
==== Front
Clin Res Cardiol
Clin Res Cardiol
Clinical Research in Cardiology
1861-0684
1861-0692
Springer Berlin Heidelberg Berlin/Heidelberg

37389661
2256
10.1007/s00392-023-02256-7
Original Paper
Role of dietary sodium restriction in chronic heart failure: systematic review and meta-analysis
Urban Szymon 1
Fułek Michał 2
http://orcid.org/0000-0001-8207-1723
Błaziak Mikołaj blaziak.mikolaj@gmail.com

1
Fułek Katarzyna 3
Iwanek Gracjan 1
Jura Maksym 4
Grzesiak Magdalena 5
Szymański Oskar 5
Stańczykiewicz Bartłomiej 6
Ptaszkowski Kuba 7
Zymlinski Robert 1
Ponikowski Piotr 1
Biegus Jan 1
1 https://ror.org/01qpw1b93 grid.4495.c 0000 0001 1090 049X Institute of Heart Diseases, Wroclaw Medical University, Wrocław, Poland
2 https://ror.org/01qpw1b93 grid.4495.c 0000 0001 1090 049X Department and Clinic of Internal Medicine, Occupational Diseases, Hypertension and Clinical Oncology, Wroclaw Medical University, Wroclaw, Poland
3 https://ror.org/01qpw1b93 grid.4495.c 0000 0001 1090 049X Department and Clinic of Otolaryngology, Head and Neck Surgery, Wroclaw Medical University, Wroclaw, Poland
4 https://ror.org/01qpw1b93 grid.4495.c 0000 0001 1090 049X Department of Physiology and Pathophysiology, Wroclaw Medical University, Wroclaw, Poland
5 https://ror.org/01qpw1b93 grid.4495.c 0000 0001 1090 049X Student Scientific Organisation, Institute of Heart Disease, Wroclaw Medical University, Wroclaw, Poland
6 https://ror.org/01qpw1b93 grid.4495.c 0000 0001 1090 049X Division of Consultation Psychiatry and Neuroscience, Department of Psychiatry, Wroclaw Medical University, Wroclaw, Poland
7 https://ror.org/01qpw1b93 grid.4495.c 0000 0001 1090 049X Department of Clinical Biomechanics and Physiotherapy in Motor System Disorders, Wroclaw Medical University, Wroclaw, Poland
30 6 2023
30 6 2023
2024
113 9 13311342
30 4 2023
22 6 2023
© The Author(s) 2023
2023
https://creativecommons.org/licenses/by/4.0/ Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
Background

Dietary sodium restriction remains a guidelines-approved lifestyle recommendation for chronic heart failure (CHF) patients. However, its efficacy in clinical outcome improvement is dubious.

Objective

The study evaluated whether dietary sodium restriction in CHF reduces clinical events.

Methods

We performed a systematic review of the following databases: Academic Search Ultimate, ERIC, Health Source Nursing/Academic Edition, MEDLINE, Embase, Clinicaltrials.gov and Cochrane Library (trials) to find studies analysing the impact of sodium restriction in the adult CHF population. Both observational and interventional studies were included. Exclusion criteria included i.e.: sodium consumption assessment based only on natriuresis, in-hospital interventions or mixed interventions—e.g. sodium and fluid restriction in one arm only. The review was conducted following PRISMA guidelines. Meta-analysis was performed for the endpoints reported in at least 3 papers. Analyses were conducted in Review Manager (RevMan) Version 5.4.1.

Results

Initially, we screened 9175 articles. Backward snowballing revealed 1050 additional articles. Eventually, 9 papers were evaluated in the meta-analysis. All-cause mortality, HF-related hospitalizations and the composite of mortality and hospitalisation were reported in 8, 6 and 3 articles, respectively. Sodium restriction was associated with a higher risk of the composite endpoint (OR 4.12 [95% CI 1.23–13.82]) and did not significantly affect the all-cause mortality (OR 1.38 [95% CI 0.76–2.49]) or HF hospitalisation (OR 1.63 [95% CI 0.69–3.88]).

Conclusions

In a meta-analysis, sodium restriction in CHF patients worsened the prognosis in terms of a composite of mortality and hospitalizations and did not influence all-cause mortality and HF hospitalisation rate.

Graphical abstract

Supplementary Information

The online version contains supplementary material available at 10.1007/s00392-023-02256-7.

Keywords

Heart failure
Sodium
Salt
NaCl
issue-copyright-statement© Springer-Verlag GmbH Germany, part of Springer Nature 2024
==== Body
pmcIntroduction

For many years, sodium restriction has been recommended as a key dietary intervention for patients with heart failure (HF) [1]. This recommendation was based on the belief that a low-sodium diet would reduce fluid retention and decrease the risk of HF hospitalizations [2]. Whilst this assumption was based on the fact that in HF, water and sodium homeostasis are greatly disturbed, and any interference may lead to clinical deterioration. However, recent studies have cast doubt on the effectiveness of this intervention, with some suggesting that it may even be harmful [3].

One of the main criticisms of sodium restriction in the management of HF is that the evidence supporting its implementation is relatively weak and based on early experiments that involved assessing the pathological responses of HF patients to sodium loading [4]. Thus, these experiments may not accurately reflect the effects of long-term sodium restriction. On the other hand, the burden of pharmacological and non-pharmacological recommendations in HF is significant and often challenging to maintain in the long run [5–7].

Given these unclear or conflicting perspectives, there is a significant need to evaluate the effect of recommended low-sodium diet in HF. In our meta-analysis, we aim to provide a comprehensive evaluation of the existing evidence on the benefits and risks of sodium restriction in the management of HF.

Methods

Search strategy

Initially, we screened the following databases: Academic Search Ultimate, ERIC, Health Source Nursing/Academic Edition, MEDLINE, Embase, Clinicaltrials.gov and Cochrane Library (trials) for the relevant articles. No restrictions regarding the publication date were determined, screening and papers export were performed on 11.10.2022. The keywords differed slightly in different sources.

In EMBASE, Academic Search Ultimate, ERIC, Health Source Nursing/Academic Edition and Cochrane Library, keywords were as follows: ((diet*) OR (eat*) OR (ingestion) OR (feed) OR (micronutrient) OR (macronutrient) OR (intake*) OR (nutri*) OR (consump*)) AND ((heart failure) OR (ventricular dysfunction) OR (HF) OR (HFpEF) OR (HFrEF) OR (cardiomyopat*) OR (((cardia*) OR (myocardial)) AND ((failure) OR (insufficienc*)))) AND ((sodi*) OR (salt)). In the CochraneLibrary, trials section was screened for suitable papers, and Cochrane Reviews were screened for the reviews available for the backward snowballing, but non-relevant reviews were identified. Searching in Clinicaltrials.gov included the following conditions: Condition or disease: ((heart failure) OR (ventricular dysfunction) OR (HF) OR (HFpEF) OR (HFrEF) OR (cardiomyopat*) OR (((cardia*) OR (myocardial)) AND ((failure) OR (insufficienc*)))) Other terms: ((diet*) OR (eat*) OR (ingestion) OR (feed) OR (micronutrient) OR (macronutrient) OR (intake*) OR (nutri*) OR (consump*)) OR ((sodi*) OR (salt)). Only studies with the status of completed, terminated or unknown were screened. Studies which analysed children were excluded from the search engine.

All the records (n = 9175) were exported into the Excel file, and duplicates were removed (n = 395); further, two independent reviewers (S.U., M.F.) screened the titles, abstracts and full texts.

In the second step, backward snowballing was performed by 2 reviewers (O.S. and M.G.). Both references of included articles and papers which cited them were screened for the relevant records. Reviews and editorials were also screened [1, 2, 8–10], and 1050 records were identified.

Eligibility criteria

Inclusion criteria were defined as: studies analysing the impact of dietary sodium restriction on HF patients’ outcome, full-text, peer-reviewed articles written in English, the population of heart failure patients of age > 18 years, both interventional and observational studies, reporting of at least one of the endpoints of interest: all-cause, cardiovascular or HF-related mortality; all-cause, cardiovascular or HF-related hospitalisation, emergency department visit, and HF decompensation.

Exclusion criteria were as follows: studies analysing the amount of the added salt (not the total dietary sodium restriction), case reports or review articles, studies based on the animal models, mixed interventions, e.g. studies that limited both sodium and fluids only in the intervention arm, in-hospital intervention only and studies in which the time of the intervention was shorter than the follow-up time.

Studies which assessed the sodium consumption based only on the natriuresis were excluded, as it was shown that such a method of sodium consumption evaluation is unsatisfactory in the patients treated with loop diuretics [11] The review was performed following PRISMA guidelines [12] and was registered in PROSPERO (CRD42023391133).

