We performed a post-hoc analysis, including data-driven (median changes after 1 month in the placebo group) definitions of diuretic-like and K-sparing effects, since there is no consensual definition of these effects. The diuretic-like effect was assessed by a meaningful proposed (8) indirect estimation of plasma volume changes: a validated (upon comparison with a radio-labeled gold standard) method integrating hematocrit changes, which is routinely being used to estimate plasma volumes in patients scheduled plasma exchanges (30- 31), or even ultrafiltration in the HF setting (32), whereas of note, no specific validation has been reported so far in the HF setting. However, sensitivity analyses performed in a subset of our study population showed significant positive correlations between BNP variations (presumably mainly triggered by variations in the level of congestion ) and plasma volume variations. Moreover, this formula also contains hemoglobin ratios, and therefore controls for hemoglobin changes, which may matter in HF patients, within a cardiorenal anemia syndrome setting (34). We have elected to describe the diuretic and K-sparing effects at 1 month after randomization. Therefore, it is unknown whether these effects persist throughout long-term chronic drug exposure. Generally, long-term pharmacological effects of diuretics are difficult to characterize. In addition, considering values at later time points would have introduced a number of confounders and would have resulted in loss of observations due to event occurrence or dropout, and in loss of power and external validity. In addition, we have previously reported that the clinical benefit of eplerenone in EPHESUS was already statistically significant at 1 month (35). Therefore, we believe that, although partially speculative, our findings and interpretations are acceptable. In any case, stemming from a post hoc analysis, they are mainly hypothesis generating and should be confirmed by further investigations. Importantly, our data are derived from a randomized controlled trial, thus allowing us to assess reliably the association between eplerenone use and the tested cardiovascular outcomes. However, even though we focused our analysis on the first month of follow-up, a minority of patients equally distributed between the 2 study groups (overall: 8.3%; eplerenone group: 7.9%, placebo group: 8.7%, p = 0.28) could not be included in the analysis because of unavailable data at month 1. In the meantime, within the EPHESUS whole study population, the number of deaths was higher (153 of 3,313, 4.6%) in the placebo group, compared with the eplerenone group (107 of 3,319, 3.2%, p = 0.003). These already reported early beneficial effects on mortality (35) were not taken into account in our survival analyses, which used a starting point of 1 month post-enrollment. This may have contributed to the fact that the reported beneficial effects of eplerenone on all-cause death, cardiovascular death, and sudden cardiac death (4) were no longer found to be statistically significant in our substudy.