- Click here for explanation of classification scheme.

To evaluate the effects of dietary sodium restriction at two levels on neurohormonal and cytokine activation, body hydration and clinical outcomes in compensated congestive heart failure (CHF) patients (New York Heart Association Class II) over a period of 12 months.

• Previously hospitalized patients (previous 30 days) who had a recent event of decompensated CHF
• Heart failure consistent with the definition of New York Heart association (NYHA) functional classification of CHF
• Uncompensated CHF (dyspnea, weakness, lower-limb edema or anasarca)
• NYHA Class IV that was unresponsive to treatment with oral high doses of furosemide up to 240mg to 500mg per day and combinations of diuretics, angiotensin-converting enzyme inhibitors, digitalis, β-blockers and nitrates and to be under this therapy at least two weeks before hospitalization
• Left ventricular ejection fraction less than 35%
• Serum creatinine less than 2mg per dL, blood urea nitrogen (BUN) less than 60mg per dL, reduced urinary volume less than 500ml per 24 hours and low natriuresis (60mEq or less per 24 hours).

 

 . 

• Patients with cerebral vascular disease, dementia, cancer, uncompensated diabetes or severe hepatic disease
• Patients requiring pacemaker implantation
• Patients with alcoholic habit.

 

Recruitment

Patients were recruited from the Biomedical Department of Internal and Specialist Medicine of the University Hospital of Palermo and also from the Department of Cardiology after being discharge from the hospital, between September 2005 and August 2007.

Design

Randomized clinical trial.

Blinding Used

Double-blind.

Intervention

• Groups include:
  • Group A: Moderate sodium intake [120mmol (2,760mg) Na per day + 1,000ml per day of fluid intake]
  • Group B: Low sodium intake [80mmol (1.840mg) Na per day + 1,000ml per day of fluid intake].
• All patients received 125mg to 250mg bid of furosemide a day
• Patients were also given a list of equivalent food in sodium they could use as substitute. All patients received the same amount of saturated fat, fruit and vegetables.

Statistical Analysis

• Analysis was by intention to treat and according to absolute risk reduction; it was calculated by the number needed to treat to prevent one event
• Event distributions were calculated with Kaplan-Meier method and compared them by long-rank analysis
• Two-tailed Student T-test was used to identify differences between groups and analysis of variance for repeated measures with Bonferroni pot-hoc test correction for intragroup data
• Nominal data were analyzed by the chi-square test
• When variables were significant at univariate analysis, they were tested by the multivariate Cox proportional hazards regression model to assess their independent effect on the development of events during the follow-up. Results were expressed as hazard ratio with 95% confidence interval.
• Analysis were performed using SPSS. All tests were two-sided and P<0.05 was considered to be statistically significant. Results were expressed as means ±SD. 

Timing of Measurements

• Patients were evaluated every week for the first month, every two weeks for the next two months and every month for the remainder of the study
• Physical examination including body weight, blood pressure, heart rate, bioelectrical impedance analysis (BIA) was performed at every follow-up
• Laboratory assessment  (serum Na, K, Cl, bicarbonate, albumin, uric acid, glycemia, creatinine, urea, urinary sodium excretion and diuresed volume), a chest x-ray, electrocardiogram, echocardiogram were obtained at baseline, after six and 12 months of follow-up in all patients
• Neurohormonal biomarkers and cytokine measurements were also performed at the same period. The diet and fluid intake were reported weekly during follow-up.

Dependent Variables

• Neurohumoral biomarkers: Brain natriuretic peptide (BNP), plasma renin activity (PRA) and aldosterone were measured by radioimmunoassay
• Cytokines: IL-6, IL-10, TNF-α were measured using an enzyme-linked immunosorbent assay
• Hospital readmission
• Mortality.

Independent Variables

Sodium intake (low vs. moderate).

• Initial N: 173 (68 female, 105 male)
  • 86 (30 female, 56 male) in the moderate sodium diet group
  • 87 (34 female, 53 male) in the low sodium diet
• Attrition (final N):
  • At 12 months, 60 low sodium diet group and 74 moderate sodium diet group.
  • 15 patients, seven from the low sodium and eight from the moderate sodium restriction group were lost because they did not perform the scheduled controls and were excluded from the final analysis
• Age: 72.5±8 years
• Other relevant demographics:
  • Angiotensin-converting enzyme inhibitors, digitalis, anti-aldosterone, β-blockers and nitrates therapy obtained during hospitalization was continued after discharge
  • Correction of therapy was only carried out in readmitted patients
  • All patients with diabetes received insulin therapy; however, oral anti-diabetes drugs were discouraged after discharge and follow-up
  • Patient's etiologies: 84 coronary artery disease, 57 hypertensive heart disease, 32 dilatative cardiomyopathy who met the entry criteria
  • No patients were excluded during follow- up due to renal deterioration (creatinine higher than 2.0mg), but only the readmitted patients had an increase in plasma creatinine levels higher than 2.0mg.
• Anthropometrics: At baseline both groups had the same body weight. After six and 12 months, only the patients on the low-sodium diet had a significantly increase in the BW (P<0.01)
• Location: Palermo, Italy.