Data collection and analysis

After the screening, data extraction was performed by 2 independent reviewers (K.F. and M.G.), and the discrepancies were solved by the discussion with the input of the third investigator (S.U.). Authors of the papers with missing data necessary for the quantitative analysis were contacted to obtain relevant information. Data regarding study design, inclusion and exclusion criteria, sample size, age and sex of participants, method of sodium consumption assessment, amount of sodium restriction, length of follow-up, mortality, HF hospitalisations, composite endpoint compounds and occurrence and serum creatinine levels were extracted. Studies with no events in both arms were not included in the meta-analysis [13].

We used random effect with the Mantel–Haenszel test to analyse categorical variables. The odds ratio and 95% confidence intervals (CI) were calculated for the outcomes. Continuous variables were assessed using the inverse variance method and random effects model. Heterogeneity was evaluated using I2 (I2 > 50% was considered significant heterogeneity). Meta-regression was performed to assess the impact of the year of publication on the outcomes assessed in at least 6 studies [14]. Funnel plots for the publication bias assessment were not performed due to the limited number of included studies [15]. Review Manager version 5.4.1 (The Cochrane Collaboration, 11–13 Cavendish Square, London, W1G 0AN United Kingdom) was used for the statistical analysis, and Biorender was used to create the figures.

Subgroup and sensitivity analysis

Trial-level subgroup analysis was performed to investigate the source of the heterogeneity. We assessed the effect in the following subgroups: follow-up longer and shorter than 1 year; heart failure with reduced ejection fraction (HFrEF) population only and merged HFrEF and heart failure with preserved ejection fraction (HFpEF); and sodium restriction below 2 g per day. Sensitivity analysis, which included randomised control trials and observational studies separately, was performed for the selected outcomes.

Risk of bias assessment

The risk of bias (ROB) in the selected studies was assessed using Cochrane-designed tools. Risk of Bias 2 and ROBIN-I were used for randomised trials and observational studies respectively [16, 17]. Two independent reviewers (S.U. and O.S.) performed a quality evaluation, and the discussion resolved all the discrepancies. The study was considered low risk when the ROB was assessed as a low risk in all the domains.

Grading the quality of evidence

The overall quality of the acquired evidence was evaluated using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach [18]. Each outcome was assessed separately for randomised and observational studies. GradePRO GDT (McMaster University and Evidence Prime Inc.) was used to create a Summary of Findings and Certainty of Evidence table.

Results

The results of the search are displayed in Fig. 1. The research revealed 9 articles, including 2210 participants—1130 in the sodium-restricted (SR) and 1080 in the sodium-liberal (SL) group. Five studies were RCTs, 2 prospective cohort studies and 2 propensity score matching registry analyses. Patients were observed from 12 weeks to 3 years (mean follow-up time 15.77 months). Three studies included the HFrEF population exclusively, whilst 6 studies analysed the subjects regardless of the ejection fraction. In 5 studies, researchers restricted sodium consumption to 2 g per day or less, and 5 studies included only patients with accurately chosen NYHA class. Men constituted 64% of patients, and the mean age was 67 years. The characteristic of the included studies is described in Table 1.Fig. 1 Flowchart of the systematic review process. Excel files with the screened articles and exclusion reasons at every stage are available at request

Table 1 Characteristic of the included studies

Author	Study design	Population	Sample size	SR group, n	SL group, n	Males n, (%)	Mean age, years	Amount of sodium restriction	Control group recommendations	Sodium consumption assessment method	
Ezekowitz et al. [3]	RCT	NYHA II–III, HFpEF and HFrEF	806	397	409	538 (66)	67 [58–74]	< 1500 mg of sodium/day	Usual care with general advice to restrict dietary sodium	3-day food record	
Ivey-Miranda et al. [38]	RCT	NYHA I–II, HFrEF	70	37	33	47 (67)	60 ± 12	2000 mg of sodium/day	3000 mg of sodium/day	Food frequency questionnaire, 24-h food diary and 24-h urine collection	
Senturk et al. [39]	Observational, registry PSM analysis	No specified NYHA, HFrEF	236	118	118	159 (67)	65 ± 11	Declaration of complying with SR	Declaration of not complying with SR	Patients self-assessment	
Hummel et al. [40]	RCT	No specified NYHA, HFpEF and HFrEF	66	33	33	46 (70)	71 ± 8	1500 mg of sodium/day	Usual care with general advice to restrict dietary sodium	3-day food record, urinary sodium and potassium assessment, and meal delivery records	
Doukky et al. [41]	Observational, registry PSM analysis	NYHA II–III, HFpEF and HFrEF	260	130	130	113 (44)	63.5 ± 13	< 2500 mg of sodium/day	> 2500 mg of sodium/day	Food frequency questionnaire	
Song et al. [42]	Prospective, cohort study	No Specified NYHA, HFpEF and HFrEF	244	132	112	162 (66)	61 ± 12	< 3000 mg of sodium/day	> 3000 mg of sodium/day	4-day food record	
Arcand et al. [43]	Prospective, cohort study	No Specified NYHA, HFrEF	123	82	41	94 (76)	60 ± 12	Low and middle sodium intake tertiles: < 2800 mg/day	High sodium intake tertile: ≥ 2800 mg/day	3-day food record	
Parinello et al. [44]	RCT	NYHA II, HFrEF	173	87	86	105 (61)	73 ± 7	1800 mg of sodium/day	2800 mg of sodium/day	Food diary and telephone interview 1/week	
Paterna et al. [45]	RCT	NYHA II, HFrEF	232	114	118	144 (62)	73 ± 8	1800 mg of sodium/day	2800 mg of sodium/day	Food diary and telephone interview 1/week	
Per protocol data are shown—intended values of sodium restriction and the number of enrolled patients are displayed. Age is presented as mean ± standard deviation, except study by Ezekowitz et al.—median [interquartile range]

SR sodium restriction, SL sodium-liberal, RCT randomised controlled trials, PSM propensity score matching, NYHA New York heart association, HFpEF heart failure with preserved ejection fraction, HFrEF heart failure with reduced ejection fraction

Four parameters, i.e. all-cause mortality, HF hospitalisation, a composite of mortality and readmission and serum creatinine level, were reported in at least 3 studies; therefore, quantitative analysis of these features was performed. A summary of the findings is shown in Table 2. Forrest plots of the merged analyses are displayed in Fig. 2. Specific subgroup data with the accurate number of patients with events are available in the Supplementary material (Figure S1).Table 2 Summary of findings of the included studies

Author	Duration of follow-up, months	Mortality n, (%)	HF hospitalisation n, (%)	Composite of death and hospitalisation n, (%)	Creatinine mg/dl, mean ± SD	
Ezekowitz et al. [3]	12	SR 22 (6); SL 17 (4)	NR	NR	NR	
Ivey-Miranda et al. [38]	5	NR	NR	SR 8 (21); SL 7 (21)	SR 1.16 ± 0.06; SL 1.20 SD 0.06	
Senturk et al. [39]	20	SR 35 (10); SL 36 (31)	SR 70 (59); SL 87 (74)	NR	NR	
Hummel et al. [40]	3	SR 0 (0); SL 1 (3)	SR 7 (21); SL 13 (39)	NR	SR 1.4 ± 0.4; SL 1.3 SD 0.5	
Doukky et al. [41]	36	SR 24 (19); SL 14 (11)	SR 42 (32); SL 26 (20)	NR	NR	
Song et al. [42]	12	SR 3 (2); SL 3 (3)	SR 14 (11); SL 8 (7)	NR	NR	
Arcand et al. [43]	28	SR 2 (2); SL 6 (15)	NR	NR	NR	
Parinello et al. [44]	12	SR 20 (23); SL 4 (5)	SR 44 (51); SL 12 (14)	SR 64 (73); SL 16 (19)	SR 2.1 ± 0.5; SL 1.45 SD 0.4	
Paterna et al. [45]	6	SR 15 (13); SL 6 (5)	SR 30 (26); SL 9 (8)	SR 45 (39); SL 15 (13)	SR 2.1 ± 0.5; SL 1.45 SD 0.4	
Mean follow-ups are presented in the observational studies

SR sodium-restricted, SL sodium-liberal, NR not reported, SD standard deviation

Fig. 2 Forrest plots of the sodium-restricted vs sodium-liberal diet for the analysed outcomes. Forrest plots of the subgroup analyses are available in Supplement Figure S1. A All-cause mortality; B HF hospitalisation; C composite of mortality and readmission; D serum creatinine level

All-cause mortality

All-cause mortality was reported in 8 studies with 2140 participants. The death occurred in 121 (11.07%) in the SR group and 87 (8.31%) in the SL group. Dietary sodium restriction did not significantly affect mortality in HF patients (OR 1.38 [95% CI 0.76–2.49]). It was close to significance in the RCTs analysis, reaching (OR 2.30 [95% CI 0.98–5.41], p = 0.06). The effect remained neutral in subgroup and sensitivity analysis: (OR 0.87 [95% CI 0.39–1.96]) in observational studies, (OR 1.28 [95% CI 0.65–2.50]) and (OR 1.69 [95% CI 0.28–10.35]) in studies with > 1-year and < 1-year follow-up respectively, (OR 1.86 [95% CI 0.93–3.75]) in studies which restricted sodium consumption to 2 g per day, (OR 1.51 [95% CI 0.24–9.67]) and (OR 1.45 [95% CI 0.92–2.28]) in studies which included HFrEF only and in HFpEF and HFrEF respectively.

