Endothelin receptor antagonists for pulmonary arterial hypertension

Review question

Do endothelin receptor antagonists increase how much a person is capable of exercising (exercise capacity), improve symptoms, or reduce death in people with pulmonary arterial hypertension (PAH)?

Background

Pulmonary arterial hypertension is a devastating disease characterised by an increase in pulmonary vascular resistance which leads to right heart failure and ultimately death.

Endothelin receptor antagonists are a class of strong vasodilators (medications that open (dilate) blood vessels) capable of stopping the process of cell division, which could dilate and result in a favourable pulmonary arterial structural alteration.

Study characteristics

We reviewed the evidence from randomised studies (studies in which people are assigned to one of two or more treatment groups using a random method). After a thorough search and assessment of the medical literature, we identified 17 studies with a total of 3322 participants for inclusion in the review. A vast majority of the participants had PAH without known cause (idiopathic). The evidence is current to November 2020.

Key results

Endothelin receptor antagonists probably increase exercise capacity, improve World Health Organization functional class (a measurement of how severe a person's pulmonary hypertension symptoms are), and may improve death rates and symptoms in people with PAH; however they may also increase the risk of liver damage, although this was rare. The question of the effects of endothelin receptor antagonists on PAH has now likely been answered.

Certainty of the evidence

Overall, the evidence presented is of moderate certainty due to the high occurrence of missing data.

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.

Read the full 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 strategy: 

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.

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