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Meta-Analysis
. 2021 Mar 26;3(3):CD004434.
doi: 10.1002/14651858.CD004434.pub6.

Endothelin receptor antagonists for pulmonary arterial hypertension

Chao Liu  1 , Junmin Chen  2 , Yanqiu Gao  3 , Bao Deng  3 , Kunshen Liu  3
Affiliations
Meta-Analysis

Endothelin receptor antagonists for pulmonary arterial hypertension

Chao Liu et al. Cochrane Database Syst Rev. .

Abstract

Background: Pulmonary arterial hypertension is a devastating disease that leads to right heart failure and premature death. Endothelin receptor antagonists have shown efficacy in the treatment of pulmonary arterial hypertension.

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

Search methods: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, and the reference sections of retrieved articles. The searches are current as of 4 November 2020.

Selection criteria: We included randomised trials and quasi-randomised trials involving participants with pulmonary arterial hypertension.

Data collection and analysis: Two of five review authors selected studies, extracted data and assessed study quality according to established criteria. We used standard methods expected by Cochrane. The primary outcomes were exercise capacity (six-minute walk distance, 6MWD), World Health Organization (WHO) or New York Heart Association (NYHA) functional class, Borg dyspnoea scores and dyspnoea-fatigue ratings, and mortality.

Main results: We included 17 randomised controlled trials involving a total of 3322 participants. Most trials were of relatively short duration (12 weeks to six months). Sixteen trials were placebo-controlled, and of these nine investigated a non-selective ERA and seven a selective ERA. We evaluated two comparisons in the review: ERA versus placebo and ERA versus phosphodiesterase type 5 (PDE5) inhibitor. The abstract focuses on the placebo-controlled trials only and presents the pooled results of selective and non-selective ERAs. After treatment, participants receiving ERAs could probably walk on average 25.06 m (95% confidence interval (CI) 17.13 to 32.99 m; 2739 participants; 14 studies; I2 = 34%, moderate-certainty evidence) further than those receiving placebo in a 6MWD. Endothelin receptor antagonists probably improved more participants' WHO functional class (odds ratio (OR) 1.41, 95% CI 1.16 to 1.70; participants = 3060; studies = 15; I2 = 5%, moderate-certainty evidence) and probably lowered the odds of functional class deterioration (OR 0.43, 95% CI 0.26 to 0.72; participants = 2347; studies = 13; I2 = 40%, moderate-certainty evidence) compared with placebo. There may be a reduction in mortality with ERAs (OR 0.78, 95% CI 0.58, 1.07; 2889 participants; 12 studies; I2 = 0%, low-certainty evidence), and pooled data suggest that ERAs probably improve cardiopulmonary haemodynamics and may reduce Borg dyspnoea score in symptomatic patients. Hepatic toxicity was not common, but may be increased by ERA treatment from 37 to 67 (95% CI 34 to 130) per 1000 over 25 weeks of treatment (OR 1.88, 95% CI 0.91 to 3.90; moderate-certainty evidence). Although ERAs were well tolerated in this population, several cases of irreversible liver failure caused by sitaxsentan have been reported, which led the licence holder for sitaxsentan to withdraw the product from all markets worldwide. As planned, we performed subgroup analyses comparing selective and non-selective ERAs, and with the exception of mean pulmonary artery pressure, did not detect any clear subgroup differences for any outcome.

Authors' conclusions: For people with pulmonary arterial hypertension with WHO functional class II and III, endothelin receptor antagonists probably increase exercise capacity, improve WHO functional class, prevent WHO functional class deterioration, result in favourable changes in cardiopulmonary haemodynamic variables compared with placebo. However, they are less effective in reducing dyspnoea and mortality. The efficacy data were 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 people treated with ERAs. The question of the effects of ERAs on pulmonary arterial hypertension has now likely been answered.. The combined use of ERAs and phosphodiesterase inhibitors may provide more benefit in pulmonary arterial hypertension; however, this needs to be confirmed in future studies.

Trial registration: ClinicalTrials.gov NCT00070590 NCT00077584.

PubMed Disclaimer

Conflict of interest statement

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

Chao Liu: none known Junmin Chen: none known Yanqiu Gao: none known Bao Deng: none known Kunshen Liu: none known

