torbicki A, et al. 2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension. European Respiratory Journal 2015;46(4):903.

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Guignabert C, Tu L, Le HM, Ricard N, Sattler C, Seferian A, et al. Pathogenesis of pulmonary arterial hypertension: lessons from cancer. European Respiratory Review 2013;22(130):543.

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Horinouchi T, Terada K, Higashi T, Miwa S. Endothelin receptor signaling: new insight into its regulatory mechanisms. Journal of Pharmacological Sciences 2013;123(2):85-101.

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Khair RM, Nwaneri C, Damico RL, Kolb T, Hassoun PM, Mathai SC. The minimal important difference in Borg dyspnea score in pulmonary arterial hypertension. Annals of the American Thoracic Society 2016;13(6):842-9.

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Klinger JR, Elliott CG, Levine DJ, Bossone E, Duvall L, Fagan K, et al. Therapy for pulmonary arterial hypertension in adults: update of the CHEST guideline and Expert Panel Report. CHEST 2019;155(3):565-86.

Madonna 2015

Madonna R, Cocco N, De Caterina R. Pathways and drugs in pulmonary arterial hypertension – focus on the role of endothelin receptor antagonists. Cardiovascular Drugs Therapy 2015;29(5):469-79.

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Mathai SC, Puhan MA, Lam D, Wise RA. The minimal important difference in the 6-minute walk test for patients with pulmonary arterial hypertension. American Journal of Respiratory and Critical Care Medicine 2012;186(5):428-33.

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Miyamoto S, Nagaya N, Satoh T, Kyotani S, Sakamaki F, Fujita M, et al. Clinical correlates and prognostic significance of six-minute walk test in patients with primary pulmonary hypertension. Comparison with cardiopulmonary exercise testing. American Journal of Respiratory and Critical Care Medicine 2000;161:487-92.

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Rich S, Kaufmann E, Levy PS. The effect of high doses of calcium-channel blockers on survival in primary pulmonary hypertension. New England Journal of Medicine 1992;327(2):76-81.

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Seibold J, Badesch D, Galiè N, Langleben D, Naeije R, Simonneau G, et al. Sitaxsentan, a selective endothelin-a receptor antagonist, improves exercise capacity in pulmonary arterial hypertension (PAH) associated with connective tissue disease (CTD). CHEST2005;128(4):219S.

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Shao D, Park JE, Wort SJ. The role of endothelin-1 in the pathogenesis of pulmonary arterial hypertension. Pharmacological Research 2011;63(6):504-11.

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Wang S, Yu M, Zheng X, Dong S. A Bayesian network meta-analysis on the efficacy and safety of eighteen targeted drugs or drug combinations for pulmonary arterial hypertension. Drug Delivery 2018;25(1):1898-909.

Zhuang 2014

Zhuang Y, Jiang B, Gao H, Zhao W. Randomized study of adding tadalafil to existing ambrisentan in pulmonary arterial hypertension. Hypertension Research 2014;37(6):507-12.

References to other published versions of this review

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Liu 2004

Liu C, Chen J. Endothelin receptor antagonists for pulmonary arterial hypertension. Cochrane Database of Systematic Reviews 2004, Issue 4. Art. No: CD004434. [DOI: 10.1002/14651858.CD004434.pub2]

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Liu C, Chen J. Endothelin receptor antagonists for pulmonary arterial hypertension. Cochrane Database of Systematic Reviews 2006, Issue 3. Art. No: CD004434. [DOI: 10.1002/14651858.CD004434.pub3]

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Liu C, Chen J, Gao Y, Deng B, Liu K. Endothelin receptor antagonists for pulmonary arterial hypertension. Cochrane Database of Systematic Reviews 2009, Issue 3. Art. No: CD004434. [DOI: 10.1002/14651858.CD004434.pub4]

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Liu C, Chen J, Gao Y, Deng B, Liu K. Endothelin receptor antagonists for pulmonary arterial hypertension. Cochrane Database of Systematic Reviews 2013, Issue 2. Art. No: CD004434. [DOI: 10.1002/14651858.CD004434.pub5]

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Ir a:

AMBITION

Study characteristics

Methods

Study design: Randomised controlled trial

Study grouping: Parallel group

Participants

Baseline characteristics

Combination (ambrisentan plus tadalafil) therapy

  • No. randomised to group: 253

  • Age (mean ± SD): 54.5 ± 14.3

  • Female sex (%): 188 (74)

  • Hypertension (%): 104 (41)

  • Diabetes (%): 19 (8)

  • CAD (%): 16 (6)

  • Idiopathic PAH (%): 127 (50)

  • Heritable PAH (%): 7 (3)

  • PAH associated with CTD (%): 103 (41)

  • PAH associated with CHD (%): 5 (2)

  • PAH associated with human immunodeficiency (%): 5 (2)

  • PAH associated with drug use or toxin exposure (%): 6 (2)

  • PAP mmHg (mean ± SD): 48.1 ± 12.4

  • Cardiac index, L/min/m2 (mean ± SD): 2.41 ± 0.64

  • PVR, dyn/s/cm5 (mean ± SD): 824.1 ± 467.0

  • 6MWD, m (mean ± SD): 353.5 ± 87.9

  • WHO FC II (%): 76 (30)

  • WHO FC III (%): 177 (70)

Ambrisentan monotherapy

  • No. randomised to group: 126

  • Age (mean ± SD): 53.9 ± 14.7

  • Female sex (%): 100 (79)

  • Hypertension (%): 52 (41)

  • Diabetes (%): 13 (10)

  • CAD (%): 2 (2)

  • Idiopathic PAH (%): 72 (57)

  • Heritable PAH (%): 3 (2)

  • PAH associated with CTD (%): 44 (35)

  • PAH associated with CHD (%): 1 (1)

  • PAH associated with human immunodeficiency (%): 2 (2)

  • PAH associated with drug use or toxin exposure (%): 4 (3)

  • PAP, mmHg (mean ± SD): 50.4 ± 12.5

  • Cardiac index, L/min/m2 (mean ± SD): 2.41 ± 0.66

  • PVR, dyn/s/cm5 (mean ± SD): 852.4 ± 394.7

  • 6MWD, m (mean ± SD): 354.2 ± 92.3

  • WHO FC II (%): 38 (30)

  • WHO FC III (%): 88 (70)

Tadalafil monotherapy

  • No. randomised to group: 121

  • Age (mean ± SD): 54.5 ± 15.2

  • Female sex (%): 100 (83)

  • Hypertension (%): 43 (36)

  • Diabetes (%): 17 (14)

  • CAD (%): 2 (2)

  • Idiopathic PAH (%): 66 (55)

  • Heritable PAH (%): 4 (3)

  • PAH associated with CTD (%): 40 (33)

  • PAH associated with CHD (%): 3 (2)

  • PAH associated with human immunodeficiency (%): 2 (2)

  • PAH associated with drug use or toxin exposure (%): 6 (5)

  • PAP, mmHg (mean ± SD): 48.1 ± 12.6

  • Cardiac index, L/min/m2 (mean ± SD): 2.45 ± 0.77

  • PVR, dyn/s/cm5 (mean ± SD): 798.0 ± 409.4

  • 6MWD, m (mean ± SD): 349.2 ± 91.6

  • WHO FC II (%): 41 (34)

  • WHO FC III (%): 80 (66)

Interventions

Intervention characteristics

Combination (ambrisentan plus tadalafil) therapy

  • Timing: once daily

  • Co‐interventions: anticoagulant, calcium‐channel blocker, diuretic, aldosterone antagonist

  • Compliance: high

  • Duration of treatment period: 24 weeks

Ambrisentan monotherapy

  • Timing: once daily

  • Co‐interventions: anticoagulant, calcium‐channel blocker, diuretic, aldosterone antagonist

  • Compliance: high

  • Duration of treatment period: 24 weeks

Tadalafil monotherapy

  • Timing: once daily

  • Co‐interventions: anticoagulant, calcium‐channel blocker, diuretic, aldosterone antagonist

  • Compliance: high

  • Duration of treatment period: 24 weeks

Outcomes

6MWD

Mortality

WHO FC improved

WHO FC deteriorated

Identification

Sponsorship source: Gilead Sciences and GlaxoSmithKline

Country: Italy

Setting: International, multicentre study

Comments: p. 843, the end of study

Author's name: Nazzareno Galiè

Institution: Department of Experimental, Diagnostic, and Specialty Medicine, University of Bologna

Email: [email protected]

Address: Massarenti 9, Bologna 40138, Italy

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Judgement comment: Randomisation was performed centrally by the study sponsors using an interactive voice‐response system. p. 836, the first paragraph in section "study procedures"

Allocation concealment (selection bias)

Low risk

"Matching placebo tablets were administered to maintain blinding" in appendix materials. p. 22

Blinding (performance bias and detection bias)
All outcomes

Low risk

Judgement comment: "Matching placebo tablets were administered to maintain blinding" in appendix materials. p. 22

Incomplete outcome data (attrition bias)
All outcomes

High risk

Outcome data were missing in 3 intervention groups and missing data were not balanced. 21.7% (55/253) participants discontinued from the combination therapy group, 34.1% (43/126) participants from the ambrisentan group, and 24.0% (29/121) participants from the tadalafil group.

Selective reporting (reporting bias)

Low risk

Reported as per protocol published at ClinicalTrials.gov.
ARIES‐1

Study characteristics

Methods

Multicentre, randomised, placebo‐controlled, parallel, double‐blind trial. Randomisation was conducted centrally according to a computer‐generated random number.

Participants

Baseline characteristics

Placebo

  • n = 67

  • Age (mean ± SD): 48 ± 16

  • Female sex (%): 59 (88)

  • Idiopathic PAH (%): 43 (64)

  • PAH associated with CTD (%): 21 (31)

  • PAH associated with human immunodeficiency (%): 2 (3)

  • PAH associated with drug use or toxin exposure (%): 1 (2)

  • PAP mmHg (mean ± SD): 50 ± 15

  • Cardiac index, L/min/m2 (mean ± SD): 2.5 ± 0.8

  • PVR, dyn/s/cm5 (mean ± SD): 868 ± 518

  • 6MWD, m (mean ± SD): 342 ± 73

  • WHO FC I (%): 2 (3)

  • WHO FC II (%): 23 (34)

  • WHO FC III (%): 41 (46)

  • WHO FC IV (%): 1 (2)

Ambrisentan (5 mg/day)

  • n = 67

  • age (mean ± SD): 53 ± 14

  • Female sex (%): 56 (84)

  • Idiopathic PAH (%): 42 (63)

  • PAH associated with CTD (%): 19 (28)

  • PAH associated with human immunodeficiency (%): 3 (5)

  • PAH associated with drug use or toxin exposure (%): 2 (3)

  • PAP mmHg (mean ± SD): 47 ± 13

  • Cardiac index, L/min/m2 (mean ± SD): 2.5 ± 0.9

  • PVR, dyn/s/cm5 (mean ± SD): 834 ± 424

  • 6MWD, m (mean ± SD): 340 ± 77

  • WHO FC I (%): 1 (2)

  • WHO FC II (%): 20 (30)

  • WHO FC III (%): 40 (60)

  • WHO FC IV (%): 6 (9)

Ambrisentan (10 mg/day)

  • n = 67

  • Age (mean ± SD): 49 ± 16

  • Female sex (%): 53 (79)

  • Idiopathic PAH (%): 41 (61)

  • PAH associated with CTD (%): 22 (33)

  • PAH associated with human immunodeficiency (%): 2 (3)

  • PAH associated with drug use or toxin exposure (%): 2 (3)

  • PAP mmHg (mean ± SD): 51 ± 16

  • Cardiac index, L/min/m2 (mean ± SD): 2.6 ± 0.7

  • PVR, dyn/s/cm5 (mean ± SD): 912 ± 465

  • 6MWD, m (mean ± SD): 341 ± 78

  • WHO FC I (%): 2 (3)

  • WHO FC II (%): 22 (33)

  • WHO FC III (%): 36 (54)

  • WHO FC IV (%): 7 (10)

Interventions

Participants were randomised to receive placebo or ambrisentan 5 or 10 mg orally daily for 12 weeks.

  • Timing: once daily

  • Co‐interventions: bosentan, sitaxsentan, sildenafil, epoprostenol, iloprost, or treprostinil was prohibited.

  • Compliance: high

  • Duration of treatment period: 12 weeks

Outcomes

Primary outcomes: change from baseline in 6MWD

Secondary outcomes: change from baseline in WHO FC, Borg dyspnoea index and time to clinical worsening, plasma BNP and 36‐item Short Form Health Survey (SF‐36) physical functioning scale

Identification

‐

Notes

The combined data of ARIES‐1 and ARIES‐2 showed that 21 participants discontinued in the placebo group in ARIES‐1 and ARIES‐2, 6 participants in the ambrisentan 2.5 mg group, 9 participants in the ambrisentan 5 mg group, and 5 participants in the ambrisentan 10 mg group.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

"A central randomisation scheme stratified by PAH cause (idiopathic versus other PAH causes) was used to assign participants."

Allocation concealment (selection bias)

Low risk

Confirmed with the study sponsor: a central randomisation scheme was used to assign participants, and matching placebo tablets were administered to maintain blinding.

Blinding (performance bias and detection bias)
All outcomes

Low risk

Confirmed with the study sponsor: a central randomisation scheme was used to assign participants, and matching placebo tablets were administered to maintain blinding.

Incomplete outcome data (attrition bias)
All outcomes

High risk

Outcome data were missing in the intervention groups, and missing data were not balanced. A total of 41 participants in ARIES‐1 and ARIES‐2 studies discontinued prematurely during the 12‐week treatment period: 21 (15.9%) receiving placebo and 20 (7.6%) receiving
ambrisentan.

Selective reporting (reporting bias)

Low risk

Prespecified primary outcome was reported in the results. ClinicalTrials.gov Identifier: NCT00091598

ARIES‐2

Study characteristics

Methods

Multicentre, randomised, placebo‐controlled, parallel, double‐blind trial. Randomisation was conducted centrally according to a computer‐generated random number.

