Circulation

ORIGINAL RESEARCH ARTICLE

Cost-Effectiveness of a Household Salt

Substitution Intervention: Findings From 20 995
Participants of the Salt Substitute and Stroke Study
Ka-Chun Li, MSc; Liping Huang , PhD; Maoyi Tian , PhD; Gian Luca Di Tanna , PhD; Jie Yu , MD, PhD;
Xinyi Zhang, MPH; Xuejun Yin , MPH; Yishu Liu, MSc; Zhixin Hao, MD; Bo Zhou, PhD; Xiangxian Feng, PhD;
Zhifang Li, MSc; Jianxin Zhang, PhD; Jixin Sun, MSc; Yuhong Zhang, MMed; Yi Zhao, PhD; Ruijuan Zhang, MSc;
Yan Yu, PhD; Nicole Li, MD, PhD; Lijing L. Yan, PhD; Darwin R. Labarthe, PhD; Paul Elliott , MB, BS, PhD;
Yangfeng Wu , MD, PhD; Bruce Neal , MB, ChB, PhD; Thomas Lung , PhD*; Lei Si , PhD*

BACKGROUND: SSaSS (Salt Substitute and Stroke Study), a 5-year cluster randomized controlled trial, demonstrated that
replacing regular salt with a reduced-sodium, added-potassium salt substitute reduced the risks of stroke, major adverse
cardiovascular events, and premature death among individuals with previous stroke or uncontrolled high blood pressure living
in rural China. This study assessed the cost-effectiveness profile of the intervention.

METHODS: A within-trial economic evaluation of SSaSS was conducted from the perspective of the health care system and
consumers. The primary health outcome assessed was stroke. We also quantified the effect on quality-adjusted life-years
(QALYs). Health care costs were identified from participant health insurance records and the literature. All costs (in Chinese
yuan [¥]) and QALYs were discounted at 5% per annum. Incremental costs, stroke events averted, and QALYs gained were
estimated using bivariate multilevel models.
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RESULTS: Mean follow-up of the 20 995 participants was 4.7 years. Over this period, replacing regular salt with salt substitute
reduced the risk of stroke by 14% (rate ratio, 0.86 [95% CI, 0.77–0.96]; P=0.006), and the salt substitute group had on
average 0.054 more QALYs per person. The average costs ( ¥1538 for the intervention group and ¥1649 for the control
group) were lower in the salt substitute group (¥110 less). The intervention was dominant (better outcomes at lower cost)
for prevention of stroke as well as for QALYs gained. Sensitivity analyses showed that these conclusions were robust,
except when the price of salt substitute was increased to the median and highest market prices identified in China. The salt
substitute intervention had a 95.0% probability of being cost-saving and a >99.9% probability of being cost-effective.

CONCLUSIONS: Replacing regular salt with salt substitute was a cost-saving intervention for the prevention of stroke and
improvement of quality of life among SSaSS participants.

Key Words: cardiovascular diseases ◼ cost savings ◼ salts ◼ stroke

S
troke and ischemic heart disease are leading
contributors to premature death and disability in
China, accounting for 4.1 million deaths and 80.7
million disability-adjusted life-years in 2019.1,2 The iden-
tification of effective, cost-effective, and scalable inter-
ventions to address this disease burden is a public health
priority. High blood pressure caused by excess dietary
sodium consumption and inadequate dietary potassium

Correspondence to: Maoyi Tian, PhD, School of Public Health, Harbin Medical University, 157 Baojian Road, Nangang District, Harbin 150081, China. Email maoyi.
tian@hrbmu.edu.cn
*T. Lung and L. Si contributed equally.
This work was presented as an abstract at the American College of Cardiology Scientific Sessions, April 2–4, 2022.
Supplemental Material is available at https://www.ahajournals.org/doi/suppl/10.1161/CIRCULATIONAHA.122.059573.
Continuing medical education (CME) credit is available for this article. Go to http://cme.ahajournals.org to take the quiz.
For Sources of Funding and Disclosures, see page 1540.
© 2022 American Heart Association, Inc.
Circulation is available at www.ahajournals.org/journal/circ

