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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; I 2 = 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; I 2 = 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; I 2 = 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; I 2 = 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., (Copyright © 2021 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

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.

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 Strategy: We searched CENTRAL (Cochrane Central Register of Controlled Trials), MEDLINE, EMBASE, and the reference section of retrieved articles. Searches are current as of Februray 2008., Selection Criteria: Randomised controlled trials (RCTs) or quasi-randomised controlled 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: Five new studies have been added to this updated review, which now includes 11 randomised controlled trials involving 1457 patients. All the trials were of relatively short duration (12 weeks to 6 months). After treatment, patients treated with endothelin receptor antagonists could walk on average 33.7 metres (95% confidence interval [CI] 24.9 to 42.5 metres) further than those treated with placebo in a 6 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] 1.6; 95% confidence interval [CI] 1.2 to 2.1), and reduced the odds of functional class deterioration compared to placebo (OR 0.26; 95% CI 0.16 to 0.42 ). There was a trend for endothelin receptor antagonists to reduce mortality (OR 0.48; 95% CI 0.21 to 1.09), and limited data suggest that endothelin receptor antagonists improve Borg dyspnoea score and cardiopulmonary haemodynamics in symptomatic patients. Hepatic toxicity was not common, and endothelin receptor antagonists were well tolerated in this population., 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.

Pulmonary arterial hypertension (PAH) is a devastating disease that leads to right heart failure and premature death. Historically, we are restricted by limited options for drug treatment. Over the past decade, with advances in our understanding of pathophysiological and molecular mechanisms, many new therapeutic strategies (synthetic prostacyclin and prostacyclin analogues, endothelin receptor antagonists and sildenafil) have been developed for the treatment of PAH, and the clinical efficacy has been tested in many randomized-controlled trials (RCTs). In this overview, we review the evidence for the use of historical and new treatments that arises from the Cochrane Collaboration of Systematic Reviews and from recent RCTs.