salt substitute decreases subsequent strokes and death

 A recent Chinese study found that changing regular salt to a salt substitute with 75% sodium chloride and 25% potassium chloride in patients with a prior stroke was associated with a reduced risk of stroke recurrence and death: see htn salt substitute dec stroke JAMAcardiol2025 in dropbox, or doi:10.1001/jamacardio.2024.5417, in a subgroup analysis of the SSaSS study (Salt Substitute and Stroke Study)

 

Details:

--15,249 people who had had a self-reported stroke in 600 Northern Chinese villages in this open-label, cluster randomized clinical trial

    -- these villages were randomized to either continuing regular salt (100% sodium chloride) versus a salt substitute (75% sodium chloride and 25% potassium chloride)

--baseline data was collected on participants of their demographics, disease history, medication use, and salt-related knowledge and behaviors; also 24-hour urinary sodium and potassium excretions were measured along with blood pressure every 12 months among a random sample of participants, with sample sizes varying from 826 to 1907 participants in the different villages

 

-- mean age 64, 46% female, 68% had less education than primary school

-- past smoker 37%, current smoker 20%, BMI 25

-- mean blood pressure 148/87

-- disease history: hypertension 85%, TIA 18%, ischemic heart disease 14%, congestive heart failure 2%, peripheral arterial disease 4%, diabetes 11%

-- medications: diuretics 9%, ACE/ARB 18%, beta-blocker 5%, calcium channel antagonist 40%, other antihypertensives 41%, any hypertensive 76%, statins 15%, aspirin or antiplatelet agent 46%

-- knowledge and behaviors related to salt:

    -- trying to reduce salt intake 65%, eating pickled vegetables most days 25%, adding salt to most meals 9%, adding MSG to most meals 42%, trying to eat less if the food is very salty 74%, having heard about salt substitute 7%, households using salt substitute 2%

    -- knowing that too much salt affects health 57%, knowing that too much salt affects the risk of stroke 34%, knowing that too much salt affects blood pressure 47%

 

-- main outcomes and measures: recurrent stroke (any acute disturbance of focal neurologic function leading to death or symptoms lasting more than 24 hours), comparing those taking the salt substitute versus those taking regular salt

-- secondary outcome: mortality from any cause

-- key safety outcome: hyperkalemia

 

-- Median follow-up of 61.2 months

  

Results:

-- 24-hour urinary sodium and potassium excretion during follow-up period:

     -- 24-hour sodium excretion: salt substitute group versus regular salt group: -7.96 mmol (-13.90 to -2.01)

     -- 24-hour potassium excretion: salt substitute group versus regular salt group: 16.93 mmol (14.87 to 18.99 mmol)

-- systolic blood pressure difference: salt substitute versus regular salt group: -2.05 mmHg (-3.03 to -1.08 mmHg)

 

-- a total of 2735 recurrent strokes occurred during the follow-up

    -- 691 strokes were fatal, 2044 were nonfatal

-- a total of 3242 deaths were recorded

 

-- recurrent strokes, per salt groups:

    -- salt substitute group: 16.8% (1295 of 7703)

    -- regular salt group: 19.1% (1440 of 7546)

        -- 14% fewer in those on salt substitute, RR 0.86 (0.77-0.95), p=0.005

            -- hemorrhagic strokes: 5.2 vs 7.5 events per 1000 person-yrs; 30% reduction, RR 0.70 (0.56-0.87), p=0.002

            -- recurrent undetermined strokes: 4.5 vs 5.8 per 1000 person-yrs; 21% reduction, RR 0.79 (0.62-0.99), p=0.04

            -- recurrent ischemic strokes: 26.3 vs 28.3 per 1000 person-yrs; 8% fewer but not statistically significant, RR 0.92 (0.81-1.04), p=0.11

 

-- Death rates, per salt groups:

    -- salt substitute group: 1549 (20.%)

    -- regular salt group: 1693 (22.4%)

        -- 12% fewer in those on salt substitute, RR 0.88 (0.82-0.96), p=0.003

-- deaths from vascular causes:

    -- salt substitute group: 915 (11.9%)

    -- regular salt group: 999 (13.2%)

        -- 12% fewer in those on salt substitute, RR 0.88 (0.79-0.99), p=0.03

-- deaths from non-vascular causes:

    -- salt substitute group: 263 (3.4%)

    -- regular salt group: 294 (3.9%)

        -- 13% fewer but not statistically significant, RR 0.87 (0.72-1.04), p=0.12

--stroke-related deaths:

