hypertension: salt substitute dec risk of stroke

 A large Chinese trial found that using salt substitutes with a high potassium level not only lowered blood pressure but decreased the risk of stroke, major cardiovascular events, and death from any cause, in the Salt Substitute and Stroke Study (SSaSS): see htn salt substitute china nejm2021 in dropbox, orDOI: 10.1056/NEJMoa2111437

 

Details: 

-- 20,995 people were involved in an open-label, cluster-randomized trial from 600 villages in rural China, with the goals of recruiting approximately 35 persons from each village and to follow them for five years 

-- all had a history of stroke or were >60yo and had hypertension, the latter defined as systolic blood pressure >140 mmHg if on blood pressure lowering medication or >160 mmHg if not

-- exclusion criteria included known serious kidney disease, use of a potassium sparing diuretic, or use of a potassium supplement

-- mean age 65 years, 50% female, 73% history of stroke, 88% history of hypertension 

-- mean blood pressure 154/89 mmHg, 79% were on at least one blood pressure medication (42% CCB, 23% ACE or ARB, 12% diuretic, 6% beta blocker, 1% alpha blocker) 

-- mean baseline 24-hour urinary sodium excretion was 4.3 g (slightly above the average global intake), and mean 24-hour urinary potassium excretion was 1.4 g 

-- intervention: using a salt substitute (75% sodium chloride and 25% potassium chloride) versus control group (regular salt, 100% sodium chloride), with sufficient salt provided for an average of 20 g per person per day 

-- follow up at six-month intervals 

-- primary outcome: stroke 

-- secondary outcomes: major adverse cardiovascular events (a composite of nonfatal stroke, nonfatal acute coronary syndrome, or death from vascular causes) and death from any cause 

-- safety outcomes: hyperkalemia, and sudden death 

-- the trial was scheduled to be completed in the first quarter of 2020 but was delayed until the first quarter of 2021 because of the Covid-19 pandemic, though use of the assigned salt substitute versus regular salt was continued during this period 

-- 15,130 of the participants were seen face-to-face at the scheduled final follow-up visit 

-- mean and median durations of follow-up were 5 years 

-- 92% of the participants in the salt substitute group and 6% in the regular salt group reported using a salt substitute  

 

Results: 

-- mean difference, comparing those on salt substitute vs regular salt:  24-hour urinary sodium excretion was 350 mg less; 24-hour urinary potassium excretion was 803 mg more

-- blood pressure: 

    -- systolic blood pressure: mean difference -3.34 mmHg in the group on salt substitute (-4.51 to -2.18 mmHg) 

    -- diastolic blood pressure: mean difference -0.67 mmHg (-1.39 to 0.05) 

-- rate of stroke: 

    -- salt substitute: 29.14 events per 1000 person-years 

    -- regular salt: 33.65 events per 1000 person-years 

        -- 14% decrease, rate ratio 0.86 (0.77-0.96), p=0.006 

    -- these results were consistent for all of the subgroups assessed (age >65 vs <65; sex; education level; presence of cerebrovascular disease; diabetes; antihypertensive drug use; systolic blood pressure greater than versus less than 153 mmHg; diastolic blood pressure greater than versus less than 89 mmHg; BMI greater than or less than 24.6) 

-- major cardiovascular events 

    -- salt substitute: 49.09 events per 1000 person-years 

    -- regular salt: 56.29 events per 1000 person-years 

    -- 13% decrease, rate ratio 0.87 (0.80-0.94), p<0.001 

-- breakdown of cardiovascular events: 

    -- death from vascular causes: 22.9 versus 26.3 events per 1000 person-years, 13% benefit, rate ratio 0.87 (0.79-0.96) 

    -- nonfatal acute coronary syndrome: 3.8 versus 5.1 events per 1000 person-years, 30% benefit, rate ratio 0.70 (0.52-0.93) 

    -- nonfatal stroke: 22.4 versus 24.9 events per 1000 person-years, strong trend to 10% benefit, rate ratio 0.90 (0.80-1.01) 

-- these results were evident within 12 months after the beginning of the study and the curves splayed apart somewhat over the five-year study 

-- serious adverse events attributed to the hyperkalemia: not significantly higher with salt substitute than with regular salt, 3.35 versus 3.30 events per 1000 person-years, rate ratio 1.04 (0.80-1.37), p=0.76. However, potassium levels were not routinely measured, and it was up to the researchers' best guess in many cases (there were only two participants who had definite or probable hyperkalemia, one in the salt substitute group and one in the regular salt group) 

-- no increase in sudden death risk 

 

Commentary: 

