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

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.

Keywords: Canrenone; Drug concentrations; Heart failure; Spironolactone.

Figure 1.. Canrenone concentrations in the ATHENA-HF trial.

A) Previous low-dose stratum randomized to low-dose spironolactone (Low-dose group); B) Naïve stratum randomized to high-dose spironolactone group (High-dose-naïve group); C) Previous low-dose stratum randomized to high-dose spironolactone group (High-dose-previous group); D) Between group comparison at baseline, 48 and 96 hours. Data presented as median and interquartile range. All between group comparisons performed using Kruskal-Wallis test. *p < 0.05; # p < 0.005; †p < 0.0001

Figure 2.. 7-α-thiomethyl-spironolactone concentrations in the ATHENA-HF trial

A) Previous low-dose stratum randomized to low-dose spironolactone (Low-dose group); B) Naïve stratum randomized to high-dose spironolactone group (High-dose-naïve group); C) Previous low-dose stratum randomized to high-dose spironolactone group (High-dose-previous group); D) Between group comparison at baseline, 48 and 96 hours. Data presented as median and interquartile range. All between group comparisons performed using Kruskal-Wallis test. *p < 0.05; # p < 0.005; †p < 0.0001

Figure 3.. Observed and theoretical canrenone concentrations in patients randomized to high-dose spironolactone who were not treated with spironolactone prior to hospitalisation.

The figure illustrates anticipated canrenone concentrations in the scenario where canrenone would have an elimination half-life of 16 hours (red line) and 48 hours (blue line). The black dots represent the median canrenone concentrations measured at baseline, 48 and 96 hours in patients randomized to high-dose spironolactone who did not receive spironolactone group before hospital admission.