SSaSS Trial

  • Post category:Journal Club

CardioNerds Journal Club is a monthly forum for CardioNerds to discuss and breakdown recent publications on twitter and are produced with a corresponding infographic and detailed blog post. For more information, check out the CardioNerds Journal Club Page. This Journal Club focuses on the SSaSS Trial.

Table of contents for the SSaSS Trial summary:

September 16, 2021

Effect of Salt Substitution on Cardiovascular Events and Death

The SSaSS Trial

Bruce Neal, M.B., Ch.B., Ph.D., Yangfeng Wu, M.D., Ph.D., Xiangxian Feng, Ph.D., Ruijuan Zhang, M.Sc., Yuhong Zhang, M.Med., Jingpu Shi, Ph.D., Jianxin Zhang, Ph.D., Maoyi Tian, Ph.D., Liping Huang, Ph.D., Zhifang Li, M.Sc., Yan Yu, Ph.D., Yi Zhao, Ph.D., Bo Zhou, Ph.D., Jixin Sun, M.Sc., Yishu Liu, M.Sc., Xuejun Yin, M.P.H., Zhixin Hao, M.D., Jie Yu, M.D., Ph.D., Ka-Chun Li, M.Sc., Xinyi Zhang, M.P.H., Peifen Duan, M.Sc., Faxuan Wang, Ph.D., Bing Ma, M.Sc., Weiwei Shi, Ph.D., Gian Luca Di Tanna, Ph.D., Sandrine Stepien, M.Sc., Sana Shan, M.Sc., Sallie-Anne Pearson, Ph.D., Nicole Li, M.D., Ph.D., Lijing L. Yan, Ph.D., Darwin Labarthe, Ph.D., and Paul Elliott, M.B., B.S., Ph.D.

N Engl J Med 2021; 385:1067-1077. DOI: 10.1056/NEJMoa2105675

  • The average American consumes an excess of the daily recommended dietary sodium content – estimated at 10.4 g of salt per day for men and 7.3 g per day for women1
  • Dietary sodium has been found to have a direct, dose-response effect on blood pressure2
  • A decrease in dietary sodium has been correlated with proportionate decrease in blood pressure, cardiovascular disease, and stroke.3-4 Further studies have found that reduced sodium and increased potassium intake results in improved hypertension control without worsening renal function.5-6
  • Epidemiologic models have suggested reducing the average salt intake by 3g/day could save 194,000 to 392,000 quality-adjusted life-years and 10 – 24 USD billion annually7 based upon the estimated >50 million Americans who are diagnosed with hypertension8
  • Dietary interventions, including the DASH diet, have been proposed to reduce blood pressure and cardiovascular risk with modest reductions in mean systolic and diastolic blood pressure9

Inclusion and Exclusion Criteria:


  • Random assignment of villages to salt substitute versus regular salt
  • General advice about stroke prevention and reduced salt intake was provided to both groups
  • Follow-up conducted at 6-month intervals for a total of five years


Participant Characteristics:

  • 20,995 participants total from 600 villages: 4,172 participants died during the trial, and all living participants underwent final follow-up assessment
  • In the salt-substitute group, 91% reported using salt-substitute at the end of the trial vs. 6.4% in the regular salt group
  • Mean age 65.4 years, 49.5% female, 72.6% with prior stroke, 88.4% with diagnosed hypertension.
  • 79.3% of participants were on at least one blood pressure lowering medication
    • 41.8% calcium antagonist
    • 22.8% ACEi/ARB
    • 11.5% diuretic
    • 5.7% beta-blocker
    • 0.9% alpha-blocker


Primary, Secondary, and Safety Outcomes

  • Reduction in 24-hour urinary sodium excretion
  • Significant reduction in fatal or nonfatal stroke events (29.14 vs. 33.65 events per 1000 person-years)
  • Reduction in MACE (49.1 events vs. 56.3 events per 1000 person-years) and death from any cause (39.3 events vs. 44.6 events per 1000 person-years
  • Point estimates favor salt substitute with regard to all exploratory outcomes
  • 2 participants developed hyperkalemia, and 313 participants identified as having possible hyperkalemia (p = 0.76)