-- this study affirms that lower sodium/higher potassium intake by a salt substitute improves not only blood pressure but also decreases major cardiovascular events, and this was generally true across subgroups and prespecified exploratory outcomes. And there was no apparent association with serious adverse effects 

-- the results of the study are not surprising, since the known role of potassium in lowering hypertension dates back decades, as well as the role of sodium in increasing hypertension

    -- the Agency for Healthcare Research and Quality confirmed these observations, see http://gmodestmedblogs.blogspot.com/2018/08/sodium-and-potassium-in-hypertension.html 

    -- the 2015 nutrition guidelines similarly attest to the positive role of potassium in lowering blood pressure, referring to a systematic review on the benefits of potassium for both blood pressure and stroke prevention (see htn potassium lowers BP bmj 2013 in dropbox, or doi: 10.1136/bmj.f1378), noting the dramatic decrease in potassium intake in modern society, see http://gmodestmedblogs.blogspot.com/2015/02/new-nutrition-draft-guidelines.html 

-- the only really surprising thing to me is that clinicians in general, at least in the United States, seem to focus more on sodium restriction (which is remarkably hard to do in our society, our efforts are largely unsuccessful, and only is useful for the salt-sensitive individuals) as opposed to potassium augmentation, as found in many of the myriad of salt substitutes on the market 

-- though I should mention that there are questions as to what the appropriate target for sodium restriction is, see the Institute of Medicine report in 2013: http://gmodestmedblogs.blogspot.com/2013/11/dietary-sodium-and-disease.html 

-- the effects on blood pressure found in the study were consistent with the measured 24-hour urinary sodium and potassium excretion 

-- other nonpharmacologic approaches to hypertension, with huge number of studies in the literature, have found benefit from stress relief (a multitude of studies showing that acute stressors lead to significant transient increases in blood pressure and that chronic stressors are associated with increased hypertension as well as increased left ventricular mass on echocardiogram; and social support systems mitigate some of these hypertensive effects), diet (eg, see http://gmodestmedblogs.blogspot.com/2018/12/mediterranean-diet-dec-cad-and.html ), and exercise even in those with resistant hypertension (see https://www.ahajournals.org/doi/10.1161/hypertensionaha.112.197780 ).

-- by their calculation in this study, the use of salt substitute in China would lead to 365,000 fewer strokes, 461,000 fewer premature deaths, and 1,204,000 fewer vascular events 

 

Limitations: 

-- this study was limited to rural Chinese people, and may not be generalizable to a more diverse or urban population 

-- this study was also limited to those with a history of stroke or at least 60 years of age with hypertension, potentially limiting generalizability to hypertensive people without a stroke and younger than that age 

-- there were no routine measurements of serum potassium levels in the study 

-- there was no imperative to avoid other medications causing increased potassium including beta blockers, trimethoprim/sulfamethoxazole, or the array of lesser used medications associated with hyperkalemia 

-- there was likely incomplete adherence to the use of salt substitute (e.g. from consumption of regular salt outside the home, adding salt when the allotment of salt substitute was inadequate, use of salt substitute in the control group), which might have attenuated the treatment effects (though the 24-hour urinary excretion of potassium was higher in the salt substitute group, this measurement reflects the consumption of sodium/potassium just for that day and may not be a stable assessment for the study duration)

-- although patients with serious kidney disease were excluded, this was all by patient report, and subject to bias 

    -- and there was no clinical data to support either the presence or extent of kidney disease

-- they only tested one salt substitute (25% potassium chloride, 75% sodium chloride), and there would likely be differences with alterations of this ratio 

 

So, the reason I bring up this study is to reinforce that there are important nonpharmacologic approaches to hypertension control, specifically around diet (including potassium...), exercise, stress relief/support systems. There are many very inexpensive salt substitutes with differing amounts of potassium on the market, and though some of my patients have not liked the taste of the pure potassium ones, mixtures are often well tolerated. 

Addendum to yesterday's blog on ACE-I vs ARB's (http://gmodestmedblogs.blogspot.com/2021/09/hypertension-use-arbs-over-ace-i.html ), which i forgot to include:  losartan has the unique effect for ARBs to lower uric acid levels which may well be associated with cardioprotection.  see http://gmodestmedblogs.blogspot.com/2018/10/allopurinol-use-may-decrease-ckd.html for a blog on allopurinol decreasing CKD but a reference to several other blogs on uric acid/cardiac effects and an evolutionary perspective. losartan seems to be the best at lowering uric acid, though it seems that several calcium channel blockers are also effective, as noted in this blog (or see htn and uric acid losartan ccbs bmj 2012 in dropbox, or doi:10.1136/bmj.d8190)

geoff

 

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