Meta-regression analysis showed no significant association between the year of the publication and the all-cause mortality (β = − 0.05, 95% CI = − 0.16 to 0.05, p = 0.325).

HF hospitalisations

HF-related hospitalisations occurrence was assessed in 6 studies with 1211 patients. The endpoint took place in 207 (33.71%) patients in SR and 155 (25.96%) in the SL population. Sodium restriction did not significantly affect the HF hospitalisations rate (OR 1.63 [95% CI 0.69–3.88]). The comparable results have been accomplished in the analysis of the following subgroups: RCTs (OR 2.36 [95% CI 0.54–10.24]); observational studies (OR 1.13 [95% CI 0.46–2.77]); follow-up longer (OR 1.74 [95% CI 0.61–4.95]) and shorter (OR 1.38 [95% CI 0.14–13.74]) than 1 year; sodium restriction equal or below 2 g/d (OR 2.14 [95% CI 0.68–6.77]); HFrEF analysis only (OR 2.38 [95% CI 0.45–12.66]) and merged HFpEF and HFrEF (OR 1.13 [95% CI 0.45–2.83]).

The meta-regression revealed a significant impact of the year of publication on the effect size regarding the HF hospitalisation occurrence (β = − 0.19, 95% CI = − 0.26 to − 0.12, p < 0.0001).

Composite endpoint

The composite endpoint of all-cause mortality and hospitalisation was analysed in 3 papers (475 participants). The composite endpoint occurred in 117 (49.16%) patients in SR and 38 (16.04%) in SL cohorts. A diet with a restricted amount of administered sodium significantly increased the risk of death or hospitalisation (OR 4.12 [95% CI 1.23–13.82]). Due to the low number of studies, no subgroup analysis regarding this outcome was performed.

Serum creatinine level

Serum creatinine level at the end of the follow-up was reported in 4 studies (541 participants). The mean difference between the groups was estimated as 0.34 mg/dL [95% CI − 0.1 to 0.78]) suggesting that serum creatinine may be higher in the SR population. The results, however, did not reach statistical significance (p = 0.13).

Risk of bias and certainty of the evidence

The results of the ROB assessment are displayed in Fig. 3. The quality of evidence assessed by GRADE criteria for the observational studies was very low. The quality of the evidence in RCTs was: moderate for all-cause mortality, very low for HF hospitalisation and moderate for a composite of mortality and hospitalisations (Table 3).Fig. 3 Risk of bias (ROB) in the included studies. ROB was assessed separately for the randomised (left side) and observational studies (right side). Cochrane tools, i.e. risk of bias 2 for randomised trials and ROBINS-I for the observational studies, were used. Red colour marks high ROB, green low ROB. The yellow colour describes the risk as some concerns in randomised data and moderate in observational data

Table 3 Summary of findings and certainty of evidence table

Outcomes	No of participants (studies) follow-up	Certainty of the evidence (GRADE)	Relative effect (95% CI)	Anticipated absolute effects	
Risk with regular diet	Risk difference with dietary sodium restriction	
All-cause mortality—RCT only	1277 (4 RCTs)	⨁⨁⨁◯

Moderatea

	OR 2.30 (0.98–5.41)	43 per 1000	51 more per 1000 (1 fewer to 154 more)	
All-cause mortality—Observational studies	863 (4 observational studies)	⨁◯◯◯

Very lowb,c,d

	OR 0.87 (0.39–1.96)	147 per 1000	17 fewer per 1000 (84 fewer to 106 more)	
Composite of all-cause mortality and hospitalisation	475 (3 RCTs)	⨁⨁⨁◯

Moderatee

	OR 4.12 (1.23–13.82)	160 per 1000	280 more per 1000 (30 more to 565 more)	
HF hospitalisation—RCT studies	471 (3 RCTs)	⨁◯◯◯

Very lowd,e

	OR 2.36 (0.54–10.24)	143 per 1000	140 more per 1000 (61 fewer to 488 more)	
HF hospitalisation—Observational studies	740 (3 observational studies)	⨁◯◯◯

Very lowb,d,e

	OR 1.13 (0.46–2.77)	336 per 1000	28 more per 1000 (147 fewer to 248 more)	
CI confidence interval, OR odds ratio

aNumber of events does not meet the optimal information size of 400 events, 95% CI includes no effect and appreciable harm

bSome limitations for multiple criteria, mainly serious bias in the selection of participants into the study in all studies and serious bias due to confounding in half of the studies

cSubstantial inconsistency that can be partially explained as a result of different cut off for the amount of sodium in sodium reduced diet as well as different participation of HFpEF

dThe number of events does not meet the optimal information size of 400 events, 95% CI includes no effect and appreciable benefit and harm

eConsiderable inconsistency that can be partialy explained as a result of different cut off for amount of sodium in sodium reduced diet as well as different participation of HFpEF

Discussion

In this interventional and observational data meta-analysis, we evaluated current evidence for dietary sodium restriction in the HF population. Our data showed that the sodium restriction does not provide benefit in terms of outcome improvement. Importantly, these results remained neutral regardless of the: type of study (RCT vs observational), left ventricular ejection fraction, duration of follow-up and amount of sodium restriction. Further, sodium restriction showed no benefit in any of the analysed outcomes. Its impact on all-cause mortality and HF hospitalisations was insignificant, whilst it was meaningful in terms of the composite of mortality and hospitalisation. Sodium restriction significantly increased the risk of the composite endpoint (OR 4.12 [95% CI 1.23–13.82], p = 0.02).

Noteworthy, our analysis is the first one to show the aggregated impact of sodium restriction on serum creatinine levels, which seems to be numerically higher in the SR group, without reaching statistical significance (+ 0.34 mg/dL [95% CI − 0.1 to 0.78], p = 0.13). This finding may be partly explained by the prognostic role the increased natriuresis plays in the decongestion process [19]. Further studies are warranted to elucidate the phenomenon comprehensively.

Current ESC guidelines mention the role of dietary sodium restriction in 2 parts. First, they recommend avoiding excessive salt intake < 5 mg/day. Importantly, they also highlight the gaps in the knowledge regarding the topic [6].

SODIUM-HF [3] was the most numerous RCT that analysed the effect of dietary sodium restriction in HF. Its results have considerably questioned the long-lasting, guidelines-supported paradigm. Following the trial, the authors prepared a meta-analysis of the existing evidence on that topic [8]. Collin-Ramirez et al. showed that the sodium restriction presented a neutral effect on the analysed endpoints, i.e. all-cause mortality (OR 0.95 [95% CI 0.58–1.58]), cardiovascular hospitalisation (OR 0.79 [95% CI 0.54–1.15]) and the composite of all-cause death and hospitalisation (OR 0.81 [95% CI 0.60–1.09]). Similar events were analysed in both of the meta-analyses. However, in our study, SR was associated with a slightly higher risk regarding all the outcomes, even reaching the statistical significance in the composite endpoint.

Some essential differences in the construction of studies may explain the differences and, therefore, require clarification. First, differences in inclusion criteria for our analysis resulted in a slightly larger number of patients (and events) being examined. Second, opposite to the authors’ findings, we did not include studies that analysed salt and fluid restriction in one of the arms. Whilst the fluid restriction is also being questioned as a standard of care [20, 21], its conjunction with sodium restriction may confound the results, potentially contributing to the lower incidence of the endpoints in the Colin–Ramirez study. Moreover, our meta-analysis comprises solely outpatient interventions. Finally, we have not included studies which based the sodium consumption assessment exclusively on natriuresis, as it was shown to be inappropriate in the patients on loop diuretics [11]. Although natriuresis is a marker of decongestive abilities and prognosis in acutely decompensated HF patients, its utility and interpretation in chronic HF are much more complicated and related to many uncontrollable factors, not just diet [22, 23]. Thus, the assumption that the population presenting higher natriuresis is the population with higher sodium consumption—the SL group—will favour it regarding the prognosis.

