Effects of Repletion of Sodium Chloride on Natriuresis, Blood Pressure, and Neurohormonal Activity in Patients With Chronic Heart Failure With Reduced Ejection Fraction

Official title

Impact of Sodium Chloride Supplementation for Natriuresis, Blood Pressure and Neurohormonal Activity in Chronic Heart Failure With Reduced Ejection Fraction and Low Serum Sodium Concentration - Double-blinded, Placebo-controlled, Prospective Trial

Overview

The study is a single-center, prospective, randomized, placebo-controlled, double-blind trial conducted at the Institute of Heart Diseases and the Department of Cardiology of Wroclaw Medical University Hospital. It aims to evaluate the effects of three-month oral sodium chloride supplementation (3 g/day, equivalent to 1.2 g of sodium) versus placebo (lactose) in patients with chronic heart failure with reduced ejection fraction (HFrEF) and low serum sodium, who have not reached the maximum recommended doses of guideline-directed medical therapy (GDMT). A total of 30 patients will be enrolled, with 15 randomized to the experimental group receiving sodium chloride and 15 to the control group receiving placebo. Patient selection will involve careful screening, including recent serum sodium measurements, to ensure all inclusion and exclusion criteria are met. Participants will attend bi-weekly visits to assess clinical parameters (medical history, EVEREST heart failure symptoms score, blood pressure, body weight), biochemical markers (serum: morphology, urea, creatinine, sodium, chloride, potassium, NT-proBNP, aldosterone, renin; urine: urea, creatinine, sodium, chloride, potassium), and the safety of supplementation (body weight, serum sodium and chloride, exercise tolerance). Visits will also allow attempts to optimize GDMT doses where clinically feasible, based on objective criteria (e.g., systolic blood pressure \>110 mmHg and/or diastolic blood pressure \>60 mmHg). Capsules containing sodium chloride or placebo will be prepared according to pharmacy standards to ensure intestinal release and maintain blinding. The Primary Investigator will remain blinded to treatment allocation. Follow-up will include both in-person and telephone visits, monitoring clinical status and safety parameters throughout the study period. Sample size was calculated based on previous studies in this field, to achieve a type I error probability of 0.05 and a power of 0.80. At the end of the three-month supplementation, participants will undergo a comprehensive final assessment. Study data will be analyzed statistically to determine the effects of sodium chloride supplementation on natriuresis, blood pressure, neurohormonal activity, and the potential for optimizing GDMT in HFrEF patients with low serum sodium.

Detailed description

Heart failure (HF) is a complex clinical syndrome characterized by symptoms and signs resulting from structural and/or functional cardiac abnormalities that lead to elevated intracardiac pressure and/or reduced cardiac output at rest or during exertion. The pathophysiology of HF is strongly associated with neurohormonal activation, including increased activity of the renin-angiotensin-aldosterone system, vasopressin, endothelin, and natriuretic peptides. Pharmacological therapies targeting these pathways, collectively referred to as guideline-directed medical therapy (GDMT) in HF with reduced ejection fraction (HFrEF), significantly reduce mortality and unplanned hospitalizations when administered at recommended doses.

Despite advances in treatment, HF remains a progressive disease characterized by recurrent episodes of decompensation and poor long-term outcomes. Epidemiological data indicate that HF affects approximately 1-2% of the general population and is associated with high annual mortality and frequent hospital admissions. Neurohormonal disturbances contribute to sodium and water retention, leading to fluid accumulation and the need for diuretic therapy to restore euvolemia. Although diuretics effectively relieve congestion-related symptoms, they do not improve long-term outcomes and may contribute to electrolyte disturbances, particularly hyponatremia, which is itself associated with worse outcomes in advanced HF.

For many years, strict dietary sodium restriction was considered a cornerstone of HF management because excessive sodium intake was believed to promote fluid retention due to impaired renal autoregulation. However, recent evidence has challenged this paradigm. Studies conducted in the era of modern neurohormonal blockade have demonstrated that sodium restriction does not improve clinical outcomes in HF patients. The SODIUM-HF trial showed no clinical benefit from dietary sodium restriction, while other studies, including those by Dauw et al., demonstrated that oral sodium chloride supplementation of 3 g/day is safe in HF patients, does not increase fluid overload, and may improve natriuresis while reducing plasma renin activity.

