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Meta-Analysis
. 2013 Feb 28;2013(2):CD004434.
doi: 10.1002/14651858.CD004434.pub5.

Endothelin receptor antagonists for pulmonary arterial hypertension

Chao Liu  1 , Junmin Chen, Yanqiu Gao, Bao Deng, Kunshen Liu
Affiliations
Meta-Analysis

Endothelin receptor antagonists for pulmonary arterial hypertension

Chao Liu et al. Cochrane Database Syst Rev. .

Update in

Abstract

Background: Pulmonary arterial hypertension is a devastating disease, which leads to right heart failure and premature death. Recent evidence suggests that endothelin receptor antagonists may be promising drugs in the treatment of pulmonary arterial hypertension.

Objectives: To evaluate the efficacy of endothelin receptor antagonists in pulmonary arterial hypertension.

Search methods: We searched CENTRAL (Cochrane Central Register of Controlled Trials), MEDLINE, EMBASE, and the reference section of retrieved articles. Searches are current as of January 2012.

Selection criteria: We included randomised trials (RCTs) and quasi-randomised trials involving patients with pulmonary arterial hypertension.

Data collection and analysis: Five review authors independently selected studies, assessed study quality and extracted data.

Main results: We included 12 randomised controlled trials involving 1471 patients. All the trials were of relatively short duration (12 weeks to six months). After treatment, patients treated with endothelin receptor antagonists could walk on average 33.71 metres (95% confidence interval (CI) 24.90 to 42.52 metres) further than those treated with placebo in a six-minute walk test. Endothelin receptor antagonists improved more patients' World Health Organization/New York Heart Association (WHO/NYHA) functional class status than placebo (odds ratio (OR) 1.60; 95% CI 1.20 to 2.14), and reduced the odds of functional class deterioration compared with placebo (OR 0.26; 95% CI 0.16 to 0.42). There was a reduction in mortality that did not reach statistical significance on endothelin receptor antagonists (OR 0.57; 95% CI 0.26 to 1.24), and limited data suggest that endothelin receptor antagonists improve the Borg dyspnoea score and cardiopulmonary haemodynamics in symptomatic patients. Hepatic toxicity was not common, and endothelin receptor antagonists were well tolerated in this population. However, several cases of irreversible liver failure caused by sitaxsentan have been reported that led to license holder for sitaxsentan to withdraw the product from all markets worldwide.

Authors' conclusions: Endothelin receptor antagonists can increase exercise capacity, improve WHO/NYHA functional class, prevent WHO/NYHA functional class deterioration, reduce dyspnoea and improve cardiopulmonary haemodynamic variables in patients with pulmonary arterial hypertension with WHO/NYHA functional class II and III. However, there was only a trend towards endothelin receptor antagonists reducing mortality in patients with pulmonary arterial hypertension. Efficacy data are strongest in those with idiopathic pulmonary hypertension. The irreversible liver failure caused by sitaxsentan and its withdrawal from global markets emphasise the importance of hepatic monitoring in patients treated with endothelin receptor antagonists.

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Conflict of interest statement

This systematic review was supported by a grant from WHO while CL in residence at the Australasian Cochrane Centre. Dr Chao Liu participated in training from the Australasian Cochrane Centre (including the Cochrane Review Completion Program) while in Australia.