Given these, our meta-analysis was based on the different inclusion criteria and aimed to analyse the effect of the isolated sodium restriction. Our results complement the work mentioned above, providing further evidence for the SR ineffectiveness, which stemmed from the studies performed in a different setting (Fig. 4).Fig. 4 Central illustration summarising most important findings. OR odds ratio, HF heart failure, MD mean difference

Omitting its possible harmful effect, the assumption that the sodium restriction in HF may be unjustified has profound clinical implications. HF patients receive a long list of recommendations, some of which are troublesome and inconvenient for the patients [5]. Presuming that the patients have the limited ability to cover all the physicians’ advice, as we take care of the patient’s compliance, we should focus on communicating and underlining indications with a reliable, evidence-based effect. In the same manner, as physicians should fight polipharmacy [24], they should try to eliminate unreasonable recommendations that may distract patient attention from the essential ones.

This review focuses on the role of dietary sodium consumption in the chronic HF population. The detailed description of the results of sodium studies in AHF is beyond the scope of this article, however, it requires a brief comment. Traditionally, both fluid and sodium net negative balance were considered therapeutic goals during the AHF therapy, and high urine sodium excretion is a marker of good diuretic response [25] and reflects neurohormonal activation in AHF [26]. Thus, intuitively increasing the sodium intake during AHF would be contraindicated [27]. Some recent data from trials [28] and metanalyses [29] questioned this paradigm showing the neutral-to-superior outcomes whilst using oral or intravenous sodium loading during decongestive therapy in AHF. Summarising the recent data from acute and chronic HF populations, which challenges the previous beliefs, it seems that the role of sodium in the pathophysiology of HF has not been fully understood.

There are important differences regarding the outcome and efficacy of therapeutic interventions in HFrEF and HFpEF [6]. Our review included only the analysis HFrEF population or HFrEF and HFpEF due to the lack of data on HFpEF populations only. In both of the subgroups, sodium restriction did not present a significant effect on the analysed outcomes. However, the group of HFpEF and HFrEF seems to present numerically (but not statistically) lower risk associated with the restricted diet for heart failure hospitalisation OR 1.13 vs 2.38, in HFrEF and HFpEF vs HFrEF only, respectively. This seems coherent with the previous evidence. In SODIUM-HF, the most numerous RCT by now, the population with EF > 40% presented a lower risk of cumulative events (HR 0.82 vs 1.05 for EF > 40% vs EF < 40%, respectively) associated with sodium restriction diet [3]. Similarly, in the aforementioned meta-analysis of the RCTs, in the HFpEF population, dietary sodium restriction was associated with the lower risk of all-cause mortality (OR 0.75 vs 0.87 in HFpEF vs HFrEF, respectively) [30]. All of the above results were not statistically significant and are derived from the subgroup analyses of relatively small subpopulations with wide confidence intervals; thus, these should be treated rather as a weak signal than a definitive conclusion. Further studies, especially performed in the isolated HFpEF population, are warranted to analyse the differences between the role of dietary sodium in HFrEF and HFpEF.

We presume that these potential differences in prognosis may stem from the meaningful pathophysiological distinctions between HFpEF and HFrEF. HFpEF was shown to be associated with the increased burden of comorbidities [31], making this population highly heterogeneous compared to HFrEF.

Notably, the meta-regression showed an association between the year of the performed study and HF hospitalisation. It is an interesting finding, suggesting that the dietary sodium restriction may have been more harmful in the past than currently. We may only hypothesise that it may be caused by the advances in modern pharmacotherapy, especially by the wider use of RAA-affecting drugs and the more aggressive up-titration of its doses. Accurate elucidation of this phenomenon would require further studies and a better understanding of the complexity of sodium handling in heart failure.

Sodium-glucose co-transporter 2 (SGLT2) inhibitors have recently emerged as the cornerstone of heart failure (HF) therapy [6]. The exact mechanism of their beneficial action remains unclear, and their pathophysiological effects are currently being intensively investigated. One of the proposed mechanisms for their positive impact on heart failure is their influence on sodium homeostasis [32]. SGLT2 has been demonstrated to enhance diuresis [33, 34] and reduce sodium concentrations in skin tissue [35]. However, the available data on dietary sodium intake is outdated in the context of widespread SGLT2 inhibitor use in HF patients. Consequently, it is currently impossible to assess the intervention's effect size based on the existing retrospective data. Further trials conducted in SGLT2-treated patient populations are necessary to evaluate its interaction with varying levels of dietary sodium intake.

Our study is not free from limitations. The scheduled analysis design, which included both interventional and observational studies, was, per se, associated with the higher ROB. Different scales are designed to assess the ROB in the observational and interventional studies [36, 37], which makes it difficult to compare the reliability of the included studies. Moreover, analysed studies were published between 2008 and 2022—during this period, 4 European and American guidelines were published. Patients’ management, e.g. recommended pharmacotherapy, did change remarkably, which may impact the generalizability of the results. Further, the analysed studies presented considerable heterogeneity—they differed in terms of design, e.g. time of follow-up, included population, amount of sodium restriction and concomitant interventions. Finally, there was an inherent problem with blinding the participants and the personnel due to the nature of the studied, nutritional intervention.

Supplementary Information

Below is the link to the electronic supplementary material.Supplementary file1 (DOCX 1279 KB)

Funding

No funding was received for conducting this study.

Data availability

All data supporting the findings of this study are available within the paper and its Supplementary Information. Excel files with the screened articles and exclusion reasons at every stage as well as Risk of Bias assessment tables are available at request. 

Declarations

Conflict of interest

Prof. Piotr Ponikowski has received personal fees for consultancy and Speakers Bureau from AstraZeneca, Boehringer Ingelheim, Vifor Pharma, Servier, Bayer, Bristol Myers Squibb, Respocardia, Berlin-Chemie, Cibiem, Novartis, and Renal Guard; other support for participation in clinical trials from Boehringer Ingelheim, Amgen, Vifor Pharma, Bayer, Bristol Myers Squibb, Cibiem, Novartis, and RenalGuard; and research grants to his institution from Vifor Pharma. All other authors have no conflicts of interest to declare that are relevant to the content of this article. 

Szymon Urban and Michał Fułek contributed equally to this work.
==== Refs
References

