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Systematic Review of Randomized Controlled Trials of Endothelin Receptor Antagonists for Pulmonary Arterial Hypertension

Abstract

Background

There are currently three Food and Drug Administration approved endothelin receptor antagonists (ERAs): bosentan, ambrisentan, and macitentan. There is a growing body of evidence that demonstrates the beneficial effects of ERAs in patients with pulmonary arterial hypertension (PAH).

Objectives

To compare the available evidence from randomized clinical trials for specific outcomes of different endothelin antagonists for the treatment of PAH.

Methods

A multi-database search of randomized controlled trials up to March 15, 2016 was conducted for those that would measure functional parameters of patients with PAH treated with ERA monotherapy versus placebo. Studies that analyzed 6-min walking distance, pulmonary vascular resistance, pulmonary arterial pressure, or WHO functional status were incorporated for analysis. A total of 15 trials and 2 subanalyses were compiled and quality and abovementioned outcomes were compared among studies.

Results

A constant decrease in pulmonary vascular resistance and pulmonary arterial pressure was globally reported among the different studies, resulting in increased 6-min walking distance and functional status compared to placebo.

Conclusions

Although this evidence clearly shows the benefit of ERAs, studies, which compare ERAs against one another and with other therapies for progressive PAH, have been lacking. Larger and longer studies are necessary to define the role of ERAs as standalone agents and in combination therapies.

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Abbreviations

6MWD:

6-min walking distance

ARIES:

Ambrisentan in pulmonary arterial hypertension efficacy study

ASD:

Atrial septal defect

BREATHE:

Bosentan randomized trial of endothelin antagonist therapy

CTEPH:

Chronic thromboembolic pulmonary hypertension

EARLY:

Endothelin antagonist trial in mildly symptomatic pulmonary arterial hypertension patients

ERA:

Endothelin receptor antagonist

FC:

Functional class

NO:

Nitric oxide

PAH:

Pulmonary arterial hypertension

PAP:

Pulmonary artery pressure

PVR:

Pulmonary vascular resistance

RCT:

Randomized controlled trial

SERAPHIN:

Study with a endothelin receptor antagonist in pulmonary arterial hypertension to improve clinical outcome

STRIDE:

Sitaxsentan to relieve impaired exercise

VSD:

Ventricular septal defect

References

  1. 1.

    Levin ER (1995) Mechanisms of disease: endothelins. N Engl J Med 333:356–363

    CAS  Article  PubMed  Google Scholar 

  2. 2.

    Rubin LJ (2012) Endothelin receptor antagonists for the treatment of pulmonary artery hypertension. Life Sci 91:517–521

    CAS  Article  PubMed  Google Scholar 

  3. 3.

    Ohkita M, Tawa M, Kitada K, Matsumura Y (2012) Pathophysiological roles of endothelin receptors in cardiovascular diseases. J Pharmacol Sci 119:302–313

    CAS  Article  PubMed  Google Scholar 

  4. 4.

    Channick RN, Simonneau G, Sitbon O, Robbins IM, Frost A, Tapson VF et al (2001) Effects of the dual endothelin-receptor antagonist bosentan in patients with pulmonary hypertension: a randomised placebo-controlled study. Lancet 358:1119–1123

    CAS  Article  PubMed  Google Scholar 

  5. 5.

    Barst RJ, Langleben D, Frost A, Horn EM, Oudiz R, Shapiro S et al (2004) Sitaxsentan therapy for pulmonary arterial hypertension. Am J Respir Crit Care Med 169:441–447

    Article  PubMed  Google Scholar 

  6. 6.

    Pulido T, Adzerikho I, Channick RN, Delcroix M, Galie N, Ghofrani HA et al (2013) Macitentan and morbidity and mortality in pulmonary arterial hypertension. N Engl J Med 369:809–818

    CAS  Article  PubMed  Google Scholar 

  7. 7.

    Rubin LJ, Badesch DB, Barst RJ, Galie N, Black CM, Keogh A et al (2002) Bosentan therapy for pulmonary arterial hypertension. N Engl J Med 346:896–903

    CAS  Article  PubMed  Google Scholar 

  8. 8.

    Barst RJ, Langleben D, Badesch D, Frost A, Lawrence EC, Shapiro S et al (2006) Treatment of pulmonary arterial hypertension with the selective endothelin-A receptor antagonist sitaxsentan. J Am Coll Cardiol 47:2049–2056

    CAS  Article  PubMed  Google Scholar 

  9. 9.