Figures

1
1
Study flow diagram.
2
2
'Risk of bias' summary: review authors' judgements about each risk of bias item for each included study.
1.1
1.1
Comparison 1 Endothelin receptor antagonists versus placebo, Outcome 1 Change from baseline in six‐minute walk.
1.2
1.2
Comparison 1 Endothelin receptor antagonists versus placebo, Outcome 2 Proportion of patients with improved functional class.
1.3
1.3
Comparison 1 Endothelin receptor antagonists versus placebo, Outcome 3 Proportion of patients with deteriorated functional class.
1.4
1.4
Comparison 1 Endothelin receptor antagonists versus placebo, Outcome 4 Change from baseline in Borg dyspnoea index.
1.5
1.5
Comparison 1 Endothelin receptor antagonists versus placebo, Outcome 5 Mortality.
1.6
1.6
Comparison 1 Endothelin receptor antagonists versus placebo, Outcome 6 Change from baseline in mean pulmonary artery pressure.
1.7
1.7
Comparison 1 Endothelin receptor antagonists versus placebo, Outcome 7 Change from baseline in pulmonary vascular resistance.
1.8
1.8
Comparison 1 Endothelin receptor antagonists versus placebo, Outcome 8 Change from baseline in cardiac Index.
1.9
1.9
Comparison 1 Endothelin receptor antagonists versus placebo, Outcome 9 Hepatic toxicity.
2.1
2.1
Comparison 2 Endothelin receptor antagonists versus sildenafil, Outcome 1 Six‐minute walk.
2.2
2.2
Comparison 2 Endothelin receptor antagonists versus sildenafil, Outcome 2 Symptoms.
2.3
2.3
Comparison 2 Endothelin receptor antagonists versus sildenafil, Outcome 3 Mortality.
2.4
2.4
Comparison 2 Endothelin receptor antagonists versus sildenafil, Outcome 4 Cardiac Index.
See this image and copyright information in PMC

Update of

References

References to studies included in this review

ARIES‐1 {published data only}
    1. US Food and Drug Administration. Center for drug evaluation and research. Letairis (Ambrisentan) Tablets: Medical Review(s). http://www.fda.gov/cder/foi/nda/2007/022081s000TOC.htm (Accessed March 20, 2008).
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ARIES‐2 {published data only}
    1. US Food and Drug Administration. Center for drug evaluation and research. Letairis (Ambrisentan) Tablets: Medical Review(s). http://www.fda.gov/cder/foi/nda/2007/022081s000TOC.htm (Accessed March 20, 2008).
    1. 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. - PubMed
ASSET‐1 {published data only}
    1. Barst RJ, Mubarak KK, Machado RF, Ataga KI, Benza RL, Castro O, et al. Exercise capacity and haemodynamics in patients with sickle cell disease with pulmonary hypertension treated with bosentan: results of the ASSET studies. British Journal of Haematology 2010;149(3):426‐35. - PMC - PubMed
BREATHE‐1 {published data only}
    1. US Food and Drug Administration. Center for drug evaluation and research.Tracleer (Bosentan) Tablets: Medical Review(s). http://www.fda.gov/cder/foi/nda/2001/21‐290_Tracleer.htm Vol. Accessed March 20, 2008.
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BREATHE‐5 {published data only}
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    1. 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. - PubMed
EARLY {published and unpublished data}
    1. 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. - PubMed
Galiè 2003 {published data only}
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SERAPH {published data only}
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STRIDE‐1 {published and unpublished data}
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    1. Therapeutic Goods Administration (TGA), Australia. Public Summary Documents by Product: Thelin. http://www.health.gov.au/internet/main/publishing.nsf/Content/pbac‐psd‐s... (Accessed April 25, 2008).
    1. Barst RJ, Langleben D, Frost E, Horn EM, Oudiz R, Shapiro S, et al. Sitaxsentan therapy for pulmonary arterial hypertension. Amercian Journal of Respiratory and Critical Care Medicine 2004;169:441‐7. - PubMed
STRIDE‐1 (100mg) {published data only}
    1. 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 March 22, 2008.
    1. Barst RJ, Langleben D, Frost E, Horn EM, Oudiz R, Shapiro S, et al. Sitaxsentan therapy for pulmonary arterial hypertension. Amercian Journal of Respiratory and Critical Care Medicine 2004;169:441‐7. - PubMed
STRIDE‐1 (300mg) {published data only}
    1. 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 March 22, 2008).
    1. Barst RJ, Langleben D, Frost E, Horn EM, Oudiz R, Shapiro S, et al. Sitaxsentan therapy for pulmonary arterial hypertension. Amercian Journal of Respiratory and Critical Care Medicine 2004;169:441‐7. - PubMed
STRIDE‐2 {published data only}
    1. 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 March 22, 2008).
    1. Therapeutic Goods Administration (TGA), Australia. Public Summary Documents by Product: Thelin. http://www.health.gov.au/internet/main/publishing.nsf/Content/pbac‐psd‐s... (Accessed April 25, 2008).
    1. 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. - PubMed
STRIDE‐2 (100mg) {published data only}
    1. 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 March 22, 2008).
    1. Therapeutic Goods Administration (TGA), Australia. Public Summary Documents by Product: Thelin. http://www.health.gov.au/internet/main/publishing.nsf/Content/pbac‐psd‐s... (Accessed April 25, 2008).
    1. 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. - PubMed
STRIDE‐2 (50mg) {published data only}
    1. 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 March 22, 2008).
    1. Therapeutic Goods Administration (TGA), Australia. Public Summary Documents by Product: Thelin. http://www.health.gov.au/internet/main/publishing.nsf/Content/pbac‐psd‐s... (Accessed April 25, 2008).
    1. 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. - PubMed
STRIDE‐4 {published data only}
    1. 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 March 22, 2008).
STRIDE‐4 (100mg) {published data only}
    1. 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 March 22, 2008).
STRIDE‐4 (50mg) {published data only}
    1. 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 March 22, 2008).

