SSaSS – Salt Substitutes and Cardiovascular Events

Effect of Salt Substitution on Cardiovascular Events and Death.

Neal B, Wu Y, Feng X, et al.

N Engl J Med. 2021 Sep 16;385(12):1067-1077. [Full text]

Summary by Kevin Jiang

Healthcare professionals commonly recommend low sodium diet as a key tenant when discussing dietary recommendations. Sodium reduction across numerous retrospective studies has led to consistent, though modest, improvements in blood pressure, particularly in groups with higher baseline blood pressure. The outcomes of sodium reduction on cardiovascular disease have been somewhat mixed. There is a clear consensus that reduction benefits those with the highest sodium intake [1, 2], but otherwise is somewhat controversial, specifically with reductions to very low sodium intake levels [1].

Some prior prospective randomized trials have demonstrated reductions in blood pressure with sodium reduction and concurrent increased potassium supplementation; however, these prior trials were not powered nor had adequate length of follow up to assess the effect on clinical outcomes like major adverse cardiovascular events and mortality. The Salt Substitute and Stroke Study (SSaSS) was designed sufficiently large to address that key question.

Patient population and Design

SSaSS was an open-label, cluster-randomized trial in 600 rural villages in China of 20,995 men and women with either a history of stroke or ≥60 years old with poorly controlled blood pressure (SBP ≥140 mmHg on antihypertensives or ≥160 mmHg not on medications). The population would be considered high risk for carvdiovascular events with elevated blood pressure, a mean age of 65.4 years, and 72.6% with prior stroke.

The villages were randomized in a 1:1 ratio with the intervention arm receiving 75% NaCl and 25% potassium chloride salt substitute for all household cooking averaging 20g/person/day. Both the control and intervention arm were counseled on reduced salt intake. Exclusion criteria included use of potassium-sparing diuretic (not counting ACE/ARB), use of potassium supplement, or serious kidney disease. Baseline characteristics of age, gender, blood pressure, disease history, use of antihypertensives (and type of antihypertensive), and mean 24-hr urinary sodium and potassium excretion were all balanced between the groups.

The primary outcome was stroke with secondary outcomes of major adverse cardiovascular events (composite of nonfatal stroke, nonfatal ACS, or death from vascular causes) and all-cause mortality. A safety outcomes was clinical hyperkalemia though routine serum potassium measurements were not performed. Follow-ups scheduled to occur at 6-month intervals for trial outcomes with a subset receiving blood pressure and 24-hour urinary sodium and potassium checks.


Vital status was known for 100% of participants at 5 year follow up and 90% of alive patients were followed up in-person at conclusion of study (the rest followed up via family contacts or medical record linkage). Median follow up was 5.12 years with 91.7% salt-substitute and 6.4% of control group reported use of salt substitute.

As expected, the intervention arm had lower 24hr urinary sodium excretion (mean difference -350mg) and higher 24hr potassium excretion (mean difference 803mg).

For the primary outcome of stroke, the salt substitute intervention arm saw significant lower rates of stroke (29.14 events vs. 33.65 events per 1000 person-years; RR 0.86; 95% CI, 0.77 to 0.96; P=0.006), of the secondary outcomes of major adverse cardiovascular events (49.1 events vs. 56.3 events per 1000 person-years; RR 0.87; 95% CI, 0.80 to 0.94; P<0.001) and all-cause mortality (39.3 events vs. 44.6 events per 1000 person-years; RR 0.88; 95% CI, 0.82 to 0.95; P<0.001).

There was no significant difference in definite, probable or possible hyperkalemic events between the groups.


There are not very many large-scale randomized prospective dietary trials given the funding requirements and difficulty in implementation and adherence monitoring at large scale. This study focused on a simple intervention and targeted rural Chinese villages where meals are almost exclusively home cooked to improve adherence (commercial food preservation adds substantial sodium chloride to the diet). This trial strengthens prior research and supports sodium reduction with increased potassium intake on blood pressure, but more importantly on cardiovascular outcomes, such as stroke.

Though it was a large population, the population demographics are distinct. The typical rural Chinese diet utilizes a large amount of sodium not just for cooking but also for preserving meats and vegetables given limitations in refrigeration and cultural practices (hence the allocated 20g/person/day salt). In contrast, the average Western diet has a daily salt intake 9-12 g/day. Applied to a more moderate or even a low-salt diet, salt substitution may not produce the same magnitude of benefits as in this study.

Additionally, we must analyze other cultural differences that contribute to higher baseline blood pressure and cardiovascular events like smoking. The study population had a 18.8% rate of current smokers and 33.5% significant past smoking history compared to 14.9% current smokers in the US. It must also be emphasized that this study focused on an inherently high-risk patient population in those with either history of stroke or uncontrolled hypertension.

Overall, the simplicity of the intervention and the magnitude of effect (NNT 22.2 to prevent one stroke per 1000 person-years) are compelling. If this can be more widely adopted into practice in the western diet is still an open question. But it does emphasize the importance of a holistic approach in healthcare.

F: Follow up5 years
R: RandomizationYes
I: Intention to treatNo
S: Similar at baselineYes
B: BlindingNo
E: Equal treatmentYes
S: Source (funding)Research grants from National Health and Medical Research Council of Australia; salt substitute purchased by investigators but donated by Jiangsu Tech for years 3 – 4 

  1. Cook NR, He FJ, MacGregor GA, Graudal N. Sodium and health-concordance and controversy. BMJ. 2020 Jun 26;369:m2440.
  2. Nakamura K, Miyoshi T. The optimal amount of salt intake. Hypertens Res. 2019 May;42(5):752-753.