Massive SSaSS Study Shows Switch to Salt Substitute Cuts Stroke, CVD

(UPDATED) Use of a salt substitute appears to be a simple, low-cost intervention that can cut the risk of stroke, major cardiovascular events, and all-cause mortality in older adults with a history of stroke or high blood pressure, a new study suggests.

In the Salt Substitute and Stroke Study (SSaSS), an open-label, cluster-randomized trial conducted across 600 villages in rural China, the salt stand-in lowered the risk of stroke by 14% and cut the risk of major adverse cardiovascular events by 13% when compared with normal salt use. In addition, the risk of all-cause mortality was slashed by 12% among those who used the salt substitute. 

Importantly, the dietary switch was safe and well tolerated, with investigators observing no evident risk of clinical hyperkalemia.  

“There’s about 10 million major adverse cardiovascular events each year in China,” said lead investigator Bruce Neal, MD (George Institute for Global Health, Sydney, Australia), during a press conference announcing the results. “Last year, a study was done modeling the effect of salt substitution and estimated that about 10%, or 1 million, of these events could be avoided each year. Our study now confirms that benefit and suggests the benefit might be slightly greater.”

A key question is whether the results from SSaSS, which was presented during the Hot Line session at the European Society of Cardiology (ESC) Congress 2021 and published simultaneously in the New England Journal of Medicine, can be generalized to other populations. Neal has little doubt they can. 

“The way the body manages sodium, potassium, and the associations with blood pressure are highly constant across diverse populations around the world,” he said. “Almost certainly, everyone, except the few people with serious kidney disease, who should be avoiding salt anyway, could switch to using a salt substitute and expect to see some sort of benefit.” 

Barbara Casadei, MD, DPhil (University of Oxford, England), who moderated the Hot Line session, was very enthusiastic in her praise of the trial, particularly the magnitude of benefit in this pragmatic study of high-risk patients. “Sometimes there is advantage in having a limited budget,” she said. “You really focused on the essentials, and you got a fantastic result.”

Similarly, Bryan Williams, MD (University College London, England), the discussant who followed Neal’s presentation, congratulated the SSaSS investigators for their trial, saying it was “probably the most important study for public health at the [ESC] meeting, and indeed, probably for many meetings to come—it’s a really powerful message from this study.”    

Williams noted that the role of dietary salt in cardiovascular disease is frequently debated at cardiology meetings, often in fractious terms and particularly as it relates to health policy. While all the major guidelines recommend reducing the amount of salt in the diet, mainly because it lowers blood pressure, the present study shows that reducing dietary salt leads to a reduction in major cardiovascular events, said Williams. “Those who doubted the potential benefits of salt restriction in terms of cardiovascular disease prevention must now conclude that they were wrong,” said Williams. “Really, the debate stops here. The data is in. Now, global public health interventions are needed to implement these incredibly important findings.”

Salim Yusuf, MBBS, DPhil (McMaster University/Population Health Research Institute, Hamilton, Canada), who has waded into the salt wars and previously debated the appropriate amount of sodium in the diet, also called SSaSS an “important study” with excellent results. Nonetheless, he said it needs to be considered carefully. Primarily, he highlighted the population studied, noting that the relationship between elevated sodium intake and risk of CVD is particularly strong in these higher-risk patients, but less so in those without hypertension or younger individuals. 

“This is a highly selected group,” said Yusuf, referring to the SSaSS participants. “It’s a population that is extremely sensitive to the effects of this kind of salt. I would say we shouldn’t, at the moment, extrapolate this beyond the types of people that were studied.” 

Additionally, he noted the mean intake of sodium at baseline among those studied was 4.3 g, which is higher than it is in North America where daily sodium intake is roughly 3.5 g per day. “So, it’s unclear that the results can be applied to North America, Western Europe, or to many regions of the world where sodium intake is lower,” Yusuf told TCTMD. It would be of “great interest” to see if a similar salt-substitution study conducted in a Western population would yield the same reduction in stroke, mortality, and MACE, he added. 

Reducing Stroke, MACE, and Mortality

The large pragmatic SSaSS study included 20,995 participants who had a history of stroke or who were 60 years or older and had poorly controlled blood pressure (systolic BP ≥ 140 mm Hg if treated with antihypertensive medication or ≥ 160 mm Hg if untreated). The mean duration of follow-up was 4.74 years.  

Regarding the primary stroke endpoint, there were 29.14 events per 1,000 person-years in the salt-substitute arm compared with 33.65 strokes in those who continued to use regular salt, a statistically significant difference (P = 0.006). There were 6.78 fatal strokes per 1,000 person-years in the intervention arm compared with 8.79 fatal strokes in the regular salt users (RR 0.77; 95% CI 0.65-0.91). Regarding MACE, there 49.1 events vs 56.3 events per 1,000 person-years in the salt substitute and regular salt groups, respectively (P < 0.001). There was also a reduction in nonfatal ACS (RR 0.70; 95% CI 0.52-0.93) and, as noted, a decrease in all-cause mortality (RR 0.88; 95% CI 0.82-0.95).