Participants

Baseline characteristics

Placebo

  • n = 65

  • Age (mean ± SD): 51 ± 14

  • Female sex (%): 44 (68)

  • Idiopathic PAH (%): 42 (65)

  • PAH associated with CTD (%): 22 (34)

  • PAH associated with human immunodeficiency (%): 1 (2)

  • PAH associated with drug use or toxin exposure (%): 0 (0)

  • PAP mmHg (mean ± SD): 51 ± 13

  • Cardiac index, L/min/m2 (mean ± SD): 2.4 ± 0.7

  • PVR, dyn/s/cm5 (mean ± SD): 971 ± 579

  • 6MWD, m (mean ± SD): 343 ± 86

  • WHO FC I (%): 2 (3)

  • WHO FC II (%): 24 (37)

  • WHO FC III (%): 37 (57)

  • WHO FC IV (%): 2 (3)

Ambrisentan (5 mg/day)

  • n = 64

  • Age (mean ± SD): 52 ± 15

  • Female sex (%): 48 (75)

  • Idiopathic PAH (%): 42 (66)

  • PAH associated with CTD (%): 19 (30)

  • PAH associated with human immunodeficiency (%): 2 (3)

  • PAH associated with drug use or toxin exposure (%): 1 (2)

  • PAP mmHg (mean ± SD): 48 ± 14

  • Cardiac index, L/min/m2 (mean ± SD): 2.5 ± 0.7

  • PVR, dyn/s/cm5 (mean ± SD): 800 ± 396

  • 6MWD, m (mean ± SD): 347 ± 84

  • WHO FC I (%): 0 (0)

  • WHO FC II (%): 34 (53)

  • WHO FC III (%): 29 (45)

  • WHO FC IV (%): 1 (2)

Ambrisentan (5 mg/day)

  • n = 63

  • Age (mean ± SD): 50 ± 16

  • Female sex (%): 51 (81)

  • Idiopathic PAH (%): 41 (65)

  • PAH associated with CTD (%): 21 (33)

  • PAH associated with human immunodeficiency (%): 1 (2)

  • PAH associated with drug use or toxin exposure (%): 0 (0)

  • PAP mmHg (mean ± SD): 48 ± 14

  • Cardiac index, L/min/m2 (mean ± SD): 2.4 ± 0.8

  • PVR, dyn/s/cm5 (mean ± SD): 931 ± 672

  • 6MWD, m (mean ± SD): 355 ± 84

  • WHO FC I (%): 1 (2)

  • WHO FC II (%): 28 (44)

  • WHO FC III (%): 33 (52)

  • WHO FC IV (%): 1 (2)

Interventions

Participants were randomised to receive placebo or ambrisentan 2.5 or 5 mg daily for 12 weeks.

  • Timing: once daily

  • Co‐interventions: bosentan, sitaxsentan, sildenafil, epoprostenol, iloprost, or treprostinil was prohibited.

  • Compliance: high

  • Duration of treatment period: 12 weeks

Outcomes

Primary outcomes: change from baseline in 6MWD

Secondary outcomes: change from baseline in WHO FC, Borg dyspnoea index and time to clinical worsening, plasma BNP and 36‐item Short Form Health Survey (SF‐36) physical functioning scale

Identification

‐

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

"A central randomisation scheme stratified by PAH cause (idiopathic versus other PAH causes) was used to assign participants."

Allocation concealment (selection bias)

Low risk

Confirmed with the study sponsor: a central randomisation scheme was used to assign participants, and matching placebo tablets were administered to maintain blinding.

Blinding (performance bias and detection bias)
All outcomes

Low risk

Confirmed with the study sponsor: a central randomisation scheme was used to assign participants, and matching placebo tablets were administered to maintain blinding.

Incomplete outcome data (attrition bias)
All outcomes

High risk

Outcome data were missing in the intervention groups, and missing data were not balanced. A total of 41 participants in ARIES‐1 and ARIES‐2 studies discontinued prematurely during the 12‐week treatment period: 21 (15.9%) receiving placebo and 20 (7.6%) receiving
ambrisentan.

Selective reporting (reporting bias)

Low risk

Prespecified primary outcome was reported in the results. ClinicalTrials.gov Identifier: NCT00091598

BREATHE‐1

Study characteristics

Methods

Multicentre, randomised, placebo‐controlled, parallel, double‐blind trial. Randomisation was conducted according to a computer‐generated random number.

Participants

Baseline characteristics

Placebo

  • n = 69

  • Age (mean ± SD): 47.2 ± 16.2

  • Female sex (%): 54 (78)

  • Idiopathic PAH (%): 48 (70)

  • PAH associated with CTD (%): 21 (30)

  • PAP mmHg (mean ± SD): 53 ± 17

  • Cardiac index, L/min/m2 (mean ± SD): 2.4 ± 0.7

  • PVR, dyn/s/cm5 (mean ± SD): 880 ± 540

  • 6MWD, m (mean ± SD): 344 ± 76

  • WHO FC III (%): 65 (94)

  • WHO FC IV (%): 4 (6)

Bosentan

  • n = 144

  • Age (mean ± SD): 48.7 ± 15.8

  • Female sex (%): 114 (79)

  • Idiopathic PAH (%): 102 (71)

  • PAH associated with CTD (%): 32 (29)

  • PAP mmHg (mean ± SD): 55 ± 16

  • Cardiac index, L/min/m2 (mean ± SD): 2.4 ± 0.8

  • PVR, dyn/s/cm5 (mean ± SD): 1014 ± 678

  • 6MWD, m (mean ± SD): 330 ± 74

  • WHO FC III (%): 130 (90)

  • WHO FC IV (%): 14 (10)

Interventions

Intervention group: 62.5 mg bosentan twice daily for the first 4 weeks followed by the target dose (125 mg or 250 mg twice daily) for 12 weeks

Control group: placebo

  • Timing: twice daily

  • Co‐interventions: antithrombotic agents, diuretics, and calcium‐channel blockers

  • Compliance: high

  • Duration of treatment period: 16 weeks

Outcomes

Primary outcomes: change from baseline in 6MWD

Secondary outcomes: Borg dyspnoea index; WHO FC

Identification

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Randomised allocation by pharmacy‐controlled randomisation

Allocation concealment (selection bias)

Low risk

Confirmed with the study sponsor: a central randomisation scheme was used to assign participants, and matching placebo tablets were administered to maintain blinding.

Blinding (performance bias and detection bias)
All outcomes

Low risk

Confirmed with the study sponsor: a central randomisation scheme was used to assign participants, and matching placebo tablets were administered to maintain blinding.

Incomplete outcome data (attrition bias)
All outcomes

High risk

9% participants discontinued from the placebo group due to suffering clinical worsening of symptoms of PAH or syncope occurred, as compared with no participants in the bosentan group. The missing data were not balanced between groups.

Selective reporting (reporting bias)

Unclear risk

We did not have access to the study protocol.
BREATHE‐2

Study characteristics

Methods

Multicentre, randomised, placebo‐controlled, parallel, double‐blind trial. Randomisation was conducted according to a computer‐generated random number.

Participants

Baseline characteristics

Placebo/epoprostenol

  • n = 11

  • Age (mean ± SD): 47 ± 19

  • Female sex (%): 6 (55)

  • Idiopathic PAH (%): 10 (91)

  • PAH associated with CTD (%): 1 (9)

  • PAP mmHg (mean ± SD): 60.9 ± 2.9

  • Cardiac index, L/min/m2 (mean ± SD): 1.7 ± 0.2

  • PVR, dyn/s/cm5 (mean ± SD): 1426 ± 140

  • WHO FC III (%): 8 (73)

  • WHO FC IV (%): 3 (17)

Bosentan/epoprostenol

  • n = 22

  • Age (mean ± SD): 45 ± 17

  • Female sex (%): 17 (77)

  • Idiopathic PAH (%): 17 (77)

  • PAH associated with CTD (%): 4 (23)

  • PAP mmHg (mean ± SD): 59.2 ± 4.0

  • Cardiac index, L/min/m2 (mean ± SD): 1.7 ± 0.1

  • PVR, dyn/s/cm5 (mean ± SD): 1511 ± 129

  • WHO FC III (%): 17 (77)

  • WHO FC IV (%): 4 (23)

Interventions

33 participants with PAH started prostacyclin treatment (2 ng/kg/min starting dose, up to 14 ± 2 ng/kg/min at week 16) and were randomised for 16 weeks in a 2:1 ratio to bosentan (62.5 mg twice daily for 4 weeks then 125 mg twice daily) or placebo.

  • Timing: once daily

  • Co‐interventions: antithrombotic agents, diuretics

  • Compliance: high

  • Duration of treatment period: 16 weeks

Outcomes

Primary outcomes: change from baseline to week 16 in TPR
Secondary outcomes: change in cardiac index, PVR, mPAP, and mRAP, 6MWD, NYHA FC and dyspnoea‐fatigue rating

Identification

‐

Notes

The standard deviations of change from baseline in 6MWD were estimated from figures.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Randomised allocation by pharmacy‐controlled randomisation

Allocation concealment (selection bias)

Low risk

Confirmed with the study sponsor: a central randomisation scheme was used to assign participants, and matching placebo tablets were administered to maintain blinding.

Blinding (performance bias and detection bias)
All outcomes

Low risk

Confirmed with the study sponsor: a central randomisation scheme was used to assign participants, and matching placebo tablets were administered to maintain blinding.

Incomplete outcome data (attrition bias)
All outcomes

High risk

Outcome data were missing (1/11 in the placebo group versus 4/22 in the bosentan group), and missing data were not balanced.

Selective reporting (reporting bias)

Unclear risk

We did not have access to the study protocol.
BREATHE‐5

Study characteristics

Methods

Multicentre, randomised, placebo‐controlled, parallel, double‐blind trial. Randomisation was conducted according to a computer‐generated random number.

Participants

Baseline characteristics

Placebo

  • n = 17

  • age (mean ± SD): 44.2 ± 8.5

  • Female sex (%): 10 (59)

  • PAH associated with CHD (%): 17 (100)

  • PAP mmHg (mean ± SD): 72.1 ± 19.4

  • PVR, dyn/s/cm5 (mean ± SD): 2870 ± 1209

  • 6MWD, m (mean ± SD): 366.4 ± 67.5

  • WHO FC III (%): 17 (100)

Bosentan

  • n = 37

  • age (mean ± SD): 37.2 ± 12.0

  • Female sex (%): 23 (62)

  • PAH associated with CHD (%): 37 (100)

  • PAP mmHg (mean ± SD): 77.8 ± 15.2

  • PVR, dyn/s/cm5 (mean ± SD): 3425 ± 1410

  • 6MWD, m (mean ± SD): 331.9 ± 82.8

  • WHO FC III (%): 37 (100)

Interventions

Intervention group: 62.5 mg bosentan twice daily for the first 4 weeks followed by the target dose (125 mg twice daily) for 12 weeks. Participants who did not tolerate the target dose of 125 mg twice daily could be down titrated to the starting dose (62.5 mg twice daily).

Control group: placebo

  • Timing: once daily

  • Co‐interventions: prostanoids, phosphodiesterase‐V inhibitors, and endothelin receptor antagonists were not allowed.

  • Compliance: high

  • Duration of treatment period: 16 weeks

Outcomes

Primary outcomes: change from baseline in SpO2 and PVR index

Secondary outcomes: change from baseline in 6MWD, WHO FC, cardiac index, PVR, PAP, and RAP

Identification

‐

Notes

Standard deviations were estimated from standard errors.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

"Randomization was controlled by study medication packaging (Almedica HPS AG, Reinach, Switzerland)."

Allocation concealment (selection bias)

Low risk

"The investigators, participants, monitors, and sponsor personnel remained blinded to the treatment until closure of the clinical database." p. 49

Blinding (performance bias and detection bias)
All outcomes

Low risk

"The investigators, participants, monitors, and sponsor personnel remained blinded to the treatment until closure of the clinical database." p. 49

Incomplete outcome data (attrition bias)
All outcomes

High risk

Outcome data were missing. 2/17 (11.8%) in the placebo group versus 2/37 (5.4%) in the bosentan group discontinued from the study. Missing data were balanced.

Selective reporting (reporting bias)

Unclear risk

We did not have access to the study protocol.
Channick 2001

Study characteristics

Methods

Multicentre, randomised, parallel trial comparing bosentan with placebo for 12 weeks. Randomisation was computer generated with a block size of 3.

Participants

Baseline characteristics

Placebo

  • n = 11

  • Age (mean ± SD): 47.4 ± 14.0

  • Female sex (%): 11 (100)

  • Idiopathic PAH (%): 10 (91)

  • PAH associated with CTD (%): 1 (9)

  • PAP mmHg (mean ± SD): 56 ± 10

  • Cardiac index, L/min/m2 (mean ± SD): 2.5 ± 1.0

  • PVR, dyn/s/cm5 (mean ± SD): 942 ± 430

  • 6MWD, m (mean ± SD): 355 ± 82

  • WHO FC III (%): 11 (100)

Bosentan

  • n = 21

  • Age (mean ± SD): 52.2 ± 12.2

  • Female sex (%): 18 (81)

  • Idiopathic PAH (%): 17 (81)

  • PAH associated with CTD (%): 4 (19)

  • PAP mmHg (mean ± SD): 54 ± 13

  • Cardiac index, L/min/m2 (mean ± SD): 2.4 ± 0.7

  • PVR, dyn/s/cm5 (mean ± SD): 896 ± 425

  • 6MWD, m (mean ± SD): 360 ± 86

  • WHO FC III (%): 21 (100)

Interventions

Intervention group: 62.5 mg bosentan twice daily for the first 4 weeks followed by the target dose (125 mg twice daily)

Control group: placebo

  • Timing: twice daily

  • Co‐interventions: warfarin and calcium channel blockers

  • Compliance: high

  • Duration of treatment period: 16 weeks

Outcomes

Primary outcomes: 6MWD

Secondary outcomes: cardiopulmonary haemodynamics (cardiac index, PVR, mPAP, and mRAP), WHO FC

Identification

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

"Randomisation was computer generated using Drug Labelling System with a block size of three."

Allocation concealment (selection bias)

Low risk

Confirmed with the study sponsor: a central randomisation scheme was used to assign participants, and matching placebo tablets were administered to maintain blinding.

Blinding (performance bias and detection bias)
All outcomes

Low risk

Confirmed with the study sponsor: a central randomisation scheme was used to assign participants, and matching placebo tablets were administered to maintain blinding.

Incomplete outcome data (attrition bias)
All outcomes

High risk

Outcome data were missing (2/11) in the placebo group, but not in the bosentan group (0/21). Missing data were not balanced.