1534 May 17, 2022 Circulation. 2022;145:1534–1541. DOI: 10.1161/CIRCULATIONAHA.122.059573

 Li et al
Clinical Perspective
What Is New?
• Household use of reduced-sodium salt substitute
compared with continued use of regular salt was a
cost-saving intervention for the prevention of stroke
and improvement of quality of life in individuals with
a high risk of stroke living in rural China.
• The cost-effectiveness of the household salt sub-
stitute intervention was sensitive to the cost of salt
substitute but robust to varying other parameters.
• This analysis provides the first direct evidence of
cost-effectiveness of household use of salt substi-
tute on cardiovascular outcomes.
What Are the Clinical Implications?
• Use of salt substitute by patients at high risk of car-
diovascular disease is a practical and cost-effective
way of reducing cardiovascular risk.
• The magnitude of the benefit will depend on how
much dietary salt is replaced with salt substitute
and the cost-effectiveness will depend primarily on
the price of the salt substitute.
Nonstandard Abbreviations and Acronyms
HSU health state utility
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QALY quality-adjusted life-year
SSaSS Salt Substitute and Stroke Study
consumption underlies much cardiovascular disease in
China.2 Average sodium intake in Chinese adults (4.1
g/d) is about double the recommended maximum intake
(2 g/d), and average potassium consumption (1.5 g/d) is
below half the recommended minimum (3.5 g/d).3,4
The beneficial effects on blood pressure of lowering
sodium intake5,6 or supplementing potassium consump-
tion7 are well established. Likewise, there is longstand-
ing evidence describing the blood pressure–lowering
effect of reduced-sodium added-potassium salt substi-
tutes.8 The recently completed SSaSS (Salt Substitute
and Stroke Study) has, for the first time, demonstrated
that salt substitution also lowers the risk of stroke, major
cardiovascular events, and death.9
On the basis of modeling studies, populationwide
sodium reduction is advocated by the World Health Orga-
nization as a “best buy” for the prevention of noncommu-
nicable diseases.10 Salt substitution in food production
may also be a cost-saving or cost-effective intervention
for the prevention of cardiovascular disease,11–13 but
previous model-based health economic analyses have
all relied on extrapolating effects on blood pressure to
reductions in clinical events. The cost-effectiveness of
household salt substitution on the basis of random-
Circulation. 2022;145:1534–1541. DOI: 10.1161/CIRCULATIONAHA.122.059573
Cost-Effectiveness of Salt Substitution
ized trials that assessed effects on major outcomes is
unknown. In this study, we evaluated the cost-effective-
ORIGINAL RESEARCH
ness profile of the salt substitute intervention in SSaSS.
ARTICLE
METHODS
Data access can be requested through a secure environment
aligned with China’s Cyber Security Law from Professor Bruce
Neal (bneal@georgeinstitute.org.au) 1 year after publication.
Study Design and Participants
We conducted a within-trial economic evaluation of SSaSS
from the joint perspective of the health care system and study
participants during the mean trial follow-up period of 4.74 years
accrued between July 2014 and June 2020. The joint per-
spective reflects health care costs paid by the system and out-
of-pocket health care costs and costs of regular salt and salt
substitute. Full details of the trial design and health economic
analysis plan are available in previous reports.14,15 Briefly, 600
villages selected from 10 counties in 5 provinces in northern
China participated in the study. The villages were randomly
assigned in a 1:1 ratio to the intervention group, in which
participants were provided with salt substitute, or the control
group, in which the participants continued the use of regular
salt. We collected 24-hour urine samples in a random subgroup
of the trial participants every 12 months. Study participants
were individuals at high risk of stroke on the basis of either a
history of stroke or age ≥60 years with uncontrolled high blood
pressure. Power calculations and sample size estimations have
been reported previously.14 There was 90% power (P=0.05)
to detect the effect on the primary stroke outcome assuming
a sample size of 21 000 participants, a 13% or greater rela-
tive risk reduction, 600 clusters, 35 participants in each clus-
ter, and an intracluster correlation coefficient of 0.04. The trial
received ethics approval from the University of Sydney Ethics
Committee (2013/888) and the Peking University Institutional
Review Board (IRB00001052-13069). Informed consent was
obtained from all participants.
Intervention and Comparator
In the intervention villages, participants were provided with salt
substitute free of charge in a sufficient quantity to replace all
use of regular salt for cooking, seasoning, and preserving foods
in the home. The quantity provided was an average of 20 g/d
for each person in the household.9 Intervention group partici-
pants were encouraged to use the salt substitute more spar-
ingly than they would have used regular salt and to avoid the
use of regular salt. Participants in the control villages continued
their daily use of regular salt.
Health Outcomes
The primary health outcome assessed in SSaSS was fatal
and nonfatal stroke and this outcome was the focus for this
analysis. Stroke outcomes were identified from face-to-face
interviews with participants or their carers and from searches
of routinely collected data held within the administrative data-
bases of the New Rural Cooperative Medical Scheme and the
National Mortality Surveillance System. Detailed data for all
potential outcome events were sought from multiple sources
May 17, 2022 1535
 Li et al Cost-Effectiveness of Salt Substitution

with review by an end point adjudication committee masked to Table 1. Key Health State Utility, Health Care Utilization,
treatment allocation to maximize the reliability of event iden- and Cost Data Used in the Analysis
ORIGINAL RESEARCH

tification and assignment of diagnoses. Only events deemed Parameters Values Reference
definite or probable were included in the primary analyses.9
ARTICLE

Baseline HSU, y, M/F 18

Quality-adjusted life-years (QALYs) were derived using the
EuroQol- 5 Dimension (EQ-5D), which measures health-related 25–34 0.997/0.998
quality of life in 5 dimensions: mobility, self-care, usual activities, 35–44 0.994/0.995
pain/discomfort, and anxiety/depression. The EQ-5D is recom- 45–54 0.990/0.990
mended for use in cost-effectiveness analysis in China.16 Serial
55–64 0.983/0.979
EQ-5D data were not collected in SSaSS, so health state util-
ity (HSU) data were drawn from the literature and combined 65–74 0.970/0.961
with disease states and survival time for each study participant. 75+ 0.936/0.920
Baseline HSU was randomly assigned by sex and age from a
HSU decrements, 1/6/12/24 months
β-distribution17 using EQ-5D-3 L norms for rural Chinese popula-
Ischemic stroke −0.19/−0.15/−0.15/−0.19 20
tions (Table 1).18 For individuals who experienced a cardiovascu-
lar event, an HSU decrement was applied according to the time Hemorrhagic stroke −0.23/−0.14/−0.17/−0.03
from the event (1 month, 6 months, 12 months, and 24 months; Undetermined stroke −0.27/−0.19/−0.23/−0.39
Table 1).19–21 For those who did not have a cardiovascular event
Myocardial infarction −0.20/−0.19/−0.18/−0.20 21
during the trial, sex-specific decrements associated with increas-
ing age18 were applied each year until the end of follow-up. Unstable angina −0.27/−0.25/−0.27/−0.27
Other acute coronary syndrome −0.23/−0.22/−0.22/−0.23
Price of salts, ¥/1 kg
Costs
Wholesale price, salt substitute 5.6 Trial audit
Health care costs comprised inpatient care costs, outpatient
visit costs, and outpatient medication costs. Inpatient costs for Wholesale price, regular salt 2.5