SSaSS Trial Conclusions

  • Participants using the salt substitute (75% NaCl, 25% KCl) had significantly lower rates of stroke, major adverse cardiovascular events, and death from any cause at five years of follow-up in this randomized, controlled trial.
  • There was no significant increase in the risk of hyperkalemia, though individuals with renal dysfunction or those taking potassium-sparing diuretics or potassium supplements were excluded from the trial.
  • Routine lab work was not performed, though a systematic review of records for adverse events attributable to hyperkalemia was undertaken.
  • The salt substitute may represent a low-cost intervention available to both the domestic and international community for stroke and cardiovascular disease risk mitigation 

Limitations & Considerations

  • Serial lab monitoring was not performed for detection of hyperkalemia, and therefore subclinical hyperkalemia may not have been detected
  • A dose-response effect was not measured as only one preparation of salt substitute was used rather than graded dosages
  • Blinding to the intervention was not performed, though bias was limited by objective endpoints, including MACE and sudden cardiac death
  1. U.S. Department of Agriculture, Agricultural Research Service. 2008. Nutrient intakes from food: mean amounts consumed per individual, one day, 2005–2006. (Accessed January 15, 2010, at opens in new tab.)
  2. Cogswell ME, Mugavero K, Bowman BA, Frieden TR. Dietary sodium and cardiovascular disease risk — measurement matters. N Engl J Med 2016;375:580-586.
  3. He FJ, MacGregor GA. Effect of longer-term modest salt reduction on blood pressure. Cochrane Database Syst Rev 2004;3:CD004937-CD004937
  4. Panel on Dietary Reference Intakes for Electrolytes and Water, Standing Committee on the Scientific Evaluation of Dietary Reference Intakes, Food and Nutrition Board, Institute of Medicine. Dietary reference intakes for water, potassium, sodium, chloride, and sulfate. Washington, DC: National Academies Press, 2005.
  5. Huang L, Trieu K, Yoshimura S, et al. Effect of dose and duration of reduction in dietary sodium on blood pressure levels: systematic review and meta-analysis of randomised trials. BMJ 2020;368:m315-m315.
  6. Aburto NJ, Ziolkovska A, Hooper L, Elliott P, Cappuccio FP, Meerpohl JJ. Effect of lower sodium intake on health: systematic review and meta-analyses. BMJ 2013;346:f1326-f1326.
  7. Bibbins-Domingo K, Chertow GM, Coxson PG, et al. Projected effect of dietary salt reductions on future cardiovascular disease. N Engl J Med 2010;362:590-599
  8. The sixth report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Arch Intern Med 1997;157:2413-2446
  9. Sacks FM, Svetkey LP, Vollmer WM, et al. Effects on blood pressure of reduced dietary sodium and the Dietary Approaches to Stop Hypertension (DASH) diet. N Engl J Med 2001;344:3-10

The published archive features curated twitter highlights from the journal club event.


Dr. Jessie Hotlzman, @jholtzman3, Internal Medicine Chief Resident at UCSF, San Francisco, CA.


Dr. Hussain Khalid, @HussainMKCards, Cardiology Fellow at University of Florida


Dr. Devesh Rai, @DeveshRaiMD, Cardiology fellow at Rochester General Hospital, Rochester, NY


Dr. Tommy Das, @ThomasMDas, Cardiology fellow at the Cleveland Clinic, Cleveland, OH


Dr. Rick Ferraro, @RichardAFerraro, Cardiology Fellow at the Johns Hopkins Hospital, Baltimore, MD.

#CardsJC Deputy Director

Dr. Devesh Rai, @DeveshRaiMD, Cardiology fellow at Rochester General Hospital, Rochester, NY

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