References to studies excluded from this review

ASSET‐2 {published data only}
    1. 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. - PMC - PubMed
Barst 2011 {published data only}
    1. 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 & Lung Transplantation 2011;30(6):632‐43. - PubMed
Benza 2007 {published data only}
    1. Benza RL, Mehta S, Keogh A, Lawrence EC, Oudiz RJ, Barst RJ. Sitaxsentan treatment for patients with pulmonary arterial hypertension discontinuing bosentan. The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation 2007;26(1):63‐9. - PubMed
Bose 2009 {published data only}
    1. Bose N, Bena JF, Trunick CM, Bork DJ, Krishnan G, Petrich J, 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 2009;62(Suppl 10):574. - PMC - PubMed
BUILD‐2 {unpublished data only}
    1. Efficacy and Safety of Oral Bosentan in Pulmonary Fibrosis Associated With Scleroderma. http://clinicaltrials.gov/ct2/show/NCT00070590.
Burgess 2008 {published data only}
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Coyne 2005 {published data only}
    1. Coyne TC, Garces PC, Kramer W. No clinical interaction between sitaxsentan and sildenafil [Abstract]. American Thoracic Society 2005 International Conference; May 20‐25; San Diego, California. 2005:[A57] [Poster: K70].
Denault 2010 {published data only}
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Dhaun 2011 {published data only}
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Faoro 2009a {published data only}
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Faoro 2009b {published data only}
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Frey 2008 {published data only}
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Galiè 2005b {published data only}
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Galiè 2009b {published data only}
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Galiè 2009c {published data only}
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Galiè 2010 {published data only}
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Ghofrani 2010 {published data only}
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Gillies 2011 {published data only}
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Givertz 2000 {published data only}
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Gomberg‐Maitland 2005 {published data only}
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Gotzkowsky 2010 {published data only}
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Hoeper 2006 {published data only}
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Huez 2009 {published data only}
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Iversen 2010 {published data only}
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Jais 2008 {published data only}
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Kalra 2002 {published data only}
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Kaluski 2008a {published data only}
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Kaluski 2008b {published data only}
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Kefford 2010 {published data only}
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King 2008 {published data only}
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Korn 2004 {published data only}
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Lee 2009 {published data only}
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McLaughlin 2003 {published data only}
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McLaughlin 2006 {published data only}
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McLaughlin 2010 {published data only}
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Mereles 2006 {published data only}
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Modesti 2006 {published data only}
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Naeije 2010 {published data only}
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Nakahara 2010 {published data only}
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Oudiz 2007 {published data only}
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Oudiz 2009 {published data only}
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RAPID‐1 {unpublished data only}
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Reesink 2010 {published data only}
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Robbins 2006 {published data only}
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Seheult 2009 {published data only}
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Seibold 2010 {published data only}
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Shenoy 2011 {published data only}
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Simonneau 2010 {published data only}
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References to studies awaiting assessment

Palazzini 2010 {published data only (unpublished sought but not used)}
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References to other published versions of this review

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