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.

中文翻译：

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失代偿性心力衰竭中的螺内酯代谢物浓度：来自 ATHENA-HF 试验的见解。

目标在醛固酮靶向神经激素联合尿钠排泄治疗心力衰竭 (ATHENA-HF) 中，高剂量螺内酯（每天 100 毫克）与常规治疗 [安慰剂或持续低剂量螺内酯（每天 25 毫克）相比，并未改善患者的疗效终点已经接受螺内酯]治疗急性心力衰竭（HF）。我们假设高剂量组中低浓度的螺内酯长效活性代谢物 [坎利酮和 7α-硫代甲基螺内酯 (7α-TMS)] 可能导致这些中性结果。方法和结果 在随机分配至先前未接受过螺内酯治疗的高剂量螺内酯患者中（初治高剂量，n = 112），与基线相比，48 和 96 小时以及 48 至 96 小时坎利酮和 7α-TMS 的浓度增加h (所有 P < 0.005), 表明在 48 小时内尚未达到稳态浓度。在先前接受低剂量、高剂量螺内酯（先前高剂量，n = 37）的患者中，与基线相比，48 和 96 小时的坎利酮浓度增加（均 P < 0.0005），在 48 和 96 小时之间略有增加96 小时（P = 0.0507）。在 48 小时时，两个高剂量组的两种代谢物浓度均高于低剂量螺内酯组（P < 0.0001）。此外，两种代谢物的浓度在既往高剂量患者中高于高剂量初治患者（P < 0.01），表明既往使用螺内酯是显着的，并且在高剂量患者中尚未达到稳态。 48 小时时的幼稚患者。我们发现代谢物浓度和终点之间相关性的证据有限且不一致。