1. Yancy CW The Uncertainty of sodium restriction in heart failure: we can do better than this JACC Heart Fail 2016 4 1 39 41 10.1016/J.JCHF.2015.11.005 26738951
Yancy CW (2016) The Uncertainty of sodium restriction in heart failure: we can do better than this. JACC Heart Fail 4(1):39–41. 10.1016/J.JCHF.2015.11.00526738951 10.1016/J.JCHF.2015.11.005
2. Gupta D Georgiopoulou VV Kalogeropoulos AP Dunbar SB Reilly CM Sands JM Fonarow GC Jessup M Gheorghiade M Yancy C Butler J Dietary sodium intake in heart failure Circulation 2012 126 4 479 485 10.1161/CIRCULATIONAHA.111.062430 22825409
Gupta D, Georgiopoulou VV, Kalogeropoulos AP, Dunbar SB, Reilly CM, Sands JM, Fonarow GC, Jessup M, Gheorghiade M, Yancy C, Butler J (2012) Dietary sodium intake in heart failure. Circulation 126(4):479–485. 10.1161/CIRCULATIONAHA.111.06243022825409 10.1161/CIRCULATIONAHA.111.062430
3. Ezekowitz JA Colin-Ramirez E Ross H Escobedo J Macdonald P Troughton R Saldarriaga C Alemayehu W McAlister FA Arcand JA 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 Ezekowitz J McAlister F Pandey AS Reduction of dietary sodium to less than 100 Mmol in heart failure (SODIUM-HF): an international, open-label, randomized, controlled trial Lancet 2022 399 10333 1391 1400 10.1016/S0140-6736(22)00369-5 35381194
Ezekowitz JA, Colin-Ramirez E, Ross H, Escobedo J, Macdonald P, Troughton R, Saldarriaga C, Alemayehu W, McAlister FA, Arcand JA, 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, Ezekowitz J, McAlister F, Pandey AS (2022) Reduction of dietary sodium to less than 100 Mmol in heart failure (SODIUM-HF): an international, open-label, randomized, controlled trial. Lancet 399(10333):1391–1400. 10.1016/S0140-6736(22)00369-535381194 10.1016/S0140-6736(22)00369-5
4. Chaney E Shaw A Pathophysiology of fluid retention in heart failure Contrib Nephrol 2010 164 46 53 10.1159/000313720 20427993
Chaney E, Shaw A (2010) Pathophysiology of fluid retention in heart failure. Contrib Nephrol 164:46–53. 10.1159/00031372020427993 10.1159/000313720
5. van der Wal MHL Jaarsma T Moser DK Veeger NJGM van Gilst WH van Veldhuisen DJ Compliance in heart failure patients: the importance of knowledge and beliefs Eur Heart J 2006 27 4 434 440 10.1093/EURHEARTJ/EHI603 16230302
van der Wal MHL, Jaarsma T, Moser DK, Veeger NJGM, van Gilst WH, van Veldhuisen DJ (2006) Compliance in heart failure patients: the importance of knowledge and beliefs. Eur Heart J 27(4):434–440. 10.1093/EURHEARTJ/EHI60316230302 10.1093/EURHEARTJ/EHI603
6. McDonagh TA Metra M Adamo M Baumbach A Böhm M Burri H Čelutkiene J Chioncel O Cleland JGF Coats AJS Crespo-Leiro MG Farmakis D Gardner RS Gilard M Heymans S Hoes AW Jaarsma T Jankowska EA Lainscak M Lam CSP Lyon AR McMurray JJV Mebazaa A Mindham R Muneretto C Piepoli MF Price S Rosano GMC Ruschitzka F Skibelund AK de Boer RA Schulze PC Abdelhamid M Aboyans V Adamopoulos S Anker SD Arbelo E Asteggiano R Bauersachs J Bayes-Genis A Borger MA Budts W Cikes M Damman K Delgado V Dendale P Dilaveris P Drexel H Ezekowitz J Falk V Fauchier L Filippatos G Fraser A Frey N Gale CP Gustafsson F Harris J Iung B Janssens S Jessup M Konradi A Kotecha D Lambrinou E Lancellotti P Landmesser U Leclercq C Lewis BS Leyva F Linhart A Løchen ML Lund LH Mancini D Masip J Milicic D Mueller C Nef H Nielsen JC Neubeck L Noutsias M Petersen SE Petronio AS Ponikowski P Prescott E Rakisheva A Richter D Schlyakhto E Seferovic P Senni M Sitges M Sousa-Uva M Tocchetti CG Touyz R Tschoepe C Waltenberger J Krim M Hayrapetyan H Moertl D Mustafayev I Kurlianskaya A Depauw M Kušljugić Z Gatzov P Agathangelou P Melenovský V Løgstrup BB Mostafa AM Uuetoa T Lassus J Logeart D Kipiani Z Chrysohoou C Sepp R Ingimarsdóttir IJ O’Neill J Gotsman I Iacoviello M Bajraktari G Lunegova O Kamzola G Massih TA Benlamin H Žaliaduonyte D Noppe S Moore A Vataman E Boskovic A Bennis A Manintveld OC Kostovska ES Gulati G Straburzyńska-Migaj E Silva-Cardoso J Rimbaş RC Lopatin Y Foscoli M Stojkovic S Goncalvesova E Fras Z Segovia J Lindmark K Maeder MT Bsata W Abid L Altay H Voronkov L Davies C Abdullaev T Baigent CN Antoniou S Collet JP Halvorsen S Koskinas KC 2021 ESC guidelines for the diagnosis and treatment of acute and chronic heart failure Eur Heart J 2021 42 36 3599 3726 10.1093/EURHEARTJ/EHAB368 34447992
McDonagh TA, Metra M, Adamo M, Baumbach A, Böhm M, Burri H, Čelutkiene J, Chioncel O, Cleland JGF, Coats AJS, Crespo-Leiro MG, Farmakis D, Gardner RS, Gilard M, Heymans S, Hoes AW, Jaarsma T, Jankowska EA, Lainscak M, Lam CSP, Lyon AR, McMurray JJV, Mebazaa A, Mindham R, Muneretto C, Piepoli MF, Price S, Rosano GMC, Ruschitzka F, Skibelund AK, de Boer RA, Schulze PC, Abdelhamid M, Aboyans V, Adamopoulos S, Anker SD, Arbelo E, Asteggiano R, Bauersachs J, Bayes-Genis A, Borger MA, Budts W, Cikes M, Damman K, Delgado V, Dendale P, Dilaveris P, Drexel H, Ezekowitz J, Falk V, Fauchier L, Filippatos G, Fraser A, Frey N, Gale CP, Gustafsson F, Harris J, Iung B, Janssens S, Jessup M, Konradi A, Kotecha D, Lambrinou E, Lancellotti P, Landmesser U, Leclercq C, Lewis BS, Leyva F, Linhart A, Løchen ML, Lund LH, Mancini D, Masip J, Milicic D, Mueller C, Nef H, Nielsen JC, Neubeck L, Noutsias M, Petersen SE, Petronio AS, Ponikowski P, Prescott E, Rakisheva A, Richter D, Schlyakhto E, Seferovic P, Senni M, Sitges M, Sousa-Uva M, Tocchetti CG, Touyz R, Tschoepe C, Waltenberger J, Krim M, Hayrapetyan H, Moertl D, Mustafayev I, Kurlianskaya A, Depauw M, Kušljugić Z, Gatzov P, Agathangelou P, Melenovský V, Løgstrup BB, Mostafa AM, Uuetoa T, Lassus J, Logeart D, Kipiani Z, Chrysohoou C, Sepp R, Ingimarsdóttir IJ, O’Neill J, Gotsman I, Iacoviello M, Bajraktari G, Lunegova O, Kamzola G, Massih TA, Benlamin H, Žaliaduonyte D, Noppe S, Moore A, Vataman E, Boskovic A, Bennis A, Manintveld OC, Kostovska ES, Gulati G, Straburzyńska-Migaj E, Silva-Cardoso J, Rimbaş RC, Lopatin Y, Foscoli M, Stojkovic S, Goncalvesova E, Fras Z, Segovia J, Lindmark K, Maeder MT, Bsata W, Abid L, Altay H, Voronkov L, Davies C, Abdullaev T, Baigent CN, Antoniou S, Collet JP, Halvorsen S, Koskinas KC (2021) 2021 ESC guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur Heart J 42(36):3599–3726. 10.1093/EURHEARTJ/EHAB36834447992 10.1093/EURHEARTJ/EHAB368
7. Heidenreich PA Bozkurt B Aguilar D Allen LA Byun JJ Colvin MM Deswal A Drazner MH Dunlay SM Evers LR Fang JC Fedson SE Fonarow GC Hayek SS Hernandez AF Khazanie P Kittleson MM Lee CS Link MS Milano CA Nnacheta LC Sandhu AT Stevenson LW Vardeny O Vest AR Yancy CW 2022 AHA/ACC/HFSA guideline for the management of heart failure: a report of the American college of cardiology/American heart association joint committee on clinical practice guidelines Circulation 2022 145 18 E895 E1032 10.1161/CIR.0000000000001063 35363499
Heidenreich PA, Bozkurt B, Aguilar D, Allen LA, Byun JJ, Colvin MM, Deswal A, Drazner MH, Dunlay SM, Evers LR, Fang JC, Fedson SE, Fonarow GC, Hayek SS, Hernandez AF, Khazanie P, Kittleson MM, Lee CS, Link MS, Milano CA, Nnacheta LC, Sandhu AT, Stevenson LW, Vardeny O, Vest AR, Yancy CW (2022) 2022 AHA/ACC/HFSA guideline for the management of heart failure: a report of the American college of cardiology/American heart association joint committee on clinical practice guidelines. Circulation 145(18):E895–E1032. 10.1161/CIR.000000000000106335363499 10.1161/CIR.0000000000001063
