Effect of salt substitute and medication use among high cardiovascular risk patients

Effect of salt substitute and medication use among high cardiovascular risk patients | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Effect of salt substitute and medication use among high cardiovascular risk patients Zijing Qi, shuai Tang, Yubing Hao, Yanxing Li, Tianyou Hao, Hongmei Yang, and 5 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4333779/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Introduction: Previous studies have shown that the protective effect of salt substitute varied between the hypertensive population and the normotensive population, but it was not clear whether it was related to cardiovascular drugs. The purpose of this study is to explore the effect of salt substitutes and anti-hypertensive drugs on blood pressure and adverse cardiovascular events. Methods: 4211 people with a history of stroke or hypertension from 120 villages in Shanxi Province who participated in an open-label cluster randomized controlled trial (SSaSS) were included in this study. Generalized linear mixed models and linear mixed models were used to explore the effect of salt substitute on blood pressure and adverse cardiovascular events in different group of population respectively, adjusting for the stratification variables at randomization (village) as well as potential confounding variables. Results: Salt substitute reduced the risk of adverse cardiovascular events in participants who took anti-hypertensive drugs(28.63 events vs. 35.96 events per 1000 person-years; rate ratio, 0.75, 95% CI, 0.59 to 0.95; P=0.016) while no significant effect among the participants who did not take any anti-hypertensive drugs. Salt substitute reduced the blood pressure in participants who took anti-hypertensive drugs with a mean SBP difference of -4.38mmHg (95% CI: -6.08 to -2.67, P<0.001) and a mean DBP difference of -1.31mmHg (95% CI: -2.42 to -0.21, P=0.020), while no significant blood pressure difference among the participants who did not take any anti-hypertensive drugs. Conclusions: Combining salt substitute with anti-hypertensive drugs could reduce blood pressure and the risk of cardiovascular events. Health sciences/Diseases/Cardiovascular diseases Health sciences/Medical research/Epidemiology salt substitute medication blood pressure cardiovascular events Figures Figure 1 Figure 2 1. Introduction Cardiovascular diseases (CVD) are the leading cause of death in worldwide and China, and the health and economic burden of CVD is rising along with the intensification of population aging 1 – 3 . It is estimated that approximately 330 million individuals are affected by CVD and 245 million cases of hypertension in China 4 . Secondary prevention based on anti-hypertensive drug has been widely used to control the main risk factors 5 . At present, the improvement of the burden of cardiovascular disease is largely related to insisting on drug treatment and controlling risk factors in a targeted manner. In addition, reducing sodium intake are a fundamental lifestyle change to blood pressure control and reduction of cardiovascular diseases 5 – 9 . Guidelines on CVD prevention 10 , 11 recommends sodium reduction before and concurrently with pharmacologic interventions for high risk patients 12 , 13 . Salt substitute, which replaces a proportion of sodium chloride in regular salt with potassium chloride, combines the benefits of sodium reduction and potassium supplementation and is expected to become a more cost-effective non-pharmacological intervention 14 , 15 . As a salt reduction strategy, salt substitute has been proved to be effective in lowering blood pressure and preventing cardiovascular events 16 – 18 . Previous studies show that salt substitute could greatly reduce blood pressure in hypertensive people compared with the normotensive people, but it was not clear whether this effect was related to the use of anti-hypertensive drugs. However, it was uncertain whether the combination of salt substitute and anti-hypertensive drugs could better lower blood pressure and even prevent adverse cardiovascular events. In this study, we used data from the SSaSS study collected in Shanxi Province to investigate the combination of salt substitute and anti-hypertensive drugs on blood pressure changes and adverse cardiovascular events among cardiovascular high-risk population. 