Endothelin receptor antagonists for pulmonary arterial hypertension

Pulmonary hypertension is an increase in blood pressure in the pulmonary artery, pulmonary vein, or pulmonary capillaries, together known as the lung vasculature, leading to shortness of breath, dizziness, fainting, and other symptoms, all of which are exacerbated by exertion. The World Health Organization (WHO) has reclassified pulmonary hypertension into five groups based on their mechanisms rather than associated conditions. We have focused on pulmonary arterial hypertension (PAH) only in this review. Pulmonary arterial hypertension is a devastating disease characterised by an increase in pulmonary vascular resistance which leads to right ventricular failure and ultimately death.

Tradiational therapies for pulmonary arterial hypertension include prostacyclin and its analogues, calcium channel blockers, nitric oxide (NO), and important adjunctive therapies, such as anticoagulants and oxygen. Endothelin receptor antagonists have recently been proposed as an alternative to these traditional therapies. This review includes twelve trials on 1471 participants. Endothelin receptor antagonists can improve exercise capacity, symptoms, and cardiopulmonary haemodynamic variables in people with symptomatic pulmonary arterial hypertension over a period of three to six months treatment. There is uncertainty as to whether endothelin receptor antagonists reduce mortality in this population. The most severe potential side effect was hepatic toxicity which was not common in these short-term trials.

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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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 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.

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