ET-1 is a very potent vasoconstrictor; its use results in increased pulmonary vascular resistance [Raja, 2010a
]. It also has proliferative effects on vascular smooth muscle cells [Raja and Dreyfus, 2008
]. Blockade of the endothelin receptor has been used in the treatment of PAH. Several endothelin receptor antagonists (ERAs) have been identified and differ in their selectivity toward the ET-A and ET-B receptors. Currently, both selective and nonselective ERAs are approved and available for treating PAH.
Bosentan (Tracleer®; Actelion Pharmaceuticals Ltd, Allschwil, Switzerland) shows 20:1 ET-A/ET-B selectivity, ambrisentan (Letairis®; Gilead Sciences, Foster City, CA, USA) has 100:1 selectivity, and sitaxsentan (Thelin®; Encysive Pharmaceuticals, Houston, TX, USA) has 6500:1 selectivity.
The Bosentan Trial of Endothelin Antagonist Therapy (BREATHE-1) study revealed the ability of oral bosentan in patients with PAH to improve 6 min walk test distance, improve Borg dyspnea scores and time to clinical worsening as early as 16 weeks after initiating therapy. A 44 m placebo-adjusted difference in 6 min walk test distance in the BREATHE-1 patient population treated with bosentan was noted [Rubin et al. 2002
]. The recommended treatment dosage is 125 mg twice daily after careful uptitration. Bosentan can increase transaminase levels in a reversible pattern. As a result of the potential for elevated transaminases, patients receiving bosentan require monthly monitoring of liver function during continuous therapy. It is recommended that if the transaminase levels are increased to at least three times the upper limit of normal, the dosage either needs to be held or decreased until the transaminase levels return to a normal range before resuming therapy.
Ambrisentan is a more selective ET-A receptor antagonist and is currently clinically available. The Ambrisentan in Pulmonary Artery Hypertension, Randomized, Double-Blinded, Placebo-Controlled, Multicenter, Efficacy Study I and II (ARIES I and II) demonstrated the efficacy of ambrisentan in improving 6 min walk test distance and time to clinical worsening, and the drug has received Food and Drug Administration (FDA) approval for functional class II and III patients. Although ambrisentan is in the same pharmacologic class as bosentan and its use requires transaminase monitoring, elevation of transaminases was not seen in any patient treated with ambrisentan. Side effects more commonly seen were nasal congestion, peripheral edema, and headaches [Galiè et al. 2008
Sitaxsentan, the most selective ET-A receptor antagonist clinically available, which has been approved for use in Europe, Canada, and Australia but not in the USA, was recently voluntarily withdrawn by Pfizer. Even though the Sitaxsentan to Relieve Impaired Exercise trials (STRIDE 1 and 2) did show 6 min walk test distance improvement and functional class improvement, there had been reported prior cases of fatal hepatitis at higher doses in the STRIDE 2 patient population comparable with placebo [Barst et al. 2006
]. This withdrawal was prompted by a review of emerging safety information from clinical trials and postmarketing reports regarding concerns about idiosyncratic, fatal hepatic failure.
It is important to mention that a clinically meaningful difference between the three approved ERAs with respect to their endothelin receptor selectivity has not been demonstrated to date. In clinical practice, therefore, other features are likely to be of greater relevance when considering treatment, such as the potential for serious drug–drug interactions, convenience of the dosing schedule, and rates of limiting side effects. These characteristics bear more relation to the chemical or pharmacologic properties of the drug than to receptor selectivity itself.
A recently published robust meta-analysis confirmed the therapeutic benefit of ERAs but concluded that they have no proven effect on mortality [Ryerson et al. 2010
]. It is important, however, to highlight that there has been no definitive study proving a survival benefit for any ERA, owing to the fact that long-term, placebo-controlled studies are perceived as ethically unjustifiable and randomized, controlled trials are not powered to detect a mortality benefit.