hospitalizations related to cardiovascular events were extracted  Market price, salt substitute 12.9* 31
from the New Rural Cooperative Medical Scheme data where (minimum, 6.5; maximum, 80.0)
available and included both the costs borne by the New Rural Outpatient visit costs, mean annual visit/average visit cost, ¥
Cooperative Medical Scheme as well as out-of-pocket pay- Ischemic stroke 1.58/456 23
ments made by the participant. For nonfatal events without cost
Hemorrhagic stroke 1.72/427
data in the New Rural Cooperative Medical Scheme, multiple
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imputation was used to estimate the missing information by Undetermined stroke 2.15/386
event type (nonfatal stroke or nonfatal acute coronary syn- Acute coronary syndrome 13.05/24.5 24
drome) using age, sex, province, and history of cardiovascular Outpatient medication costs, ¥/dose 27
disease and diabetes at baseline for the imputation process.
 CCB (minimum, 0.75; maxi- 1.74†
For fatal events that did not have cost records (2578/4172
mum, 2.36)
[61.8%]), we assumed these deaths occurred at home and
involved no inpatient cost in the base-case analysis.22  Antiplatelet agent (minimum, 2.47†
0.50; maximum, 5.38)
Outpatient visit costs were applied to individuals who had
nonfatal cardiovascular events with costs of services derived ARB or ACEI 0.37
from the literature (Table 1)23,24 and on the basis of event type  Statin (minimum, 0.51; maxi- 1.75†
and the number of consultations required until the comple- mum, 2.99)
tion of participant follow-up. Outpatient medication costs were Diuretic 0.15
estimated on the basis of data about the use of main cardio- β-Blocker 1.05
protective medication classes collected for living study partici-
pants during the final follow-up and supplemented with data ACEI indicates angiotensin-converting enzyme inhibitor; ARB, angiotensin
receptor blocker; CCB, calcium channel blocker; HSU, health state utility; and
about recommended regimens defined by Chinese cardiovas-
¥, Chinese yuan.
cular prevention guidelines.25,26 Unit prices were taken from *Median market price of salt substitute in China.
the National Essential Medicines List in China,27 and where a †Mean price of medications.
medicine class had more than 1 cited price, the mean was used
(Table 1). For those who experienced nonfatal events and had The unit cost of salt substitute was drawn from the procure-
missing outpatient medication data, the weighted average cost ment contract with the local manufacturer in each province
was used. Outpatient medication costs were calculated until and the cost per participant was calculated on the basis of the
the end of the trial period or before death. average daily quantity supplied per participant (20 g)9 until the
Intervention costs were the cost of salt substitute and the end of the trial period or death. The cost of regular salt for
cost of supporting health promotion materials. Salt substitute the control group was calculated using the same assumptions
was provided free of charge for the household in SSaSS but to except that the unit cost was obtained from the national price
reflect the most likely implementation of a future salt substitu- surveillance system. The unit cost of health promotion materials
tion program (in which consumers buy salt substitute instead of for the intervention group was determined from trial records.
regular salt), the cost of salt substitute was calculated on a per- All costs were converted using the consumer price index and
participant basis and added to the overall cost of intervention. presented in 2014 Chinese yuan (¥; Table 1).

1536 May 17, 2022 Circulation. 2022;145:1534–1541. DOI: 10.1161/CIRCULATIONAHA.122.059573

 Li et al Cost-Effectiveness of Salt Substitution

Statistical Analysis Table 2. Baseline Characteristics

ORIGINAL RESEARCH
Incremental cost-effectiveness ratios were calculated as the Regular Salt substi-
additional cost per stroke averted and per QALY gained dur- salt group tute group Total
Characteristics (n=10 491) (n=10 504) (n=20 955)

ARTICLE
ing the trial. A willingness to pay threshold value for QALY
equivalent to the gross domestic product per capita in China Age, y 65.5 (8.5) 65.2 (8.5) 65.4 (8.5)
(¥64 957 in 2020) was used as a recommended indicator of Female 49.2 49.7 49.5
cost-effectiveness.16 An annual discount rate of 5% was used
Salt intake, g/d
for costs and QALYs in the base-case analysis.16 Incremental
costs, strokes averted, and QALYs gained were estimated Urinary sodium 4.2 (1.8) 4.4 (1.8) 4.3 (1.8)

