Clinical Context

Replacing sodium chloride with potassium chloride has been demonstrated to have salutary effects on blood pressure, and these effects inspired Neal and colleagues to conduct a randomized trial of salt substitute featuring 75% sodium chloride and 25% potassium chloride vs traditional salt with 100% sodium chloride. The study involved 20,995 participants in more than 600 villages in rural China, and the results of this study were published in the September 16, 2021, issue of the New England Journal of Medicine.^[1] Participants were at least 60 years of age and had a history of hypertension and stroke.

The salt substitute cohort experienced an odds ratio (OR) of 0.86 (95% confidence interval [CI], 0.77-0.96) for recurrent stroke, 0.87 (95% CI, 0.80-0.94) for cardiovascular events, and 0.88 (95% CI, 0.82-0.95) for mortality. Moreover, the salt substitute was not associated with higher rates of hyperkalemia compared with traditional salt.

This trial was one of the most important studies of salt substitute to date. The current meta-analysis provides a broad overview of the effects of salt substitutes on important outcomes.

Study Synopsis and Perspective

Dietary salt substitutes not only lower blood pressure but also have a clear effect on hard clinical endpoints, lowering the risk for myocardial infarction (MI), stroke, death from all causes, and cardiovascular disease (CVD), a meta-analysis shows.

The blood pressure–mediated protective effects of salt substitutes on CVD and death are likely to apply to the roughly 1.28 billion people around the world who have high blood pressure, the researchers say.

"These findings are unlikely to reflect the play of chance and support the adoption of salt substitutes in clinical practice and public health policy as a strategy to reduce dietary sodium intake, increase dietary potassium intake, lower blood pressure and prevent major cardiovascular events," they write.

The study was published online August 10 in Heart.^[2]

In salt substitutes, a proportion of sodium chloride is replaced with potassium chloride. Salt substitutes are known to help lower blood pressure, but less is known about their effect on hard clinical endpoints, Maoyi Tian, PhD, from Harbin Medical University, Harbin, China, and the George Institute for Global Health, Sydney, Australia, and colleagues note in their article.

In the landmark Salt Substitute and Stroke Study (SSaSS), salt substitutes cut the risk for MI, stroke, and early death, as reported previously by theheart.org | Medscape Cardiology.^[3]

But SSaSS was conducted in China, and it was unclear whether these benefits would apply to people in other parts of the world.

To investigate, Dr Tian and colleagues pooled data from 21 relevant parallel-group, step-wedge, or cluster randomized controlled trials published through August 2021, with 31,949 participants. The trials were conducted in Europe, the Western Pacific Region, the Americas, and South-East Asia and reported the effect of a salt substitute on blood pressure or clinical outcomes.

A meta-analysis of blood pressure data from 19 trials that included 29,528 participants showed that salt substitutes lowered systolic blood pressure (SBP) by 4.61 mm Hg (95% CI, −6.07 to −3.14) and diastolic blood pressure (DBP) by 1.61 mm Hg (95% CI, −2.42 to −0.79).

The proportion of sodium chloride in the salt substitutes varied from 33% to 75%; the proportion of potassium ranged from 25% to 65%.

Each 10% lower proportion of sodium chloride in the salt substitute was associated with a 1.53 mm Hg (95% CI, −3.02 to −0.03; P=.045) greater reduction in SBP and a 0.95 mm Hg (95% CI, −1.78 to −0.12; P=.025) greater reduction in DBP.

Reductions in blood pressure appeared consistent irrespective of country, age, sex, history of high blood pressure, weight, baseline blood pressure, and baseline levels of urinary sodium and potassium.

Pooled data on clinical outcomes from 5 trials that included 24,306 participants, mostly from the SSaSS, and showed clear protective effects of salt substitutes on total mortality (risk ratio [RR], 0.89; 95% CI, 0.85-0.94), CV mortality (RR, 0.87; 95% CI, 0.81-0.94), and CV events (RR, 0.89; 95% CI, 0.85-0.94).

Dr Tian and colleagues write, "Broader population use of salt substitute is supported by the absence of any detectable adverse effect of salt substitutes on hyperkalaemia in this review."

They note, however, that all of the trials took "pragmatic steps to exclude participants at elevated risk of hyperkalaemia, seeking to exclude those with chronic kidney disease or using medications that elevate serum potassium."

Offering perspective on the study, Harlan Krumholz, MD, from Yale New Haven Hospital and Yale School of Medicine, New Haven, Connecticut, said it provides "useful information by bringing together the trial evidence on salt substitutes. The evidence is dominated by the SSaSS, but the others add context."

Dr Krumholz said that at this point, he thinks salt substitutes "could be included in recommendations to patients.

"SSaSS was conducted in villages in China, so that is where the evidence is strongest and most relevant, but this is a low-cost and seemingly safe strategy that could be tried by anyone without contraindications, such as kidney disease or taking a potassium-sparing medication or potassium supplement," Dr Krumholz told theheart.org | Medscape Cardiology.

Johanna Contreras, MD, heart failure and transplant cardiologist at the Mount Sinai Hospital in New York, agrees that in the absence of contraindications, salt substitutes should be recommended.

"Americans put salt on everything and don't even think about it. The salt substitutes are very helpful," Dr Contreras told theheart.org | Medscape Cardiology.

"People who don't have high blood pressure should limit salt intake because what we have seen is that if you have high blood pressure in your family--even if you don't have high blood pressure in your 20s or 30s--you're likely to develop high blood pressure," Dr Contreras said.

"Therefore, it's wise early on to start protecting yourself and using low salt and salt substitutes," she added.

The study had no specific funding. Dr Tian, Dr Krumholz, and Dr Contreras have disclosed no relevant financial relationships.

Heart. Published online August 10, 2022.

Clinical Implications

• This previous randomized controlled trial demonstrated that a salt substitute cohort was associated with a reduction in the risks for stroke, cardiovascular events, and mortality of 12% to 14%. Moreover, the salt substitute was not associated with higher rates of hyperkalemia compared with traditional salt.
• In the current meta-analysis, salt substitute was associated with reductions in SBP and DBP in all subgroups studied. Based largely on the results of 1 trial in a high-risk population, salt substitute was associated with lower risks for cardiovascular events and all-cause mortality.
• Implications for the healthcare team: The healthcare team should advocate for the use of salt substitute among patients at elevated risk for cardiovascular events.

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