Combination diuretic therapy in acute heart failure

This commentary refers to ‘Combining loop with thiazide diuretics for decompensated heart failure: the CLOROTIC trial’, by J.C. Trullàs et al., https://doi.org/10.1093/eurheartj/ehac689 and the discussion piece ‘Combination diuretic therapy in acute heart failure’, by Y. Xin et al., https://doi.org/10.1093/eurheartj/ehad189. Li et al. comment on different aspects of combining loop with thiazide diuretics for decompensated heart failure (the combining loop with thiazide diuretics for decompensated heart failure (CLOROTIC) trial)1,2 with special emphasis on baseline left-ventricle ejection fraction (LVEF) and estimated glomerular filtration rate (eGFR). We would like to thank Li et al. for their interest and comments in our work. Firstly, the mean LVEF was 55% (57% and 55% in the placebo and hydrochlorothiazide groups, respectively), and although it is true that patients with preserved (≥ 50%) LVEF predominated in the study (65%), the CLOROTIC trial also included patients with reduced (< 40%) and mildly reduced (40%–49%) LVEF values, 25% and 10%, respectively. On the other hand, in the subgroup analysis, there was no significant interaction when analysing the LVEF according to whether it was higher or lower than 50%, indicating that there was no significant difference in the main outcome results in relation to this variable. Despite this, we are carrying out a post-hoc analysis to specifically assess the diuretic response of hydrochlorothiazide across the entire range of LVEF. Secondly, the mean eGFR was 43 mL/min/1.73m2, but the range was wide (between 14 and 109 mL/min/1.73 m2) meaning that not all patients were in the same category of renal disfunction on admission: 54 (23%), 55 (24%), and 121 (53%) patients had eGFR values ≥ 60 mL/min/1.73 m2, from 45 to 59 mL/min/1.73 m2, and < 45 mL/min/1.73 m2, respectively. Worsening renal function in patients with acute heart failure must be adequately interpreted. Although it has been classically related with increased morbidity and mortality, more contemporary studies suggest that the association between worsening renal function and clinical outcomes depends on diuretic response. In two large cohorts of patients with acute heart failure, worsening renal function was not associated with worse outcomes when patients had a good diuretic response.3 The fact that in the CLOROTIC trial, worsening renal function was not associated with higher mortality or readmissions, suggests that it must be interpreted in the context of good diuretic response. However, as renal function was not monitored in the follow-up visits, we cannot guarantee that this deterioration in renal function was transient. Finally, it is unclear if the efficacy and safety of combined diuretic therapy differ across the spectrum of baseline eGFR. In this sense, and as for LVEF, in the subgroup analysis, there was no interaction according to baseline creatinine and eGFR, and we are also carrying out a post-hoc analysis, stratifying the main results of the CLOROTIC trial (including primary, secondary, and safety endpoints) according to the baseline eGFR. The data underlying this article will be shared on reasonable request to the corresponding author.