using bivariate multilevel models, which allow for the correla- Urinary potassium 1.4 (0.6) 1.4 (0.6) 1.4 (0.6)
tion between costs and health outcomes at both the individual Education
and the cluster level (village). Multilevel models are the rec-
Primary school or lower 72.6 72.3 72.5
ommended method to handle clustered data in trial-based
economic evaluations, assuming a hierarchical structure and Junior high school 22.4 23.2 22.8
using maximum likelihood estimation.28,29 In the QALY analysis, Senior high school or above 5.0 4.5 4.7
QALYs were adjusted for baseline HSU.30 Disease history
A range of 1-way sensitivity analyses were performed
Stroke 72.0 73.3 72.7
to test the robustness of base-case results. The variations
included (1) using lowest, median, and highest market price  Uncontrolled high blood 59.2 59.4 59.3
pressure
for salt substitute in China31; (2) using alternative discount
rates of 0% and 8% as recommended by the Chinese Transient ischemic attack 14.9 13.2 14.1
Pharmacoeconomic Guidelines16; (3) using lowest and high- Ischemic heart disease 15.7 16.4 16.1
est unit prices for outpatient medication costs; (4) including Congestive heart failure 2.5 2.5 2.5
only inpatient costs for health care costs; (5) assuming 0,
Peripheral arterial disease 3.6 5.1 4.4
10%, and 30% of fatal events occurred at home with 0 inpa-
tient health care costs; and (6) assigning inpatient costs for Diabetes 10.5 10.6 10.6
all hospitalizations, not just hospitalizations for cardiovascu- Values are mean (SD) or %.
lar causes. For the analyses of QALYs, we also assessed the
effects of (7) using the lower and upper bounds of the 95% to −4]), and lower mean outpatient medication costs
CI for the baseline HSU and (8) varying the HSU decre-
(¥−40 [95% CI, −62 to −18]; Table 3). The incremen-
ments applied by ±20%. Nonparametric bootstrapping with
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tal cost for replacing regular salt with salt substitute

5000 replications was performed to quantify uncertainty,
which was presented using an incremental cost-effective-
ness plane.32
All analyses were done using Stata 17 (StataCorp) and
reporting was done in line with the Consolidated Health
Economic Evaluation Reporting Standards (Supplemental
Material).33
RESULTS
A total of 20 995 participants from 600 villages were
enrolled into SSaSS, with 10 504 individuals in the 300
salt substitute intervention villages and 10 491 individu-
als in the 300 control villages (Table 2). The mean age
was 65.4 years at baseline and 49.5% of participants
were female. There was no statistical difference in base-
line characteristics between the salt substitute group and
the regular salt group.
Within the mean trial follow-up period of 4.74 years,
replacing regular salt with salt substitute reduced
the risk of stroke by 14% (risk ratio, 0.86 [95% CI,
0.77 to 0.96]; P=0.006).9 The intervention compared
with control also resulted in higher QALYs by 0.054
(95% CI, 0.012 to 0.095) per person (Table 3), which
equates to ≈20 more days in full health per person.
The salt substitute group incurred lower mean inpatient
health care costs (¥−164 [95% CI, −355 to −96]),
lower mean outpatient visit costs (¥−21 [95% CI, −38
was ¥115 (95% CI, 114 to 116) per person for the
duration of the study. After accounting for the costs of
health care services, regular salt, and salt substitute,
the total costs were on average lower in the salt substi-
tute group (¥−110 [95% CI, −239 to −19]) compared
with the regular salt group. With higher effectiveness
and a lower cost, the salt substitute intervention was
cost-saving, and a dominant strategy compared with
the use of regular salt for the prevention of stroke and
the preservation of quality of life.
The cost-saving result in the primary analysis was
robust to varying of all key assumptions (Table 4), except
for increasing the unit price of salt substitute to the
median and highest market prices identified in China.
Using the median market price of salt substitute at
¥12.9/kg increased the average total cost to ¥1755
with an incremental cost-effectiveness ratio at ¥5512
per stroke averted and ¥1980 per QALY gained. If the
highest market price of salt substitute at ¥80.0/kg was
used, this increased the average total cost to ¥3879 with
an incremental cost-effectiveness ratio of ¥115 552 per
stroke averted and ¥41 559 per QALY gained. Never-
theless, salt substitute was still a cost-effective interven-
tion under the Chinese cost-effectiveness threshold of
¥64 957 per QALY gained. The cost-effectiveness plane
(Figure) shows that the salt substitute intervention has
a 95.0% probability (4752/5000 replications) of being

Circulation. 2022;145:1534–1541. DOI: 10.1161/CIRCULATIONAHA.122.059573 May 17, 2022 1537

 Li et al Cost-Effectiveness of Salt Substitution

Table 3. Health Outcomes and Costs Over the Trial Period

ORIGINAL RESEARCH

Regular Salt substi- Rate ratio

salt group tute group (95% CI) or mean P value or
Variable (n=10 491) (n=10 504) difference* 95% CI
ARTICLE

Nonfatal and fatal stroke, rate per 1000 person-years 33.65 29.14 0.86 (0.77 to 0.96) 0.006
QALYs, per person, mean 4.090 4.155 0.054 0.012 to 0.095
Health care costs, mean cost, ¥ 1570 1345 −225 −355 to −96
Inpatient care 1190 1026 −164 −275 to −54
Outpatient visits 184 163 −21 −38 to −4
Outpatient medications 196 156 −40 −62 to −18
Cost for replacing regular salt with salt substitute 78 193 115 114 to 116
Salts 78 192 114 113 to 114
Health promotion materials 0 1 1 —
Total costs 1649 1538 −110 −239 to 19

QALY indicates quality-adjusted life-year; and ¥, Chinese yuan.