2. Methods 2.1. Study design and participants The SSaSS was an open-label, cluster-randomized trial involving 600 villages in five provinces (Hebei, Liaoning, Ningxia, Shanxi, and Shaanxi) in Northern China 19 . Two counties from each province were selected based on prior collaboration and approximately 35 participants were recruited from each village. Participants were at high cardiovascular risk with a history of stroke and/or ≥ 60 years old with poorly controlled blood pressure (systolic blood pressure ≥ 140mmHg if receiving blood-pressure-lowering medication or ≥ 160 mm Hg if not) 17 . In this analysis, participants from Shanxi Province were included. Recruitment in Shanxi province was done from July 2014 to August 2014. After all participants had been recruited and all baseline survey data had been collected, randomization was stratified according to county (60 villages in each county) with the use of a central computerized process. Villages were randomly allocated to either the intervention or control group at a 1:1 ratio. Participants in the intervention group were provided with enough salt substitute free of charge to replace all household use of regular salt. The salt substitute used for the intervention comprised 75% sodium chloride and 25% potassium chloride. Participants in the control group continued to use regular salt. Central ethics approval was obtained from the ethics committee of The University of Sydney and Peking University Health Science Centre. All participants provided informed content. 2.2. Follow-up and Outcomes Follow-up for major adverse cardiovascular outcomes was conducted between August 2014 and October 2019 at 6-month intervals through a combination of face-to-face visits to participants and searching routinely collected health data – New Rural Cooperative Medical Scheme and National Mortality Surveillance System. If a possible event was identified through the face-to-face visits or routinely collected health data, additional information was sought from participants, their family members and any medical facilities that the participant had visited during the illness, whenever possible. All suspected outcomes were ascertained by an independent adjudication committee with any information available. As one of the process surveys, blood pressure was measured at 12-month intervals. In the process evaluation survey in the middle follow-up year (in total 6 surveys), the same number of intervention villages and control villages were randomly selected to form sub-samples (at least 12 villages). And approximately 20 participants were invited from each village. Blood pressure was measured using automated blood pressure monitors. However, in this study, the pairwise blood pressure difference between baseline survey and the end of the trial was used as the change of blood pressure. Participants who did not participate in the terminal blood pressure measurement due to illness (such as hospitalization) were replaced by the blood pressure value of their last follow-up visit. 2.3. Statistical analysis The primary study endpoints were major adverse cardiovascular events. The secondary outcome of interest in this analysis was the difference between the salt substitute group and the regular salt group in the change of blood pressure from baseline to the end of the trial under different medication subgroups. To determine the effect of salt substitute on blood pressure and cardiovascular event risk, we used a linear mixed model and a generalized linear model for data analysis respectively, adjusting for the cluster variables (village) as well as potential confounding variables. After adjusting the potential confounding factors including age, sex(male = 1; female = 2), BMI(>24.6 = 1;≤24.6 = 2), baseline blood pressure(SBP>141 = 1;≤141 = 2; DBP>79 = 1;≤79 = 2), disease history(stroke or not;hypertension or not) and cardiovascular (use of anti-hypertensive agent or not, use of anti-platelet agent or not, and use of lipid-lowering agent or not), as well as the cluster variable, the incidence of endpoint events and Risk Ratio between the salt substitute group and the regular salt group were analyzed under different anti-hypertensive drugs stratification. The blood pressure changes of each participant from baseline to the end of the trial were set as dependent variable, and the effects of different anti-hypertensive drugs and salt substitute on blood pressure were evaluated by linear mixed model. Taking the incidence of each participant as the dependent variable, the generalized linear mixed model was used to evaluate the effects of different anti-hypertensive drugs and salt substitution on major cardiovascular adverse events. The main analysis was based on the intention-to-treat principle. Two-sided p values less than 0.05 were considered statistically significant and we did not adjust for multiple testing. Analyses were performed with the use of SPSS statistical software (IBM SPSS Statistics for Windows, Version 27.0. Armonk, NY, USA) and R version 4.3.2 and R studio version 2022.12.0 Build 353. Packages “forestplot” were used for statistical analysis and summarizing results. 