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Randomized Controlled Trial
. 2025 Jun;27(6):960-971.
doi: 10.1002/ejhf.3597. Epub 2025 Feb 11.

Salt repletion and diuretic response: The role of serum chloride. A post-hoc analysis of the SALT-HF trial on furosemide and hypertonic saline solution administration in ambulatory patients with worsening heart failure

Julio Núñez #  1 , Gema Miñana #  1 , Rafael de la Espriella  1   2 , Isabel Zegrí-Reiriz  3 , Josep Comín-Colet  2   4 , Jorge Rubio Gracia  5 , Jose Luis Morales-Rull  6 , Pau Llàcer  7 , Pablo Diez-Villanueva  8 , Javier de Juan Bagudá  2   9 , Carolina Ortiz Cortés  10 , Josebe Goirigolzarri-Artaza  11 , Jose Manuel García-Pinilla  2   12 , Elvira Barrios  13 , Susana Del Prado Díaz  2   14 , Santiago Jiménez-Marrero  2   4 , Maria Alejandra Restrepo-Córdoba  11 , Jeffrey Testani  15 , Marta Cobo Marcos  16
Affiliations
Randomized Controlled Trial

Salt repletion and diuretic response: The role of serum chloride. A post-hoc analysis of the SALT-HF trial on furosemide and hypertonic saline solution administration in ambulatory patients with worsening heart failure

Julio Núñez et al. Eur J Heart Fail. 2025 Jun.

Abstract

Aims: The efficacy of combining hypertonic saline solution (HSS) with loop diuretics in worsening heart failure (WHF) remains uncertain. Hypochloraemia has been associated with reduced diuretic efficacy. Some authors propose that chloride repletion may enhance natriuretic and diuretic responses. This post-hoc analysis of the SALT-HF trial evaluated the effect of single-dose administration of HSS plus intravenous (IV) furosemide versus IV furosemide, stratified by baseline serum chloride.

Methods and results: The analysis included 148 ambulatory patients with WHF from the double-blind, randomized SALT-HF trial. Participants received either an IV single dose of HSS plus furosemide or IV furosemide. The endpoints were 3-h urinary sodium excretion and diuresis, 7-day congestion score, and 30-day adverse events according to chloride levels. Multivariable linear and logistic regression models assessed the relationship between the intervention and the endpoints. The mean baseline serum chloride level was 100 ± 4 mmol/L. Sixteen patients (10.8%) were identified as hypochloraemic (serum chloride <96 mmol/L), balanced between treatment groups. Patients with hypochloraemia showed a lower natriuretic response (p < 0.05). Interaction analysis revealed a between-treatment differential natriuretic effect based on the chloride levels (pinteraction = 0.008). HSS plus furosemide increased natriuresis compared to furosemide at lower chloride levels. No differential between-treatment effect was found for 3-h diuresis. Similar heterogeneous results were found for the 7-day clinical congestion score and 30-day heart failure events, with a benefit with HSS in patients with lower chloride levels.

Conclusion: In ambulatory patients with WHF and hypochloraemia, adding HSS to furosemide may improve short-term natriuretic response and outcomes. These findings suggest that chloride supplementation may help overcome diuretic resistance in these patients.

Keywords: Chloride; Congestion; Diuretic response; Heart failure; Hypertonic saline solution.

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References

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