*Adjusted for baseline health state utility.

cost-saving in regard to QALYs and a >99.9% probability
(4999/5000 replications) of being cost-effective.
DISCUSSION
This within-trial economic evaluation of SSaSS clearly
showed that salt substitute protected against stroke with
a lower cost compared with using regular salt. The salt
substitute intervention was a cost-saving intervention in
the base-case analysis and in all sensitivity analyses ex-
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accounted for ≈40% of health care costs.34 The additional
cost for purchasing salt substitute compared with regular
salt was also assumed to be borne by consumers in this
analysis because this would be the most likely real-world
implementation scenario. Because the price premium
on salt substitute compared with regular salt might be
a disincentive to consumers, government-funded price
subsidy might be a mechanism to encourage uptake by
making the switch cost neutral to consumers.35
The cost-saving result was sensitive to the cost of

cept when the price of salt substitute was included at
median or maximum market price in China. Even with
these higher prices, salt substitute was still clearly cost-
effective when compared with the cost-effectiveness
threshold in China.
Salt substitution was cost-saving because the addi-
tional costs associated with salt substitution were off-
set by savings in health care costs, primarily through a
reduction in the numbers of nonfatal events requiring
hospitalization.9 Salt substitution also saved costs in out-
patient visits and outpatient medications, although they
represented a small part of the total health care cost. The
wholesale price of salt substitute (¥5.6/kg) used in the
trial was about double the wholesale cost of regular salt
(¥2.5/kg),31 but both were low-cost commodities. Our
analyses indicate that in the SSaSS setting, salt substi-
tution would be cost-saving at the lowest local market
price of salt substitute (¥6.5/kg) and cost-effective up
to an estimated unit price of salt substitute at ¥120/
kg, which is 1.5 times the current highest market price
(¥80/kg) and 10.3 times the price of a widely available
salt substitute in China (¥11.6/kg).
Our analysis was done using a joint perspective, which
measured and included the costs to all the main bearers.
Inpatient and outpatient health care services were mainly
paid by the public health insurance scheme (≈60% of
health care costs), although out-of-pocket payment
salt substitute but not to the other assumptions that
were varied. Costs of salt substitute and health care
as well as the composition of salt substitute vary mark-
edly across settings,31 as do food preparation practices
and dietary patterns.36 These are likely to affect the
feasibility of salt substitution, the costs of interven-
tion, the magnitude of the health gains, and the asso-
ciated health care cost savings. The participants in
SSaSS were a high-risk population with a high level of
sodium consumption who experienced large absolute
benefits,14 which is a scenario in which the cost-effec-
tiveness of intervention might be optimized. However,
given the cost-saving nature of salt substitution in
SSaSS, and the favorable findings in previous mod-
eled cost-effectiveness studies,11–13 the SSaSS results
make it highly probable that salt substitution would be
cost-effective in many other populations where the
majority of sodium intake derives from household con-
sumption.37 For populations where most dietary sodium
comes from foods prepared outside the home, benefits
of salt substitution could be achieved by replacing salt
used as an ingredient for foods prepared at restaurants
or in food manufacturing facilities.
A recent modeling study projected that nationwide
implementation of salt substitution in China could poten-
tially avert 461 000 cardiovascular deaths and 743 000
nonfatal cardiovascular events each year.38 This could

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 Li et al Cost-Effectiveness of Salt Substitution

Table 4. One-Way Sensitivity Analyses

ORIGINAL RESEARCH
Mean total costs, ¥ Mean QALYs
ICER, ¥ ICER, ¥
Regular Salt substi- per stroke Regular Salt substi- per QALY

ARTICLE
Variables salt group tute group Difference averted salt group tute group Difference† gained
Base case 1649 1538 −110 Cost-saving 4.090 4.155 0.054 Cost-saving
Changes in price of salt substitute
Lowest market price of salt substitute 1649 1551 −98 Cost-saving 4.090 4.155 0.054 Cost-saving
Median market price of salt substitute 1649 1755 106 5512 4.090 4.155 0.054 1980
Highest market price of salt substitute 1649 3879 2230 115 552 4.090 4.155 0.054 41 559
Changes in discount rate
0% discount rate 1857 1733 −125 Cost-saving 4.504 4.578 0.061 Cost-saving
8% discount rate 1542 1439 −103 Cost-saving 3.878 3.938 0.050 Cost-saving
Changes in price of medications
Low unit price of medications 1523 1439 −84 Cost-saving 4.090 4.155 0.054 Cost-saving
High unit price of medications 1793 1653 −140 Cost-saving 4.090 4.155 0.054 Cost-saving
Changes in health care cost
 Health care cost included inpatient 1268 1219 −49 Cost-saving 4.090 4.155 0.054 Cost-saving
cost only*
 0% deaths occurred at home with 0 2432 2243 −189 Cost-saving 4.090 4.155 0.054 Cost-saving
inpatient cost*
 10% deaths occurred at home with 0 2297 2135 −162 Cost-saving 4.090 4.155 0.054 Cost-saving
inpatient cost*
 30% deaths occurred at home with 0 2074 1910 −164 Cost-saving 4.090 4.155 0.054 Cost-saving
inpatient cost*
 Health care cost included all hospital- 10 649 10 088 −560 Cost-saving 4.090 4.155 0.054 Cost-saving
izations cost
Changes in baseline HSU
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Lower bound of 95% CI 1649 1538 −110 NA 4.020 4.084 0.052 Cost-saving
Upper bound of 95% CI 1649 1538 −110 NA 4.159 4.224 0.055 Cost-saving
Changes in HSU decrements
All decrements decrease by 20% 1649 1538 −110 NA 4.100 4.164 0.052 Cost-saving
All decrements increase by 20% 1649 1538 −110 NA 4.080 4.146 0.055 Cost-saving

HSU indicates health state utility; ICER, incremental cost-effectiveness ratio; NA, not applicable; QALY, quality-adjusted life-year; and ¥, Chinese yuan.
*Inpatient costs comprised hospitalizations of the cardiovascular events only.
†Adjusted for baseline HSU.