    Galie N, Beghetti M, Gatzoulis MA, Granton J, Berger RMF, Lauer A et al (2006) Bosentan therapy in patients with eisenmenger syndrome: a multicenter, double-blind, randomized, placebo-controlled study. Circulation 114:48–54

    CAS  Article  PubMed  Google Scholar 

  10. 10.

    Galie N, Rubin LJ, Hoeper MM, Jansa P, Al-Hiti H, Meyer GMB et al (2008) Treatment of patients with mildly symptomatic pulmonary arterial hypertension with bosentan (EARLY study): a double-blind, randomised controlled trial. Lancet 371:2093–2100

    CAS  Article  PubMed  Google Scholar 

  11. 11.

    Galie N, Olschewski H, Oudiz RJ, Torres F, Frost A, Ghofrani HA et al (2008) 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 117:3010–3019

    CAS  Article  PubMed  Google Scholar 

  12. 12.

    Jais X, D’Armini AM, Jansa P, Torbicki A, Delcroix M, Ghofrani HA et al (2008) Bosentan for treatment of inoperable chronic thromboembolic pulmonary hypertension. J Am Coll Cardiol 52:2127–2134

    CAS  Article  PubMed  Google Scholar 

  13. 13.

    Berger RMF, Beghetti M, Galie N, Gatzoulis MA, Granton J, Lauer A et al (2010) Atrial septal defects versus ventricular septal defects in BREATHE-5, a placebo-controlled study of pulmonary arterial hypertension related to eisenmenger’s syndrome: a subgroup analysis. Int J Cardiol 144:373–378

    Article  PubMed  Google Scholar 

  14. 14.

    Barst RJ, Mubarak KK, Machado RF, Ataga KI, Benza RL, Castro O et al (2010) Exercise capacity and haemodynamics in patients with sickle cell disease with pulmonary hypertension treated with bosentan: results of the ASSET studies. Br J Haematol 149:426–435

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  15. 15.

    Mohamed WA, Ismail M (2012) A randomized, double-blind, placebo-controlled, prospective study of bosentan for the treatment of persistent pulmonary hypertension of the newborn. J Perinatol 32:608–613

    CAS  Article  PubMed  Google Scholar 

  16. 16.

    Sandoval J, Torbicki A, Souza R, Ramirez A, Kurzyna M, Jardim C et al (2012) Safety and efficacy of sitaxsentan 50 and 100 mg in patients with pulmonary arterial hypertension. Pulm Pharmacol Ther 25:33–39

    CAS  Article  PubMed  Google Scholar 

  17. 17.

    Benigni A, Remuzzi G (1999) Endothelin antagonists. Lancet 353:133–138

    CAS  Article  PubMed  Google Scholar 

  18. 18.

    Mylona P, Cleland JGF (1999) Update of REACHE-1 and MERIT-HF clinical trials in heart failure. Eur J Heart Fail 1:197–200

    CAS  Article  PubMed  Google Scholar 

  19. 19.

    Formulary (Internet) (2011) Pfizer voluntarily withdraws sitaxsentan from the market worldwide and halts ongoing clinical trials. http://formularyjournal.modernmedicine.com/. Cited 2 Nov 2013

  20. 20.

    FDA Label (Internet) (2013)Highlights of prescribing information: Letairis (ambrisentan). www.accessdata.fda.gov. Cited 2 Aug 2013; Revised 10/2012

  21. 21.

    FDA Label (Internet) (2013)Highlights of prescribing information: Tracleer (bosentan). www.accessdata.fda.gov.Cited 2 Aug 2013; Revised: 10/2012

  22. 22.

    FDA Label (Internet) (2013)Highlights of prescribing information: Opsumit (macitentan). www.accessdata.fda.gov. Cited 27 Oct 2013; Revised: October 2013

  23. 23.

    Barst RJ, Rubin LJ, Long WA, McGoon MD, Rich S, Badesch DB et al (1996) A comparison of continuous intravenous epoprostenol (prostacyclin) with conventional therapy for primary pulmonary hypertension. N Engl J Med 334:296–301

    CAS  Article  PubMed  Google Scholar 

  24. 24.

    Galie N, Ghofrani HA, Torbicki A, Barst RJ, Rubin LJ, Badesch D et al (2005) Sildenafil citrate therapy for pulmonary arterial hypertension. N Engl J Med 353:2148–2157

    CAS  Article  PubMed  Google Scholar 

  25. 25.

