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.
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Article Info
Publication History
Published online: June 10, 2013
Accepted:
April 11,
2013
Received in revised form:
April 11,
2013
Received:
March 8,
2013
Footnotes
This work was supported by grants HL105301 to Dr. Leopold; HL61795 , HL48743 , HL107192 , HL070819 , and HL108630 to Dr. Loscalzo; 1K08HL111207-01A1 to Dr. Maron from the US National Institutes of Health (Bethesda, Maryland) and the Lerner Foundation (Boston, Massachusetts) at Brigham and Women's Hospital (Dr. Maron) and grant 11POST6720000 to Dr. Maron from the American Heart Association (Dallas, Texas).
See page 725 for disclosure information.
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Copyright
© 2013 Elsevier Inc. Published by Elsevier Inc. All rights reserved.