Selective reporting (reporting bias)

Unclear risk

We did not have access to the study protocol.
COMPASS‐2

Study characteristics

Methods

Study design: Randomised controlled trial

Study grouping: Parallel group

Participants

Baseline characteristics

Bosentan

  • n = 159

  • Sex ‐ female (%): 125 (78.6)

  • Age years, mean ± SD: 52.9 ± 15.4

  • Idiopathic PAH (%): 99 (62.3)

  • Familial PAH (%): 3 (1.9)

  • PAH secondary to CTD (%): 43 (27.0)

  • PAH associated with CHD (%): 9 (5.7)

  • PAH secondary to drugs and toxins (%): 5 (3.1)

  • 6MWD, m, mean ± SD: 363.1 ± 78.5

  • WHO FC II (%): 71 (44.7)

  • WHO FC III (%): 88 (55.3)

  • WHO FC IV (%): 0 (0)

  • Baseline sildenafil dose mg, mean ± SD: 77.8 ± 48.5

Placebo

  • n = 175

  • Sex ‐ female (%): 128 (73.1)

  • Age years, mean ± SD: 54.7 ± 15.7

  • Idiopathic PAH (%): 114 (65.1)

  • Familial PAH (%): 2 (1.1)

  • PAH secondary to CTD (%): 45 (25.7)

  • PAH associated with CHD (%): 11 (6.3)

  • PAH secondary to drugs and toxins (%): 3 (1.7)

  • 6MWD, m, mean ± SD: 357.6 ± 73.1

  • WHO FC (%): 69 (39.4)

  • WHO FC III (%): 104 (59.4)

  • WHO FC IV (%): 2 (1.1)

  • Baseline sildenafil dose mg, mean ± SD: 81.1 ± 45.1

Interventions

Intervention characteristics

Bosentan

  • Timing: twice daily

  • Co‐interventions: sildenafil

  • Compliance: high

  • Duration of treatment period: 16 weeks

Placebo

  • Timing: twice daily

  • Co‐interventions: sildenafil

  • Compliance: high

  • Duration of treatment period: 16 weeks

Outcomes

Mortality

WHO FC improved

WHO FC worsened

Change in 6MWD

Hepatic toxicity

Identification

Sponsorship source: Actelion Pharmaceuticals Ltd.

Setting: International, multicentre, university‐based hospital

Author's name: Vallerie McLaughlin

Institution: University of Michigan Health System

Email: [email protected]

Address: Department of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan Health System, Ann Arbor, MI 48109‐5853, USA

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

"COMPASS‐2 was a prospective, international, randomised, double‐blind, placebo‐controlled, event‐driven trial"

Allocation concealment (selection bias)

Low risk

"COMPASS‐2 was a prospective, international, randomised, double‐blind, placebo‐controlled, event‐driven trial (www.clinicaltrials.gov identifier number NCT00303459)."

Blinding (performance bias and detection bias)
All outcomes

Low risk

Confirmed with the study sponsor: a central randomisation scheme was used to assign participants, and matching placebo tablets were administered to maintain blinding.

Incomplete outcome data (attrition bias)
All outcomes

High risk

25.7% participants were discontinued from the placebo group and 31.4% from the bosentan group.

Selective reporting (reporting bias)

Low risk

Reported according to the protocol published at ClinicalTrials.gov.
EARLY

Study characteristics

Methods

Multicentre, randomised, placebo‐controlled, parallel, double‐blind trial

Participants

Baseline characteristics

Placebo

  • n = 92

  • Age (mean ± SD): 44.2 ± 16.5

  • Female sex (%): 58 (63)

  • Idiopathic PAH (%): 58 (63)

  • PAH associated with CTD (%): 16 (17)

  • PAH associated with CHD (%): 15 (16)

  • PAH associated with human immunodeficiency (%): 2 (2)

  • PAP mmHg (mean ± SD): 52.3 ± 16.0

  • Cardiac index, L/min/m2 (mean ± SD): 2.7 ± 0.6

  • PVR, dyn/s/cm5 (mean ± SD): 805 ± 369

  • 6MWD, m (mean ± SD): 431 ± 91

  • WHO FC II (%): 92 (100)

Bosentan

  • n = 93

  • Age (mean ± SD): 45.2 ± 17.9

  • Female sex (%): 71 (76)

  • Idiopathic PAH (%): 54 (58)

  • PAH associated with CTD (%): 16 (17)

  • PAH associated with CHD (%): 18 (19)

  • PAH associated with human immunodeficiency (%): 5 (5)

  • PAP mmHg (mean ± SD): 52.5 ± 18.9

  • Cardiac index, L/min/m2 (mean ± SD): 2.7 ± 0.8

  • PVR, dyn/s/cm5 (mean ± SD): 839 ± 531

  • 6MWD, m (mean ± SD): 438 ± 86

  • WHO FC II (%): 93 (100)

Interventions

Participants treated with either bosentan at an initial dose of 62.5 mg twice daily, uptitrating to 125 mg twice daily after 4 weeks, or remaining at 62.5 mg twice daily if bodyweight < 40 kg, or placebo for a 6‐month double‐blind treatment period.

  • Timing: twice daily

  • Co‐interventions: oral anticoagulants, sildenafil, and calcium channel blockers

  • Compliance: high

  • Duration of treatment period: 6 months

Outcomes

Primary outcomes: PVR and change from baseline in 6MWD

Secondary outcomes: time to clinical worsening, change from baseline to month 6 in WHO FC, Borg dyspnoea index, mPAP, cardiac index, RAP, and mixed venous oxygen saturation

Identification

‐

Notes

Standard deviations were estimated from confidence intervals.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

"Participants were randomly assigned in a one to one ratio to receive either bosentan using a centralised integrated voice recognition system."

Allocation concealment (selection bias)

Low risk

"This system assigned a unique randomisation number to each participant and designated the correct blinded study medication to be dispensed, both at the start of study treatment and at each scheduled visit. This code was accessible only to authorised individuals who were not involved in the conduct or analysis of the study, until the time of unblinding."

Blinding (performance bias and detection bias)
All outcomes

Low risk

"This system assigned a unique randomisation number to each participant and designated the correct blinded study medication to be dispensed, both at the start of study treatment and at each scheduled visit. This code was accessible only to authorised individuals who were not involved in the conduct or analysis of the study, until the time of unblinding."

Incomplete outcome data (attrition bias)
All outcomes

Low risk

12.9% (12/93) participants discontinued bosentan, and 10.8% (10/92) participants discontinued placebo. Missing data were balanced.

Selective reporting (reporting bias)

Low risk

Prespecified primary outcome reported in the results. ClinicalTrials.gov Identifier: NCT00091715

EDITA

Study characteristics

Methods

Study design: Randomised controlled trial

Study grouping: Parallel group

Participants

Baseline characteristics

Placebo

  • n = 19

  • Female sex (%): 14 (73.7)

  • Age ‐ year, mean ± SD: 54.89 ± 11.23

  • PAH associated with CTD (%): 19 (100.0)

  • 6MWD, m, mean ± SD: 448.11 ±82.64

  • WHO FC II (%): 15 (78.9)

  • WHO FC III (%): 4 (21.1)

  • PAP, mmHg, mean ± SD: 21.32 ± 2.43

  • Cardiac index, L/min/m2 of body surface area, mean ± SD: 3.20 ± 0.85

  • PVR, Wood units, mean ± SD: 2.09 ± 0.61

Ambrisentan (10 mg/day)

  • n = 19

  • Female sex (%): 16 (84.2)

  • Age ‐ year, mean ± SD: 58.79 ± 10.75

  • PAH associated with CTD (%): 19 (100.0)

  • 6MWD, m, mean ± SD: 470.21 ±77.03

  • WHO FC II (%): 17 (89.5)

  • WHO FC III (%): 2 (10.5)

  • PAP, mmHg, mean ± SD: 19.84 ± 3.58

  • Cardiac index, L/min/m2 of body surface area, mean ± SD: 2.84 ± 0.64

  • PVR, Wood units, mean ± SD: 2.22 ± 0.93

Interventions

Intervention characteristics

Placebo

  • Timing: once daily

  • Co‐interventions: not mentioned

  • Compliance: low

  • Duration of treatment period: 6 months

Ambrisentan (10 mg/day)

  • Co‐interventions: not mentioned

  • Compliance: high

  • Duration of treatment period: 6 months

Outcomes

Change in mean PAP

Change in WHO FC

Change in cardiac index

Change in PVR

Symptoms of SSc

Quality of life (SF‐36)

Lung function tests, right
Heart dimensions and function

NT‐proBNP

Measures of disease‐related progression

Identification

Sponsorship source: GlaxoSmithKline

Setting: Single‐centre, university‐based hospital

Author's name: Ekkehard Grünig

Institution: Centre for Pulmonary Hypertension, Thoraxklinik at Heidelberg University Hospital

Email: [email protected]‐heidelberg.de

Address: Röntgenstrasse 1, 69126 Heidelberg, Germany

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Judgement comment: "The EDITA study was a single‐center (PH Center, Thoraxklinik at Heidelberg University Hospital, Heidelberg, Germany) investigator‐initiated trial using a prospective, randomised, double‐blind (patient and investigator), parallel group, placebo‐controlled, phase IIA clinical study design. Patients were randomised 1:1 to either ambrisentan or placebo by simple randomisation." p. 3 in the study section

Allocation concealment (selection bias)

Low risk

"Placebo tablets with the same color and shape as ambrisentan were provided by GlaxoSmithKline." p. 3 in the study section

Blinding (performance bias and detection bias)
All outcomes

Low risk

"Placebo tablets with the same color and shape as ambrisentan were provided by GlaxoSmithKline." p. 3 in the study section

Incomplete outcome data (attrition bias)
All outcomes

High risk

Outcome data were missing in the intervention group and placebo group, and missing data were not balanced. 2/19 participants discontinued from the intervention group, and 4/19 participants discontinued from the placebo group.

Selective reporting (reporting bias)

Low risk

Reported as per protocol published at ClinicalTrials.gov.
Galiè 2003

Study characteristics

Methods

This trial report is on a subset of participants from the BREATHE‐1 study.

Participants

Baseline characteristics

Placebo

  • n = 29

  • Age (mean ± SD): 44.9 ± 19.2

  • Female sex (%): 24 (82.8)

  • Idiopathic PAH (%): 23 (79.3)

  • PAH associated with CTD (%): 4 (13.8)

  • PAP mmHg (mean ± SD): 58 ± 19

  • Cardiac index, L/min/m2 (mean ± SD): 2.3 ± 0.7

  • 6MWD, m (mean ± SD): 334 ± 76

  • WHO FC III (%): 28 (96.6)

  • WHO FC IV (%): 1 (3.4)

Bosentan

  • n = 56

  • Age (mean ± SD): 45.1 ± 15.6

  • Female sex (%): 48 (85.7)

  • Idiopathic PAH (%): 48 (85.7)

  • PAH associated with CTD (%): 7 (12.5)

  • PAP mmHg (mean ± SD): 56 ± 15

  • Cardiac index, L/min/m2 (mean ± SD): 2.4 ± 0.8

  • 6MWD, m (mean ± SD): 335 ± 83

  • WHO FC III (%): 49 (87.5)

  • WHO FC IV (%): 7 (12.5)

Interventions

Same as BREATHE‐1

Outcomes

Cardiac index

Identification

‐

Notes

This is a subgroup analysis of BREATHE‐1 study.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

See BREATHE‐1.

Allocation concealment (selection bias)

Low risk

See BREATHE‐1.

Blinding (performance bias and detection bias)
All outcomes

Low risk

See BREATHE‐1.

Incomplete outcome data (attrition bias)
All outcomes

High risk

2 out of 29 participants in the placebo group and 1 out of 56 in the
bosentan group discontinued the study medication. The missing data were not balanced between groups.

Selective reporting (reporting bias)

Unclear risk

We did not have access to the study protocol.
MAESTRO

Study characteristics

Methods

Study design: Randomised controlled trial

Study grouping: Parallel group

Participants

Baseline characteristics

Macitentan

  • n = 114

  • Female sex (%): 82 (71.9)

  • Age ‐ year (median, range): 33 (12 to 82)

  • Down syndrome, n (%): 10 (8.8)

  • 6MWD, m, mean (SD): 368.7 (74.5)

  • WHO FC II (%): 69 (60.5)

  • WHO FC III (%): 45 (39.5)

  • SpO2 at rest, %: 84.4 ± 5.6

  • Mean PAP, mmHg (mean ± SD): 77.4 ± 15.1

  • Mean RAP, mmHg (mean ± SD): 7.9 ± 5.2

  • PVR, dyn/s/cm5 (mean ± SD): 1807.5 ± 792.8

  • PDE5 inhibitors, n (%): 35 (30.7)

  • Simple cardiac defect, n (%): 91 (79.8)

  • Complex cardiac defect, n (%): 23 (20.2)

Placebo

  • n = 112

  • Female sex (%): 68 (60.7)

  • Age ‐ year (median, range): 31 (13 to 62)

  • Down syndrome, n (%): 10 (8.9)

  • 6MWD, m, mean (SD): 380.3 (76.3)

  • WHO FC II (%): 66 (58.9)

  • WHO FC III (%): 46 (41.1)

  • SpO2 at rest, %: 85.2 ± 5.1

  • Mean PAP, mmHg (mean ± SD): 79.9 ± 17.3

  • Mean RAP, mmHg (mean ± SD): 7.7 ± 4.5

  • PVR, dyn/s/cm5 (mean ± SD): 1828.1 ± 937.4

  • PDE5 inhibitors, n (%): 27 (24.1)

  • Simple cardiac defect, n (%): 80 (71.4)

  • Complex cardiac defect, n (%): 32 (28.6)

Interventions

Intervention characteristics

Macitentan

  • Timing (e.g. frequency, duration of each episode): once daily

  • Co‐interventions: stable background therapy for other cardiopulmonary diseases (e.g. antiarrhythmics, oral anticoagulants, digoxin, supplemental oxygen) was also allowed. Diuretics were allowed if the dose was stable for at least 1 week prior to randomisation. Iron supplementation was allowed if initiated at least 3 months prior to randomisation.

  • Compliance: high

  • Duration of treatment period: 16 weeks

Placebo

  • Timing (e.g. frequency, duration of each episode): once daily

  • Co‐interventions: stable background therapy for other cardiopulmonary diseases (e.g. antiarrhythmics, oral anticoagulants, digoxin, supplemental oxygen) was also allowed. Diuretics were allowed if the dose was stable for at least 1 week prior to randomisation. Iron supplementation was allowed if initiated at least 3 months prior to randomisation.

  • Compliance: high

  • Duration of treatment period: 16 weeks

Outcomes

6MWD

Mortality

WHO FC improved

WHO FC deteriorated

mPAP

PVR

Change from baseline in 6MWD
SPO2

Change in SPO2

Change in PAP

Change in PVR

Identification

Sponsorship source: Actelion Pharmaceuticals Ltd.

Country: International study

Setting: Tertiary referral hospital

Author's name: Michael A Gatzoulis

Institution: The Royal Brompton Hospital

Email: [email protected]

Address: Sydney Street, London, SW3 6NP, UK

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

"Randomization was based on a prespecified randomisation schedule using randomisation lists generated by an independent Contract Research Organization (Almac Clinical Technologies) and their centralized randomisation system, via an Interactive Voice Response System or Interactive Web Response System."