3. Results 3.1 Baseline characteristics A total of 4211 participants at high cardiovascular risk were included in the analysis (Figure 1). The mean age for all participants was 63.44 years old at baseline, 56.33% were male, 96.96% had a history of stroke, and 90.00% reported having received a diagnosis of hypertension; 87.63% took anti-hypertensive agent, 57.58% took anti-platelet agent, 22.89% took lipid-lowering agent.Among the participants who used at least one blood pressure-lowering medication, 59.27% were using calcium antagonist, 17.62% were using angiotensin-converting to enzyme inhibitor or angiotensin-receptor blocker (ARB/ACEi), 11.90% were using diuretic. Demographic characteristics of salt substitute group and regular salt group are basically balanced (Table 1). Supplementary Table 1 lists the baseline characteristics from the two groups of the participants who took anti-hypertensive drugs or not. 3.2 Effect of medication use and salt substitute on the risk of adverse cardiovascular events During a mean follow-up period of 4.66 years, a total of 660 participants had 731 major adverse cardiovascular events, and 779 participants died. The salt substitute showed a significant role in reducing the risk of adverse cardiovascular events (34.22 events vs. 40.25 events per 1000 person-years; rate ratio, 0.86; 95% CI, 0.74 to 0.99; P = 0.038), after adjusting the confounding factors. The salt substitute reduced risk of adverse cardiovascular events (25.59 vs.32.58; rate ratio 0.82, 95%CI: 0.69 to 0.96, P = 0.016) among the participants who took anti-hypertensive agent, while no significant effect in the participants who did not take any anti-hypertensive drugs.(Table 2). Among the people taking different anti-hypertensive agent, the significant effect of salt substitute was also observed in the subgroups taking ACEI/ARB (4.57 vs.7.87, rate ratio 0.61, 95%CI: 0.43 to 0.88, p = 0.01) and α -blocker (0.20 vs.1.23, rate ratio 0.19, 95%CI: 0.04 to 0.80, p = 0.02). Using diuretic, Calcium antagonist or β -blocker did not impact the effect of salt substitute on the risk of adverse cardiovascular events of the sample population (P >0.05) (Figure2). 3.3 Effect of medication use and salt substitute on blood pressure Using anti-hypertensive agent combined salt substitute had a significant effect on lowering systolic blood pressure, with a mean difference of -4.38 mmHg (95% CI: -6.08 to -2.67, p<0.001) between the salt substitute group and the regular salt group. While among participants who did not take any anti-hypertensive agent, the mean SBP change from baseline to the end of trial were not being statistically significant with a mean difference of 0.89mmHg(95%CI:-2.32 to 4.10;P=0.590) between the salt substitute group and the regular salt group (Table 3). Among participants who took different anti-hypertensive drugs, the systolic blood pressure of participants taking calcium antagonists, ACEI/ARB or diuretics was significantly lower in the salt substitute group than that in the regular salt group, but there was no significant difference in the diastolic blood pressure group (Table 4). 4. Discussion Through the five-year follow-up intervention in high cardiovascular risk patients with a history of stroke or hypertension from 120 villages of Shanxi Province, the results emphasized that combining salt substitute with anti-hypertensive drug therapy significantly decrease blood pressure and the incidence of major cardiovascular adverse events. Prior studies which focused on the relationship between sodium reduction and salt substitution had demonstrated that salt reduction was additive to anti-hypertensive treatments 20 – 22 . However, a meta-analysis showed that use of anti-hypertensive agent had little effect on the BP effects of sodium reduction 23 . There were two reasons for this result: all the studies included in the meta-analysis were experimental studies, not population studies and the subjects included involved both hypertensive patients and non-hypertensive patients. In the present trial, combining anti-hypertensive agent with salt substitute reducing systolic blood pressure by 4.38 mmHg (P < 0.001) and diastolic blood pressure for 1.31 mmHg (P for interaction = 0.020) than with regular salt, which was consistent with the result of a pilot study in hypertension patients that salt substitute showed potential in reducing blood pressure and reducing use of anti-hypertensive agents 24 . Maintaining long-term stability of blood pressure is also conducive to reducing the risk of cardiovascular adverse events 25 . All kinds of anti-hypertensive drugs could reduce the risk of cardiovascular events in high-risk population to varying degrees. However prior study have emphasized that the protective effect of risk reduction came from the reduction of blood pressure itself, rather than the specificity of any certain anti-hypertensive drugs 26 . The results of this study showed that salt substitute reduced the risk of adverse cardiovascular events in participants taking ACEI/ARB (RR: 0.61; 95%CI: 0.43 ~ 0.88; P = 0.008) is particularly effective. Whether the combination of salt substitute and specific anti-hypertensive drugs could offer more significant protective effect needs to be verified