    Gabbay E, Fraser J, McNeil K (2007) Review of bosentan in the management of pulmonary arterial hypertension. Vasc Health Risk Manag 3:887–900

    CAS  PubMed  PubMed Central  Google Scholar 

  26. 26.

    Wilkins MR, Paul GA, Strange JW, Tunariu N, Gin-Sing W, Banya WA et al (2005) Sildenafil versus endothelin receptor antagonist for pulmonary hypertension (SERAPH) study. Am J Respir Crit Care Med 171:1292–1297

    Article  PubMed  Google Scholar 

  27. 27.

    Benza RL, Barst RJ, Galie N, Frost A, Girgis RE, Highland KB et al (2008) Sitaxsentan for the treatment of pulmonary arterial hypertension. Chest 134:775–782

    Article  PubMed  Google Scholar 

  28. 28.

    Channick RN (2013) Combination therapy in pulmonary arterial hypertension. Am J Cardiol 111(suppl):16C–20C

    Article  PubMed  Google Scholar 

  29. 29.

    Gabler NB, French B, Strom BL, Palevsky HI, Taichman DB, Kawut SM et al (2012) Validation of 6-min walk distance as a surrogate end point in pulmonary arterial hypertension trials. Circulation 126:349–356

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  30. 30.

    Savarese G, Paolillo S, Costanzo P, D’Amore C, Cecere M, Losco T et al (2012) Do changes of 6-minute walk distance predict clinical events in patients with pulmonary arterial hypertension? A metaanalysis of 22 randomized trials. J Am Coll Cardiol 60:1192–1201

    Article  PubMed  Google Scholar 

  31. 31.

    McLaughlin VV (2006) Survival in patients with pulmonary arterial hypertension treated with first-line bosentan. Eur J Clin Invest 36(Suppl. 3):10–15

    CAS  Article  PubMed  Google Scholar 

  32. 32.

    McLaughlin VV, Sitbon O, Badesch DB, Barst RJ, Black C, Galie N et al (2005) Survival with first-line bosentan in patients with primary pulmonary hypertension. Eur Respir J 25:244–249

    CAS  Article  PubMed  Google Scholar 

  33. 33.

    Oudiz RJ, Galie N, Olschewski H, Torres F, Frost A, Ghofrani HA et al (2009) Long-term ambrisentan therapy for the treatment of pulmonary arterial hypertension. J Am Coll Cardiol 54:1971–1981

    Article  PubMed  Google Scholar 

  34. 34.

    Jadad AR et al (1996) Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials 17:1–12

    CAS  Article  PubMed  Google Scholar 

  35. 35.

    Aversa M, Porter S, Granton J (2015) Comparative safety and tolerability of endothelin receptor antagonists in pulmonary arterial hypertension. Drug Saf 38(5):419–435

    CAS  Article  PubMed  Google Scholar 

  36. 36.

    Zhang HD, Zhang R, Jiang X, Sun K, Wu DC, Jing ZC (2015) Effects of oral treatments on clinical outcomes in pulmonary arterial hypertension: a systematic review and meta-analysis. Am Heart J 170(1):96–103, 103.e1–14

    Article  PubMed  Google Scholar 

  37. 37.

    Jing ZC et al (2010) Efficacy, safety and tolerability of bosentan in Chinese patients with pulmonary arterial hypertension. J Heart Lung Transplant 29(2):150–156

    Article  PubMed  Google Scholar 

  38. 38.

    Surie S, Reesink HJ, Marcus JT, van der Plas MN, Kloek JJ, Vonk-Noordegraaf A, Bresser P (2013) Bosentan treatment is associated with improvement of right ventricular function and remodeling in chronic thromboembolic pulmonary hypertension. Clin Cardiol 36(11):698–703

    Article  PubMed  Google Scholar 

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Correspondence to Suvitesh Luthra.

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Kuntz, M., Leiva-Juarez, M.M. & Luthra, S. Systematic Review of Randomized Controlled Trials of Endothelin Receptor Antagonists for Pulmonary Arterial Hypertension. Lung 194, 723–732 (2016). https://doi.org/10.1007/s00408-016-9928-6

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Keywords

  • Pulmonary arterial hypertension
  • Bosentan
  • Endothelin antagonists
  • Macitentan
  • Sitaxsentan
  • Ambrisentan