lead to a substantial reduction in health care costs, favor-
ing nationwide scale-up of the intervention.
Our analyses benefit from being the first to assess
the cost-effectiveness of salt substitution on the basis
of direct data from a large-scale trial that showed clear
effects on cardiovascular outcomes and mortality. This
meant that we could avoid the need to make a series of
assumptions that were common in previous estimates that
modeled the cost-effectiveness of salt substitution.11–13
There were also important limitations. The serial HSU data
required for calculating QALYs were not collected as part
of the trial follow-up and had to be imputed from external
sources. This meant that the QALY effects reported were
derived mainly from external data sources and, although
the direction of the main effects we observed is unlikely
to have been influenced, there may have been quantita-
tive overestimation or underestimation of effects as a
consequence. Likewise, there were missing cost data for
outpatient visits and details about outpatient medication
use and costs also had to be imputed from the literature.
There were health insurance records for only approxi-
mately one-third of the deaths in SSaSS, and although
this correlates well with previous reports that indicate that
approximately two-thirds of deaths in rural China occur at
home,22 it is possible that some hospitalization costs for
fatal events may have been missed. Given that there were
more fatal events in the control group, the inpatient cost
associated with fatal events was likely underestimated
and the cost-effectiveness result may be conservative.
Varying these and other key assumptions did not materi-
ally affect the cost-saving conclusions.
CONCLUSIONS
Salt substitution is the only salt reduction interven-
tion with grade 1 evidence demonstrating cost-saving

Circulation. 2022;145:1534–1541. DOI: 10.1161/CIRCULATIONAHA.122.059573 May 17, 2022 1539