in a wider range of people. In terms of cardiovascular endpoint events, a significant risk reduction was observed in salt substitute group among the participants who took anti-hypertensive agents, especially for subgroup in use of only one kind of anti-hypertensive drugs. On the one hand, it might be related to the size of sample population: the proportion of participants taking one kind of anti-hypertensive drug(42.06%) was slightly larger than that taking two kind of anti-hypertensive drugs(36.55%) and those taking more two kind of anti-hypertensive drugs (9.02%). The larger the sample population, the more endpoint events can be observed. On the other hand, it might be related to the risk of cardiovascular events: participants who take kinds of anti-hypertensive drugs represent their own high risk of uncontrolled blood pressure to a certain extent 27 , thus the protective effect of salt substitute might be limited in such patients. Nevertheless, to the best of our knowledge, the study represented the pioneering investigation into the combined effects between salt substitutes and various medications. This study also has some limitations. First, our sample population was derived solely from the SSASS trial conducted in Shanxi province. The relatively small sample size might restrict the extrapolation of the result. More interaction between different medications and salt substitute need to be studied in a wider population. Second, diseases often required an extended period for their occurrence and progression, while both medication treatment and salt substitution necessitate the preventive effect of also needs a long period. Prolonged utilization of salt substitution is likely to yield superior outcomes in terms of blood pressure control as well as disease prevention compared to short-term use alone. Regrettably, this study only encompassed a five-year follow-up period with limited incidence rates that might have constrained the evaluation of such interactions. Consequently, future research endeavors will focus on conducting longer post-intervention follow-ups to comprehensively observe the interplay between salt substitute usage and medication use. In conclusion, our study found combining salt substitute with anti-hypertensive agent could be significantly conducive to blood pressure control and the risk reduction of major adverse cardiovascular events among high cardiovascular risk patients with a history of stroke or hypertension. Declarations Funding This study was a sub-study supported by the National Health and Medical Research Council of Australia (NHMRC) Project Grant (APP1049417), NHMRC Program Grant (APP1052555), and NHMRC Centre for Research Excellence Grant (APP1117300). Conflicts of interests The authors declare no conflict of interest. Ethics approval The ethic of this study has been approved by according to the guidelines of the Declaration of Helsinki and was approved by the Center for Health Sciences at Peking University in China (Peking University Institutional Review Board, IRB00001052-13069, September 2013) and the Institutional Review Board at the University of Sydney, Australia (University of Sydney Ethics Committee, 2013/888, June 2013). Informed consent Informed consent was obtained from all subjects involved in the study. Contributors Conceptualization, Z.Q., S.T. and Z.L; methodology, L.H., M.T., X.F. and Z.L; software, Z.Q., S.T.; validation, Y.H., Y.L., T.H., H.Y. and Y.S; formal analysis, Y.H., Y.L., T.H., H.Y. and Y.S; investigation, Y.H., Y.L., T.H., H.Y. and Y.S.; resources, T.H., H.Y.; data curation, Y.L.; writing—original draft preparation, Z.Q. and S.T.; writing—review and editing, Z.Q., S.T., Y.H., L.H., M.T., X.F. and Z.L.; visualization, T.H., H.Y. and Y.S.; supervision, L.H.,M.T., X.F. and Z.L.; project administration, X.F. and Z.L.; funding acquisition, Z.L. All authors have read and agreed to the published version of the manuscript. Data availability The data that support the findings of this study are available from the corresponding author, upon reasonable request. References Mensah, G. A., Roth, G. A. & Fuster, V. The Global Burden of Cardiovascular Diseases and Risk Factors: 2020 and Beyond. Journal of the American College of Cardiology 74, 2529–2532, doi: 10.1016/j.jacc.2019.10.009 (2019). Roth, G. A. et al. Global Burden of Cardiovascular Diseases and Risk Factors, 1990–2019: Update From the GBD 2019 Study. Journal of the American College of Cardiology 76, 2982–3021, doi: 10.1016/j.jacc.2020.11.010 (2020). Zhao, D., Liu, J., Wang, M., Zhang, X. & Zhou, M. J. N. R. C. Epidemiology of cardiovascular disease in China: current features and implications. 