title: 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.
authors.affiliation: Veterans Affairs Boston Healthcare System, Department of Cardiology, 1400 VFW, Parkway, Boston, MA, USA. bmaron@partners.org
authors.forename: Bradley A
authors.initials: BA
authors.lastname: Maron
authors.forename: Aaron B
authors.initials: AB
authors.lastname: Waxman
authors.forename: Alexander R
authors.initials: AR
authors.lastname: Opotowsky
authors.forename: Hunter
authors.initials: H
authors.lastname: Gillies
authors.forename: Christiana
authors.initials: C
authors.lastname: Blair
authors.forename: Reza
authors.initials: R
authors.lastname: Aghamohammadzadeh
authors.forename: Joseph
authors.initials: J
authors.lastname: Loscalzo
authors.forename: Jane A
authors.initials: JA
authors.lastname: Leopold
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000959:Antihypertensive Agents / Q000627:therapeutic use*; D004232:Diuretics / Q000627:therapeutic use*; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D005080:Exercise Test; D065627:Familial Primary Pulmonary Hypertension; D005260:Female; D006801:Humans; D006976:Hypertension, Pulmonary / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D020097:Natriuretic Peptide, Brain / Q000097:blood; D010666:Phenylpropionates / Q000627:therapeutic use*; D010865:Pilot Projects; D011724:Pyridazines / Q000627:therapeutic use*; D012720:Severity of Illness Index; D013148:Spironolactone / Q000627:therapeutic use*; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000959:Antihypertensive Agents; D004232:Diuretics; D010666:Phenylpropionates; D011724:Pyridazines; D020097:Natriuretic Peptide, Brain; D013148:Spironolactone; C467894:ambrisentan