 Li et al
ORIGINAL RESEARCH
ARTICLE
protection against clinical events and should be consid-
ered by all countries planning or implementing sodium
reduction campaigns. Salt substitution should be particu-
larly high up the priority list for countries where a large
proportion of dietary sodium derives from discretionary
salt that can be easily substituted. Modeling studies that
use the SSaSS findings to project effects for more di-
verse population groups and different jurisdictions will be
Downloaded from http://ahajournals.org by on February 17, 2024
key to estimating cost-effectiveness for other settings.
ARTICLE INFORMATION
Received February 7, 2022; accepted March 9, 2022.
Affiliations
The George Institute for Global Health, University of New South Wales, Syd-
ney, Australia (K.-C.L., L.H., M.T., G.L.D.T., J.Y., X.Y., Y.L., N.L., B.N., T.L., L.S.).
School of Public Health, Harbin Medical University, China (M.T.). Department of
Cardiology, Peking University Third Hospital, Beijing, China (J.Y.). The George
Institute for Global Health at Peking University Health Science Center, Bei-
jing, China (X.Z., Z.H., L.L.Y., Y.W.). First Hospital of China Medical University,
Shenyang, China (B.Z.). Changzhi Medical College, China (X.F., Z.L.). Center for
Disease Control of Hebei, Shijiazhuang, China (J.Z., J.S.). Ningxia Medical Uni-
versity, Yinchuan, China (Y. Zhang, Y. Zhao). Xi’an Jiaotong University School
of Medicine, Xi’an, China (R.Z., Y.Y.). Global Health Research Centre, Duke
Kunshan University, Kunshan, China (L.L.Y.). Northwestern University Feinberg
School of Medicine, Chicago, IL (D.R.L.). School of Public Health, Imperial Col-
lege London, United Kingdom (P.E., B.N.). Peking University Clinical Research
Institute, Beijing, China (Y.W.). Sydney School of Public Health, University of
Sydney, Australia (T.L.).
Acknowledgments
The authors thank the Salt Substitute and Stroke Study implementation team and
local collaborators and Jingpu Shi, PhD, Department of Evidence-Based Medi-
cine, First Hospital of China Medical University, who died on October 27, 2020,
for his leadership and support for implementing the Salt Substitute and Stroke
Study in Liaoning Province.
Sources of Funding
The Salt Substitute and Stroke Study was funded by grants APP1164206 and
APP1049417 from the National Health and Medical Research Council of Austra-
lia. Salt substitute was donated by Jiangsu Sinokone Technology Co Ltd for years
3 and 4 of the trial. The authors declare no competing interests.
1540 May 17, 2022 Circulation. 2022;145:1534–1541. DOI: 10.1161/CIRCULATIONAHA.122.059573
Cost-Effectiveness of Salt Substitution
Figure. Incremental cost-
effectiveness plane of 5000 bootstrap
replications.
The incremental cost-effectiveness plane
shows 5000 bootstrap replications of
incremental cost and quality-adjusted
life-year (QALY) pairs. The blue oval
represents the 95% confidence ellipse
of the bootstrap replications on the
cost-effectiveness plane. The green line
denotes the willingness to pay threshold,
which is ¥64 957/QALY gained. CNY
indicates Chinese yuan.
Disclosures
None.
Supplemental Material
Consolidated Health Economic Evaluation Reporting Standards 2022 Checklist
REFERENCES
1. Vos T, Lim SS, Abbafati C, Abbas KM, Abbasi M, Abbasifard M,
Abbasi-Kangevari M, Abbastabar H, Abd-Allah F, Abdelalim A, et al. Global
burden of 369 diseases and injuries in 204 countries and territories, 1990–
2019: a systematic analysis for the Global Burden of Disease Study 2019.
Lancet. 2020;396:1204–1222. doi: 10.1016/S0140-6736(20)30925-9
2. Zhou M, Wang H, Zeng X, Yin P, Zhu J, Chen W, Li X, Wang L, Wang L, Liu
Y, et al. Mortality, morbidity, and risk factors in China and its provinces, 1990-
2017: a systematic analysis for the Global Burden of Disease Study 2017.
Lancet. 2019;394:1145–1158. doi: 10.1016/S0140-6736(19)30427-1
3. Du S, Wang H, Zhang B, Popkin BM. Dietary potassium intake remains
low and sodium intake remains high, and most sodium is derived from
home food preparation for Chinese adults, 1991–2015 trends. J Nutr.
2020;150:1230–1239. doi: 10.1093/jn/nxz332
4. World Health Organization. Salt reduction. Published 2020. Accessed August
20, 2021. https://www.who.int/news-room/fact-sheets/detail/salt-reduction
5. He FJ, Tan M, Ma Y, MacGregor GA. Salt reduction to prevent hypertension
and cardiovascular disease: JACC state-of-the-art review. J Am Coll Cardiol.
2020;75:632–647. doi: 10.1016/j.jacc.2019.11.055
6. Huang L, Trieu K, Yoshimura S, Neal B, Woodward M, Campbell NRC, Li
Q, Lackland DT, Leung AA, Anderson CAM, et al. Effect of dose and du-
ration of reduction in dietary sodium on blood pressure levels: systematic
review and meta-analysis of randomised trials. BMJ. 2020;368:m315. doi:
10.1136/bmj.m315
7. Filippini T, Naska A, Kasdagli MI, Torres D, Lopes C, Carvalho C, Moreira P,
Malavolti M, Orsini N, Whelton PK, et al. Potassium intake and blood pres-
sure: a dose-response meta-analysis of randomized controlled trials. J Am
Heart Assoc. 2020;9:e015719. doi: 10.1161/JAHA.119.015719
8. Hernandez AV, Emonds EE, Chen BA, Zavala-Loayza AJ, Thota P, Pasupuleti
V, Roman YM, Bernabe-Ortiz A, Miranda JJ. Effect of low-sodium salt sub-
stitutes on blood pressure, detected hypertension, stroke and mortality.
Heart. 2019;105:953–960. doi: 10.1136/heartjnl-2018-314036
9. Neal B, Wu Y, Feng X, Zhang R, Zhang Y, Shi J, Zhang J, Tian M, Huang L,
Li Z, et al. Effect of salt substitution on cardiovascular events and death. N
Engl J Med. 2021;385:1067–1077. doi: 10.1056/NEJMoa2105675
10. World Health Organization. ‘Best buys’ and other recommended interven-
tions for the prevention and control of noncommunicable diseases. Pub-
lished 2017. Accessed August 20, 2021. https://www.who.int/ncds/man-
agement/WHO_Appendix_BestBuys.pdf
 Li et al
11. Nghiem N, Blakely T, Cobiac LJ, Cleghorn CL, Wilson N. The health
gains and cost savings of dietary salt reduction interventions, with equi-
ty and age distributional aspects. BMC Public Health. 2016;16:423. doi:
10.1186/s12889-016-3102-1
12. Aminde LN, Cobiac L, Veerman JL. Cost-effectiveness analysis of popula-
tion salt reduction interventions to prevent cardiovascular disease in Cam-
eroon: mathematical modelling study. BMJ Open. 2020;10:e041346. doi:
10.1136/bmjopen-2020-041346
13. Taylor C, Hoek AC, Deltetto I, Peacock A, Ha DTP, Sieburg M, Hoang D,
Trieu K, Cobb LK, Jan S, et al. The cost-effectiveness of government actions