Allocation concealment (selection bias)

Low risk

"Participants and sites remained blinded to their previous treatment allocation."

Blinding (performance bias and detection bias)
All outcomes

Low risk

"Participants and sites remained blinded to their previous treatment allocation."

Incomplete outcome data (attrition bias)
All outcomes

Low risk

97% participants in the macitentan group and 98% participants in the placebo group completed the study.

Selective reporting (reporting bias)

Low risk

Reported as per protocol published at ClinicalTrials.gov.
PORTICO

Study characteristics

Methods

Study design: Randomised controlled trial

Study grouping: Parallel group

Participants

Baseline characteristics

Macitentan (10 mg)

  • n = 43

  • Female sex (%): 21 (49%)

  • Age ‐ year, mean (SD): 58.0 (8.7)

  • Body mass index, kg/m2, mean (SD): 29.0 (4.8)

  • PAH therapy: 27 (63%)

  • 6MWD, m, mean (SD): 385.8 (100.0)

  • PVR, dyn/s/cm5, mean (SD): 552.4 (192.8)

  • Mean PAP, mmHg, mean (SD): 46.4 (7.9)

  • Cardiac index, L/min/m2, mean (SD): 3.1 (0.8)

  • Mixed venous oxygen saturation, %, mean (SD): 69.2% (9.9)

  • Presence of oesophageal varices: 26 (60%)

  • Presence of ascites: 12 (28%)

  • WHO FC I: 1 (2%)

  • WHO FC II: 27 (62·8%)

  • WHO FC III: 15 (35%)

Placebo

  • n = 42

  • Female sex (%): 20 (48%)

  • Age ‐ year, mean (SD): 59.0 (9.5)

  • Body mass index, kg/m2, mean (SD): 29.3 (4.0)

  • PAH therapy: 27 (64%)

  • 6MWD at baseline, m, mean (SD): 383.2 (108.9)

  • PVR, dyn/s/cm5, mean (SD): 521.7 (163.3)

  • Mean PAP, mmHg, mean (SD): 43.8 (8.5)

  • Cardiac index, L/min/m2, mean (SD): 2.9 (0.8)

  • Mixed venous oxygen saturation, %, mean (SD): 69.9% (5.3)

  • Presence of oesophageal varices: 28 (67%)

  • Presence of ascites: 10 (24%)

  • WHO FC I: 1 (2%)

  • WHO FC II: 23 (55%)

  • WHO FC III: 18 (43%)

Interventions

Intervention characteristics

Macitentan (10 mg)

  • Timing (e.g. frequency, duration of each episode): once daily

  • Compliance: high

  • Duration of treatment period: 12 weeks

Placebo

  • Timing: once daily

  • Compliance: high

  • Duration of treatment period: 12 weeks

Outcomes

Change in 6MWD

Mortality

WHO FC improved

Change in mPAP

Change in cardiac index

Change in PVR

WHO FC deteriorated

Identification

Sponsorship source: Actelion Pharmaceuticals Ltd.

Country: International study

Author's name: Olivier Sitbon

Email: olivier.sitbon@u‐psud.fr

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

"Participants were randomly assigned in a 1:1 ratio, with block sizes of four, via an interactive voice and web response system (by independent contract research organisation Almac) to receive either macitentan 10 mg or matching placebo orally once a day."

Judgement comment: p. 596, the first paragraph in section "randomisation and masking"

Allocation concealment (selection bias)

Low risk

"Participants were randomly assigned in a 1:1 ratio, with block sizes of four, via an interactive voice and web response system (by independent contract research organisation Almac) to receive either macitentan 10 mg or matching placebo orally once a day."

Judgement comment: p. 596, the first paragraph in section "randomisation and masking"

Blinding (performance bias and detection bias)
All outcomes

Low risk

Confirmed with the study sponsor: matching placebo tablets were administered to maintain blinding.

Incomplete outcome data (attrition bias)
All outcomes

High risk

9.4% participants in the macitentan group and 2.4% participants in the placebo group discontinued the study. Missing data were observed and imbalanced between groups.

Selective reporting (reporting bias)

Low risk

Judgement comment: there was no obvious selective outcome reporting based on the protocol reported in ClinicalTrials.gov.

SERAPH

Study characteristics

Methods

Single‐centre, randomised, head‐to‐head, double‐blind trial

Participants

Baseline characteristics

Sildenafil

  • n = 14

  • Age, mean (range): 44.4 (28 to 62)

  • Female sex (%): 11 (78)

  • Idiopathic PAH (%): 12 (86)

  • PAH associated with CTD (%): 2 (14)

  • Cardiac index, L/min/m2 (mean ± SD): 2.3 ± 0.1

  • 6MWD, m (mean ± SD): 290 ± 88.5

  • WHO FC III (%): 14 (100)

Bosentan

  • n = 12

  • Age, mean (range): 41.1 (27 to 55)

  • Female sex (%): 10 (83)

  • Idiopathic PAH (%): 11 (92)

  • PAH associated with CTD (%): 1 (8)

  • Cardiac index, L/min/m2 (mean ± SD): 2.2 ± 0.1

  • 6MWD, m (mean ± SD): 304.6 ± 74.1

  • WHO FC III (%): 12 (100)

Interventions

Intervention group: bosentan (62.5 mg twice daily for first 4 weeks, then uptitrated to 125 mg twice daily)

  • Timing: twice daily

  • Co‐interventions: warfarin, diuretics, digoxin, and calcium channel blockers

  • Compliance: high

  • Duration of treatment period: 16 weeks

Control group: sildenafil (50 mg twice daily during the first 4 weeks, then uptitrated to 50 mg 3 times daily)

  • Timing: 3 times daily

  • Co‐interventions: warfarin, diuretics, digoxin, and calcium channel blockers

  • Compliance: high

  • Duration of treatment period: 16 weeks

Outcomes

Primary outcome: change in right ventricle mass from baseline
Secondary outcomes: change from baseline in 6MWD, cardiac index, Borg dyspnoea index, quality of life, and plasma B‐type natriuretic peptide level from baseline

Identification

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

"The medication was blinded in identical‐looking gelatin capsules and randomised using a computer generated random list by the Hammersmith Hospital pharmacy."

Allocation concealment (selection bias)

Low risk

"The medication was blinded in identical‐looking gelatin capsules and randomised using a computer generated random list by the Hammersmith Hospital pharmacy."

Blinding (performance bias and detection bias)
All outcomes

Low risk

"The medication was blinded in identical‐looking gelatin capsules and randomised using a computer generated random list by the Hammersmith Hospital pharmacy."

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Only 1 participant discontinued sildenafil because of death, and none discontinued bosentan during the study.

Selective reporting (reporting bias)

Unclear risk

We did not have access to the study protocol.
SERAPHIN

Study characteristics

Methods

Study design: Randomised controlled trial

Study grouping: Parallel group

Participants

Baseline characteristics

Placebo

  • n = 249

  • Female sex (%): 184 (73.9)

  • Age ‐ year, mean ± SD: 46.7 ± 17.03

  • Idiopathic PAH (%): 126 (51.0)

  • Heritable PAH (%): 3 (1.2)

  • PAH associated with CTD (%): 81 (32.8)

  • PAH associated with CHD (%): 26 (10.5)

  • PAH associated with HIV infection (%): 3 (1.2)

  • PAH associated with drug use or toxin exposure (%): 8 (3.2)

  • 6MWD, m, mean ± SD: 352 ± 110.6

  • WHO FC I (%): 0

  • WHO FC II (%): 129 (51.8)

  • WHO FC III (%): 116 (46.6)

  • WHO FC IV (%): 4 (1.6)

  • PAP, mmHg, mean ± SD: 53.1 ± 18.1

  • Cardiac index, L/min/m2 of body surface area, mean ± SD: 2.44 ± 0.80

  • PVR, dyn/s/cm5, mean ± SD: 996 ± 784.3

Macitentan (3 mg)

  • n = 248

  • Female sex (%): 187 (75.4)

  • Age ‐ year, mean ± SD: 44.5 ± 16.26

  • Idiopathic PAH (%): 144 (58.3)

  • Heritable PAH (%): 8 (3.2)

  • PAH associated with CTD (%): 70 (28.3)

  • PAH associated with CHD (%): 15 (6.1)

  • PAH associated with HIV infection (%): 1 (0.4)

  • PAH associated with drug use or toxin exposure (%): 9 (3.6)

  • 6MWD, m, mean ± SD: 364 ± 95.5

  • WHO FC I (%): 0

  • WHO FC II (%): 138 (55.6)

  • WHO FC III (%): 105 (42.3)

  • WHO FC IV (%): 5 (2.0)

  • PAH, mmHg, mean ± SD: 55.1 ± 16.7

  • Cardiac index, L/min/m2 of body surface area, mean ± SD: 2.36 ± 0.79

  • PVR, dyn/s/cm5, mean ± SD: 1044 ± 624.2

Macitentan (10 mg)

  • n = 242

  • Female sex (%): 194 (80.2)

  • Age ‐ year, mean ± SD: 45.5 ± 14.99

  • Idiopathic PAH (%): 134 (55.6)

  • Heritable PAH (%): 2 (0.8)

  • PAH associated with CTD (%): 73 (30.3)

  • PAH associated with CHD (%): 21 (8.7)

  • PAH associated with HIV infection (%): 6 (2.5)

  • PAH associated with drug use or toxin exposure (%): 5 (2.1)

  • 6MWD, m, mean ± SD: 363 ± 93.2

  • WHO FC I (%): 1 (0.4)

  • WHO FC II (%): 120 (49.6)

  • WHO FC III (%): 116 (47.9)

  • WHO VC IV (%): 5 (2.1)

  • PAP, mmHg, mean ± SD: 53.5 ± 17.6

  • Cardiac index, L/min/m2 of body surface area, mean ± SD: 2.36 ± 0.78

  • PVR, dyn/s/cm5, mean ± SD: 1040 ± 672.5

Interventions

Intervention characteristics

Placebo

  • Timing: once daily

  • Co‐interventions: concomitant treatment with oral phosphodiesterase type 5 inhibitors, oral or inhaled prostanoids, calcium‐channel blockers, or l‐arginine was allowed.

  • Compliance: high

  • Duration of treatment period: 115 weeks (median)

Macitentan (3 mg)

  • Timing: once daily

  • Co‐interventions: concomitant treatment with oral phosphodiesterase type 5 inhibitors, oral or inhaled prostanoids, calcium‐channel blockers, or l‐arginine was allowed.

  • Compliance: high

  • Duration of treatment period: 115 weeks (median)

Macitentan (10 mg)

  • Timing: once daily

  • Co‐interventions: concomitant treatment with oral phosphodiesterase type 5 inhibitors, oral or inhaled prostanoids, calcium‐channel blockers, or l‐arginine was allowed.

  • Compliance: high

  • Duration of treatment period: 115 weeks (median)

Outcomes

Change in 6MWD

Mortality

WHO FC improved

Change in mPAP

Change in cardiac index

Change in PVR

Identification

Sponsorship source: Actelion Pharmaceuticals

Setting: Muticentre, international, university‐based hospital

Author's name: Tomás Pulido

Institution: Ignacio Chávez National Heart Institute

Email: [email protected]

Address: Ignacio Chávez National Heart Institute, Juan Badiano 1, 4th Fl., Mexico City, 14080 Mexico

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Participants were randomly assigned via an interactive voice and web response system.

Allocation concealment (selection bias)

Low risk

Confirmed with the study sponsor: a central randomisation scheme was used to assign participants, and matching placebo tablets were administered to maintain blinding.

Blinding (performance bias and detection bias)
All outcomes

Low risk

"An independent clinical event committee adjudicated, in a blinded fashion"

Incomplete outcome data (attrition bias)
All outcomes

High risk

59.2% participants discontinued placebo versus 45.7% participants discontinued macitentan. The missing data were not balanced.

Selective reporting (reporting bias)

Low risk

Judgement comment: clinicaltrials.gov/ct2/show/NCT00660179
STRIDE‐1

Study characteristics

Methods

Multicentre, randomised, placebo‐controlled, parallel, double‐blind trial. Randomisation was conducted centrally according to a computer‐generated random number.

Participants

Baseline characteristics

Placebo

  • n = 60

  • Age (mean ± SD): 48 ± 14

  • Female sex (%): 47 (78)

  • Idiopathic PAH (%): 37 (62)

  • PAH associated with CTD (%): 9 (15)

  • PAH associated with CHD (%): 14 (23)

  • PAP mmHg (mean ± SD): 52 ± 16

  • Cardiac index, L/min/m2 (mean ± SD): 2.4 ± 0.8

  • PVR, dyn/s/cm5 (mean ± SD): 911 ± 504

  • 6MWD, m (mean ± SD): 413 ± 105

  • WHO FC II (%): 22 (37)

  • WHO FC III (%): 36 (60)

  • WHO FC IV (%): 2 (3)

Sitaxsentan 100 mg

  • n = 55

  • Age (mean ± SD): 45 ± 14

  • Female sex (%): 47 (85)

  • Idiopathic PAH (%): 23 (42)

  • PAH associated with CTD (%): 16 (29)

  • PAH associated with CHD (%): 16 (29)

  • PAP mmHg (mean ± SD): 54 ± 17

  • Cardiac index, L/min/m2 (mean ± SD): 2.4 ± 0.8

  • PVR, dyn/s/cm5 (mean ± SD): 1026 ± 694

  • 6MWD, m (mean ± SD): 394 ± 114

  • WHO FC II (%): 16 (29)

  • WHO FC III (%): 39 (71)

  • WHO FC IV (%): 0 (0)

Sitaxsentan 300 mg

  • n = 563

  • Age (mean ± SD): 44 ± 12

  • Female sex (%): 47 (75)

  • Idiopathic PAH (%): 34 (54)

  • PAH associated with CTD (%): 17 (27)

  • PAH associated with CHD (%): 12 (19)

  • PAP mmHg (mean ± SD): 54 ± 14

  • Cardiac index, L/min/m2 (mean ± SD): 2.3 ± 0.7

  • PVR, dyn/s/cm5 (mean ± SD): 946 ± 484

  • 6MWD, m (mean ± SD): 387 ± 110

  • WHO FC II (%): 21 (33)

  • WHO FC III (%): 42 (67)

  • WHO FC IV (%): 0 (0)

Interventions

Intervention group: 100 mg once daily or 300 mg once daily

Control group: placebo

  • Timing: once daily

  • Co‐interventions: warfarin, diuretics, calcium‐channel blockers, digoxin, supplemental oxygen

  • Compliance: high

  • Duration of treatment period: 12 weeks

Outcomes

Primary outcomes: peak oxygen consumption

Secondary outcomes: 6MWD, NYHA FC, PAP, cardiac index, and PVR

Identification

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

"Randomization was performed centrally and stratified by centre in blocks according to a computer‐generated random number table."