16, 203–212 (2019). Report on Cardiovascular Health and Diseases in China 2021: An Updated Summary. Biomedical and environmental sciences: BES 35, 573–603, doi: 10.3967/bes2022.079 (2022). Pharmacological blood pressure lowering for primary and secondary prevention of cardiovascular disease across different levels of blood pressure: an individual participant-level data meta-analysis. Lancet (London, England) 397, 1625–1636, doi: 10.1016/s0140-6736(21)00590-0 (2021). Karunathilake, S. P. & Ganegoda, G. U. Secondary Prevention of Cardiovascular Diseases and Application of Technology for Early Diagnosis. BioMed research international 2018, 5767864, doi: 10.1155/2018/5767864 (2018). Francula-Zaninovic, S. & Nola, I. A. Management of Measurable Variable Cardiovascular Disease' Risk Factors. Current cardiology reviews 14, 153–163, doi: 10.2174/1573403x14666180222102312 (2018). Leong, D. P. et al. Reducing the Global Burden of Cardiovascular Disease, Part 2: Prevention and Treatment of Cardiovascular Disease. Circulation research 121, 695–710, doi: 10.1161/circresaha.117.311849 (2017). Mehta, S. et al. Cardiovascular preventive pharmacotherapy stratified by predicted cardiovascular risk: a national data linkage study. European journal of preventive cardiology 28, 1905–1913, doi: 10.1093/eurjpc/zwaa168 (2022). Carey, R. M., Wright, J. T., Jr., Taler, S. J. & Whelton, P. K. Guideline-Driven Management of Hypertension: An Evidence-Based Update. Circulation research 128, 827–846, doi: 10.1161/circresaha.121.318083 (2021). Atar, D. et al. New cardiovascular prevention guidelines: How to optimally manage dyslipidaemia and cardiovascular risk in 2021 in patients needing secondary prevention? Atherosclerosis 319, 51–61, doi: 10.1016/j.atherosclerosis.2020.12.013 (2021). Gasperi, V., Catani, M. V. & Savini, I. Platelet Responses in Cardiovascular Disease: Sex-Related Differences in Nutritional and Pharmacological Interventions. Cardiovascular therapeutics 2020, 2342837, doi: 10.1155/2020/2342837 (2020). Korhonen, M. J. et al. Lifestyle Changes in Relation to Initiation of Antihypertensive and Lipid-Lowering Medication: A Cohort Study. Journal of the American Heart Association 9, e014168, doi: 10.1161/jaha.119.014168 (2020). Yuan, Y. et al. Salt substitution and salt-supply restriction for lowering blood pressure in elderly care facilities: a cluster-randomized trial. Nature medicine 29, 973–981, doi: 10.1038/s41591-023-02286-8 (2023). Yu, J. et al. Effects of a reduced-sodium added-potassium salt substitute on blood pressure in rural Indian hypertensive patients: a randomized, double-blind, controlled trial. The American journal of clinical nutrition 114, 185–193, doi: 10.1093/ajcn/nqab054 (2021). Sun, H., Ma, B., Wu, X., Wang, H. & Zhou, B. Long-Term Effect of Salt Substitute on All-Cause and Cardiovascular Disease Mortality: An Exploratory Follow-Up of a Randomized Controlled Trial. Frontiers in cardiovascular medicine 8, 645902, doi: 10.3389/fcvm.2021.645902 (2021). Neal, B. et al. Effect of Salt Substitution on Cardiovascular Events and Death. The New England journal of medicine 385, 1067–1077, doi: 10.1056/NEJMoa2105675 (2021). Zhou, B. et al. Intake of low sodium salt substitute for 3years attenuates the increase in blood pressure in a rural population of North China - A randomized controlled trial. International journal of cardiology 215, 377–382, doi: 10.1016/j.ijcard.2016.04.073 (2016). Neal, B. et al. Rationale, design, and baseline characteristics of the Salt Substitute and Stroke Study (SSaSS)-A large-scale cluster randomized controlled trial. American heart journal 188, 109–117, doi: 10.1016/j.ahj.2017.02.033 (2017). He, F. J., Tan, M., Ma, Y. & MacGregor, G. A. Salt Reduction to Prevent Hypertension and Cardiovascular Disease: JACC State-of-the-Art Review. Journal of the American College of Cardiology 75, 632–647, doi: 10.1016/j.jacc.2019.11.055 (2020). Greer, R. C. et al. Potassium-Enriched Salt Substitutes as a Means to Lower Blood Pressure: Benefits and Risks. Hypertension (Dallas, Tex. : 1979) 75, 266–274, doi: 10.1161/hypertensionaha.119.13241 (2020). Sudano, I., Osto, E. & Ruschitzka, F. Blood Pressure-Lowering Therapy. Handbook of experimental pharmacology 270, 25–45, doi: 10.1007/164_2020_372 (2022). Filippini, T. et al. Blood Pressure Effects of Sodium Reduction: Dose-Response Meta-Analysis of Experimental Studies. Circulation 143, 1542–1567, doi: 10.1161/circulationaha.120.050371 (2021). Mu, L. et al. A pilot study on efficacy and safety of a new salt substitute with very low sodium among hypertension patients on regular treatment. Medicine 99, e19263, doi: 10.1097/md.0000000000019263 (2020). Lu, J. et al. Secondary prevention of cardiovascular disease in China. Heart (British Cardiac Society) 106, 1349–1356, doi: 10.1136/heartjnl-2019-315884 (2020). Thomopoulos, C., Parati, G. & Zanchetti, A. Effects of blood pressure lowering on outcome incidence in hypertension: 4. Effects of various classes of antihypertensive drugs – Overview and meta-analyses. 