Background: Pulmonary arterial hypertension (PAH) develops from an abnormal interaction between the endothelium and smooth muscle cells in the pulmonary arteries and is characterized by a progressive increase in pulmonary vascular resistance resulting from vascular remodeling, vasoconstriction, and cellular proliferation. A rapidly progressive disease with limited therapeutic options, PAH may progress to right ventricular failure and death. Endothelin (ET-1), a potent vasoconstrictor, has vascular remodeling properties that contribute to the acceleration of the disease. ET-1 predominantly binds to two receptors, endothelin-A (ET(A)) and endothelin-B (ET(B)) receptors. ET(A) receptors are found on smooth muscle cells only and, when activated, induce vasoconstriction and cellular proliferation. ET(B) receptors on smooth muscle cells, when activated, cause vasoconstriction, whereas those on endothelial cells produce vasodilation and clear circulating ET-1. Therefore, a clinically important question arises as to whether selective ET(A) receptor antagonism is superior to nonselective dual-receptor antagonism in the treatment of PAH.
Scope: To review clinical trials that studied safety and efficacy of various endothelin receptor antagonists (ETRAs) for the treatment of PAH and address the rationale for the use of either a nonselective or a selective ETRA.
Findings: Nonselective blockade of both ET receptors with the ETRA bosentan has demonstrated benefit in PAH, as have sitaxsentan and ambrisentan, two investigational agents with more selectivity for the ET(A) receptor. Data from placebo-controlled studies and long-term, open-label studies suggest that all ETRAs have similar efficacy, though there is some evidence suggesting that selective ETRAs may have a safer profile.
Conclusion: Both selective and nonselective ETRAs have proven to be efficacious in treatment of PAH patients, and selective ETRAs may have a slightly safer profile. However, because PAH is a rare disease and trials have relatively small numbers of patients, it is difficult to quantify the magnitude of the difference between the different agents.