    -- salt substitute group: 312 (4.1%)

    -- regular salt group: 379 (5.0%)

        -- 21% fewer, RR 0.79 (0.67-0.95), p=0.01

 

-- of note,  the relative protective effect of the salt substitute was evident within the first year, and for recurrent strokes by about the 6 month mark and benefit persisted for the rest of the study

-- subgroup analyses: no significant difference for recurrent stroke or total mortality by age, sex, educational backround, BMI, BP, diabetes, and antihypertensive meds used at baseline

-- no significant difference in terms of hyperkalemia, RR 1.01 (0.74-1.38), p=0.96

Commentary:

-- approximately ½ of US adults have hypertension, and excessive sodium intake can be responsible for the development of hypertension and its downstream effects on cardiovascular, renal, and other major consequences

-- although a meta-analysis of 37 studies in 14 countries found a stroke recurrence rate of 10.4% at one year and 14.8% at five years, the rate of strokes in China are statistically significantly higher at 17% at one year and 41% at five years

    -- stroke is the major killer and cause of disability in rural China

-- a 2021 prior SSaSS study of more people (20,995) from the 600 villages who had a stroke or were >60yo and had hypertension found that the overall rate of stroke and several cardiovascular outcomes (death from vascular causes, nonfatal acute coronary syndromes, and nonfatal strokes) were decreased with this salt substitute (though the rate of nonfatal strokes was not quite statistically significant): https://gmodestmedblogs.blogspot.com/2021/09/hypertension-salt-substitute-dec-risk.html

    -- this current SSaSS substudy was limited to those people who had had a previous stroke, finding that after 61.2 months, those taking salt substitute had a reduced risk of recurrent events for total strokes (both fatal and nonfatal stroke), as well as reduced risks of death, driven by a protective effect on vascular events

    -- the absolute event rate of stroke recurrence was decreased 5.5 per 1000 person-years with a 14% relative risk reduction. the benefit was especially significant for reducing hemorrhagic strokes and stroke-related deaths, two of the worst outcomes

    -- the absolute event rate of all-cause mortality was decreased by 5.8 per 1000 person-years with a 12% relative risk reduction

 -- a post-hoc analysis of the SSaSS trial of cause-specific cardiovascular outcomes (documenting 695 acute coronary syndromes, 454 heart failure events, and 230 arrhythmia events) found that all had reduced rates in those in the salt substitute group: https://www.ahajournals.org/doi/10.1161/HYPERTENSIONAHA.123.22410

-- many studies have shown that reducing dietary sodium and increasing dietary potassium lowers blood pressure, that these changes are synergistic, and that salt substitutes reduce blood pressure in the long-term and across diverse population groups (eg, see https://gmodestmedblogs.blogspot.com/2018/08/sodium-and-potassium-in-hypertension.html )

 -- this SSaSS study found a small decrease in systolic blood pressure of 2.05 mmHg, consistent with the degree of changes found in the 24-hour urinary sodium and potassium excretions

    -- the authors of this  current study note that this small decrease in systolic blood pressure is overall consistent with their clinical outcomes, with meta-analyses finding that a 1 mmHg decrease in systolic blood pressure was associated with a 5% decreased risk of stroke...

        -- but, this meta-analysis was based on patients with initially quite high systolic BPs (in the 160-190 mmHg range) and not on medications:  https://doi.org/10.2337/dc11-s245

        -- i am really not sure how to square these numbers with the current study: at baseline this current SSaSS study had 85% of the patients having hypertension (mean 148/87) and 76% on antihypertensive meds, without any information of what the baseline untreated blood pressure was or how long they were on hypertension meds, and therefore the applicability of the 1mm decrease in systolic BP leading to a 5% decreased stroke risk is unclear

        -- in addition, the stroke risk in the SSaSS study is actually higher than in this meta-analysis since enrollees had a prior stroke

        -- on the other hand, a different study did find a significant 5mmHg decrease in systolic BP was associated with a 10% decreased risk of cardiovascular disease, both in those with and without a history of cardiovascular disease and not related to the initial SBP, and it seemed to be a linear relationship (https://pmc.ncbi.nlm.nih.gov/articles/PMC9288358/ )

            -- however, the quoted study in the article found that a 1mmHg decrease in systolic BP was associated with a 5% decrease in strokes; this last study found a 5mmHg decrease in systolic was associated with a 10% decreased risk in overall cardiovascular disease (effectively equivalent to a 1mm decrease in systolic associated with a 2% decrease in clinical events). this study comparison assumes linearity of the relationships, and that the decreases in non-stroke cardiovascular diseases was similar to the stroke ones in the study (which was found in the post-hoc analysis of the SSaSS study mentioned above