8. Colin-Ramirez E Sepehrvand N Rathwell S Ross H Escobedo J Macdonald P Troughton R Saldarriaga C Lanas F Doughty R McAlister FA Ezekowitz JA Sodium restriction in patients with heart failure: a systematic review and meta-analysis of randomized clinical trials Circ Heart Fail 2023 10.1161/CIRCHEARTFAILURE.122.009879 36802691
Colin-Ramirez E, Sepehrvand N, Rathwell S, Ross H, Escobedo J, Macdonald P, Troughton R, Saldarriaga C, Lanas F, Doughty R, McAlister FA, Ezekowitz JA (2023) Sodium restriction in patients with heart failure: a systematic review and meta-analysis of randomized clinical trials. Circ Heart Fail. 10.1161/CIRCHEARTFAILURE.122.00987936802691 10.1161/CIRCHEARTFAILURE.122.009879
9. Mahtani KR Heneghan C Onakpoya I Tierney S Aronson JK Roberts N Hobbs FDR Nunan D Reduced salt intake for heart failure: a systematic review JAMA Intern Med 2018 178 12 1693 1700 10.1001/JAMAINTERNMED.2018.4673 30398532
Mahtani KR, Heneghan C, Onakpoya I, Tierney S, Aronson JK, Roberts N, Hobbs FDR, Nunan D (2018) Reduced salt intake for heart failure: a systematic review. JAMA Intern Med 178(12):1693–1700. 10.1001/JAMAINTERNMED.2018.467330398532 10.1001/JAMAINTERNMED.2018.4673
10. Hummel SL Konerman MC Dietary sodium restriction in heart failure: a recommendation worth its salt? JACC Heart Fail 2016 4 1 36 38 10.1016/J.JCHF.2015.10.003 26738950
Hummel SL, Konerman MC (2016) Dietary sodium restriction in heart failure: a recommendation worth its salt? JACC Heart Fail 4(1):36–38. 10.1016/J.JCHF.2015.10.00326738950 10.1016/J.JCHF.2015.10.003
11. Arcand JA Floras JS Azevedo E Mak S Newton GE Allard JP Evaluation of 2 methods for sodium intake assessment in cardiac patients with and without heart failure: the confounding effect of loop diuretics Am J Clin Nutr 2011 93 3 535 541 10.3945/AJCN.110.004457 21191141
Arcand JA, Floras JS, Azevedo E, Mak S, Newton GE, Allard JP (2011) Evaluation of 2 methods for sodium intake assessment in cardiac patients with and without heart failure: the confounding effect of loop diuretics. Am J Clin Nutr 93(3):535–541. 10.3945/AJCN.110.00445721191141 10.3945/AJCN.110.004457
12. Moher D Liberati A Tetzlaff J Altman DG Altman D Antes G Atkins D Barbour V Barrowman N Berlin JA Clark J Clarke M Cook D D’Amico R Deeks JJ Devereaux PJ Dickersin K Egger M Ernst E Gøtzsche PC Grimshaw J Guyatt G Higgins J Ioannidis JPA Kleijnen J Lang T Magrini N McNamee D Moja L Mulrow C Napoli M Oxman A Pham B Rennie D Sampson M Schulz KF Shekelle PG Tovey D Tugwell P Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement PLoS Med 2009 6 7 e1000097 10.1371/JOURNAL.PMED.1000097 19621072
Moher D, Liberati A, Tetzlaff J, Altman DG, Altman D, Antes G, Atkins D, Barbour V, Barrowman N, Berlin JA, Clark J, Clarke M, Cook D, D’Amico R, Deeks JJ, Devereaux PJ, Dickersin K, Egger M, Ernst E, Gøtzsche PC, Grimshaw J, Guyatt G, Higgins J, Ioannidis JPA, Kleijnen J, Lang T, Magrini N, McNamee D, Moja L, Mulrow C, Napoli M, Oxman A, Pham B, Rennie D, Sampson M, Schulz KF, Shekelle PG, Tovey D, Tugwell P (2009) Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med 6(7):e1000097. 10.1371/JOURNAL.PMED.100009719621072 10.1371/JOURNAL.PMED.1000097
13. Deeks JJ, Higgins JPT, Altman DG. Chapter 10: Analysing data and undertaking meta-analyses. In: Higgins JPT, Thomas J, Chandler J, Cumpston M, Li T, Page MJ, Welch VA (eds). Cochrane handbook for systematic reviews of interventions version 6.3 (updated February 2022). Cochrane, 2022. Available from https://www.training.cochrane.org/handbook.
14. Fu R, Gartlehner G, Grant M, Shamliyan T, Sedrakyan A, Wilt TJ, Griffith L, Oremus M, Raina P, Ismaila A, Santaguida P, Lau J, Trikalinos TA (2010) Conducting quantitative synthesis when comparing medical interventions AHRQ and the effective health care program. Methods guide for effectiveness and comparative effectiveness reviews. Agency for Healthcare Research and Quality (US)
15. Sterne JAC Sutton AJ Ioannidis JPA Terrin N Jones DR Lau J Carpenter J Rücker G Harbord RM Schmid CH Tetzlaff J Deeks JJ Peters J Macaskill P Schwarzer G Duval S Altman DG Moher D Higgins JPT Recommendations for examining and interpreting funnel plot asymmetry in meta-analyses of randomised controlled trials BMJ 2011 10.1136/BMJ.D4002 22008217
Sterne JAC, Sutton AJ, Ioannidis JPA, Terrin N, Jones DR, Lau J, Carpenter J, Rücker G, Harbord RM, Schmid CH, Tetzlaff J, Deeks JJ, Peters J, Macaskill P, Schwarzer G, Duval S, Altman DG, Moher D, Higgins JPT (2011) Recommendations for examining and interpreting funnel plot asymmetry in meta-analyses of randomised controlled trials. BMJ. 10.1136/BMJ.D400222008217 10.1136/BMJ.D4002
16. Chapter 25: Assessing risk of bias in a non-randomized study | Cochrane Training. https://training.cochrane.org/handbook/current/chapter-25. Accessed 14 Feb 2023
17. 8 Assessing risk of bias in included studies. https://handbook-5-1.cochrane.org/chapter_8/8_assessing_risk_of_bias_in_included_studies.htm. Accessed 14 Feb 2023
18. Oxman AD Grading quality of evidence and strength of recommendations BMJ 2004 328 7454 1490 10.1136/BMJ.328.7454.1490 15205295
Oxman AD (2004) Grading quality of evidence and strength of recommendations. BMJ 328(7454):1490. 10.1136/BMJ.328.7454.149015205295 10.1136/BMJ.328.7454.1490
19. Biegus J Zymliński R Sokolski M Todd J Cotter G Metra M Jankowska EA Banasiak W Ponikowski P Serial assessment of spot urine sodium predicts effectiveness of decongestion and outcome in patients with acute heart failure Eur J Heart Fail 2019 21 5 624 633 10.1002/EJHF.1428 30773755
Biegus J, Zymliński R, Sokolski M, Todd J, Cotter G, Metra M, Jankowska EA, Banasiak W, Ponikowski P (2019) Serial assessment of spot urine sodium predicts effectiveness of decongestion and outcome in patients with acute heart failure. Eur J Heart Fail 21(5):624–633. 10.1002/EJHF.142830773755 10.1002/EJHF.1428
20. Herrmann JJ Beckers-Wesche F Baltussen LEHJM Verdijk MHI Bellersen L Brunner-la Rocca HP Jaarsma T Pisters R Sanders-van Wijk S Rodwell L van Royen N Gommans DHF van Kimmenade RRJ Fluid REStriction in heart failure vs liberal fluid UPtake: rationale and design of the randomized FRESH-UP study J Card Fail 2022 28 10 1522 1530 10.1016/J.CARDFAIL.2022.05.015 35705150
Herrmann JJ, Beckers-Wesche F, Baltussen LEHJM, Verdijk MHI, Bellersen L, Brunner-la Rocca HP, Jaarsma T, Pisters R, Sanders-van Wijk S, Rodwell L, van Royen N, Gommans DHF, van Kimmenade RRJ (2022) Fluid REStriction in heart failure vs liberal fluid UPtake: rationale and design of the randomized FRESH-UP study. J Card Fail 28(10):1522–1530. 10.1016/J.CARDFAIL.2022.05.01535705150 10.1016/J.CARDFAIL.2022.05.015
21. Li Y Fu B Qian X Liberal versus restricted fluid administration in heart failure patients a systematic review and meta-analysis of randomized trials Int Heart J 2015 56 2 192 195 10.1536/IHJ.14-288 25740394
Li Y, Fu B, Qian X (2015) Liberal versus restricted fluid administration in heart failure patients a systematic review and meta-analysis of randomized trials. Int Heart J 56(2):192–195. 10.1536/IHJ.14-28825740394 10.1536/IHJ.14-288
22. Martens P Dupont M Verbrugge FH Damman K Degryse N Nijst P Reynders C Penders J Tang WHW Testani J Mullens W Urinary sodium profiling in chronic heart failure to detect development of acute decompensated heart failure JACC Heart Fail 2019 7 5 404 414 10.1016/j.jchf.2019.02.011 31047021
