de Denus Simon, Leclair Grégoire, Dubé Marie-Pierre, St-Jean Isabelle, Zada Yassamin Feroz, Oussaïd Essaïd, Jutras Martin, Givertz Michael M, Mentz Robert J, Tang W H Wilson, Ferreira João Pedro, Rouleau Jean, Butler Javed, Kalogeropoulos Andreas P
Faculty of Pharmacy, Montreal, Canada.
Montreal Heart Institute, Montreal, Canada.
Eur J Heart Fail. 2020 Aug;22(8):1451-1461. doi: 10.1002/ejhf.1802. Epub 2020 Apr 1.
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.
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.
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.
在心力衰竭患者醛固酮靶向神经激素联合利钠治疗（ATHENA-HF）研究中，高剂量螺内酯（每日100毫克）在急性心力衰竭（HF）治疗中，与常规治疗[安慰剂或已接受螺内酯治疗的患者继续使用低剂量螺内酯（每日25毫克）]相比，未改善疗效终点。我们推测，高剂量组中螺内酯的长效活性代谢产物[坎利酮和7α-硫甲基螺内酯（7α-TMS）]浓度较低可能导致了这些中性结果。
在随机分配至高剂量螺内酯且之前未接受过螺内酯治疗的患者（高剂量初治组，n = 112）中，与基线相比，坎利酮和7α-TMS浓度在48小时和96小时时升高，且在48小时至96小时之间（所有P < 0.005），表明48小时时未达到稳态浓度。在之前使用低剂量螺内酯的高剂量螺内酯患者（高剂量既往治疗组，n = 37）中，与基线相比，坎利酮浓度在48小时和96小时时升高（均P < 0.0005），在48小时至96小时之间有轻微升高（P = 0.0507）。在48小时时，两个高剂量组的两种代谢产物浓度均高于低剂量螺内酯组（P < 0.0001）。此外，高剂量既往治疗组患者的两种代谢产物浓度高于高剂量初治组患者（P < 0.01），表明之前使用螺内酯有显著影响，且高剂量初治组患者在48小时时未达到稳态。我们发现代谢产物浓度与终点之间相关性的证据有限且不一致。
高剂量螺内酯组在至少48小时内观察到螺内酯活性代谢产物浓度低于预期，这可能是ATHENA-HF试验中螺内酯缺乏药理作用的原因。