 Relevant other studies:

-- a report based on NHANES data on dietary sodium intake among persons at least 19yo in the US found that at least 86% consumed more sodium than the recommended intake of no more than 2,300 mg/d:  https://www.cdc.gov/mmwr/volumes/70/wr/mm7042a4.htm

-- a prior CDC report stratified patients by those who should have sodium consumption under the 2300 mg/d limit and those who should consume <1500 mg/d (older than 50yo, persons with hypertension, diabetes or chronic kidney disease), finding that the mean sodium intake was essentially the same (3,264mg/d in those on the 1500 mg/d and 3,512mg/d in those in the 2,300 mg/d group): https://www.cdc.gov/mmwr/preview/mmwrhtml/mm6041a1.htm

    -- these studies reinforce that it is really hard on a population level to decrease sodium consumption, given the cultural issues of food preparation, long-standing habits, the promotion of foods high in salt (the highly developed attractive flavors of potato chips, etc, as well as the over-salted foods in restaurants). All of this reinforces that the actually viable public health intervention is likely to be a harm reduction one of using salt substitutes. The balance of sodium and potassium might be different in different areas, per the local approaches to cooking/consuming foods, and the optimal sodium/potassium balance may be different in different areas

-- there is some controversy about the actual role of sodium in disease, with clinical concerns about decreasing the intake to less than 2300 mg/d: https://gmodestmedblogs.blogspot.com/2013/11/dietary-sodium-and-disease.html

-- an Institute of Medicine report found that there is a complex relationship between sodium consumption and adverse cardiovascular events: https://gmodestmedblogs.blogspot.com/2016/05/blood-pressure-and-low-sodium-diet.html

 

Limitations:

-- This study was done in rural areas of China, where there typically is a lack of sufficient health care resources and significant financial constraints. Diets there typically have very high sodium intake and low potassium intake, likely attributable to low consumption of fresh fruit and vegetables. In addition, those people who had had a prior stroke likely had increased cardiovascular vulnerability related to socioeconomic and health care-related factors.  All of this limits the generalizability of the study and results to other populations

-- this was an open-label study (concealment of the intervention was not feasible), though the outcomes were independently adjudicated

-- since the study was a secondary subgroup analysis, the results have less statistical rigor and should be considered exploratory. However, as they note, the sample was large (72.6% of the overall trial participants) and is consistent with other studies

-- not much granular data on stroke duration, stroke severity, specifics of dietary intake, physical activity, functional level, family support, community support, education, income, medications taken, medical comorbidities, etc.  These factors might well influence the outcomes of the study and limit generalizability

 

so,

-- impressive study finding that using the salt substitute (75% sodium and 25% potassium) was associated with decreased stroke risk in patients who had had a stroke and were therefore at higher risk for a recurrent stroke

-- the decreased recurrent stroke risk was largest for hemorrhagic strokes and stroke deaths, the ones with the overall worst prognoses

-- there was no increase in serum potassium levels, reinforcing the safety of substituting a mixed sodium/potassium substitute salt (high potassium salt seems to have a rather unpleasant taste characterized as having a bitter, chemical or metallic aftertaste)

-- we do know from population-based US studies that strong CDC recommendations to limit salt consumption, as noted above, have had minimal effects

    -- this supports the conclusion that once people are on a high-salt diet, it is not easy to significantly decrease sodium consumption even to the higher recommended 2300 mg/d of dietary sodium (this was confirmed in another Chinese study)

    -- which therefore supports the conclusion that it is likely much easier to use a salt substitute, such as the 75%/25% mix in this study, than just attempting to engage patients in the difficult endeavor of just decreasing salt 

    -- it would be very useful to have studies on the benefits of different levels of salt substitutes on acceptability to other populations (ie, taste) and benefits on actual clinical outcomes (eg, cardiovascular ones), and both in those with and without prior cardiovascular events.

        -- a 2024 South African study found that a 50% potassium chloride salt substitute tasted just fine (see htn salt substitute taste S AfricaNutrMetabCardio2024 in dropbox, or doi.org/10.1016/j.numecd.2023.12.015)

-- and the intervention of using salt substitute is a remarkably inexpensive one and does not rely on lots of money needed for research and development… (and it does not add to the coffers of the remarkably profitable drug companies....)

 

geoff

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