Martens P, Dupont M, Verbrugge FH, Damman K, Degryse N, Nijst P, Reynders C, Penders J, Tang WHW, Testani J, Mullens W (2019) Urinary sodium profiling in chronic heart failure to detect development of acute decompensated heart failure. JACC Heart Fail 7(5):404–414. 10.1016/j.jchf.2019.02.01131047021 10.1016/j.jchf.2019.02.011
23. Biegus J Zymliński R Fudim M Testani J Sokolski M Marciniak D Ponikowska B Guzik M Garus M Urban S Ponikowski P Spot urine sodium in acute heart failure: differences in prognostic value on admission and discharge ESC Heart Fail 2021 8 4 2597 2602 10.1002/ehf2.13372 33932273
Biegus J, Zymliński R, Fudim M, Testani J, Sokolski M, Marciniak D, Ponikowska B, Guzik M, Garus M, Urban S, Ponikowski P (2021) Spot urine sodium in acute heart failure: differences in prognostic value on admission and discharge. ESC Heart Fail 8(4):2597–2602. 10.1002/ehf2.1337233932273 10.1002/ehf2.13372
24. Unlu O Levitan EB Reshetnyak E Kneifati-Hayek J Diaz I Archambault A Chen L Hanlon JT Maurer MS Safford MM Lachs MS Goyal P Polypharmacy in older adults hospitalized for heart failure Circ Heart Fail 2020 13 11 E006977 10.1161/CIRCHEARTFAILURE.120.006977 33045844
Unlu O, Levitan EB, Reshetnyak E, Kneifati-Hayek J, Diaz I, Archambault A, Chen L, Hanlon JT, Maurer MS, Safford MM, Lachs MS, Goyal P (2020) Polypharmacy in older adults hospitalized for heart failure. Circ Heart Fail 13(11):E006977. 10.1161/CIRCHEARTFAILURE.120.00697733045844 10.1161/CIRCHEARTFAILURE.120.006977
25. Biegus J Zymliński R Testani J Marciniak D Zdanowicz A Jankowska EA Banasiak W Ponikowski P Renal profiling based on estimated glomerular filtration rate and spot urine sodium identifies high-risk acute heart failure patients Eur J Heart Fail 2021 23 5 729 739 10.1002/ejhf.2053 33190378
Biegus J, Zymliński R, Testani J, Marciniak D, Zdanowicz A, Jankowska EA, Banasiak W, Ponikowski P (2021) Renal profiling based on estimated glomerular filtration rate and spot urine sodium identifies high-risk acute heart failure patients. Eur J Heart Fail 23(5):729–739. 10.1002/ejhf.205333190378 10.1002/ejhf.2053
26. Biegus J Nawrocka-Millward S Zymliński R Fudim M Testani J Marciniak D Rosiek-Biegus M Ponikowska B Guzik M Garus M Ponikowski P Distinct renin/aldosterone activity profiles correlate with renal function, natriuretic response, decongestive ability and prognosis in acute heart failure Int J Cardiol 2021 345 54 60 10.1016/j.ijcard.2021.10.149 34728260
Biegus J, Nawrocka-Millward S, Zymliński R, Fudim M, Testani J, Marciniak D, Rosiek-Biegus M, Ponikowska B, Guzik M, Garus M, Ponikowski P (2021) Distinct renin/aldosterone activity profiles correlate with renal function, natriuretic response, decongestive ability and prognosis in acute heart failure. Int J Cardiol 345:54–60. 10.1016/j.ijcard.2021.10.14934728260 10.1016/j.ijcard.2021.10.149
27. Cox ZL Testani JM "Pouring Salt in the Wound" of sodium restriction in acute heart failure J Cardiac Fail 2023 10.1016/j.cardfail.2023.05.007
Cox ZL, Testani JM (2023) “Pouring Salt in the Wound” of sodium restriction in acute heart failure. J Cardiac Fail. 10.1016/j.cardfail.2023.05.00710.1016/j.cardfail.2023.05.007
28. Montgomery RA Mauch J Sankar P Martyn T Engelman T Martens P Faulkenberg K Menon V Estep JD Tang WHW Oral sodium to preserve renal efficiency in acute heart failure: a randomized, placebo-controlled, double-blind study J Cardiac Fail 2023 10.1016/j.cardfail.2023.03.018
Montgomery RA, Mauch J, Sankar P, Martyn T, Engelman T, Martens P, Faulkenberg K, Menon V, Estep JD, Tang WHW (2023) Oral sodium to preserve renal efficiency in acute heart failure: a randomized, placebo-controlled, double-blind study. J Cardiac Fail. 10.1016/j.cardfail.2023.03.01810.1016/j.cardfail.2023.03.018
29. Liu C Peng Z Gao X Gajic O Dong Y Prokop LJ Murad MH Kashani KB Domecq JP Simultaneous use of hypertonic saline and IV furosemide for fluid overload: a systematic review and meta-analysis Crit Care Med 2021 49 11 e1163 e1175 10.1097/CCM.0000000000005174 34166286
Liu C, Peng Z, Gao X, Gajic O, Dong Y, Prokop LJ, Murad MH, Kashani KB, Domecq JP (2021) Simultaneous use of hypertonic saline and IV furosemide for fluid overload: a systematic review and meta-analysis. Crit Care Med 49(11):e1163–e1175. 10.1097/CCM.000000000000517434166286 10.1097/CCM.0000000000005174
30. Colin-Ramirez E Sepehrvand N Rathwell S Ross H Escobedo J Macdonald P Troughton R Saldarriaga C Lanas F Doughty R McAlister FA Ezekowitz JA Sodium restriction in patients with heart failure: a systematic review and meta-analysis of randomized clinical trials Circ Heart Fail 2023 16 1 e009879 10.1161/CIRCHEARTFAILURE.122.009879 36373551
Colin-Ramirez E, Sepehrvand N, Rathwell S, Ross H, Escobedo J, Macdonald P, Troughton R, Saldarriaga C, Lanas F, Doughty R, McAlister FA, Ezekowitz JA (2023) Sodium restriction in patients with heart failure: a systematic review and meta-analysis of randomized clinical trials. Circ Heart Fail 16(1):e009879. 10.1161/CIRCHEARTFAILURE.122.00987936373551 10.1161/CIRCHEARTFAILURE.122.009879
31. Mentz RJ Kelly JP von Lueder TG Voors AA Lam CS Cowie MR Kjeldsen K Jankowska EA Atar D Butler J Fiuzat M Zannad F Pitt B O'Connor CM Noncardiac comorbidities in heart failure with reduced versus preserved ejection fraction J Am Coll Cardiol 2014 64 21 2281 2293 10.1016/j.jacc.2014.08.036 25456761
Mentz RJ, Kelly JP, von Lueder TG, Voors AA, Lam CS, Cowie MR, Kjeldsen K, Jankowska EA, Atar D, Butler J, Fiuzat M, Zannad F, Pitt B, O’Connor CM (2014) Noncardiac comorbidities in heart failure with reduced versus preserved ejection fraction. J Am Coll Cardiol 64(21):2281–2293. 10.1016/j.jacc.2014.08.03625456761 10.1016/j.jacc.2014.08.036
32. Bertero E Prates Roma L Ameri P Maack C Cardiac effects of SGLT2 inhibitors: the sodium hypothesis Cardiovasc Res 2018 114 1 12 18 10.1093/cvr/cvx149 29016751
Bertero E, Prates Roma L, Ameri P, Maack C (2018) Cardiac effects of SGLT2 inhibitors: the sodium hypothesis. Cardiovasc Res 114(1):12–18. 10.1093/cvr/cvx14929016751 10.1093/cvr/cvx149
33. Biegus J Voors AA Collins SP Kosiborod MN Teerlink JR Angermann CE Tromp J Ferreira JP Nassif ME Psotka MA Brueckmann M Salsali A Blatchford JP Ponikowski P Impact of empagliflozin on decongestion in acute heart failure: the EMPULSE trial Eur Heart J 2023 44 1 41 50 10.1093/eurheartj/ehac530 36254693
Biegus J, Voors AA, Collins SP, Kosiborod MN, Teerlink JR, Angermann CE, Tromp J, Ferreira JP, Nassif ME, Psotka MA, Brueckmann M, Salsali A, Blatchford JP, Ponikowski P (2023) Impact of empagliflozin on decongestion in acute heart failure: the EMPULSE trial. Eur Heart J 44(1):41–50. 10.1093/eurheartj/ehac53036254693 10.1093/eurheartj/ehac530
34. Wilcox CS Antihypertensive and renal mechanisms of SGLT2 (sodium-glucose linked transporter 2) inhibitors Hypertension (Dallas, Tex: 1979) 2020 75 4 894 901 10.1161/HYPERTENSIONAHA.119.11684 32114848
Wilcox CS (2020) Antihypertensive and renal mechanisms of SGLT2 (sodium-glucose linked transporter 2) inhibitors. Hypertension (Dallas, Tex: 1979) 75(4):894–901. 10.1161/HYPERTENSIONAHA.119.1168432114848 10.1161/HYPERTENSIONAHA.119.11684