33, 195–211, doi: 10.1097/hjh.0000000000000447 (2015). Cherfane, M. et al. Risk factors for uncontrolled blood pressure among individuals with hypertension on treatment: the CONSTANCES population-based study. Int J Epidemiol 53, doi: 10.1093/ije/dyae027 (2024). Tables Table 1. Bas ic characteristics of overall participants in the trial . Baseline characteristics Total (n=4211) Salt substitute (n=2106) Regular salt (n=2105) P Sex Male, n (%) 2372 (56.33) 1184 (56.22) 1188 (56.44) 0.925 Female, n (%) 1839 (43.67) 922 (43.78) 917 (43.56) 0.915 Age, years 63.44 ± 8.43 63.72 ± 8.29 63.16 ± 8.43 0.030 ≤ 64, n (%) 2284 (54.24) 1102 (52.33) 1182 (56.15) 0.092 > 64, n (%) 1927 (45.76) 1004 (47.67) 923 (43.85) 0.067 BMI, kg/m 2 24.62 ± 3.71 24.49 ± 3.82 24.76 ± 3.59 0.018 ≤ 24.60, n (%) 2235 (53.08) 1147 (54.46) 1088 (51.69) 0.216 > 24.60, n (%) 1976 (46.92) 959 (45.54) 1017 (48.31) 0.188 SBP, mm Hg 140.57 ± 21.21 140.91 ± 21.02 140.22 ± 21.40 0.291 <140 mmHg, n (%) 2215 (52.60) 1109 (52.66) 1106 (52.54) 0.957 ≥140 and <160 mmHg, n (%) 1258 (29.87) 618 (29.34) 640 (30.4) 0.530 ≥160 mmHg, n (%) 738 (17.53) 379 (18.00) 359 (17.06) 0.466 DBP, mm Hg 78.88 ± 11.15 78.90 ± 11.25 78.86 ± 11.07 0.907 <90 mmHg, n (%) 3554 (84.4) 1763 (83.71) 1791 (85.08) 0.628 ≥90 and <100 mmHg, n (%) 488 (11.59) 254 (12.06) 234 (11.12) 0.370 ≥100 mmHg, n (%) 169 (4.01) 89 (4.23) 80 (3.80) 0.492 Smoke history Ever smoked, n (%) 1723 (40.92) 868 (41.22) 855 (40.62) 0.761 Current smoker, n (%) 714 (16.96) 348 (16.52) 366 (17.39) 0.497 Disease history Stroke, n (%) 4083 (96.96) 2048 (97.25) 2035 (96.67) 0.850 Hypertension, n (%) 3790 (90.00) 1872 (88.89) 1918 (91.12) 0.446 Medication use Anti-hypertensive agent, n (%) 3690 (87.63) 1805 (85.71) 1885 (89.55) 0.183 Calcium antagonist , n (%) 2496 (59.27) 1214 (57.64) 1282 (60.90) 0.170 ACEI/ARB, n (%) 742 (17.62) 367 (17.43) 375 (17.81) 0.764 Diuretic, n (%) 501 (11.90) 266 (12.63) 235 (11.16) 0.168 β-blocker, n (%) 177 (4.20) 65 (3.09) 112 (5.32) <0.001 α-blocker , n (%) 57 (1.35) 19 (0.90) 38 (1.81) 0.012 Anti-platelet agent, n (%) 2425 (57.58) 1199 (59.63) 1226 (58.24) 0.575 Lipid-lowering agent, n (%) 964 (22.89) 488 (23.17) 476 (22.61) 0.704 Where not specified, values are mean ± SD Table 2. Effect of salt substitute on major adverse cardiovascular events under different Anti-hypertensive medication subgroups . Subgroup N no. of events per 1000 person-years Rate Ratio (95%CI) P Salt substitute Regular salt Salt substitute Regular salt Use of anti-hypertensive agent(n=3690) 1805 1885 28.63 35.96 0.82(0.69,0.96) 0.016 One kind of anti-hypertensive drugs(n=1771) 897 874 14.21 18.08 0.75(0.59,0.95) 0.019 Two kind of anti-hypertensive drugs(n=1539) 703 836 10.66 13.79 0.88(0.66,1.17) 0.379 More than two kind of anti-hypertensive drugs(n=380) 205 175 3.76 4.09 0.80(0.47,1.35) 0.399 No use of anti-hypertensive agent(n=521) 301 220 5.58 4.29 0.90(0.61,1.32) 0.594 All the participants 2106 2105 34.22 40.25 0.86(0.74,0.99) 0.038 Table 3. Effect of salt substitute on blood pressure changes under different Anti-hypertensive medication subgroups . Subgroup SBP change from baseline DBP change from baseline Salt substitute Regular salt Mean Difference (95%CI) P Salt substitute Regular salt Mean Difference (95%CI) P Use of anti-hypertensive agent(n=3690) -2.10±1.73 2.27±2.27 -4.38(-6.08,-2.67) <0.001 2.48±0.82 2.27±2.27 -1.31(-2.42,-0.21) 0.020 One kind of anti-hypertensive drugs(n=1771) -6.38±4.14 -1.70±4.13 -4.68(-6.66,-2.69) <0.001 1.33±2.42 2.69±2.41 -1.37(-2.55,-0.18) 0.025 Two kind of anti-hypertensive drugs(n=1539) -1.70±3.01 2.05±2.95 -3.75(-6.02,-1.48) 0.001 1.90±1.83 3.23±1.79 -1.33(-2.84,0.17) 0.082 More than two kind of anti-hypertensive drugs(n=380) -1.41±5.76 4.94±5.60 -6.35(-10.49,-2.21) 0.003 0.96±3.09 2.07±3.01 -1.11(-3.46,1.23) 0.352 No use of anti-hypertensive agent(n=521) -1.78±3.27 -2.67±3.24 0.89(-2.32,4.10) 0.590 4..01±1.88 2.66±1.86 1.35(-0.43,3.12) 0.136 Table 4. Effect of salt substitute on blood pressure (BP) changes under different Anti-hypertensive medication subgroups . Subgroup SBP change from baseline DBP change from baseline Salt substitute Regular salt Mean Difference (95%CI) P Salt substitute Regular salt Mean Difference (95%CI) P Use of Calcium antagonist -0.13±2.74 3.79±2.71 -3.92(-5.84,-2.01) <0.001 3.31±1.61 4.24±1.59 -0.94(-2.12,0.25) 0.123 Use of ACEI/ARB -4.80±4.48 0.99±4.38 -5.79(-9.10,-2.48) <0.001 1.04±2.65 2.56±2.58 -1.52(-3.51,0.47) 0.130 Use of Diuretic 2.14±5.89 8.21±5.93 -6.07(-9.27,-2.87) <0.001 0.37±3.26 2.18±3.28 -1.81(-3.82,0.19) 0.077 Use of β-blocker 15.88±7.13 15.63±7.23 0.25(-5.69,6.19) 0.933 7.02±3.87 5.62±3.92 1.39(-1.74,4.52) 0.380 Use of α-blocker 13.05±12.23 20.48±11.91 -7.43(-19.20,4.34) 0.209 13.03±6.92 17.68±6.66 -4.65(-11.48,2.19) 0.177 b Accounting for clustering effects (village), the combined effect of medication use and salt substitute on BP was tested using linear mixed models with the difference of BP from baseline to the latest follow-up for each participant included in the dependent variable, baseline measurement of blood pressure, group allocation (intervention vs. control), use of