Key Findings

Variables	Low Sodium Diet				Moderate Sodium Diet				P (Between Groups)
	Baseline (N=87)	Six Months (N=67)	12 Months (N=60)	P (Within the Groups)	Baseline (N=86)	Six Months (N=78)	12 Months (N=74)	P (Within the Groups)
Creatinine Clearance	56.2±6.4	46.2±4.2*	42.5±3.7*	<0.0001	56.7±6.5	56.3±6.1	56.4±6.3	0.91	0.0001
UNa (mEq per 24 hours)	102±11	77±9*	76±7*	<0.001	105±14	106±12	103±11	0.32	0.0001
BUN (mg per dL)	56.5±3.6	101±12*	105±5.8*	<0.0001	58.5±7	67±9	68.4±7.2	<0.001	0.0001
Creatinine serum (mg per dL)	1.55±0.05	1.89±0.3*	2.1±0.5*	<0.001	1.56±0.2	1.48±0.3	1.45±0.4	<0.01	0.0001
Diuresis (ml per 24 hours)	2,560±425	1,580±555*	1,525±565*	<0.0001	2,495±635	2,250±565	2,150±480	<0.048	0.0001

UNa = urinary sodium excretion; BUN = blood urea nitrogen. *Differences between groups (low vs. moderate sodium restriction).

• Restricted sodium diet (1,840mg per day) increased significantly hospital readmissions [adjusted risk reduction (ARR)=21.2, 95% CI:10.8, 31.6; P<0.0001] and mortality (ARR=14.2 , 95% CI: 5.65, 22.7; P<0.005) compared to the moderate sodium diet during the 12 months of follow-up.
• Low-sodium diet was associated approximately to 10-fold risk of cytokines and neurohormonal plasma levels increase with concomitant worse in hospital readmission and mortality [adjusted hazard ratio 9.95 (95% CI: 4.89, 20.24); P<0.001].

Other Findings

 

Variables	Low Sodium Diet				Moderate Sodium Diet				P (Between Groups)
	Baseline (N=87)	Six Months (N=67)	12 Months (N=60)	P (Within the Groups)	Baseline (N=86)	Six Months (N=78)	12 Months (N=74)	P (Within the Groups)
BNP	378±110	545±127*	681±134*	0.0001	385±135	345±155	225±130	0.001	0.0001
PRA	3.8±3.5	4.5±3.1*	5.3±2.9*	0.026	3.9±3.7	3.5±2.7	3.4±2.3	0.53	<0.04
Aldosterone (pg per ml)	304.4±158	378.6±132*	392.6±129*	0.0001	296.3±167	189±170	152.9±171	0.001	0.0001
TNF-α (pg per ml)	19.1±8.6	19.4±7.1	21.9±6.8	0.0014	17.8±9	14.7±8	12±7.8	0.001	≤0.001
IL-6 (pg per ml)	20.8±6.9	24.5±6.7	26.3±5.9	0.0001	21.3±12.5	15.2±8.7	12.8±6.5	0.001	0.0001
IL-10 (pg per ml)	68.7±5.6	66.5±5.8	64.5±5.7	0.01	62.8±5.4	74±7.3	92.1±7	0.0001	0.0001

BNP = brain natriuretic peptide; PRA = plasma renin activity.* Differences between groups (low vs. moderate sodium restriction).

All patients showed a good compliance with the prescribed treatments, only nine patients (four from the moderate sodium restriction diet, and five from the low sodium diet) during the first month increased drink fluid intake (1,500ml). However, it was corrected at subsequent control (seven days after).

 

 

 

 

 

The results appear to suggest a surprising efficacy of a new strategy to improve the chronic diuretic response by increasing sodium intake and limiting fluid intake. This counterintuitive approach underlines the need for a better understanding of factors that regulate sodium and water handling in chronic congestive HF. A larger sample of patients and further studies are required to evaluate whether this is due to the high dose of diuretic used or the low-sodium diet.

Other:

Not reported

• Some limitations of the study reported by the authors is the possibility that the sodium or diuretic dose could be changed (increased or decreased) according to the severity of HF. A different combination of sodium intake levels associated with different doses of diuretics and fluid restrictions could be more beneficial. It is possible that the high dose of diuretics used in the study associated with a low-sodium diet and high water restriction might had an unfavorably effect on the outcomes.
• Some of the strengths reported by the IOM report (2013) included "the assessment of sodium intake by the 24-hour urine and randomization by a preliminary computer algorithm; whereas some of the weaknesses were the limited generalizability due to eligibility criteria (unresponsive to treatment) and aggressive co-treatment with high dose of diuretics [furosemide (125mg to 250mg twice a day] and severe fluid restriction(1,000ml per day), the lack of co-treatment of ACE inhibitors and beta blocker in the protocol, and the confounded by worsened renal function in low Na treatment by high dose of diuretics and severe fluid restriction."

What was the baseline nutrient status (i.e., sodium)? For example, the baseline sodium status can be used as an inclusion criterion for entry into study, and recorded in the report of the trial.	Low sodium diet: 2,346mg per day (102mEq per day) Moderate sodium intake: 2,415mg per day (105mEq per day)
What was the target of sodium intake in the intervention and comparison groups?	Low sodium diet: 1,840mg per day (120mmol per day)  Moderate sodium diet: 2,760mg per day (80mmol per day)
Was the difference in sodium status (i.e., change in urinary sodium excretion) measured between groups? If so, please specify.	Low sodium group: 1,748mg per day (76mEq per day) Moderate sodium group: 2,369mg per day (103mEq per day) P<0.0001
Was the status of other nutrient (e.g., potassium and calcium) measured in order to ensure that the test nutrient (i.e., sodium) is the only nutrition-related, limiting factor in the response? If yes, please specify.	Serum potassium in the low sodium diet: 3.7mEq per L Serum potassium in the moderate sodium diet: 3.6mEq per L