35. Kolwelter J Kannenkeril D Linz P Jung S Nagel AM Bosch A Ott C Bramlage P Nöh L Schiffer M Uder M Achenbach S Schmieder RE The SGLT2 inhibitor empagliflozin reduces tissue sodium content in patients with chronic heart failure: results from a placebo-controlled randomised trial Clin Res Cardiol Offi J Ger Card Soc 2023 112 1 134 144 10.1007/s00392-022-02119-7
Kolwelter J, Kannenkeril D, Linz P, Jung S, Nagel AM, Bosch A, Ott C, Bramlage P, Nöh L, Schiffer M, Uder M, Achenbach S, Schmieder RE (2023) The SGLT2 inhibitor empagliflozin reduces tissue sodium content in patients with chronic heart failure: results from a placebo-controlled randomised trial. Clin Res Cardiol Offi J Ger Card Soc 112(1):134–144. 10.1007/s00392-022-02119-710.1007/s00392-022-02119-7
36. Higgins JPT Altman DG Gøtzsche PC Jüni P Moher D Oxman AD Savović J Schulz KF Weeks L Sterne JAC The cochrane collaboration’s tool for assessing risk of bias in randomised trials BMJ 2011 10.1136/BMJ.D5928 22096256
Higgins JPT, Altman DG, Gøtzsche PC, Jüni P, Moher D, Oxman AD, Savović J, Schulz KF, Weeks L, Sterne JAC (2011) The cochrane collaboration’s tool for assessing risk of bias in randomised trials. BMJ. 10.1136/BMJ.D592822096256 10.1136/BMJ.D5928
37. Sterne JA Hernán MA Reeves BC Savović J Berkman ND Viswanathan M Henry D Altman DG Ansari MT Boutron I Carpenter JR Chan AW Churchill R Deeks JJ Hróbjartsson A Kirkham J Jüni P Loke YK Pigott TD Ramsay CR Regidor D Rothstein HR Sandhu L Santaguida PL Schünemann HJ Shea B Shrier I Tugwell P Turner L Valentine JC Waddington H Waters E Wells GA Whiting PF Higgins JP ROBINS-I: a tool for assessing risk of bias in non-randomised studies of interventions BMJ 2016 10.1136/BMJ.I4919 27737834
Sterne JA, Hernán MA, Reeves BC, Savović J, Berkman ND, Viswanathan M, Henry D, Altman DG, Ansari MT, Boutron I, Carpenter JR, Chan AW, Churchill R, Deeks JJ, Hróbjartsson A, Kirkham J, Jüni P, Loke YK, Pigott TD, Ramsay CR, Regidor D, Rothstein HR, Sandhu L, Santaguida PL, Schünemann HJ, Shea B, Shrier I, Tugwell P, Turner L, Valentine JC, Waddington H, Waters E, Wells GA, Whiting PF, Higgins JP (2016) ROBINS-I: a tool for assessing risk of bias in non-randomised studies of interventions. BMJ. 10.1136/BMJ.I491927737834 10.1136/BMJ.I4919
38. Borrayo-Sanchez G Corazón T Ivey-Miranda JB Almeida-Gutierrez E Herrera-Saucedo R Posada-Martinez EL Chavez-Mendoza A Mendoza-Zavala GH Cigarroa-Lopez JA Magaña-Serrano JA Rivera-Leaños R Treviño-Mejia A Revilla-Monsalve C Flores-Umanzor EJ Espinola-Zavaleta N Orea-Tejeda A Garduño-Espinosa J Saturno-Chiu G Rao VS Testani JM Sodium restriction in patients with chronic heart failure and reduced ejection fraction: a randomized controlled trial Cardiol J 2021 10.5603/CJ.A2021.0098 34490604
Borrayo-Sanchez G, Corazón T, Ivey-Miranda JB, Almeida-Gutierrez E, Herrera-Saucedo R, Posada-Martinez EL, Chavez-Mendoza A, Mendoza-Zavala GH, Cigarroa-Lopez JA, Magaña-Serrano JA, Rivera-Leaños R, Treviño-Mejia A, Revilla-Monsalve C, Flores-Umanzor EJ, Espinola-Zavaleta N, Orea-Tejeda A, Garduño-Espinosa J, Saturno-Chiu G, Rao VS, Testani JM (2021) Sodium restriction in patients with chronic heart failure and reduced ejection fraction: a randomized controlled trial. Cardiol J. 10.5603/CJ.A2021.009834490604 10.5603/CJ.A2021.0098
39. Senturk B Kaya H Celik A Bekar L Gungor H Zoghi M Ural D Cavusoglu Y Temizhan A Yilmaz MB Noncompliance with dietary salt restriction and outcomes in chronic heart failure: a propensity score matching analysis from treat-Hf registry Haseki Tip Bulteni 2021 59 2 114 121 10.4274/HASEKI.GALENOS.2021.6963
Senturk B, Kaya H, Celik A, Bekar L, Gungor H, Zoghi M, Ural D, Cavusoglu Y, Temizhan A, Yilmaz MB (2021) Noncompliance with dietary salt restriction and outcomes in chronic heart failure: a propensity score matching analysis from treat-Hf registry. Haseki Tip Bulteni 59(2):114–121. 10.4274/HASEKI.GALENOS.2021.696310.4274/HASEKI.GALENOS.2021.6963
40. Hummel SL Karmally W Gillespie BW Helmke S Teruya S Wells J Trumble E Jimenez O Marolt C Wessler JD Cornellier ML Maurer MS Home-delivered meals postdischarge from heart failure hospitalization Circ Heart Fail 2018 11 8 e004886 10.1161/CIRCHEARTFAILURE.117.004886 30354562
Hummel SL, Karmally W, Gillespie BW, Helmke S, Teruya S, Wells J, Trumble E, Jimenez O, Marolt C, Wessler JD, Cornellier ML, Maurer MS (2018) Home-delivered meals postdischarge from heart failure hospitalization. Circ Heart Fail 11(8):e004886. 10.1161/CIRCHEARTFAILURE.117.00488630354562 10.1161/CIRCHEARTFAILURE.117.004886
41. Doukky R Avery E Mangla A Collado FM Ibrahim Z Poulin MF Richardson DJ Powell LH Impact of dietary sodium restriction on heart failure outcomes JACC Heart Fail 2016 4 1 24 35 10.1016/J.JCHF.2015.08.007 26738949
Doukky R, Avery E, Mangla A, Collado FM, Ibrahim Z, Poulin MF, Richardson DJ, Powell LH (2016) Impact of dietary sodium restriction on heart failure outcomes. JACC Heart Fail 4(1):24–35. 10.1016/J.JCHF.2015.08.00726738949 10.1016/J.JCHF.2015.08.007
42. Song EK Moser DK Dunbar SB Pressler SJ Lennie TA Dietary sodium restriction below 2 g per day predicted shorter event-free survival in patients with mild heart failure Eur J Cardiovasc Nurs 2014 13 6 541 548 10.1177/1474515113517574 24366983
Song EK, Moser DK, Dunbar SB, Pressler SJ, Lennie TA (2014) Dietary sodium restriction below 2 g per day predicted shorter event-free survival in patients with mild heart failure. Eur J Cardiovasc Nurs 13(6):541–548. 10.1177/147451511351757424366983 10.1177/1474515113517574
43. Arcand JA Ivanov J Sasson A Floras V Al-Hesayen A Azevedo ER Mak S Allard JP Newton GE A high-sodium diet is associated with acute decompensated heart failure in ambulatory heart failure patients: a prospective follow-up study Am J Clin Nutr 2011 93 2 332 337 10.3945/AJCN.110.000174 21084647
Arcand JA, Ivanov J, Sasson A, Floras V, Al-Hesayen A, Azevedo ER, Mak S, Allard JP, Newton GE (2011) A high-sodium diet is associated with acute decompensated heart failure in ambulatory heart failure patients: a prospective follow-up study. Am J Clin Nutr 93(2):332–337. 10.3945/AJCN.110.00017421084647 10.3945/AJCN.110.000174
44. Parrinello G di Pasquale P Licata G Torres D Giammanco M Fasullo S Mezzero M Paterna S Long-term effects of dietary sodium intake on cytokines and neurohormonal activation in patients with recently compensated congestive heart failure J Card Fail 2009 15 10 864 873 10.1016/J.CARDFAIL.2009.06.002 19944363
Parrinello G, di Pasquale P, Licata G, Torres D, Giammanco M, Fasullo S, Mezzero M, Paterna S (2009) Long-term effects of dietary sodium intake on cytokines and neurohormonal activation in patients with recently compensated congestive heart failure. J Card Fail 15(10):864–873. 10.1016/J.CARDFAIL.2009.06.00219944363 10.1016/J.CARDFAIL.2009.06.002
45. Paterna S Gaspare P Fasullo S Sarullo FM di Pasquale P Normal-sodium diet compared with low-sodium diet in compensated congestive heart failure: is sodium an old enemy or a new friend? Clin Sci (Lond) 2008 114 3 221 230 10.1042/CS20070193 17688420
Paterna S, Gaspare P, Fasullo S, Sarullo FM, di Pasquale P (2008) Normal-sodium diet compared with low-sodium diet in compensated congestive heart failure: is sodium an old enemy or a new friend? Clin Sci (Lond) 114(3):221–230. 10.1042/CS2007019317688420 10.1042/CS20070193
