Евразийский Кардиологический Журнал (Mar 2014)
AMBRISENTAN: THE POSSIBILITY OF THE TREATMENT FOR PULMONARY ARTERIAL HYPERTENSION WITH THE SELECTIVE BLOCKADE OF THE ENDOTHELIN SYSTEM
Abstract
The optimization of the drug therapy for pulmonary arterial hypertension (PAH) associated with the introduction into clinical practice of highly effective drugs of pathogenetic action affecting the main targets of disease - activating the endothelin (ET-1) system, deficiency of endogenous prostacyclin and nitric oxide. The role of ET-1 in the pathogenesis of PAH due to powerful vasoconstrictive action, the ability to induce cell proliferation and differentiation, production of growth factors, cytokines, biologically active substances. Endothelin receptor antagonists (ERAs) - is the most important class of PAH- specific therapies, including two drugs - nonselective ERA bosentan and selective ERA - ambrisentan. The evidence base related to the application ambrisentan in PAH includes three key studies: testing of different dose regimes of the drug; 2 randomized, placebo-controlled, double-blind clinical studies and the study with replacement of ERAs on ambrisentan in patients intolerant other ERAs . In the study on ambrisentan dosage regimes testing increase of the distance in 6 - minute walk distance (6-MWT) was dose-dependent. Using the drug in doses ranging from 1mg to 10 mg to 12 wks. there achieved a significant increase in 6-MWT distance of 33.9 m with 1mg dose (p=0.003) to 38.1m with 5mg (p=0.001). In two 12wk randomized, placebo-controlled studies ARIES- 1 and ARIES- 2 (Ambrisentan in PAH-a phase III, Randomized, Double-blind, placebo-controlled, multicenter, Efficacy Study of ambrisentan on Subjects with pulmonary arterial hypertension) the treatment with ambrisentan resulted to the significant increase of exercise tolerance according to 6-MWT from 22 m to 59 m when using the dose of 2.5mg (p = 0.022) and 10mg (p < 0.001), respectively. Ambrisentan treatment helped to reduce the need for lung transplantation, atrial septostomy, hospitalization for PAH progression. Achieved improvement was maintained for 2-year treatment with ambrisentan. Ambrisentan therapy was well tolerated. By 12 weeks the frequency of transaminases and bilirubin elevations was significantly lower with ambrisentan than for placebo group (0.8% versus 2.3%, respectively). Long-term follow up in the open study in 383 patients treated with ambrisentan, 95% of patients were alive at 1 year and 94 % of patients continued the treatment. Patients with adverse events when receiving bosentan or sitaksentan after translation to ambrisentan had no increase of liver transaminases. Thus, treatment with ambrisentan in PAH pts. resulted in the improvement of clinical symptoms and hemodynamic parameters, the increase in exercise tolerance and the prolongation of the time to the development of clinical deterioration. Favorable effects of long-term therapy with ambrisentan are shown for at least 2 years. In 2012 ambrisentan was approved by the Russian National Pharmacological Committee for the treatment of patients with PAH (Functional Classes II-III) at the dose of 5 mg and 10 mg PO.
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