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Neal B, et al. Effect of Salt Substitution on Cardiovascular Events and Death. N Engl J Med. 2021;385:1067-1077. PMID 34459569

One-paragraph summary

The Salt Substitute and Stroke Study cluster-randomised 600 villages in rural China — 20,995 participants with a history of stroke or aged ≥60 with high blood pressure — to a salt substitute containing 75% sodium chloride and 25% potassium chloride by mass, or to continued use of regular salt. Mean age was 65.4 years, 49.5% were female, 72.6% had a prior stroke and 88.4% a history of hypertension. Over a mean 4.74 years, stroke occurred at 29.14 versus 33.65 events per 1,000 person-years (rate ratio 0.86, 95% CI 0.77–0.96; p=0.006), major cardiovascular events at 49.09 versus 56.29 (0.87, 0.80–0.94; p<0.001) and death from any cause at 39.28 versus 44.61 (0.88, 0.82–0.95; p<0.001). Serious adverse events attributed to hyperkalaemia occurred at 3.35 versus 3.30 per 1,000 person-years (rate ratio 1.04, 95% CI 0.80–1.37; p=0.76).

Key findings

  • One of the few hypertension-focused environmental interventions with randomised evidence of reduced stroke, major cardiovascular events and all-cause mortality; “the only lifestyle intervention” was too broad because cardiovascular dietary trials outside a hypertension-defined population also have hard endpoints.
  • No detectable excess of clinical hyperkalaemia in the enrolled population.
  • The interim analysis confirmed the effect was mediated through blood pressure and urinary electrolyte change (PMID 31986290).
  • Secondary analyses extend to cardiac outcomes (PMID 38465623), fracture (PMID 39232779), gastric cancer (PMID 40264179) and recurrent stroke (PMID 39908026).
  • Meta-analysis of 21 trials and 31,949 participants found consistent pressure reduction across geographies and subgroups (−4.61 mm Hg systolic, 95% CI −6.07 to −3.14) with a dose–response by substitution fraction (PMID 35945000).

Limitations

  • Open-label cluster design; participants knew which salt they were using, though hard endpoints and death are relatively robust to that.
  • The population was selected for high stroke risk in rural China, where most sodium is added during home cooking. The PubMed and ClinicalTrials.gov searches repeated on 2026-09-01 located no salt-substitution outcome trial in a setting where most sodium is embedded in commercially processed food; the intervention has less household salt on which to act there.
  • People at high risk of hyperkalaemia — advanced chronic kidney disease, potassium-sparing diuretics — were largely excluded, so the reassuring safety result does not transfer to them.
  • Village-level randomisation means contamination and clustering effects are possible, and the effective sample size is smaller than the participant count suggests.
  • Diet, medication and other cardiovascular care were not standardised.

Why it matters

SSaSS converts the sodium–blood-pressure literature, which had been almost entirely surrogate-endpoint based and mired in an unresolved observational controversy about low intake, into hard-outcome evidence for one specific, cheap, scalable intervention. Its deeper lesson is structural: salt substitution works because it changes what is in the salt cellar rather than what a person decides each day, which is why its effect does not decay the way behaviour-dependent dietary interventions do. That asymmetry — environment-level interventions outlast behaviour-level ones — is the most transferable finding in the lifestyle literature.

Cited by wiki pages

  • overview
  • lifestyle and dietary management
  • red flags and safety concerns