At the same time, a major limitation of contemporary HF treatment remains the inability to achieve optimal GDMT dosing in many patients. Hypotension frequently prevents dose escalation or initiation of additional prognostically beneficial therapies, resulting in only approximately 40% of patients receiving all recommended medications at target doses. Therefore, strategies aimed at improving blood pressure stability and sodium balance may facilitate better optimization of HF therapy.

Based on these observations, the present study was designed to evaluate whether oral sodium chloride supplementation in patients with chronic HFrEF and low serum sodium levels may safely improve sodium handling, neurohormonal balance, blood pressure, and tolerance of GDMT. Additionally, the study aims to assess whether sodium supplementation may facilitate optimization of GDMT dosing in patients prone to hypotension.

This investigation is a single-center, prospective, randomized, placebo-controlled, double-blind trial conducted at the Institute of Heart Diseases and the Department of Cardiology of Wroclaw Medical University Hospital. Thirty patients with HFrEF, low serum sodium concentration, and suboptimal GDMT dosing will be enrolled. Participants will be randomly assigned 1:1 to one of two groups: an intervention group receiving oral sodium chloride supplementation (1 g NaCl capsules administered three times daily, totaling 3 g/day) or a placebo group receiving matching lactose capsules.

Eligibility will be confirmed through a detailed preselection process, including recent serum sodium measurements and baseline laboratory evaluation. After enrollment and informed consent, all participants will continue their current HF medications and habitual diet, without medication dose modifications during the first 14 days of supplementation. Throughout the study, patients will perform daily home measurements of blood pressure, heart rate, and body weight.

Scheduled follow-up visits will include clinical assessment of HF symptoms, anthropometric measurements, and laboratory analyses of serum and urinary electrolytes, renal function parameters, NT-proBNP, renin, and aldosterone concentrations. Safety monitoring will focus on body weight changes, exercise tolerance, blood pressure, and adherence to supplementation. Supplementation will be temporarily discontinued in cases of ≥2 kg body weight increase or worsening dyspnea/exercise tolerance. Compliance will be assessed using pill counts and patient diaries, and participants missing more than 10% of planned doses will be excluded from further analysis.

An additional objective of the study is to evaluate the feasibility of GDMT dose escalation during follow-up. Eligibility for treatment optimization will be determined using predefined blood pressure criteria, including systolic blood pressure \>110 mmHg and/or diastolic blood pressure \>60 mmHg, while maintaining patient safety and clinical stability.

The primary goals of the study are to assess the effects of oral sodium chloride supplementation on sodium retention, natriuresis, neurohormonal activity, blood pressure, and treatment safety in patients with HFrEF and low serum sodium levels. Secondary objectives include evaluation of the potential for GDMT optimization and comparison of outcomes between intervention and placebo groups, including subgroup analyses according to gender.

Interventions

• Dietary supplement Sodium chloride supplementation
  Oral supplementation with sodium chloride capsules for three months at a total daily dose of 3 g (equivalent to 1.2 g of sodium). The planned regimen is one 1 g sodium chloride capsule taken three times daily.
• Dietary supplement Placebo administration
  Three-month oral administration of lactose as a placebo, matching the active treatment in appearance and dosing schedule. The planned regimen is one capsule containing lactose three times daily.

Primary outcome measures

• Sodium Handling and Urine Dilution Response [Time frame: 3 months observation - predefined timpoints]
• Plasma renin and aldosterone assessment [Time frame: 3 months observation - in predefined timepoints]
• Mean blood pressure trajectory [Time frame: 3 months observation - in predefined timepoints]
• Body weight change assessment (safety measurement) [Time frame: 6 months observation - in predefined timpeoints]
• Blood pressure assessment (safety assessment) [Time frame: 6 moths observation - in predefined timepoints]

Secondary outcome measures (4)

• NT-proBNP change [Time frame: 3 months - predefined timepoints]
• Serum sodium concentration change [Time frame: 3 months - predefined timepoints]
• Congestion status change [Time frame: 3 months - predefined timepoints]
• Possibility of GDMT optimization [Time frame: 3 months - predefined timepoints]