Allocation concealment (selection bias)

Low risk

"Randomization was performed centrally and stratified by centre in blocks according to a computer‐generated random number table."

Blinding (performance bias and detection bias)
All outcomes

Low risk

Confirmed with the study sponsor: matching placebo tablets were administered to maintain blinding.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

8.3% (5/60) participants discontinued placebo versus 5.9% (7/118) participants sitaxsentan. The missing data was few and balanced between groups.

Selective reporting (reporting bias)

Unclear risk

We did not have access to the study protocol.
STRIDE‐2

Study characteristics

Methods

Multicentre, randomised, placebo‐controlled, parallel, double‐blind trial. Randomisation was conducted centrally according to a computer‐generated random number.

Participants

Baseline characteristics

Placebo

  • n = 62

  • Age (mean ± SD): 53 ± 15

  • Female sex (%): 47 (76)

  • Idiopathic PAH (%): 37 (60)

  • PAH associated with CTD (%): 17 (27)

  • PAH associated with CHD (%): 7 (11)

  • PAP mmHg (mean ± SD): 49 ± 14

  • Cardiac index, L/min/m2 (mean ± SD): 2.4 ± 0.7

  • PVR, Wood units (mean ± SD): 11 ± 8

  • 6MWD, m (mean ± SD): 321 ± 85

  • WHO FC II (%): 23 (37)

  • WHO FC III (%): 35 (57)

  • WHO FC IV (%): 4 (6)

Sitaxsentan 50 mg

  • n = 62

  • Age (mean ± SD): 57 ± 13

  • Female sex (%): 53 (86)

  • Idiopathic PAH (%): 34 (55)

  • PAH associated with CTD (%): 19 (31)

  • PAH associated with CHD (%): 9 (14)

  • PAP mmHg (mean ± SD): 48 ± 15

  • Cardiac index, L/min/m2 (mean ± SD): 2.7 ± 1.0

  • PVR, Wood units (mean ± SD): 10 ± 7

  • 6MWD, m (mean ± SD): 328 ± 80

  • WHO FC II (%): 21 (34)

  • WHO FC III (%): 38 (61)

  • WHO FC IV (%): 3 (5)

Sitaxsentan 100 mg

  • n = 61

  • Age (mean ± SD): 55 ± 14

  • Female sex (%): 43 (71)

  • Idiopathic PAH (%): 39 (64)

  • PAH associated with CTD (%): 18 (29)

  • PAH associated with CHD (%): 4 (7)

  • PAP mmHg (mean ± SD): 45 ± 12

  • Cardiac index, L/min/m2 (mean ± SD): 2.4 ± 0.6

  • PVR, Wood units, (mean ± SD): 10 ± 7

  • 6MWD, m (mean ± SD): 360 ± 72

  • WHO FC II (%): 26 (42)

  • WHO FC III (%): 34 (56)

  • WHO FC IV (%): 1 (2)

Bosentan

  • n = 60

  • Age (mean ± SD): 49 ± 16

  • Female sex (%): 47 (78)

  • Idiopathic PAH (%): 34 (57)

  • PAH associated with CTD (%): 20 (33)

  • PAH associated with CHD (%): 6 (10)

  • PAP mmHg (mean ± SD): 50 ± 15

  • Cardiac index, L/min/m2 (mean ± SD): 2.4 ± 0.6

  • PVR, Wood units (mean ± SD): 11 ± 5

  • 6MWD, m (mean ± SD): 337 ± 78

  • WHO FC II (%): 22 (37)

  • WHO FC III (%): 37 (62)

  • WHO FC IV (%): 1 (2)

Interventions

Participants were randomised to receive placebo, sitaxsentan 50 mg or 100 mg orally once daily, or open‐label bosentan for 18 weeks.

  • Timing: once daily

  • Co‐interventions: anticoagulants, diuretics, calcium channel blockers, digoxin, and supplemental oxygen

  • Compliance: high

  • Duration of treatment period: 18

Outcomes

Primary outcomes: change from baseline in 6MWD

Secondary outcomes: change from baseline in WHO FC, Borg dyspnoea index and time to clinical worsening

Identification

‐

Notes

STRIDE‐2 trial compared sitaxsentan with both a placebo arm and an open‐label bosentan arm, therefore we have listed data for participants treated with bosentan and placebo for reference; however, we did not pool these data with the other data.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

"Randomization was performed centrally according to a computer‐generated random number table. Randomization was 1:1:1:1."

Allocation concealment (selection bias)

Low risk

"Randomization was performed centrally and stratified by centre in blocks according to a computer‐generated random number table."

Blinding (performance bias and detection bias)
All outcomes

Low risk

Confirmed with the study sponsor: matching placebo tablets were administered to maintain blinding.

Incomplete outcome data (attrition bias)
All outcomes

High risk

17.7% (5/60) participants discontinued placebo versus 8.2% (20/245) sitaxsentan. The missing data were imbalanced between groups.

Selective reporting (reporting bias)

Unclear risk

We did not have access to the study protocol.
STRIDE‐4

Study characteristics

Methods

Multicentre, randomised, placebo‐controlled, parallel, double‐blind trial

Participants

Baseline characteristics

Placebo

  • n = 34

  • Age (mean ± SD): 40 ± 14

  • Female sex (%): 28 (82)

  • Idiopathic PAH (%): 22 (65)

  • PAH associated with CTD (%): 3 (9)

  • PAH associated with CHD (%): 9 (27)

  • PAP mmHg (mean ± SD): 64 ± 14

  • PVR, mmHg/L/min (mean ± SD): 15 ± 10

  • 6MWD, m (mean ± SD): 342 ± 82

  • WHO FC II (%): 19 (56)

  • WHO FC III (%): 14 (41)

  • WHO FC IV (%): 1 (3)

Sitaxsentan 50 mg

  • n = 32

  • Age (mean ± SD): 44 ± 13

  • Female sex (%): 25 (78)

  • Idiopathic PAH (%): 23 (72)

  • PAH associated with CTD (%): 7 (22)

  • PAH associated with CHD (%): 2 (6)

  • PAP mmHg (mean ± SD): 56 ± 17

  • PVR, mmHg/L/min (mean ± SD): 14 ± 10

  • 6MWD, m (mean ± SD): 350 ± 73

  • WHO FC II (%): 23 (72)

  • WHO FC III (%): 9 (28)

  • WHO FC IV (%): 0 (0)

Sitaxsentan 100 mg

  • n = 32

  • Age (mean ± SD): 40 ± 14

  • Female sex (%): 29 (91)

  • Idiopathic PAH (%): 22 (69)

  • PAH associated with CTD (%): 5 (16)

  • PAH associated with CHD (%): 5 (16)

  • PAP mmHg (mean ± SD): 63 ± 23

  • PVR, mmHg/L/min (mean ± SD): 14 ± 8

  • 6MWD, m (mean ± SD): 344 ± 83

  • WHO FC II (%): 18 (56)

  • WHO FC III (%): 14 (44)

  • WHO FC IV (%): 0 (0)

Interventions

Participants were randomised to receive placebo, sitaxsentan 50 mg, or sitaxsentan 100 mg orally once daily for 18 weeks.

  • Timing: once daily

  • Co‐interventions: anticoagulants, diuretics, calcium channel blockers, digoxin, and supplemental oxygen

  • Compliance: high

  • Duration of treatment period: 18 weeks

Outcomes

Primary outcomes: change from baseline in 6MWD

Secondary outcomes: change from baseline in WHO FC, Borg dyspnoea index and time to clinical worsening

Identification

‐

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

"Randomization was performed centrally and stratified by centre in blocks according to a computer‐generated random number table."

Allocation concealment (selection bias)

Low risk

"Randomization was performed centrally and stratified by centre in blocks according to a computer‐generated random number table."

Blinding (performance bias and detection bias)
All outcomes

Low risk

Confirmed with the study sponsor: matching placebo tablets were administered to maintain blinding.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

12.5% (4/32) participants discontinued placebo versus 10.9% (7/64) sitaxsentan. The missing data were balanced between groups.

Selective reporting (reporting bias)

Unclear risk

We did not have access to the study protocol.

6MWD: 6‐minute walk distance; BNP: B‐type natriuretic peptide; CAD: coronary artery disease; CHD: congenital heart disease; CTD: connective tissue disease; mPAP: mean pulmonary artery pressure; mRAP: mean right atrial pressure; NYHA FC: New York Heart Association functional class; PAH: pulmonary arterial hypertension; PAP: pulmonary artery pressure; PDE5: phosphodiesterase type 5; PH: pulmonary hypertension; PVR: pulmonary vascular resistance; RAP: right atrial pressure; SD: standard deviation; SF‐36: 36‐item Short Form Health Survey; SpO2: oxygen saturation; SSc: systemic sclerosis; WHO FC: World Health Organization functional class

Characteristics of excluded studies [ordered by study ID]

Ir a:

Study

Reason for exclusion

Ahn 2014

Participants did not have PAH.

ASSET‐2

Participants did not have PAH.

Atsmon 2013

RCT, but populations did not have PAH.

Barst 2011

Participants were not randomised to an ERA.

Baughman 2014

Participants did not have PAH.

Benza 2007

Participants were not randomised to an ERA.

Bose 2011

Participants did not have PAH.

Bruderer 2014

Participants did not have PAH.

BUILD‐2

Participants did not have PAH.

Burgess 2008

Participants did not have PAH.

Cardenas 2020

Participants did not have PAH.

Chin 2020

Participants were not randomised to an ERA.

Coyne 2005

Participants did not have PAH.

Danaietash 2019

Participants did not have PAH.

Denault 2013

Participants did not have PAH.

Dhaun 2011

Participants did not have PAH.

Escribano‐Subias 2019

Participants did not have PAH.

Faoro 2009

Participants did not have PAH.

Fatima 2018

Participants did not have PAH.

Frey 2008

Participants did not have PAH.

Galiè 2005

Participants were not randomised to an ERA.

Galiè 2009a

Participants were not randomised to an ERA.

Galiè 2009b

Long‐term follow‐up data of RCT using sitaxsentan

Galiè 2010

Participants were not randomised to an ERA.

Ghofrani 2010

Participants were not randomised to an ERA.

Ghofrani 2017

Participants did not have PAH.

Gillies 2011

Participants did not have PAH.

Gillies 2013

Participants did not have PAH.

Givertz 2000

Participants did not have PAH.

Gomberg‐Maitland 2005

Participants were not randomised to an ERA.

Gotti 2014

Participants did not have PAH.

Gotzkowsky 2010

Participants did not have PAH.

Grander 2014

Participants did not have PAH.

Grill 2020

Participants did not have PAH.

Gutierrez 2013

Participants did not have PAH.

Han 2017

Mixed population used.

Hill 2018

Participants did not have PAH.

Hoeper 2006

Participants were not randomised to an ERA.

Howard 2019

Participants did not have PAH.

Huez 2009

Participants did not have PAH.

Hurst 2016

Participants did not have PAH.

Iversen 2010

Participants were not randomised to an ERA.

Jais 2008

Participants did not have PAH.

Kalra 2002

Participants did not have PAH.

Kaluski 2008

Participants did not have PAH.

Kefford 2010

Participants did not have PAH.

Keir 2013

Participants did not have PAH.

Keir 2014

Participants did not have PAH.

King 2008

Participants did not have PAH

Kiowski 1995

Participants did not have PAH.

Koller 2017

Participants did not have PAH.

Korn 2004

Participants did not have PAH.

Lee 2009

Participants were not randomised to an ERA.

Lindegger 2014

Participants did not have PAH.

Mazzanti 2013

Duplicate publications

McLaughlin 2003

Participants were not randomised to an ERA.

McLaughlin 2006

Participants were not randomised to an ERA.

McLaughlin 2010

Participants were not randomised to an ERA.

Mereles 2006

Participants were not randomised to an ERA.

Metersky 2011

Participants did not have PAH.

Modesti 2006

Participants did not have PAH.

Naeije 2010

Participants did not have PAH.

Nakahara 2010

Participants did not have PAH.

NCT00077584

Participants did not have PAH.

Okour 2019

Participants did not have PAH.

Oudiz 2007

Long‐term follow‐up data of RCT using sitaxsentan

Oudiz 2009

Long‐term follow‐up data of RCT using sitaxsentan

Palazzini 2010

Participants did not have PAH.

Raghu 2013

Participants did not have PAH.

Raghu 2015

Participants did not have PAH.

Reesink 2010

Participants did not have PAH.

Robbins 2006

Participants were not randomised to an ERA.

Schmetterer 1998

Participants did not have PAH.

Schmidt 2001

Participants did not have PAH.

Schuuring 2013

Participants did not have PAH.

Seheult 2009

Participants did not have PAH.

Seibold 2010

Participants did not have PAH.

Sfikakis 2007

Participants did not have PAH.

Shang 2013

Participants did not have PAH.

Shang 2016

Participants did not have PAH.

Sharma 2014

Participants did not have PAH.

Shenoy 2011

Participants did not have PAH.

Sidharta 2010

Participants did not have PAH.

Sidharta 2013a

Participants did not have PAH.

Sidharta 2013b

Participants did not have PAH.

Sidharta 2014

Participants did not have PAH.

Simonneau 2010

Participants were not randomised to an ERA.

Simonneau 2017

Participants did not have PAH.

Spence 2008

Participants did not have PAH.

Spence 2009

Participants did not have PAH.

Stavros 2010

Participants did not have PAH.

Stolz 2008

Participants did not have PAH.

Surie 2013

Participants did not have PAH.

Tanaka 2017

Participants did not have PAH.

Tanaka 2019

Participants did not have PAH.

Vachiery 2018

Participants did not have PAH.

Van Der Zander 2006

Participants did not have PAH.

Van Giersbergen 2005

Participants did not have PAH.

Webb 2017

Participants did not have PAH.

Worthington 2010

Participants were not randomised to an ERA.

Wrishko 2008

Participants did not have PAH.

ERA: endothelin receptor antagonists; PAH: pulmonary arterial hypertension; RCT: randomised controlled trial

Characteristics of studies awaiting classification [ordered by study ID]

Ir a:

Dwivedi 2018

Methods

Randomisation method was not clear.

