Neal et al. 2021 — SSaSS: Effect of salt substitution on cardiovascular events and death
Citation
Neal B, Wu Y, Feng X, Zhang R, Zhang Y, Shi J, Zhang J, Tian M, Huang L, Li Z, Yu Y, Zhao Y, Zhou B, Sun J, Liu Y, Yin X, Hao Z, Yu J, Li K, Zhang X, Duan P, Wang F, Ma B, Shi W, et al. “Effect of Salt Substitution on Cardiovascular Events and Death.” New England Journal of Medicine 2021;385(12):1067–1077. doi:10.1056/NEJMoa2105675. PMID 34459569.
Study design
Cluster-randomized controlled trial. 20,995 participants enrolled across 600 villages in 5 provinces of rural China. Villages were randomly assigned to salt-substitute group or regular-salt (control) group. Mean follow-up 4.74 years (approximately 5 years). Participants were eligible if they had a history of stroke OR were aged ≥60 with uncontrolled hypertension. All participants were residents using salt in their household cooking; the intervention replaced the household salt supply.
Intervention:
- Salt substitute: ~70% sodium chloride + ~30% potassium chloride (by mass; manufactured per Chinese national standard GB 2019-2005, which specifies 70% ±10% NaCl and 30% ±10% KCl)
- Control: Regular salt (100% sodium chloride)
- Mechanism: Simultaneous sodium reduction and potassium increase via the household salt supply
Participants
- N = 20,995 (10,504 salt-substitute; 10,491 regular-salt control)
- Mean age: 65.4 years
- Female: 49.5%
- Prior stroke: 72.6% (strong secondary-prevention enrichment)
- Hypertension: 88.4%
- Setting: 600 rural villages; 5 Chinese provinces
Primary and secondary outcomes
| Outcome | Salt substitute | Control | Rate ratio | p-value |
|---|---|---|---|---|
| Stroke (primary) | 29.14/1,000 PY | 33.65/1,000 PY | 0.86 | 0.006 |
| Major cardiovascular events | 49.09/1,000 PY | 56.29/1,000 PY | 0.87 | <0.001 |
| All-cause mortality | 39.28/1,000 PY | 44.61/1,000 PY | 0.88 | <0.001 |
| Serious hyperkalemia | 3.35/1,000 PY | 3.30/1,000 PY | not diff | 0.76 |
Interpretation: The salt substitute reduced stroke by ~14%, major cardiovascular events by ~13%, and all-cause mortality by ~12% over approximately 5 years. Serious hyperkalemia was not significantly increased.
Estimated blood pressure effect
Measured systolic BP reduction attributable to the salt substitute across follow-up was −3.34 mmHg (95% CI −4.51 to −2.18 mmHg) based on 24-hour urinary electrolyte and BP sub-studies integrated over the trial period; mean 24-hour urinary sodium excretion difference was −15.2 mmol (95% CI −23.7 to −6.70 mmol) and urinary potassium excretion difference was +20.6 mmol (95% CI 18.3–23.0 mmol). This modest BP change disproportionately translates to hard endpoint benefit given the very high baseline cardiovascular risk of the population.
Mechanistic interpretation
The SSaSS result reflects two simultaneous effects of the 75/25 NaCl/KCl substitute:
- Sodium reduction — ~25% less sodium per gram of salt consumed → reduced intravascular volume and BP
- Potassium increase — ~25% KCl → estimated +50–65 mmol/day additional potassium → VSMC hyperpolarization, renal natriuresis, and independent vascular effect
The observed benefit likely reflects both effects acting synergistically. This makes SSaSS the pragmatic human validation of the companion-cation strategy (Na restriction + K repletion together) as well as the theoretical framework from cook-2009-tohp-sodium-potassium (Na/K ratio predicts CVD better than either alone).
Hyperkalemia safety caveat
While the trial found no significant increase in serious hyperkalemia, this result applies specifically to the enrolled population: rural Chinese adults without prevalent CKD. Critical extrapolation caveat: participants with known serious kidney disease were excluded from SSaSS by self-report (no routine biochemical renal-function pre-screening was performed), and CKD patients face genuine hyperkalemia risk from supplemental potassium chloride. Additionally, individuals on renin-angiotensin-aldosterone system inhibitors (ACE inhibitors, ARBs) or potassium-sparing diuretics face increased hyperkalemia risk when co-exposing to KCl-supplemented salt. Clinical translation of salt substitutes to CKD populations requires physician oversight and renal function monitoring. This is the primary safety caveat for the SSaSS result.
External validity
The trial was conducted in rural China with near-universal prior stroke or uncontrolled hypertension. Generalizability to:
- Western high-income populations: uncertain; baseline sodium intake, potassium intake, dietary culture, and health system context all differ
- Primary prevention populations (no prior stroke/CVD): not directly tested; benefit would be expected but may be smaller given lower absolute risk
- CKD populations: contraindicated without renal monitoring (see above)
Significance
SSaSS is the largest long-term pragmatic salt-substitute trial and the first with sufficient power to demonstrate hard-endpoint (stroke, death) reductions from a dietary sodium/potassium intervention. It is the evidentiary anchor for practical salt-substitute recommendations in cardiovascular-aging management.
Relationships
- Synthesized by: kong-2025-sodium-umbrella-review (umbrella review)
- Meta-analyzed with: greenwood-2024-salt-substitute-meta (Greenwood 2024 Annals of Internal Medicine; RR 0.88 for all-cause mortality from salt substitutes)
- Mechanism: cook-2009-tohp-sodium-potassium (Na/K ratio context)
- See also: sodium-restriction