Efficacy and Safety of Ambulatory Hypertonic Saline Therapy in Outpatient Heart Failure Units - SALT-HF

Published Congress: ESC HFA 2024

Link: https://onlinelibrary.wiley.com/doi/epdf/10.1002/ehf2.14720

Dr. Atik Aksoy

Background:
The traditional model presents several challenges in managing worsening heart failure (WHF) in both inpatient and outpatient settings. While hospitalization is necessary for patients with severe symptoms, it is not always mandatory for those with volume overload. Hospitalization is often preferred due to the ability to administer IV diuretic therapy and provide close monitoring. This indicates a gap in outpatient treatment options for WHF patients and underscores the need to explore more effective outpatient management strategies.
In this context, WHF clinics have developed models aiming to provide comprehensive care, allowing patients to make same-day or unscheduled visits instead of going to the emergency department. However, randomized studies evaluating different diuretic strategies in the outpatient setting have not been conducted.

Objective:
The combination of hypertonic saline solution (HSS) and intravenous (IV) loop diuretics appears to enhance the diuretic response in patients hospitalized for heart failure (HF). However, the efficacy and safety of this treatment in an outpatient setting have not yet been evaluated. The SALT-HF trial aims to investigate the efficacy and safety of hypertonic saline solution in outpatient HF patients.

Methods:
This trial is a multicenter, double-blind, randomized study involving outpatient individuals with WHF who do not meet the criteria for hospitalization. Participants were required to exhibit at least two signs of fluid volume overload, be on ? 80 mg of oral furosemide daily, and have elevated natriuretic peptide levels.
Patients were randomized in a 1:1 ratio to receive either a 1-hour infusion of IV furosemide plus hypertonic saline solution (HSS; NaCl concentration 2.6-3.4% depending on plasma sodium levels) or a 1-hour infusion of IV furosemide alone (125-250 mg based on their baseline loop diuretic dose). Clinical, laboratory, and imaging parameters were collected at baseline and on the 7th day of treatment. Additionally, a follow-up phone visit was conducted 30 days post-treatment.
The primary endpoint was the volume of diuresis within the first 3 hours after treatment initiation. Secondary endpoints included; changes in congestion markers over 7 days, changes in renal function and electrolytes over 7 days, clinical events over 30 days (need for IV diuretics, hospitalization due to WHF, cardiovascular mortality, all-cause mortality, or hospitalization due to WHF). Safety endpoints were worsening renal function defined as an increase in serum creatinine ? 0.3 mg/dL by day 7, Hypokalemia (K+ < 3.5 mEq/L) by day 7, hyperkalemia (K+ > 5.5 mEq/L) by day 7, WHF requiring intravenous outpatient diuretic therapy, emergency department visit, or rehospitalization for HF by day 30, Cardiovascular mortality by day 30, all-cause mortality and heart failure hospitalization by day 30.

Results:
Between December 2020 and March 2023, a total of 167 participants [median age, 81 years; interquartile range (IQR), 73–87; 30.5% female] were randomized across 13 centers. Half of the participants (n = 82) had an ejection fraction >50%. The majority of patients had a high level of comorbidity, with a median Charlson Index of 3 (IQR: 2–4). Common comorbidities included hypertension (85.6%, n = 143), diabetes mellitus (41%, n = 69), hypercholesterolemia (55.7%, n = 93), atrial fibrillation (80%, n = 134), and chronic kidney disease (64%, n = 107).
Patients exhibited poor functional status (NYHA class III, 69%) and various signs of congestion. The mean composite congestion score was 4.3 (standard deviation: 1.7). Edema and jugular venous distention were present in 90% (n = 151) of patients, and 71% (n = 118) showed lung B-lines on ultrasound assessment. The median inferior vena cava diameter was 23 mm (IQR: 21–25), and plasma levels of N-terminal-pro-B-type natriuretic peptide (NT-proBNP) and carbohydrate antigen 125 (CA125) were elevated (median NT-proBNP 4969 pg/mL, IQR: 2508–9328; median CA125 46 U/L, IQR: 20–114).
The mean furosemide dose was 120 mg (IQR: 80–160 mg), with 28.1% (n = 47) of patients also on thiazide diuretics and 48.5% (n = 81) on mineralocorticoid receptor antagonists.


Conclusion:

Efficacy Endpoints:

• There were no observed differences in 3-hour diuresis, 3-hour natriuresis, or 3-hour weight change.
• No differences were noted in clinical congestion scores, biomarkers, inferior vena cava diameter, or lung ultrasound B-lines.
• A significant difference in weight change was observed at the end of 7 days between treatment strategies (p = 0.048, mean difference: 0.587).

 Safety Endpoints:

• The safety profile of HSS therapy was observed to be acceptable.

Interpretations:
The hypothesis tested in the SALT-HF trial is evaluated from several crucial perspectives. First, there is an increasing need for new strategies to prevent heart failure (HF) hospitalizations. Current approaches are inadequate and negatively impact patients' quality of life. Second, no randomized studies have evaluated diuretic strategies in the outpatient setting until now, and practices in this area are often empirical. This highlights the necessity of scientifically validating the efficacy and safety of treatment approaches. Lastly, HSS therapy appears to be a promising strategy for overcoming diuretic resistance. The results of this study could provide supportive evidence for the beneficial effects of HSS therapy in outpatient WHF patients, filling a significant gap in this field.
However, the results of the SALT-HF trial have been unexpectedly neutral regarding efficacy. Several questions arise about potential reasons for this outcome: Could the limited power of the study, particularly insufficient power for the primary endpoint, affect the results? How do differences between outpatient and inpatient settings impact the outcomes? The impact of administering a single dose needs consideration. It is also important to consider that a small sample size might influence the study results. Further research is necessary to determine whether HSS therapy is ineffective. Additionally, patient selection could be a significant factor; choosing all types of patients instead of those with specific conditions like arterial underfilling and persistant congestion may complicate the interpretation of the results. These findings indicate that more research is needed on the efficacy and safety of HSS therapy. Continuing studies to develop more effective and safe treatment options for outpatient WHF patients is crucial.