Participants

Pulmonary arterial hypertension in systemic sclerosis

Inclusion criteria:

  • Male or female participants aged 18 years

  • Participants with systemic sclerosis

  • PAH diagnosed as PAP > 35 mmHg

  • NYHA FC II, III, IV

  • SSc disease duration > 1 year

Exclusion criteria:

  • Forced vital capacity < 60% predicted

  • Renal insufficiency

  • Left heart disease and other relevant cardiac conditions

  • Pregnant or breastfeeding female

  • Participants on PAH specific therapy

  • Liver disease

Interventions

Sildenafil 20 mg and bosentan 62.5 mg versus sildenafil 20 mg and placebo

Outcomes

Primary outcome measures:

  • Change in pulmonary artery pressures [ Time Frame: Baseline and 6 months ]

    • Change in pulmonary artery pressures measured by echocardiography at baseline and 6 months in participants of systemic sclerosis with PAH when treatment with single (PDE5 inhibitors at dose of 20 mg maximum up to 60 mg) versus dual therapy (PDE5 inhibitors and ERA 62.5 mg maximum up to 125 mg) for 6 months

Secondary outcome measures:

  • Change in 6MWD [ Time Frame: Baseline and 6 months ]

    • To compare change in 6MWD at baseline and 6 months when treated with single versus dual therapy

  • Time to clinical worsening (TTCW) [ Time Frame: Baseline and 6 months ]

    • To compare time to clinical worsening (TTCW) in SSc participants when treated with single versus dual therapy. TTCW is defined as first occurrence of all‐cause deaths, PAH related hospitalisation, worsening of symptoms defined as a decrease of > 15% in 6MWD, and worsening of NYHA FC.

  • Emergent side effects of sildenafil and bosentan [ Time Frame: Baseline to 6 months ]

    • To compare the emergent side effects of sildenafil and bosentan by way of comparison of serious and non‐serious side effects

Notes
Rinaldi 2018

Methods

Randomisation method was not clear.

Participants

PAH patients with WHO FC II or III

Interventions

Intervention characteristics

Combination (ambrisentan plus tadalafil) therapy

  • Timing: once daily

Ambrisentan monotherapy

  • Timing: once daily

Tadalafil monotherapy

  • Timing: once daily

Outcomes

Change in mPAP

Change in RAP

Change in PVR

Change from baseline in 6MWD

Change in MVO2

Notes

6MWD: 6‐minute walk distance; ERA: endothelin receptor antagonist; mPAP: mean pulmonary artery pressure; MVO2: mixed venous oxygen saturation; NYHA FC: New York Heart Association functional class; PAH: pulmonary arterial hypertension; PAP: pulmonary artery pressure; PDE5: phosphodiesterase type 5; PVR: pulmonary vascular resistance; RAP: right atrial pressure; NT‐proBNP; N‐terminal pro B‐type natriuretic peptide; SSc: systemic sclerosis; TPR: total pulmonary resistance; WHO FC: World Health Organization functional class

Data and analyses

Open in table viewer
Comparison 1. Endothelin receptor antagonists versus placebo

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1.1 Change from baseline in 6‐minute walk Show forest plot

14

2739

Mean Difference (IV, Random, 95% CI)

25.06 [17.13, 32.99]
Analysis 1.1
Comparison 1: Endothelin receptor antagonists versus placebo, Outcome 1: Change from baseline in 6‐minute walk

Comparison 1: Endothelin receptor antagonists versus placebo, Outcome 1: Change from baseline in 6‐minute walk

1.1.1 Non‐selective ERA

8

1860

Mean Difference (IV, Random, 95% CI)

20.51 [10.03, 31.00]

1.1.2 Selective ERA

6

879

Mean Difference (IV, Random, 95% CI)

33.48 [23.12, 43.83]

1.2 Proportion of participants with improved functional class Show forest plot

15

3060

Odds Ratio (M‐H, Fixed, 95% CI)

1.41 [1.16, 1.70]
Analysis 1.2
Comparison 1: Endothelin receptor antagonists versus placebo, Outcome 2: Proportion of participants with improved functional class

Comparison 1: Endothelin receptor antagonists versus placebo, Outcome 2: Proportion of participants with improved functional class

1.2.1 Non‐selective ERAs

9

1896

Odds Ratio (M‐H, Fixed, 95% CI)

1.45 [1.13, 1.87]

1.2.2 Selective ERAs

6

1164

Odds Ratio (M‐H, Fixed, 95% CI)

1.35 [1.01, 1.80]

1.3 Proportion of participants with deteriorated functional class Show forest plot

13

2347

Odds Ratio (M‐H, Random, 95% CI)

0.43 [0.26, 0.72]
Analysis 1.3
Comparison 1: Endothelin receptor antagonists versus placebo, Outcome 3: Proportion of participants with deteriorated functional class

Comparison 1: Endothelin receptor antagonists versus placebo, Outcome 3: Proportion of participants with deteriorated functional class

1.3.1 Non‐selective ERA

7

1121

Odds Ratio (M‐H, Random, 95% CI)

0.65 [0.30, 1.42]

1.3.2 Selective ERAs

6

1226

Odds Ratio (M‐H, Random, 95% CI)

0.31 [0.17, 0.60]

1.4 Change from baseline in Borg dyspnoea index Show forest plot

7

788

Mean Difference (IV, Random, 95% CI)

‐0.43 [‐0.90, 0.04]
Analysis 1.4
Comparison 1: Endothelin receptor antagonists versus placebo, Outcome 4: Change from baseline in Borg dyspnoea index

Comparison 1: Endothelin receptor antagonists versus placebo, Outcome 4: Change from baseline in Borg dyspnoea index

1.4.1 Non‐selective ERAs

3

240

Mean Difference (IV, Random, 95% CI)

‐0.27 [‐1.58, 1.03]

1.4.2 Selective ERAs

4

548

Mean Difference (IV, Random, 95% CI)

‐0.43 [‐1.01, 0.14]

1.5 Mortality Show forest plot

12

2889

Odds Ratio (M‐H, Fixed, 95% CI)

0.78 [0.58, 1.07]
Analysis 1.5
Comparison 1: Endothelin receptor antagonists versus placebo, Outcome 5: Mortality

Comparison 1: Endothelin receptor antagonists versus placebo, Outcome 5: Mortality

1.5.1 Non‐selective ERAs

7

1759

Odds Ratio (M‐H, Fixed, 95% CI)

0.88 [0.62, 1.23]

1.5.2 Selective ERAs

5

1130

Odds Ratio (M‐H, Fixed, 95% CI)

0.45 [0.21, 0.94]

1.6 Change from baseline in mean pulmonary artery pressure Show forest plot

8

729

Mean Difference (IV, Random, 95% CI)

‐4.65 [‐6.05, ‐3.26]
Analysis 1.6
Comparison 1: Endothelin receptor antagonists versus placebo, Outcome 6: Change from baseline in mean pulmonary artery pressure

Comparison 1: Endothelin receptor antagonists versus placebo, Outcome 6: Change from baseline in mean pulmonary artery pressure

1.6.1 Non‐selective ERAs

6

519

Mean Difference (IV, Random, 95% CI)

‐5.79 [‐7.30, ‐4.27]

1.6.2 Selective ERAs

2

210

Mean Difference (IV, Random, 95% CI)

‐2.65 [‐5.31, 0.00]

1.7 Change from baseline in pulmonary vascular resistance Show forest plot

7

586

Mean Difference (IV, Random, 95% CI)

‐236.24 [‐333.21, ‐139.26]
Analysis 1.7
Comparison 1: Endothelin receptor antagonists versus placebo, Outcome 7: Change from baseline in pulmonary vascular resistance

Comparison 1: Endothelin receptor antagonists versus placebo, Outcome 7: Change from baseline in pulmonary vascular resistance

1.7.1 Non‐selective ERAs

5

376

Mean Difference (IV, Random, 95% CI)

‐281.74 [‐395.85, ‐167.63]

1.7.2 Selective ERAs

2

210

Mean Difference (IV, Random, 95% CI)

‐173.73 [‐332.52, ‐14.94]

1.8 Pulmonary vascular resistance Show forest plot

2

175

Mean Difference (IV, Fixed, 95% CI)

‐288.59 [‐472.18, ‐104.99]
Analysis 1.8
Comparison 1: Endothelin receptor antagonists versus placebo, Outcome 8: Pulmonary vascular resistance

Comparison 1: Endothelin receptor antagonists versus placebo, Outcome 8: Pulmonary vascular resistance

1.9 Ratio of geometric mean PVR Show forest plot

3

Ratio of Geometric mean (IV, Random, 95% CI)

Subtotals only
Analysis 1.9
Comparison 1: Endothelin receptor antagonists versus placebo, Outcome 9: Ratio of geometric mean PVR

Comparison 1: Endothelin receptor antagonists versus placebo, Outcome 9: Ratio of geometric mean PVR

1.9.1 Selective ERAs

0

Ratio of Geometric mean (IV, Random, 95% CI)

Not estimable

1.9.2 Non‐selective ERAs

3

Ratio of Geometric mean (IV, Random, 95% CI)

0.69 [0.60, 0.80]

1.10 Change from baseline in cardiac index Show forest plot

7

718

Mean Difference (IV, Random, 95% CI)

0.50 [0.35, 0.65]
Analysis 1.10
Comparison 1: Endothelin receptor antagonists versus placebo, Outcome 10: Change from baseline in cardiac index

Comparison 1: Endothelin receptor antagonists versus placebo, Outcome 10: Change from baseline in cardiac index

1.10.1 Non‐selective ERAs

5

509

Mean Difference (IV, Random, 95% CI)

0.55 [0.34, 0.77]

1.10.2 Selective ERAs

2

209

Mean Difference (IV, Random, 95% CI)

0.39 [0.23, 0.54]

1.11 Change from baseline in SpO 2 Show forest plot

1

Mean Difference (IV, Fixed, 95% CI)

Totals not selected
Analysis 1.11
Comparison 1: Endothelin receptor antagonists versus placebo, Outcome 11: Change from baseline in SpO 2

Comparison 1: Endothelin receptor antagonists versus placebo, Outcome 11: Change from baseline in SpO 2

1.12 Hepatic toxicity Show forest plot

11

2250

Odds Ratio (M‐H, Random, 95% CI)

1.88 [0.91, 3.90]
Analysis 1.12
Comparison 1: Endothelin receptor antagonists versus placebo, Outcome 12: Hepatic toxicity

Comparison 1: Endothelin receptor antagonists versus placebo, Outcome 12: Hepatic toxicity

1.12.1 Non‐selective ERAs

9

1888

Odds Ratio (M‐H, Random, 95% CI)

2.33 [0.98, 5.56]

1.12.2 Selective ERAs

2

362

Odds Ratio (M‐H, Random, 95% CI)

0.89 [0.31, 2.51]
Open in table viewer
Comparison 2. Endothelin receptor antagonists versus PDE5 inhibitor

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

2.1 6‐minute walk Show forest plot

1

Mean Difference (IV, Fixed, 95% CI)

Totals not selected
Analysis 2.1
Comparison 2: Endothelin receptor antagonists versus PDE5 inhibitor, Outcome 1: 6‐minute walk

Comparison 2: Endothelin receptor antagonists versus PDE5 inhibitor, Outcome 1: 6‐minute walk

2.2 Proportion of participants with improved functional class Show forest plot

1

Odds Ratio (M‐H, Fixed, 95% CI)

Totals not selected
Analysis 2.2
Comparison 2: Endothelin receptor antagonists versus PDE5 inhibitor, Outcome 2: Proportion of participants with improved functional class

Comparison 2: Endothelin receptor antagonists versus PDE5 inhibitor, Outcome 2: Proportion of participants with improved functional class

2.3 Proportion of participants with deteriorated functional class Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected
Analysis 2.3
Comparison 2: Endothelin receptor antagonists versus PDE5 inhibitor, Outcome 3: Proportion of participants with deteriorated functional class

Comparison 2: Endothelin receptor antagonists versus PDE5 inhibitor, Outcome 3: Proportion of participants with deteriorated functional class

2.4 Symptoms Show forest plot

1

Mean Difference (IV, Fixed, 95% CI)

Totals not selected
Analysis 2.4
Comparison 2: Endothelin receptor antagonists versus PDE5 inhibitor, Outcome 4: Symptoms

Comparison 2: Endothelin receptor antagonists versus PDE5 inhibitor, Outcome 4: Symptoms

2.5 Mortality Show forest plot

2

273

Odds Ratio (M‐H, Fixed, 95% CI)

0.32 [0.07, 1.36]
Analysis 2.5
Comparison 2: Endothelin receptor antagonists versus PDE5 inhibitor, Outcome 5: Mortality

Comparison 2: Endothelin receptor antagonists versus PDE5 inhibitor, Outcome 5: Mortality

2.6 Cardiac index Show forest plot

1

Mean Difference (IV, Fixed, 95% CI)

Totals not selected
Analysis 2.6
Comparison 2: Endothelin receptor antagonists versus PDE5 inhibitor, Outcome 6: Cardiac index

Comparison 2: Endothelin receptor antagonists versus PDE5 inhibitor, Outcome 6: Cardiac index

Open in table viewer
Comparison 3. Endothelin receptor antagonists in Eisenmenger syndrome

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

3.1 Change from baseline in 6‐minute walk Show forest plot

2

280

Mean Difference (IV, Random, 95% CI)

21.49 [‐31.23, 74.21]
Analysis 3.1
Comparison 3: Endothelin receptor antagonists in Eisenmenger syndrome, Outcome 1: Change from baseline in 6‐minute walk

Comparison 3: Endothelin receptor antagonists in Eisenmenger syndrome, Outcome 1: Change from baseline in 6‐minute walk

3.1.1 Non‐selective ERA

2

280

Mean Difference (IV, Random, 95% CI)

21.49 [‐31.23, 74.21]

3.1.2 Selective ERA

0

0

Mean Difference (IV, Random, 95% CI)

Not estimable

3.2 Proportion of participants with improved functional class Show forest plot

2

280

Odds Ratio (M‐H, Fixed, 95% CI)

0.95 [0.48, 1.90]
Analysis 3.2
Comparison 3: Endothelin receptor antagonists in Eisenmenger syndrome, Outcome 2: Proportion of participants with improved functional class

Comparison 3: Endothelin receptor antagonists in Eisenmenger syndrome, Outcome 2: Proportion of participants with improved functional class

3.2.1 Non‐selective ERAs

2

280

Odds Ratio (M‐H, Fixed, 95% CI)

0.95 [0.48, 1.90]

3.2.2 Selective ERAs

0

0

Odds Ratio (M‐H, Fixed, 95% CI)

Not estimable

3.3 Proportion of participants with deteriorated functional class Show forest plot

2

280

Odds Ratio (M‐H, Random, 95% CI)

0.67 [0.09, 4.85]
Analysis 3.3
Comparison 3: Endothelin receptor antagonists in Eisenmenger syndrome, Outcome 3: Proportion of participants with deteriorated functional class

Comparison 3: Endothelin receptor antagonists in Eisenmenger syndrome, Outcome 3: Proportion of participants with deteriorated functional class

