Ambrisentan for the Treatment of Pulmonary Arterial Hypertension

Abstract

Background-Ambrisentan is a propanoic acid-based, A-selective endothelin receptor antagonist for the once-daily treatment of pulmonary arterial hypertension. Methods and Results-Ambrisentan in Pulmonary Arterial Hypertension, Randomized, Double-Blind, Placebo-Controlled, Multicenter, Efficacy Study 1 and 2 (ARIES-1 and ARIES-2) were concurrent, double-blind, placebo-controlled studies that randomized 202 and 192 patients with pulmonary arterial hypertension, respectively, to placebo or ambrisentan (ARIES-1, 5 or 10 mg; ARIES-2, 2.5 or 5 mg) orally once daily for 12 weeks. The primary end point for each study was change in 6-minute walk distance from baseline to week 12. Clinical worsening, World Health Organization functional class, Short Form-36 Health Survey score, Borg dyspnea score, and B-type natriuretic peptide plasma concentrations also were assessed. In addition, a long-term extension study was performed. The 6-minute walk distance increased in all ambrisentan groups; mean placebo-corrected treatment effects were 31 m (Pϭ0.008) and 51 m (PϽ0.001) in ARIES-1 for 5 and 10 mg ambrisentan, respectively, and 32 m (Pϭ0.022) and 59 m (PϽ0.001) in ARIES-2 for 2.5 and 5 mg ambrisentan, respectively. Improvements in time to clinical worsening (ARIES-2), World Health Organization functional class (ARIES-1), Short Form-36 score (ARIES-2), Borg dyspnea score (both studies), and B-type natriuretic peptide (both studies) were observed. No patient treated with ambrisentan developed aminotransferase concentrations Ͼ3 times the upper limit of normal. In 280 patients completing 48 weeks of treatment with ambrisentan monotherapy, the improvement from baseline in 6-minute walk at 48 weeks was 39 m. Conclusions-Ambrisentan improves exercise capacity in patients with pulmonary arterial hypertension. Improvements were observed for several secondary end points in each of the studies, although statistical significance was more variable. Ambrisentan is well tolerated and is associated with a low risk of aminotransferase abnormalities.

Guidelines for the diagnosis and treatment of pulmonary hypertension

“…Ambrisentan has been evaluated in a pilot study [145] and in two large RCTs (Ambrisentan in pulmonary arterial hypertension, Randomized, double-blind, placebo-controlled, multicentre, Efficacy Study (ARIES) 1 and 2), which have demonstrated efficacy on symptoms, exercise capacity, haemodynamics, and time to clinical worsening of patients with IPAH and PAH associated with CTD and HIV infection. The open-label continuation study has demonstrated the durability of the effects of ambrisentan for at least 1 yr [146]. Ambrisentan has been approved for the treatment of WHO-FC II and III patients.…”

“…Only three RCTs, one with the orally active prostanoid beraprost [134] and two with the selective endothelin receptors antagonist ambrisentan [146], allowed inclusion of patients with HIV-related PAH who represented, 5% of the total population.…”

Pharmacotherapy of Pulmonary Hypertension

“…This agent blocks the vasoconstrictor effect of ETA receptors while maintaining the vasodilator and clearance effects of ETB receptors. Ambrisentan has been shown to improve exercise capacity and delay clinical worsening in PAH patients [122,123], and is thought to produce less liver toxicity than bosentan, but further study is needed in children. Of note, another selective ETA receptor antagonist, Sitaxentan, was recently withdrawn from the market due to concerns about severe liver toxicity.…”

Pulmonary hypertension—“state of the art” management in 2012

“…There is genetic anticipation in familial PAH, i.e. the onset of disease occurs at an Indian Heart Journal 6401 (2012) [60][61][62][63][64][65][66][67][68][69][70][71][72][73] earlier age in successive generations. 8,9 Group 1 of Dana Point classification also includes drugs and toxins associated with development of PAH; the most notorious of these include the appetite suppressants fenfluramine and dexfenfluramine.…”

“…It was shown to improve exercise capacity in ARIES I and ARIES II study. 65 Although hepatotoxicity seems to be less common in patients taking selective ET A receptors antagonists, cases of acute hepatitis have been described. Hence liver functions should be constantly monitored.…”