to reduce sodium intake through salt substitutes in Vietnam. Arch Public
Health. 2021;79:32. doi: 10.1186/s13690-021-00540-4
14. Neal B, Tian M, Li N, Elliott P, Yan LL, Labarthe DR, Huang L, Yin X,
Hao Z, Stepien S, et al. Rationale, design, and baseline characteristics
of the Salt Substitute and Stroke Study (SSaSS): a large-scale clus-
ter randomized controlled trial. Am Heart J. 2017;188:109–117. doi:
10.1016/j.ahj.2017.02.033
15. Li KC, Tian M, Neal B, Huang L, Yu J, Liu Y, Yin X, Zhang X, Wu Y, Li
N, et al. Protocol for the economic evaluation of the China Salt Sub-
stitute and Stroke Study (SSaSS). BMJ Open. 2021;11:e045929. doi:
10.1136/bmjopen-2020-045929
16. Chinese Pharmaceutical Association. China Guidelines for Pharmacoeco-
nomic Evaluations (2020). Published 2021. Accessed August 20, 2021.
https://tools.ispor.org/PEguidelines/countrydet.asp?c=28&t=4
17. Gray AM, Clarke PM, Wolstenholme JL, Wordsworth S. Applied Methods of
Cost-Effectiveness Analysis in Healthcare. Oxford UP; 2010.
18. Yao Q, Liu C, Zhang Y, Xu L. Population norms for the EQ-5D-3L in China
derived from the 2013 National Health Services Survey. J Glob Health.
2021;11:08001. doi: 10.7189/jogh.11.08001
19. Van Wilder L, Rammant E, Clays E, Devleesschauwer B, Pauwels N,
De Smedt D. A comprehensive catalogue of EQ-5D scores in chronic dis-
ease: results of a systematic review. Qual Life Res. 2019;28:3153–3161.
doi: 10.1007/s11136-019-02300-y
20. Luengo-Fernandez R, Gray AM, Bull L, Welch S, Cuthbertson F, Rothwell
PM; Oxford Vascular Study. Quality of life after TIA and stroke: ten-year
results of the Oxford Vascular Study. Neurology. 2013;81:1588–1595. doi:
10.1212/WNL.0b013e3182a9f45f
21. Pockett RD, McEwan P, Ray J, Tran I, Shutler S, Martin S, Yousef Z, Bakhai
Downloaded from http://ahajournals.org by on February 17, 2024
A. Prospective utility study of patients with multiple cardiovascular events. J
Med Econ. 2018;21:616–621. doi: 10.1080/13696998.2018.1454453
22. Liu S, Wu X, Lopez AD, Wang L, Cai Y, Page A, Yin P, Liu Y, Li Y, Liu J, et al.
An integrated national mortality surveillance system for death registration
and mortality surveillance, China. Bull World Health Organ. 2016;94:46–57.
doi: 10.2471/BLT.15.153148
23. Zhu D, Shi X, Nicholas S, Chen S, Ding R, Huang L, Ma Y, He P. Medical ser-
vice utilization and direct medical cost of stroke in urban China. Int J Health
Policy Manag. 2022;11:277–286. doi: 10.34172/ijhpm.2020.111
24. Tao Y, Wang Y, Wu J. Study on utilization of medical resources and medical
expenses of patients with acute coronary syndrome based on generalized
linear regression analysis. Drug Eval Res. 2019;42:1851.
25. Liu L, Chen W, Zhou H, Duan W, Li S, Huo X, Xu W, Huang L, Zheng H, Liu
J, et al; Chinese Stroke Association Stroke Council Guideline Writing Com-
mittee. Chinese Stroke Association guidelines for clinical management of
Circulation. 2022;145:1534–1541. DOI: 10.1161/CIRCULATIONAHA.122.059573
Cost-Effectiveness of Salt Substitution
cerebrovascular disorders: executive summary and 2019 update of clinical
management of ischaemic cerebrovascular diseases. Stroke.Vasc Neurol.
ORIGINAL RESEARCH
2020;5:159–176. doi: 10.1136/svn-2020-000378
26. Task Force on Chinese Guidelines for the Prevention of Cardiovascu-
lar Diseases. Chinese guidelines for the prevention of cardiovascu-
ARTICLE
lar diseases (2017). Chin J Cardiol. 2018;46:10–25. doi: 10.3760/
cma.j.issn.0253-3758.2018.01.004
27. National Health Commission of the People’s Republic of China. National
Essential Medicines List (2018 edition). Published 2018. Accessed
September 29, 2021. http://www.nhc.gov.cn/yaozs/s7656/201810/
c18533e22a3940d08d996b588d941631.shtml
28. Gomes M, Ng ES, Grieve R, Nixon R, Carpenter J, Thompson SG. De-
veloping appropriate methods for cost-effectiveness analysis of clus-
ter randomized trials. Med Decis Making. 2012;32:350–361. doi:
10.1177/0272989X11418372
29. El Alili M, Van Dongen JM, Goldfeld KS, Heymans MW, Van Tulder MW,
Bosmans JE. Taking the analysis of trial-based economic evaluations to the
next level: the importance of accounting for clustering. Pharmacoeconomics.
2020;38:1247–1261. doi: 10.1007/s40273-020-00946-y
30. Manca A, Hawkins N, Sculpher MJ. Estimating mean QALYs in trial-based
cost-effectiveness analysis: the importance of controlling for baseline utility.
Health Econ. 2005;14:487–496. doi: 10.1002/hec.944
31. Yin X, Liu H, Webster J, Trieu K, Huffman MD, Miranda JJ, Marklund M, Wu
JHY, Cobb LK, Li KC, et al. Availability, formulation, labeling, and price of
low-sodium salt worldwide: environmental scan. JMIR Public Health Surveill.
2021;7:e27423. doi: 10.2196/27423
32. Drummond MF, Sculpher MJ, Claxton K, Stoddart GL, Torrance GW. Meth-
ods for the Economic Evaluation of Health Care Programmes. Oxford Univer-
sity Press; 2015.
33. Husereau D, Drummond M, Augustovski F, de Bekker-Grob E, Briggs AH,
Carswell C, Caulley L, Chaiyakunapruk N, Greenberg D, Loder E, et al;
CHEERS 2022 ISPOR Good Research Practices Task Force. Consolidated
Health Economic Evaluation Reporting Standards 2022 (CHEERS 2022)
statement: updated reporting guidance for health economic evaluations.
BMJ. 2022;376:e067975. doi: 10.1136/bmj-2021-067975
34. National Health Commission of the People’s Republic of China. China
Health Bulletin 2020. Published 2021. Accessed January 7, 2022. http://
www.nhc.gov.cn/guihuaxxs/s10743/202107/af8a9c98453c4d9593e-
07895ae0493c8.shtml
35. Li N, Yan LL, Niu W, Yao C, Feng X, Zhang J, Shi J, Zhang Y, Zhang R, Hao
Z, et al. The effects of a community-based sodium reduction program in
rural China: a cluster-randomized trial. PLoS One. 2016;11:e0166620. doi:
10.1371/journal.pone.0166620
36. Ide N, Ajenikoko A, Steele L, Cohn J, J Curtis C, Frieden TR, Cobb LK.
Priority actions to advance population sodium reduction. Nutrients.
2020;12:E2543. doi: 10.3390/nu12092543
37. Bhat S, Marklund M, Henry ME, Appel LJ, Croft KD, Neal B, Wu JHY. A
Systematic review of the sources of dietary salt around the world. Adv Nutr.
2020;11:677–686. doi: 10.1093/advances/nmz134
38. Marklund M, Singh G, Greer R, Cudhea F, Matsushita K, Micha R, Brady T,
Zhao D, Huang L, Tian M, et al. Estimated population wide benefits and risks
in China of lowering sodium through potassium enriched salt substitution:
modelling study. BMJ. 2020;369:m824. doi: 10.1136/bmj.m824
May 17, 2022 1541