medication (use of anti-hypertensive medication vs. no use of anti-hypertensive medication, use of anti-platelet medication vs. no use of anti-platelet medication, and use of lipid-lowering medication vs. no use of lipid-lowering medication), the interaction between group allocation and anti-hypertensive medication use as well as the interaction between group allocation and different kind of anti-hypertensive medication use included in the fixed effect. Additional Declarations No competing interests reported. Supplementary Files TableS1.docx Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4333779","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":299496637,"identity":"67fa520e-f4c4-42d1-90bf-a49a78b92d6b","order_by":0,"name":"Zijing Qi","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAwUlEQVRIiWNgGAWjYDACZoaEA0CKh5+Z+fAD0rRItrOlGZBmm8F5HgUJolTKtzM8PFzwy1rG+DAPgwFDjU00QS2MzQwJh2f2pfOYHeY98IDhWFpuAyEtzEC/HObtOQzUwpdgwNhwmLAWNpgW42YeAwmitPCAtPD8OMxjwEysFgmwLQ3pPBKHgYGcQIxf5PvPJH/m+WNtz99/+PCDDzU2hLUAnZbAwNjGDGEnEFYOAuwHGBj+MBOndhSMglEwCkYmAAB2hToAF0QcpAAAAABJRU5ErkJggg==","orcid":"","institution":"Shanxi Medical University","correspondingAuthor":true,"prefix":"","firstName":"Zijing","middleName":"","lastName":"Qi","suffix":""},{"id":299496640,"identity":"bc8a06f0-4cb4-4f2f-8561-cc4054bd4d62","order_by":1,"name":"shuai Tang","email":"","orcid":"","institution":"Shanxi Medical University","correspondingAuthor":false,"prefix":"","firstName":"shuai","middleName":"","lastName":"Tang","suffix":""},{"id":299496643,"identity":"67d4b057-b52d-4ed5-a654-a2ff8274a8ef","order_by":2,"name":"Yubing Hao","email":"","orcid":"","institution":"Shanxi Medical University","correspondingAuthor":false,"prefix":"","firstName":"Yubing","middleName":"","lastName":"Hao","suffix":""},{"id":299496646,"identity":"35023256-7d60-426a-8f13-8b8fcdf80919","order_by":3,"name":"Yanxing Li","email":"","orcid":"","institution":"Shanxi Medical University","correspondingAuthor":false,"prefix":"","firstName":"Yanxing","middleName":"","lastName":"Li","suffix":""},{"id":299496647,"identity":"247268a9-8b05-4e89-9726-741bc40c0277","order_by":4,"name":"Tianyou Hao","email":"","orcid":"","institution":"Affiliated Heping hospital of Changzhi medical college","correspondingAuthor":false,"prefix":"","firstName":"Tianyou","middleName":"","lastName":"Hao","suffix":""},{"id":299496648,"identity":"72e0934d-e427-4dea-a4de-743e388cc8b2","order_by":5,"name":"Hongmei Yang","email":"","orcid":"","institution":"Changzhi Medical College","correspondingAuthor":false,"prefix":"","firstName":"Hongmei","middleName":"","lastName":"Yang","suffix":""},{"id":299496649,"identity":"5ed4e0f6-7c8a-49f8-9a25-2199929c2584","order_by":6,"name":"Yijing Shen","email":"","orcid":"","institution":"Shanxi Datong University","correspondingAuthor":false,"prefix":"","firstName":"Yijing","middleName":"","lastName":"Shen","suffix":""},{"id":299496650,"identity":"a1d19206-b8c4-49cc-a4c1-bc2734cc489a","order_by":7,"name":"Liping Huang","email":"","orcid":"","institution":"University of New South Wales","correspondingAuthor":false,"prefix":"","firstName":"Liping","middleName":"","lastName":"Huang","suffix":""},{"id":299496652,"identity":"3e199847-870a-4aa1-ad48-4563ccf3c91e","order_by":8,"name":"Maoyi Tian","email":"","orcid":"","institution":"University of New South Wales","correspondingAuthor":false,"prefix":"","firstName":"Maoyi","middleName":"","lastName":"Tian","suffix":""},{"id":299496654,"identity":"bdf3e379-8871-4401-b0b5-c1341c0dea03","order_by":9,"name":"Xiangxian Feng","email":"","orcid":"","institution":"Changzhi Medical College","correspondingAuthor":false,"prefix":"","firstName":"Xiangxian","middleName":"","lastName":"Feng","suffix":""},{"id":299496655,"identity":"98dfda20-035f-4057-abab-dc671b8cd101","order_by":10,"name":"Zhifang Li","email":"","orcid":"","institution":"Shanxi Medical University","correspondingAuthor":false,"prefix":"","firstName":"Zhifang","middleName":"","lastName":"Li","suffix":""}],"badges":[],"createdAt":"2024-04-27 11:28:27","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4333779/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4333779/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":56196712,"identity":"87ba8c9c-c92a-404b-9ab5-9c3afc481acd","added_by":"auto","created_at":"2024-05-09 18:12:04","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":54216,"visible":true,"origin":"","legend":"\u003cp\u003eSee image above for figure legend.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-4333779/v1/70164c0ed4612b974dfeb0e2.png"},{"id":56196413,"identity":"6aedce11-306e-415d-ad58-077ec6b887bf","added_by":"auto","created_at":"2024-05-09 18:10:28","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":40423,"visible":true,"origin":"","legend":"\u003cp\u003eSee image above for figure legend.