Eligibility criteria

Inclusion criteria

• Chronic heart failure NYHA I-III.
• LVEF ≤40% documented in the echocardiography.
• Stable Heart Failure symptoms:

• Stable symptoms (subjectively declared by the patient) over the past three months.
• No increase in peripheral edema or body weight (declared by the patient).
• Loop diuretic dose equivalent to 80 mg of furosemide or 20 mg of torasemide daily, with no changes in the past three months.
• Age over 18 and under 85 years.
• Male or female.
• Use of guideline-directed medical therapy (GDMT), with each drug group at maximum tolerated doses but no more than half of the maximum dose.
• Systolic blood pressure <100 mmHg and/or diastolic blood pressure <60 mmHg.
• Resting heart rate up to 80 bpm.
• Serum sodium concentration <140 mmol/L, regardless of the cause.

Exclusion criteria

• Hospitalization due to heart failure decompensation within the last three months.
• Primary hypertrophic or restrictive cardiomyopathy, constrictive pericarditis.
• Systemic disease known to be associated with cardiac muscle infiltration.
• Significant valvular disease (moderate or severe stenosis of any valve, moderate or severe aortic or pulmonary regurgitation, severe tricuspid or mitral regurgitation).
• Severe renal impairment (eGFR <30 mL/min/1.73 m² based on the MDRD formula).
• Stroke or transient ischemic attack (TIA) within the last three months.
• Cardiac resynchronization therapy (CRT), ICD, ablation, or pacemaker implantation (or planned implantation) within the last three months.
• Severe lung disease or "cor pulmonale" or other causes of isolated right ventricular failure not associated with left ventricular dysfunction.
• Severe lung disease with respiratory failure requiring home oxygen therapy.
• Body weight <40 kg or ≥150 kg.
• Life expectancy <12 months according to the investigator's assessment
• Pregnancy or breastfeeding.
• Ongoing drug or alcohol abuse.
• Lactose intolerance.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Quadruple blind

Primary purpose

Basic science

Study locations

Poland · 1 center

• Institute of Heart Diseases, Wroclaw Medical University — Wroclaw

Publications

• Ezekowitz JA, Colin-Ramirez E, Ross H, Escobedo J, Macdonald P, Troughton R, Saldarriaga C, Alemayehu W, McAlister FA, Arcand J, Atherton J, Doughty R, Gupta M, Howlett J, Jaffer S, Lavoie A, Lund M, Marwick T, McKelvie R, Moe G, Pandey AS, Porepa L, Rajda M, Rheault H, Singh J, Toma M, Virani S, Zieroth S; SODIUM-HF Investigators. Reduction of dietary sodium to less than 100 mmol in heart failure PMID 35381194
• Zhao W, Qin J, Lu G, Wang Y, Qiao L, Li Y. Association between hyponatremia and adverse clinical outcomes of heart failure: current evidence based on a systematic review and meta-analysis. Front Cardiovasc Med. 2023 Dec 22;10:1339203. doi: 10.3389/fcvm.2023.1339203. eCollection 2023. PMID 38204798
• Mullens W, Damman K, Dhont S, Banerjee D, Bayes-Genis A, Cannata A, Chioncel O, Cikes M, Ezekowitz J, Flammer AJ, Martens P, Mebazaa A, Mentz RJ, Miro O, Moura B, Nunez J, Ter Maaten JM, Testani J, van Kimmenade R, Verbrugge FH, Metra M, Rosano GMC, Filippatos G. Dietary sodium and fluid intake in heart failure. A clinical consensus statement of the Heart Failure Association of the ESC. Eur J Hear PMID 38606657
• Dauw J, Meekers E, Martens P, Deferm S, Dhont S, Marchal W, Mesotten L, Dupont M, Nijst P, Tang WHW, Janssens SP, Mullens W. Sodium loading in ambulatory patients with heart failure with reduced ejection fraction: Mechanistic insights into sodium handling. Eur J Heart Fail. 2024 Mar;26(3):616-624. doi: 10.1002/ejhf.3131. Epub 2024 Jan 21. PMID 38247136

Identifiers

NCT: NCT07614295 · KB340/2025 · 2024/53/N/NZ5/02590

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