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. Analysis
Comparison 1: Endothelin receptor antagonists versus placebo, Outcome 1: Change from baseline in 6‐minute walk
1.2
1.2. Analysis
Comparison 1: Endothelin receptor antagonists versus placebo, Outcome 2: Proportion of participants with improved functional class
1.3
1.3. Analysis
Comparison 1: Endothelin receptor antagonists versus placebo, Outcome 3: Proportion of participants with deteriorated functional class
1.4
1.4. Analysis
Comparison 1: Endothelin receptor antagonists versus placebo, Outcome 4: Change from baseline in Borg dyspnoea index
1.5
1.5. Analysis
Comparison 1: Endothelin receptor antagonists versus placebo, Outcome 5: Mortality
1.6
1.6. Analysis
Comparison 1: Endothelin receptor antagonists versus placebo, Outcome 6: Change from baseline in mean pulmonary artery pressure
1.7
1.7. Analysis
Comparison 1: Endothelin receptor antagonists versus placebo, Outcome 7: Change from baseline in pulmonary vascular resistance
1.8
1.8. Analysis
Comparison 1: Endothelin receptor antagonists versus placebo, Outcome 8: Pulmonary vascular resistance
1.9
1.9. Analysis
Comparison 1: Endothelin receptor antagonists versus placebo, Outcome 9: Ratio of geometric mean PVR
1.10
1.10. Analysis
Comparison 1: Endothelin receptor antagonists versus placebo, Outcome 10: Change from baseline in cardiac index
1.11
1.11. Analysis
Comparison 1: Endothelin receptor antagonists versus placebo, Outcome 11: Change from baseline in SpO 2
1.12
1.12. Analysis
Comparison 1: Endothelin receptor antagonists versus placebo, Outcome 12: Hepatic toxicity
2.1
2.1. Analysis
Comparison 2: Endothelin receptor antagonists versus PDE5 inhibitor, Outcome 1: 6‐minute walk
2.2
2.2. Analysis
Comparison 2: Endothelin receptor antagonists versus PDE5 inhibitor, Outcome 2: Proportion of participants with improved functional class
2.3
2.3. Analysis
Comparison 2: Endothelin receptor antagonists versus PDE5 inhibitor, Outcome 3: Proportion of participants with deteriorated functional class
2.4
2.4. Analysis
Comparison 2: Endothelin receptor antagonists versus PDE5 inhibitor, Outcome 4: Symptoms
2.5
2.5. Analysis
Comparison 2: Endothelin receptor antagonists versus PDE5 inhibitor, Outcome 5: Mortality
2.6
2.6. Analysis
Comparison 2: Endothelin receptor antagonists versus PDE5 inhibitor, Outcome 6: Cardiac index
3.1
3.1. Analysis
Comparison 3: Endothelin receptor antagonists in Eisenmenger syndrome, Outcome 1: Change from baseline in 6‐minute walk
3.2
3.2. Analysis
Comparison 3: Endothelin receptor antagonists in Eisenmenger syndrome, Outcome 2: Proportion of participants with improved functional class
3.3
3.3. Analysis
Comparison 3: Endothelin receptor antagonists in Eisenmenger syndrome, Outcome 3: Proportion of participants with deteriorated functional class
3.4
3.4. Analysis
Comparison 3: Endothelin receptor antagonists in Eisenmenger syndrome, Outcome 4: Mortality
3.5
3.5. Analysis
Comparison 3: Endothelin receptor antagonists in Eisenmenger syndrome, Outcome 5: Change from baseline in mean pulmonary arterial pressure
3.6
3.6. Analysis
Comparison 3: Endothelin receptor antagonists in Eisenmenger syndrome, Outcome 6: Change from baseline in pulmonary vascular resistance
3.7
3.7. Analysis
Comparison 3: Endothelin receptor antagonists in Eisenmenger syndrome, Outcome 7: Change from baseline in SpO 2
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References

References to studies included in this review

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Bose 2011 {published data only}
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Bruderer 2014 {published data only}
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BUILD‐2 {unpublished data only}
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Burgess 2008 {published data only}
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Galiè 2009b {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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Gotti 2014 {published data only}
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Gotzkowsky 2010 {published data only}
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Grander 2014 {published data only}
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Hill 2018 {published data only}
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Howard 2019 {published data only}
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Huez 2009 {published data only}
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Hurst 2016 {published data only}
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Iversen 2010 {published data only}
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McLaughlin 2003 {published data only}
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Mereles 2006 {published data only}
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Metersky 2011 {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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NCT00077584 {unpublished data only}
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Okour 2019 {published data only}
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Oudiz 2007 {published data only}
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Palazzini 2010 {published data only}
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Raghu 2013 {published data only}
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Reesink 2010 {published data only}
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Robbins 2006 {published data only}
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Schuuring 2013 {published data only}
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Seheult 2009 {published data only}
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Sfikakis 2007 {published data only}
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Shenoy 2011 {published data only}
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Sidharta 2010 {published data only}
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Sidharta 2013a {published data only}
    1. Sidharta PN, 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. - PubMed
Sidharta 2013b {published data only}
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Sidharta 2014 {published data only}
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Simonneau 2017 {published data only}
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Spence 2008 {published data only}
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Surie 2013 {published data only}
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Vachiery 2018 {published data only}
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Webb 2017 {published data only}
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References to studies awaiting assessment

Dwivedi 2018 {published data only}
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