Does treatment response to ambrisentan vary by pulmonary arterial hypertension severity? Implications for clinicians and for the design of future clinical trials

Abstract

Recent clinical trials in pulmonary arterial hypertension have included World Health Organization functional classes I and II patients. However, the impact of baseline functional class and other measures of severity on outcomes has not been evaluated in detail. Outcomes at 12 weeks for patients grouped by functional class, haemodynamics, brain natriuretic peptide (BNP) level and 6-min walk distance (6MWD) were evaluated for patients in the Ambrisentan in Pulmonary Arterial Hypertension, Randomized, Double-Blind, Placebo-Controlled, Multicenter Efficacy Study 1 and 2 (ARIES)-1 and 2 pivotal trials of ambrisentan, a once-daily oral endothelin-1 antagonist. Long-term outcomes in the ARIES-E extension study were also evaluated. At 12 weeks, ambrisentan-treated patients with both early and late functional class showed similar improvement in 6MWD relative to placebo. However, patients with more severe disease tended to have greater improvement in 6MWD after grouping by other measures of severity. This included higher baseline BNP level, shorter baseline 6MWD and more severe baseline haemodynamics (p < 0.05 for BNP and p = NS for other comparisons, analysed as interaction terms). During long-term open label follow-up, maintenance of 6MWD improvement, freedom from clinical worsening and survival were also numerically worse for patients who were functional class III/IV at baseline. Patients with both less severe and more severe PAH benefited from ambrisentan therapy vs. placebo in 12-week clinical trials and during long-term follow up, but greater improvement vs. placebo was seen for those with higher BNP levels.