Sodium Restrictions May Only Benefit Patients at Low Risk of HF, With Justin Ezekowitz, MD

A recent secondary analysis of the SODIUM-HF trial has indicated potential heterogeneity of treatment (HTE) effects from dietary sodium restriction across baseline risk quartiles of patients with or at risk of heart failure (HF).1

Restriction of dietary sodium is frequently recommended for patients with HF, despite a lack of data explicitly proving the impact of sodium restriction on patient-centered outcomes. SODIUM-HF compared usual care with sodium dietary restriction of <1500 mg/d in patients with HF. Ultimately, the trial was neutral for the primary endpoint of cardiovascular-related hospital admission, cardiovascular-related emergency department visits, or all-cause death.1

“What we took away from the overall SODIUM-HF trial was that for some patients, there may be a loosening of recommendations around dietary sodium as an intervention, and that it may, for some patients, improve quality of life,” Justin Ezekowitz, MD, professor of medicine in cardiology at the University of Alberta and co-director of the Canadian VIGOUR Center, told HCPLive in an exclusive interview. “However, it doesn’t change clinical events, such as cardiovascular death, all-cause mortality, or heart failure hospitalizations. Now, however, when we looked at that in a secondary analysis, we identified that the intervention and its outcomes did vary across different risk quartiles.”

SODIUM-HF was an international, open-label, randomized controlled trial conducted at 26 sites in 6 countries. Enrolled patients were aged ≥18 years with chronic heart failure – defined as New York Heart Association (NYHA) functional class 2-3 – and receiving optimally tolerated guideline-directed medical therapy. Following enrollment, a total of 806 patients were randomly assigned in a 1:1 ratio to either a low-sodium diet (n = 397) or usual care (n = 409).2

During the 12-month study period, median sodium intake decreased from 2286 mg/day (interquartile range [IQR] 1653-3005) to 1658 mg/day (1301-2189) in the low sodium group versus 2119 mg/day (1673-2804) to 2073 mg/day (1541-2900) in the usual care group. By month 12, all-cause mortality occurred in 22 patients in the low sodium diet group and 17 in the usual care group (HR, 1.38; 95% CI, 0.73-2.6; P = .32), cardiovascular-related hospitalization occurred in 40 patients in the low sodium diet group and 51 patients in the usual care group (HR, 0.82; 95% CI, 0.54-1.24; P = .36), and cardiovascular-related emergency department visits occurred in 17 patients in the low sodium diet group and 15 in the usual care group (HR, 1.21; 95% CI, 0.6-2.41; P = .6).2

Ezekowitz and colleagues utilized the full dataset of SODIUM-HF for the present analysis, including the same 806 patients. The team used a risk-based approach based on the Meta-Analysis Global Group in Chronic (MAGGIC) HF risk score. The quartiles used were 0.036 to 0.102 (low), >0.102 to 0.147 (medium-low), >0.147 to 0.209 (medium-high), and >0.209 to 0.591 (high).1

Investigators found strong evidence for the interaction between MAGGIC quartile and intervention, particularly for the medium-low MAGGIC quartile (0.95 probability; % in region of practical equivalence [ROPE] 0.05). Additionally, the primary endpoint – a composite of cardiovascular-related hospital admission, cardiovascular-related emergency department visit, or all-cause death within 12 months – occurred more frequently in the high MAGGIC quartile (probability of benefit of 0.07, %ROPE of 0.05).1

Ultimately, despite these results, Ezekowitz and colleagues stated that this analysis should not change practice. However, they call for further research on the effects of sodium restriction in HF, potentially embedding the HTE concept in its design. Ezekowitz also stated that the uniform application of dietary sodium restrictions as an intervention should be reconsidered.1

“The largest trial we’ve ever done in this area is, in fact, the SODIUM-HF trial, and it shows that it was neutral for a clinical outcome,” Ezekowitz told HCPLive. “If that is our benchmark for what we implement in clinical practice, then we shouldn’t make broad, sweeping recommendations for all patients now that we recognize that we don’t operate in a vacuum. We should really think about the next trials that need to be done.”

Editor's Note: Ezekowitz reports disclosures with Bayer, Merck, Amgen, Sanofi, Novartis, Cytokinetics, and others.

References

1. Zampieri FG, Rathwell S, McAlister FA, et al. Heterogeneity in Treatment Effects in the Reduction of Dietary Sodium to Less Than 100 mmol in Heart Failure (SODIUM-HF): A Secondary Post Hoc Analysis. J Card Fail. 2026;32(2):371-381. doi:10.1016/j.cardfail.2025.01.027

2. Ezekowitz JA, Colin-Ramirez E, Ross H, et al. Reduction of dietary sodium to less than 100 mmol in heart failure (SODIUM-HF): an international, open-label, randomised, controlled trial. Lancet. 2022;399(10333):1391-1400. doi:10.1016/S0140-6736(22)00369-5