Really, the debate stops here. Bryan Williams

Overall, there was no difference in the incidence of definite, probable, or possible hyperkalemia between the two groups (3.35 events with the salt substitute vs 3.30 events with regular salt per 1,000 person years; P = 0.76). Additionally, there was no evidence of sudden cardiac death, which might arise from arrhythmias caused by hyperkalemia, said Neal. 

The salt substitute is composed of 70% sodium chloride (NaCl) and 30% potassium chloride (KCl), which differs from regular salt which is 100% NaCl. Participants in the study were provided with the salt substitute and advised to use it instead of regular salt for cooking, seasoning, and food preservation. 

“The rationale for salt substitutes is that both high dietary sodium consumption and lower dietary potassium consumption are associated with elevated blood pressure levels,” said Neal. “Potassium-enriched salt substitutes have a dual blood pressure-lowering effect because they take sodium out of the diet and put extra potassium into it. Before SSaSS, we had pretty good evidence that salt substitutes reduce blood pressure, but we lacked data about benefits on strokes and heart attacks.”

To TCTMD, Yusuf noted that the reduction in sodium was relatively small—around 8%—whereas the increase in potassium was in the range of 50% to 60%. “While it’s not easy to dissect out whether the lower sodium or the higher potassium was responsible for benefits, the likelihood is that both contributed but the major contribution came from the increased potassium,” he said.   

In the discussion, Williams also noted that the substitute resulted in only modest sodium restriction, which translated into a reduction in dietary sodium of approximately 1 g per day. While he also noted that it’s difficult to determine whether the sodium decrease or potassium increase contributed most to the reduction in stroke and MACE, Williams said that point is irrelevant.   

“Quite frankly, it doesn’t really matter because this is the intervention that works,” said Williams. He noted that most of discretionary salt use tends to occur in some of the world’s poorest regions which makes the implications of a cheap intervention “enormous.” 

Mahmoud Al Rifai, MD (Baylor College of Medicine, Houston, TX), congratulated the researchers for performing SSaSS, noting that dietary trials are extremely difficult to conduct. He pointed out that the absolute reduction in the risk of stroke, around 2%, is on par with that seen for the primary endpoint in the IMPROVE-IT study with ezetimibe. 

“You’re getting almost a similar result with a dietary salt substitute,” he said. Also, the primary endpoint in SSaSS, Al Rifai added, is a “very morbid outcome, one that changes quality of life for a long time.” The reductions in stroke, as well as the reductions in MACE and all-cause mortality, is commensurate with the 3.3-mm Hg mean difference in systolic blood pressure between the two treatment arms, he said. 

In terms of public health, he suspects the intervention could have the largest societal impact in countries or communities where access to medication is limited. 

“I think it’s a major win,” said Al Rifai. “In those high-risk populations, just a simply dietary modification would be expected to have a major benefit.” As for whether the results could be extrapolated to populations outside China, “I don’t see why not,” he said. “Genetically, I don’t see any reasons why the same benefit seen in China wouldn’t also be translated to Caucasians, African Americans, Hispanic Americans, or others.” 

Discretionary Salt Use

Though Neal said that virtually everyone could benefit from a salt substitute, the largest benefit would be seen in countries where people use a lot of discretionary salt, such as that used for cooking, preservation, or seasoning, rather than in countries were the bulk of sodium intake comes in the form of salty, processed foods. Estimates suggest that there are more than 5 billion in the world who consume more than 50% of dietary salt through discretionary use. “These people would stand to get significant health benefits from switching to a salt substitute,” said Neal. 

Salt substitutes cost roughly 50% more than regular table salt, but Neal said the price differential over a given year wouldn’t be too burdensome for the majority of the planet to make the switch. From a policy standpoint, he said governments should take action to promote substitutes instead of salt, either through taxes or warning labels on salt, or possibly through subsidies for salt-substitute manufacturers.

Philip Joseph, MD (Hamilton General Hospital/Population Health Research Institute, Canada), who wasn’t involved in the study, pointed out that one of the United Nations’ Sustainable Development Goals is to reduce premature mortality from noncommunicable diseases by one-third by 2030. 

“The only way to achieve these goals at the global level is to really find effective ways that can reduce cardiovascular disease and fatal cardiovascular disease,” said Joseph. “Most cardiovascular disease now occurs in high- and middle-income countries so we need strategies that are applicable in those resource settings. Things that are widely applicable, low-cost, and easy-to-implement are probably the best way at the population level that we’re going to reduce cardiovascular disease risk.” 

At least in this population of older patients with prior stroke or elevated blood pressure, the salt substitute is quite effective and low cost, said Joseph. Similarly, the polypill strategy, which Neal and Yusuf have both been involved in testing, is another low-cost, easy-implementable intervention. Yusuf made a similar point. The SSaSS study, along with their data from several fixed-dose combination-treatment trials—TIPS-3, HOPE-3, and PolyIran—emphasize that relatively simple interventions can have large benefits on CVD outcomes, he said. 

In an editorial, Julie Ingelfinger, MD, deputy editor of the NEJM, calls the SSaSS results “impressive.” If the approach proves feasible over time, it could have a large public health impact in China “and possibly, elsewhere,” she predicts. Like Yusuf, she cautions that patients in the study were high risk—73% had a previous stroke and 88% had a diagnosis of hypertension—so generalizability to other populations or other countries is difficult.