3.3.1 Non‐selective ERA

2

280

Odds Ratio (M‐H, Random, 95% CI)

0.67 [0.09, 4.85]

3.3.2 Selective ERAs

0

0

Odds Ratio (M‐H, Random, 95% CI)

Not estimable

3.4 Mortality Show forest plot

1

Odds Ratio (M‐H, Fixed, 95% CI)

Totals not selected
Analysis 3.4
Comparison 3: Endothelin receptor antagonists in Eisenmenger syndrome, Outcome 4: Mortality

Comparison 3: Endothelin receptor antagonists in Eisenmenger syndrome, Outcome 4: Mortality

3.4.1 Non‐selective ERAs

1

Odds Ratio (M‐H, Fixed, 95% CI)

Totals not selected

3.4.2 Selective ERAs

0

Odds Ratio (M‐H, Fixed, 95% CI)

Totals not selected

3.5 Change from baseline in mean pulmonary arterial pressure Show forest plot

2

90

Mean Difference (IV, Fixed, 95% CI)

‐4.63 [‐8.03, ‐1.23]
Analysis 3.5
Comparison 3: Endothelin receptor antagonists in Eisenmenger syndrome, Outcome 5: Change from baseline in mean pulmonary arterial pressure

Comparison 3: Endothelin receptor antagonists in Eisenmenger syndrome, Outcome 5: Change from baseline in mean pulmonary arterial pressure

3.5.1 Non‐selective ERAs

2

90

Mean Difference (IV, Fixed, 95% CI)

‐4.63 [‐8.03, ‐1.23]

3.5.2 Selective ERAs

0

0

Mean Difference (IV, Fixed, 95% CI)

Not estimable

3.6 Change from baseline in pulmonary vascular resistance Show forest plot

2

93

Mean Difference (IV, Fixed, 95% CI)

‐480.07 [‐753.34, ‐206.79]
Analysis 3.6
Comparison 3: Endothelin receptor antagonists in Eisenmenger syndrome, Outcome 6: Change from baseline in pulmonary vascular resistance

Comparison 3: Endothelin receptor antagonists in Eisenmenger syndrome, Outcome 6: Change from baseline in pulmonary vascular resistance

3.6.1 Non‐selective ERAs

2

93

Mean Difference (IV, Fixed, 95% CI)

‐480.07 [‐753.34, ‐206.79]

3.6.2 Selective ERAs

0

0

Mean Difference (IV, Fixed, 95% CI)

Not estimable

3.7 Change from baseline in SpO 2 Show forest plot

1

Mean Difference (IV, Fixed, 95% CI)

Totals not selected
Analysis 3.7
Comparison 3: Endothelin receptor antagonists in Eisenmenger syndrome, Outcome 7: Change from baseline in SpO 2

Comparison 3: Endothelin receptor antagonists in Eisenmenger syndrome, Outcome 7: Change from baseline in SpO 2

Study flow diagram.

Figuras y tablas -
Figure 1

Study flow diagram.

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'Risk of bias' summary: review authors' judgements about each risk of bias item for each included study.

Figuras y tablas -
Figure 2

'Risk of bias' summary: review authors' judgements about each risk of bias item for each included study.

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Comparison 1: Endothelin receptor antagonists versus placebo, Outcome 1: Change from baseline in 6‐minute walk

Figuras y tablas -
Analysis 1.1

Comparison 1: Endothelin receptor antagonists versus placebo, Outcome 1: Change from baseline in 6‐minute walk

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Comparison 1: Endothelin receptor antagonists versus placebo, Outcome 2: Proportion of participants with improved functional class

Figuras y tablas -
Analysis 1.2

Comparison 1: Endothelin receptor antagonists versus placebo, Outcome 2: Proportion of participants with improved functional class

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Comparison 1: Endothelin receptor antagonists versus placebo, Outcome 3: Proportion of participants with deteriorated functional class

Figuras y tablas -
Analysis 1.3

Comparison 1: Endothelin receptor antagonists versus placebo, Outcome 3: Proportion of participants with deteriorated functional class

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Comparison 1: Endothelin receptor antagonists versus placebo, Outcome 4: Change from baseline in Borg dyspnoea index

Figuras y tablas -
Analysis 1.4

Comparison 1: Endothelin receptor antagonists versus placebo, Outcome 4: Change from baseline in Borg dyspnoea index

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Comparison 1: Endothelin receptor antagonists versus placebo, Outcome 5: Mortality

Figuras y tablas -
Analysis 1.5

Comparison 1: Endothelin receptor antagonists versus placebo, Outcome 5: Mortality

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Comparison 1: Endothelin receptor antagonists versus placebo, Outcome 6: Change from baseline in mean pulmonary artery pressure

Figuras y tablas -
Analysis 1.6

Comparison 1: Endothelin receptor antagonists versus placebo, Outcome 6: Change from baseline in mean pulmonary artery pressure

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Comparison 1: Endothelin receptor antagonists versus placebo, Outcome 7: Change from baseline in pulmonary vascular resistance

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Analysis 1.7

Comparison 1: Endothelin receptor antagonists versus placebo, Outcome 7: Change from baseline in pulmonary vascular resistance

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Comparison 1: Endothelin receptor antagonists versus placebo, Outcome 8: Pulmonary vascular resistance

Figuras y tablas -
Analysis 1.8

Comparison 1: Endothelin receptor antagonists versus placebo, Outcome 8: Pulmonary vascular resistance

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Comparison 1: Endothelin receptor antagonists versus placebo, Outcome 9: Ratio of geometric mean PVR

Figuras y tablas -
Analysis 1.9

Comparison 1: Endothelin receptor antagonists versus placebo, Outcome 9: Ratio of geometric mean PVR

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Comparison 1: Endothelin receptor antagonists versus placebo, Outcome 10: Change from baseline in cardiac index

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Analysis 1.10

Comparison 1: Endothelin receptor antagonists versus placebo, Outcome 10: Change from baseline in cardiac index

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Comparison 1: Endothelin receptor antagonists versus placebo, Outcome 11: Change from baseline in SpO 2

Figuras y tablas -
Analysis 1.11

Comparison 1: Endothelin receptor antagonists versus placebo, Outcome 11: Change from baseline in SpO 2

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Comparison 1: Endothelin receptor antagonists versus placebo, Outcome 12: Hepatic toxicity

Figuras y tablas -
Analysis 1.12

Comparison 1: Endothelin receptor antagonists versus placebo, Outcome 12: Hepatic toxicity

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Comparison 2: Endothelin receptor antagonists versus PDE5 inhibitor, Outcome 1: 6‐minute walk

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Analysis 2.1

Comparison 2: Endothelin receptor antagonists versus PDE5 inhibitor, Outcome 1: 6‐minute walk

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Comparison 2: Endothelin receptor antagonists versus PDE5 inhibitor, Outcome 2: Proportion of participants with improved functional class

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Analysis 2.2

Comparison 2: Endothelin receptor antagonists versus PDE5 inhibitor, Outcome 2: Proportion of participants with improved functional class

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Comparison 2: Endothelin receptor antagonists versus PDE5 inhibitor, Outcome 3: Proportion of participants with deteriorated functional class

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Analysis 2.3

Comparison 2: Endothelin receptor antagonists versus PDE5 inhibitor, Outcome 3: Proportion of participants with deteriorated functional class

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Comparison 2: Endothelin receptor antagonists versus PDE5 inhibitor, Outcome 4: Symptoms

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Analysis 2.4

Comparison 2: Endothelin receptor antagonists versus PDE5 inhibitor, Outcome 4: Symptoms

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Comparison 2: Endothelin receptor antagonists versus PDE5 inhibitor, Outcome 5: Mortality

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Analysis 2.5

Comparison 2: Endothelin receptor antagonists versus PDE5 inhibitor, Outcome 5: Mortality

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Comparison 2: Endothelin receptor antagonists versus PDE5 inhibitor, Outcome 6: Cardiac index

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Analysis 2.6

Comparison 2: Endothelin receptor antagonists versus PDE5 inhibitor, Outcome 6: Cardiac index

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Comparison 3: Endothelin receptor antagonists in Eisenmenger syndrome, Outcome 1: Change from baseline in 6‐minute walk

Figuras y tablas -
Analysis 3.1

Comparison 3: Endothelin receptor antagonists in Eisenmenger syndrome, Outcome 1: Change from baseline in 6‐minute walk

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Comparison 3: Endothelin receptor antagonists in Eisenmenger syndrome, Outcome 2: Proportion of participants with improved functional class

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Analysis 3.2

Comparison 3: Endothelin receptor antagonists in Eisenmenger syndrome, Outcome 2: Proportion of participants with improved functional class

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Comparison 3: Endothelin receptor antagonists in Eisenmenger syndrome, Outcome 3: Proportion of participants with deteriorated functional class

Figuras y tablas -
Analysis 3.3

Comparison 3: Endothelin receptor antagonists in Eisenmenger syndrome, Outcome 3: Proportion of participants with deteriorated functional class

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Comparison 3: Endothelin receptor antagonists in Eisenmenger syndrome, Outcome 4: Mortality

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Analysis 3.4

Comparison 3: Endothelin receptor antagonists in Eisenmenger syndrome, Outcome 4: Mortality

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Comparison 3: Endothelin receptor antagonists in Eisenmenger syndrome, Outcome 5: Change from baseline in mean pulmonary arterial pressure

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Analysis 3.5

Comparison 3: Endothelin receptor antagonists in Eisenmenger syndrome, Outcome 5: Change from baseline in mean pulmonary arterial pressure

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Comparison 3: Endothelin receptor antagonists in Eisenmenger syndrome, Outcome 6: Change from baseline in pulmonary vascular resistance

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Analysis 3.6

Comparison 3: Endothelin receptor antagonists in Eisenmenger syndrome, Outcome 6: Change from baseline in pulmonary vascular resistance

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Comparison 3: Endothelin receptor antagonists in Eisenmenger syndrome, Outcome 7: Change from baseline in SpO 2

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Analysis 3.7

Comparison 3: Endothelin receptor antagonists in Eisenmenger syndrome, Outcome 7: Change from baseline in SpO 2

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Summary of findings 1. Endothelin receptor antagonists compared to placebo for pulmonary arterial hypertension

Endothelin receptor antagonists compared to placebo for pulmonary arterial hypertension

Participant or population: pulmonary arterial hypertension
Setting: clinics and hospitals
Intervention: endothelin receptor antagonists
Comparison: placebo

Outcomes

Anticipated absolute effects* (95% CI)

Relative effect
(95% CI)

№ of participants
(studies)

Certainty of the evidence
(GRADE)

Comments

Risk with placebo

Risk with endothelin receptor antagonists

Change from baseline in 6MWD (m)

mean duration of study 16.3 weeks

The weighted mean change on control was −4.56 m.

MD 25.06 higher
(17.13 higher to 32.99 higher)

‐

2739
(14 RCTs)

⊕⊕⊕⊝
Moderate1

Higher is better for 6MWD.

Proportion of participants with improved functional class

mean duration of study 16.8 weeks

175 per 1000

230 per 1000
(197 to 264)

OR 1.41
(1.16 to 1.70)

3060
(15 RCTs)

⊕⊕⊕⊝
Moderate1

Participants with high OR are more likely to achieve functional improvement.

Change from baseline in BDI

mean duration of study 14.3 weeks

The weighted mean change on control was 0.25 higher.

MD 0.43 lower
(0.90 lower to 0.04 higher)

‐

788
(7 RCTs)

⊕⊕⊝⊝Low2

Symptoms are worse with higher score of BDI.

Mortality

mean duration of study 30.2 weeks

73 per 1000

58 per 1000
(44 to 78)

OR 0.78
(0.58 to 1.07)

2889
(12 RCTs)

⊕⊕⊝⊝
Low3

Participants with lower OR are less likely to die.

Change from baseline in mean PAP (mmHg)

mean duration of study 17.1 weeks

The weighted mean change on control was 0.53 higher.

MD 4.65 lower
(6.05 lower to 3.26 lower)

‐

729
(8 RCTs)

⊕⊕⊕⊝
Moderate4

Participants are worse with higher pulmonary artery pressure.

Change from baseline in PVR (dyn/s/cm5)

mean duration of study 15.7 weeks

The weighted mean change on control was 63.55 higher.

MD 236.24 lower
(333.21 lower to 139.26 lower)

‐

586
(7 RCTs)

⊕⊕⊕⊝
Moderate4

Participants are worse with higher pulmonary vascular resistance.

Hepatic toxicity

mean duration of study 25 weeks

37 per 1000

67 per 1000
(34 to 130)

OR 1.88
(0.91 to 3.90)

2250
(11 RCTs)

⊕⊕⊕⊝
Moderate1

Participants with higher OR are more likely to suffer hepatic toxicity.

*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).

6MWD: 6‐minute walk distance; BDI: Borg dyspnoea index; CI: confidence interval; MD: mean difference; OR: odds ratio; PAP: pulmonary artery pressure; PVR: pulmonary vascular resistance; RCT: randomised controlled trial

GRADE Working Group grades of evidence
High certainty: We are very confident that the true effect lies close to that of the estimate of the effect.
Moderate certainty: We are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.
Low certainty: Our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect.
Very low certainty: We have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

1Incomplete outcome data (attrition bias) due to missing data imbalanced between intervention and control groups in most of the included studies (−1 level).
2Attrition, publication bias and wide upper confidence interval (−2 levels).
3We downgraded the evidence for the outcome of mortality by 2 levels because the study period was relatively short and events in most of the studies few, and wide upper confidence interval of odds ratio.
4The pooled analysis used raw data from subgroups of the included studies.

