A practical approach to sequential nephron blockade in acute decompensated heart failure

Acute decompensated heart failure (ADHF) is a worldwide health problem, with poor prognosis and significant morbidity and mortality. Fluid overload is the primary reason for hospitalization in ADHF. The efficacy of diuretic monotherapy is suboptimal, with a substantial proportion of patients being discharged with residual congestion that portends a poor outcome. Accordingly, the loop diuretic monotherapy from the DOSE trial achieved a successful decongestion in less than 20% of patients. Although the concept of sequential nephron blockade has regained interest following the publication of several randomized clinical trials (RCTs), the optimal approach to combination diuretic therapy is still an area of uncertainty. The selection of an adequate approach remains difficult as comparisons between different trials cannot be made due to different diuretic doses used, timing of sequential blockade, differences in study cohorts or in definitions used to define decongestion. Moreover, a direct comparison of different combination therapies in large trials is lacking. Nonetheless, the approach to the combination diuretic therapy should rather take into account the patient phenotype, the suspected nephron segment responsible for diuretic resistance, and the anticipated electrolyte and acid–base disturbances in order to select diuretic agents with divergent effects. Herein, we review the molecular mechanisms of action of diuretic agents, highlight the most recent trials evaluating combined diuretic therapy in ADHF and identify clinical scenarios, apart from diuretic resistance, for optimal association of diuretics to counteract their anticipated adverse effects.