de Denus S, Leclair G, Dubé MP, et al. - Given that 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 taking spironolactone] in the management of acute heart failure (HF) in ATHENA‐HF (Aldosterone Targeted Neurohormonal Combined with Natriuresis Therapy in Heart Failure), researchers undertook this study to test their hypothesis that low levels 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 outcomes. A rise in the levels of canrenone and 7α‐TMS at 48 and 96 h, vs baseline, and between 48 and 96 h, was noted in patients randomized to high‐dose spironolactone not earlier managed with spironolactone (high‐dose‐naïve, n = 112), this implies that steady‐state concentrations had not been reached by 48 h. Overall, findings revealed the presence of lower‐than‐anticipated concentrations of spironolactone active metabolites for at least 48 h in the high‐dose spironolactone group, as well as their likely contribution to the absence of pharmacological impacts of spironolactone in the ATHENA‐HF trial.