Figuras y tablas -
Summary of findings 1. Endothelin receptor antagonists compared to placebo for pulmonary arterial hypertension
Ir a la tabla de la revisión
Table 1. Main study characteristics across all studies

Study

N

Country

Intervention

Control

Outcomes

AMBITION

747

International

Ambrisentan + tadalafil or ambrisentan

Tadalafil + placebo

Primary outcome: time to the first event of clinical failure

Secondary outcomes: change from baseline in NT‐proBNP level, 6MWD, WHO FC, and Borg dyspnoea index

ARIES‐1

201

International

Ambrisentan (5 mg/day or 10 mg/day)

Placebo

Primary outcome: change from baseline in 6MWD

Secondary outcomes: change from baseline in WHO FC, Borg dyspnoea index and time to clinical worsening, plasma BNP, and SF‐36 physical functioning scale

ARIES‐2

192

International

Ambrisentan (2.5 mg/day or 5 mg/day)

Placebo

Primary outcome: change from baseline in 6MWD

Secondary outcomes: change from baseline in WHO FC, Borg dyspnoea index and time to clinical worsening, plasma BNP, and SF‐36

BREATHE‐1

213

International

Bosentan

Placebo

Primary outcome: change from baseline in 6MWD
Secondary outcomes: Borg dyspnoea index, WHO FC

BREATHE‐2

33

International

Bosentan

Placebo

Primary outcome: change from baseline to week 16 in TPR
Secondary outcomes: change in cardiac index, PVR, mPAP, mRAP, 6MWD, NYHA FC and dyspnoea‐fatigue rating

BREATHE‐5

54

International

Bosentan

Placebo

Primary outcome: change from baseline in SpO2 and PVR
Secondary outcomes: change from baseline in 6MWD, WHO FC, cardiac index, PVR, mPAP, and mRAP

Channick 2001

32

International

Bosentan

Placebo

Primary outcome: change from baseline in 6MWD
Secondary outcomes: cardiopulmonary haemodynamics (cardiac index, PVR, mPAP, mRAP), WHO FC

COMPASS‐2

334

International

Bosentan

Placebo

Primary outcome: time to the first morbidity/mortality event

Secondary outcomes: change in 6MWD, WHO FC, time to the first occurrence of death from any cause, hospitalisation for PAH or start of intravenous prostanoid therapy, atrial septostomy, or lung transplant.

EARLY

185

International

Bosentan

Placebo

Primary outcomes: PVR and change from baseline in 6MWD
Secondary outcomes: time to clinical worsening, change from baseline to month 6 in WHO FC, Borg dyspnoea index, mPAP, cardiac index, RAP, and SvO2

EDITA

38

Germany

Ambrisentan

Placebo

Primary outcome: change in mPAP

Secondary outcomes: change in WHO FC, change in cardiac index, change in PVR, symptoms of SSc, quality of life (SF‐36), lung function tests, right heart dimensions and function, NT‐proBNP, measures of disease‐related progression

MAESTRO

150

International

Macitentan

Placebo

Primary outcome: change from baseline in 6MWD

Secondary outcomes: change from baseline in WHO FC and Borg dyspnoea index

PORTICO

85

International

Macitentan

Placebo

Primary outcome: change from baseline to PVR

Secondary outcomes: change from baseline in RAP, mPAP, cardiac index, total pulmonary resistance, SvO2, NT‐proBNP, 6MWD, and WHO FC

SERAPH

26

British

Bosentan

Sildenafil

Primary outcome: change in right ventricle mass from baseline
Secondary outcomes: change from baseline in 6MWD, cardiac index, Borg dyspnoea index, quality of life, and plasma BNP level from baseline

SERAPHIN

742

International

Macitentan

Placebo

Primary outcome: time from the initiation of treatment to the first event related to pulmonary arterial hypertension

Secondary outcomes: change from baseline in 6MWD, percentage of participants with an improvement in WHO FC, death due to PAH or hospitalisations for PAH, and death from
any cause

STRIDE‐1

178

International

Sitaxsentan

Placebo

Primary outcome: peak oxygen consumption
Secondary outcomes: change from baseline in 6MWD, NYHA FC, PAP, cardiac index, and PVR

STRIDE‐2

245

International

Sitaxsentan

Placebo

Primary outcome: change from baseline in 6MWD
Secondary outcomes: change from baseline in WHO FC, Borg dyspnoea index and time to clinical worsening

STRIDE‐4

98

International

Sitaxsentan

Placebo

Primary efficacy endpoint was the change in 6MWD from baseline to week 18.

Secondary outcomes: changes in WHO FC from baseline at each assessment and time to clinical worsening, Borg dyspnoea index

6MWD: 6‐minute walk distance; BNP: B‐type natriuretic peptide; mPAP: mean pulmonary artery pressure; mRAP: mean right atrial pressure; MVO2: mixed venous oxygen saturation; NT‐proBNP: N‐terminal pro–brain natriuretic peptide; NYHA FC: New York Heart Association functional class; PAH: pulmonary arterial hypertension; PVR: pulmonary vascular resistance; SF‐36: 36‐item Short Form Health Survey; SpO2: oxygen saturation; SSc: systemic sclerosis; SvO2: mixed venous oxygen saturation; TPR: total pulmonary resistance;  WHO FC: World Health Organization functional class

Figuras y tablas -
Table 1. Main study characteristics across all studies
Ir a la tabla de la revisión
Table 2. Sensitivity analysis: including versus excluding combination therapy

Outcome

Including combination therapy

Excluding combination therapy

Change in 6MWD, mean with 95% CI

25.06 (17.13 to 32.99)

25.65 (16.80 to 34.49)

WHO/NYHA FC improvement, OR with 95% CI

1.41 (1.16 to 1.70)

1.52 (1.22 to 1.91)

Mortality, OR with 95% CI

0.78 (0.58 to 1.07)

0.82 (0.58 to 1.17)

6MWD: 6‐minute walk distance; CI: confidence interval; NYHA FC: New York Heart Association functional class; OR: odds ratio; WHO FC: World Health Organization functional class

Figuras y tablas -
Table 2. Sensitivity analysis: including versus excluding combination therapy
Ir a la tabla de la revisión
Table 3. Sensitivity analysis: including versus excluding PAH participants associated with SSc, or CHD, or portal hypertension

Outcome

Including combination therapy

Excluding combination therapy

Change in 6MWD, mean with 95% CI

25.06 (17.13 to 32.99)

27.90 (20.96 to 34.83)

WHO/NYHA FC improvement, OR with 95% CI

1.41 (1.16 to 1.70)

1.46 (1.19 to 1.78)

Mortality, OR with 95% CI

0.78 (0.58 to 1.07)

0.77 (0.57 to 1.05)

6MWD: 6‐minute walk distance; CHD: congenital heart disease; CI: confidence interval; NYHA FC: New York Heart Association functional class; OR: odds ratio; PAH: pulmonary arterial hypertension; SSc: systemic sclerosis; WHO FC: World Health Organization functional class

Figuras y tablas -
Table 3. Sensitivity analysis: including versus excluding PAH participants associated with SSc, or CHD, or portal hypertension
Ir a la tabla de la revisión
Comparison 1. Endothelin receptor antagonists versus placebo

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1.1 Change from baseline in 6‐minute walk Show forest plot

14

2739

Mean Difference (IV, Random, 95% CI)

25.06 [17.13, 32.99]

1.1.1 Non‐selective ERA

8

1860

Mean Difference (IV, Random, 95% CI)

20.51 [10.03, 31.00]

1.1.2 Selective ERA

6

879

Mean Difference (IV, Random, 95% CI)

33.48 [23.12, 43.83]

1.2 Proportion of participants with improved functional class Show forest plot

15

3060

Odds Ratio (M‐H, Fixed, 95% CI)

1.41 [1.16, 1.70]

1.2.1 Non‐selective ERAs

9

1896

Odds Ratio (M‐H, Fixed, 95% CI)

1.45 [1.13, 1.87]

1.2.2 Selective ERAs

6

1164

Odds Ratio (M‐H, Fixed, 95% CI)

1.35 [1.01, 1.80]

1.3 Proportion of participants with deteriorated functional class Show forest plot

13

2347

Odds Ratio (M‐H, Random, 95% CI)

0.43 [0.26, 0.72]

1.3.1 Non‐selective ERA

7

1121

Odds Ratio (M‐H, Random, 95% CI)

0.65 [0.30, 1.42]

1.3.2 Selective ERAs

6

1226

Odds Ratio (M‐H, Random, 95% CI)

0.31 [0.17, 0.60]

1.4 Change from baseline in Borg dyspnoea index Show forest plot

7

788

Mean Difference (IV, Random, 95% CI)

‐0.43 [‐0.90, 0.04]

1.4.1 Non‐selective ERAs

3

240

Mean Difference (IV, Random, 95% CI)

‐0.27 [‐1.58, 1.03]

1.4.2 Selective ERAs

4

548

Mean Difference (IV, Random, 95% CI)

‐0.43 [‐1.01, 0.14]

1.5 Mortality Show forest plot

12

2889

Odds Ratio (M‐H, Fixed, 95% CI)

0.78 [0.58, 1.07]

1.5.1 Non‐selective ERAs

7

1759

Odds Ratio (M‐H, Fixed, 95% CI)

0.88 [0.62, 1.23]

1.5.2 Selective ERAs

5

1130

Odds Ratio (M‐H, Fixed, 95% CI)

0.45 [0.21, 0.94]

1.6 Change from baseline in mean pulmonary artery pressure Show forest plot

8

729

Mean Difference (IV, Random, 95% CI)

‐4.65 [‐6.05, ‐3.26]

1.6.1 Non‐selective ERAs

6

519

Mean Difference (IV, Random, 95% CI)

‐5.79 [‐7.30, ‐4.27]

1.6.2 Selective ERAs

2

210

Mean Difference (IV, Random, 95% CI)

‐2.65 [‐5.31, 0.00]

1.7 Change from baseline in pulmonary vascular resistance Show forest plot

7

586

Mean Difference (IV, Random, 95% CI)

‐236.24 [‐333.21, ‐139.26]

1.7.1 Non‐selective ERAs

5

376

Mean Difference (IV, Random, 95% CI)

‐281.74 [‐395.85, ‐167.63]

1.7.2 Selective ERAs

2

210

Mean Difference (IV, Random, 95% CI)

‐173.73 [‐332.52, ‐14.94]

1.8 Pulmonary vascular resistance Show forest plot

2

175

Mean Difference (IV, Fixed, 95% CI)

‐288.59 [‐472.18, ‐104.99]

1.9 Ratio of geometric mean PVR Show forest plot

3

Ratio of Geometric mean (IV, Random, 95% CI)

Subtotals only

1.9.1 Selective ERAs

0

Ratio of Geometric mean (IV, Random, 95% CI)

Not estimable

1.9.2 Non‐selective ERAs

3

Ratio of Geometric mean (IV, Random, 95% CI)

0.69 [0.60, 0.80]

1.10 Change from baseline in cardiac index Show forest plot

7

718

Mean Difference (IV, Random, 95% CI)

0.50 [0.35, 0.65]

1.10.1 Non‐selective ERAs

5

509

Mean Difference (IV, Random, 95% CI)

0.55 [0.34, 0.77]

1.10.2 Selective ERAs

2

209

Mean Difference (IV, Random, 95% CI)

0.39 [0.23, 0.54]

1.11 Change from baseline in SpO 2 Show forest plot

1

Mean Difference (IV, Fixed, 95% CI)

Totals not selected

1.12 Hepatic toxicity Show forest plot

11

2250

Odds Ratio (M‐H, Random, 95% CI)

1.88 [0.91, 3.90]

1.12.1 Non‐selective ERAs

9

1888

Odds Ratio (M‐H, Random, 95% CI)

2.33 [0.98, 5.56]

1.12.2 Selective ERAs

2

362

Odds Ratio (M‐H, Random, 95% CI)

0.89 [0.31, 2.51]
Figuras y tablas -
Comparison 1. Endothelin receptor antagonists versus placebo
Ir a la tabla de la revisión
Comparison 2. Endothelin receptor antagonists versus PDE5 inhibitor

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

2.1 6‐minute walk Show forest plot

1

Mean Difference (IV, Fixed, 95% CI)

Totals not selected

2.2 Proportion of participants with improved functional class Show forest plot

1

Odds Ratio (M‐H, Fixed, 95% CI)

Totals not selected

2.3 Proportion of participants with deteriorated functional class Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

2.4 Symptoms Show forest plot

1

Mean Difference (IV, Fixed, 95% CI)

Totals not selected

2.5 Mortality Show forest plot

2

273

Odds Ratio (M‐H, Fixed, 95% CI)

0.32 [0.07, 1.36]

2.6 Cardiac index Show forest plot

1

Mean Difference (IV, Fixed, 95% CI)

Totals not selected
Figuras y tablas -
Comparison 2. Endothelin receptor antagonists versus PDE5 inhibitor
Ir a la tabla de la revisión
Comparison 3. Endothelin receptor antagonists in Eisenmenger syndrome

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

3.1 Change from baseline in 6‐minute walk Show forest plot

2

280

Mean Difference (IV, Random, 95% CI)

21.49 [‐31.23, 74.21]

3.1.1 Non‐selective ERA

2

280

Mean Difference (IV, Random, 95% CI)

21.49 [‐31.23, 74.21]

3.1.2 Selective ERA

0

0

Mean Difference (IV, Random, 95% CI)

Not estimable

3.2 Proportion of participants with improved functional class Show forest plot

2

280

Odds Ratio (M‐H, Fixed, 95% CI)

0.95 [0.48, 1.90]

3.2.1 Non‐selective ERAs

2

280

Odds Ratio (M‐H, Fixed, 95% CI)

0.95 [0.48, 1.90]

3.2.2 Selective ERAs

0

0

Odds Ratio (M‐H, Fixed, 95% CI)

Not estimable

3.3 Proportion of participants with deteriorated functional class Show forest plot

2

280

Odds Ratio (M‐H, Random, 95% CI)

0.67 [0.09, 4.85]

3.3.1 Non‐selective ERA

2

280

Odds Ratio (M‐H, Random, 95% CI)

0.67 [0.09, 4.85]

3.3.2 Selective ERAs

0

0

Odds Ratio (M‐H, Random, 95% CI)

Not estimable

3.4 Mortality Show forest plot

1

Odds Ratio (M‐H, Fixed, 95% CI)

Totals not selected

3.4.1 Non‐selective ERAs

1

Odds Ratio (M‐H, Fixed, 95% CI)

Totals not selected

3.4.2 Selective ERAs

0

Odds Ratio (M‐H, Fixed, 95% CI)

Totals not selected

3.5 Change from baseline in mean pulmonary arterial pressure Show forest plot

2

90

Mean Difference (IV, Fixed, 95% CI)

‐4.63 [‐8.03, ‐1.23]

3.5.1 Non‐selective ERAs

2

90

Mean Difference (IV, Fixed, 95% CI)

‐4.63 [‐8.03, ‐1.23]

3.5.2 Selective ERAs

0

0

Mean Difference (IV, Fixed, 95% CI)

Not estimable

3.6 Change from baseline in pulmonary vascular resistance Show forest plot

2

93

Mean Difference (IV, Fixed, 95% CI)

‐480.07 [‐753.34, ‐206.79]

3.6.1 Non‐selective ERAs

2

93

Mean Difference (IV, Fixed, 95% CI)

‐480.07 [‐753.34, ‐206.79]

3.6.2 Selective ERAs

0

0

Mean Difference (IV, Fixed, 95% CI)

Not estimable

3.7 Change from baseline in SpO 2 Show forest plot

1

Mean Difference (IV, Fixed, 95% CI)

Totals not selected
Figuras y tablas -
Comparison 3. Endothelin receptor antagonists in Eisenmenger syndrome
Ir a la tabla de la revisión