Spironolactone metabolite concentrations in decompensated heart failure: insights from the ATHENA-HF trial

• Type of Material: Article
• Authors: Simon de Denus, Montreal Heart Institute; Grégoire Leclair, Montreal Heart Institute; Marie-Pierre Dubé, Montreal Heart Institute; Isabelle St-Jean, Montreal Heart Institute; Yassamin Feroz Zada, Montreal Heart Institute; Essaïd Oussaïd, Montreal Heart Institute; Martin Jutras, Montreal Heart Institute; Michael M Givertz, Harvard Medical School; Robert J Mentz, Duke University; Wilson WH Tang, Cleveland Clinic; João P Ferreira, Université de Lorraine; Jean Rouleau, Montreal Heart Inst; Javed Butler, Emory University; Andreas Kalogeropoulos, Emory University
• Language: English
• Date: 2020-08-01
• Publisher: WILEY
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2020 European Society of Cardiology
• Final Published Version (URL): http://dx.doi.org/10.1002/ejhf.1802
• Title of Journal or Parent Work: EUROPEAN JOURNAL OF HEART FAILURE
• Volume: 22
• Issue: 8
• Start Page: 1451
• End Page: 1461
• Grant/Funding Information: This project was also supported by the Université de Montréal Beaulieu-Saucier Chair in Pharmacogenomics and the Montreal Heart Institute Foundation.; Research reported in this article was supported by the National Heart, Lung, and Blood Institute of the National Institutes of Health under award U10 HL084904 (for the Coordinating Center) and awards U10 HL110297, U10 HL110342, U10 HL110309, U10 HL110262, U10 HL110338, U10 HL110312, U10 HL110302, U10 HL110336, and U10 HL110337 (for Regional Clinical Centers).
• Keywords: RATIONALE; ALDOSTERONE; Drug concentrations; Spironolactone; RELATIVE POTENCY; CANRENONE; Canrenone; Cardiovascular System & Cardiology; Cardiac & Cardiovascular Systems; Science & Technology; CLINICAL PHARMACOKINETICS; DESIGN; PROBNP LEVELS; Life Sciences & Biomedicine; Heart failure; THERAPY; PHARMACODYNAMICS

Abstract

Aims: In Aldosterone Targeted Neurohormonal Combined with Natriuresis Therapy in Heart Failure (ATHENA-HF), high-dose spironolactone (100 mg daily) did not improve efficacy endpoints over usual care [placebo or continued low-dose spironolactone (25 mg daily) in patients already receiving spironolactone] in the treatment of acute heart failure (HF). We hypothesized that low concentrations of the long-acting active metabolites of spironolactone [canrenone and 7α-thiomethylspironolactone (7α-TMS)] in the high-dose group could have contributed to these neutral results. Methods and results: In patients randomized to high-dose spironolactone not previously treated with spironolactone (high-dose-naïve, n = 112), concentrations of canrenone and 7α-TMS increased at 48 and 96 h compared to baseline, and between 48 and 96 h (all P ' 0.005), indicating that steady-state concentrations had not been reached by 48 h. In patients previously on low-dose, high-dose spironolactone (high-dose-previous, n = 37), concentrations of canrenone increased at 48 and 96 h compared to baseline (both P ' 0.0005), with a marginal increase between 48 and 96 h (P = 0.0507). At 48 h, both high-dose groups had higher concentrations of both metabolites than the low-dose spironolactone group (P ' 0.0001). Moreover, concentrations of both metabolites were higher in high-dose-previous vs. high-dose-naïve patients (P ' 0.01), indicating that previous spironolactone use was significant, and that steady-state has not been reached in high-dose-naïve patients at 48 h. We found limited and inconsistent evidence of correlation between metabolite concentrations and endpoints. Conclusions: Lower-than-anticipated concentrations of spironolactone active metabolites were observed for at least 48 h in the high-dose spironolactone group and may have contributed to the absence of pharmacological effects of spironolactone in the ATHENA-HF trial.