Effectiveness of spironolactone plus ambrisentan for treatment of pulmonary arterial hypertension (from the [ARIES] study 1 and 2 trials)

Abstract

In translational models of pulmonary arterial hypertension (PAH), spironolactone improves cardiopulmonary hemodynamics by attenuating the adverse effects of hyperaldosteronism on endothelin type-B receptor function in pulmonary endothelial cells. This observation suggests that coupling spironolactone with inhibition of endothelin type-A receptor-mediated pulmonary vasoconstriction may be a useful treatment strategy for patients with PAH. We examined clinical data from patients randomized to placebo or the selective endothelin type-A receptor antagonist ambrisentan (10 mg/day) and in whom spironolactone use was reported during ARIES-1 and -2, which were randomized, double-blind, placebo-controlled trials assessing the effect of ambrisentan for 12 weeks on clinical outcome in PAH. From patients randomized to placebo (n = 132) or ambrisentan (n = 67), we identified concurrent spironolactone use in 21 (15.9%) and 10 (14.9%) patients, respectively. Compared with patients treated with ambrisentan alone (n = 57), therapy with ambrisentan + spironolactone improved change in 6-minute walk distance by 94% at week 12 (mean ± SE, +38.2 ± 8.1 vs +74.2 ± 27.4 m, p = 0.11), improved plasma B-type natriuretic peptide concentration by 1.7-fold (p = 0.08), and resulted in a 90% relative increase in the number of patients improving ≥1 World Health Organization functional class (p = 0.08). Progressive illness, PAH-associated hospitalizations, or death occurred as an end point for 5.3% of ambrisentan-treated patients; however, no patient treated with ambrisentan + spironolactone reached any of these end points. In conclusion, these pilot data suggest that coupling spironolactone and endothelin type-A receptor antagonism may be clinically beneficial in PAH. Prospective clinical trials are required to further characterize our findings.

Figure 1

Schematic representation of the biological hypothesis supporting combination spironolactone (SPIRO) plus endothelin type-A receptor (ET_A) antagonism for the treatment of PAH. Stimulation of pulmonary smooth muscle cells (PSMC) ET_A and endothelin type-B receptor (ET_B) are the major and minor signaling pathways, respectively, that modulate endothelin-1 (ET-1)-dependent pulmonary vasoconstriction in PAH. In contrast, pulmonary artery endothelial cell (PAEC) ET_B stimulation by ET-1 promotes pulmonary vasodilation. In PAH, hyperaldosteronism is associated with a pulmonary vasculopathy that is due, in part, to increased oxidant stress levels that inhibits ET_B function. Therefore, 2 potential treatment targets within the aldosterone-endothelin receptor axis are exposed: ET_A to inhibit the major pulmonary vasoconstrictor pathway and the mineralocorticoid receptor (MR) to preserve ET_B-dependent vasodilation.

Figure 2

Change frombaseline in the 6-MWD. Mean±SE change from baseline in the 6-MWD at week 4, 8, and 12 in the placebo (n = 111), spironolactone (n = 21), ambrisentan (10 mg/day, n = 57), and ambrisentan + spironolactone (n = 10) treatment groups. p Values reflect comparisons among groups at week 12.

Figure 3

The effect of treatment on BNP concentrations. The percent change at week 12 from baseline in geometric mean plasma BNP concentration with 95% CIs are presented for patients in the placebo (n = 83), spironolactone (SPIRO, n = 12), ambrisentan (10 mg/day, n = 43), and ambrisentan + spironolactone (n = 10) treatment groups.

Figure 4

The effect of treatment on World Health Organization (WHO) functional class. The percentage of patients in whom an improvement by ≥1 WHO functional class is reported at week 4, 8, and 12 for the placebo (n = 111), spironolactone (n = 21), ambrisentan (10 mg/day, n = 57), and ambrisentan + spironolactone (n = 10) treatment groups.