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-4333779/v1/958f81096192a17ea94003f8.png"},{"id":88877851,"identity":"eb65c173-fedf-4cbf-ae03-5a4d9b47a47d","added_by":"auto","created_at":"2025-08-12 10:31:57","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1259658,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4333779/v1/3a357fc9-e4ab-44b7-a8dd-be05698b2d19.pdf"},{"id":56196538,"identity":"09df7a01-1693-48a0-bc11-0eae1452aec0","added_by":"auto","created_at":"2024-05-09 18:11:16","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":18152,"visible":true,"origin":"","legend":"","description":"","filename":"TableS1.docx","url":"https://assets-eu.researchsquare.com/files/rs-4333779/v1/95a11bc803ce10100956c061.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Effect of salt substitute and medication use among high cardiovascular risk patients","fulltext":[{"header":"1. Introduction","content":"\u003cp\u003eCardiovascular diseases (CVD) are the leading cause of death in worldwide and China, and the health and economic burden of CVD is rising along with the intensification of population aging\u003csup\u003e\u003cspan additionalcitationids=\"CR2\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e. It is estimated that approximately 330\u0026nbsp;million individuals are affected by CVD and 245\u0026nbsp;million cases of hypertension in China\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e. Secondary prevention based on anti-hypertensive drug has been widely used to control the main risk factors\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e. At present, the improvement of the burden of cardiovascular disease is largely related to insisting on drug treatment and controlling risk factors in a targeted manner. In addition, reducing sodium intake are a fundamental lifestyle change to blood pressure control and reduction of cardiovascular diseases\u003csup\u003e\u003cspan additionalcitationids=\"CR6 CR7 CR8\" citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eGuidelines on CVD prevention\u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e,\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e recommends sodium reduction before and concurrently with pharmacologic interventions for high risk patients\u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e,\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e. Salt substitute, which replaces a proportion of sodium chloride in regular salt with potassium chloride, combines the benefits of sodium reduction and potassium supplementation and is expected to become a more cost-effective non-pharmacological intervention \u003csup\u003e\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e,\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e. As a salt reduction strategy, salt substitute has been proved to be effective in lowering blood pressure and preventing cardiovascular events\u003csup\u003e\u003cspan additionalcitationids=\"CR17\" citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003e. Previous studies show that salt substitute could greatly reduce blood pressure in hypertensive people compared with the normotensive people, but it was not clear whether this effect was related to the use of anti-hypertensive drugs.\u003c/p\u003e \u003cp\u003eHowever, it was uncertain whether the combination of salt substitute and anti-hypertensive drugs could better lower blood pressure and even prevent adverse cardiovascular events. In this study, we used data from the SSaSS study collected in Shanxi Province to investigate the combination of salt substitute and anti-hypertensive drugs on blood pressure changes and adverse cardiovascular events among cardiovascular high-risk population.\u003c/p\u003e"},{"header":"2. Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003e2.1. Study design and participants\u003c/h2\u003e \u003cp\u003eThe SSaSS was an open-label, cluster-randomized trial involving 600 villages in five provinces (Hebei, Liaoning, Ningxia, Shanxi, and Shaanxi) in Northern China\u003csup\u003e\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e. Two counties from each province were selected based on prior collaboration and approximately 35 participants were recruited from each village. Participants were at high cardiovascular risk with a history of stroke and/or \u0026ge;\u0026thinsp;60 years old with poorly controlled blood pressure (systolic blood pressure\u0026thinsp;\u0026ge;\u0026thinsp;140mmHg if receiving blood-pressure-lowering medication or \u0026ge;\u0026thinsp;160 mm Hg if not)\u003csup\u003e\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e. In this analysis, participants from Shanxi Province were included.\u003c/p\u003e \u003cp\u003eRecruitment in Shanxi province was done from July 2014 to August 2014. After all participants had been recruited and all baseline survey data had been collected, randomization was stratified according to county (60 villages in each county) with the use of a central computerized process. Villages were randomly allocated to either the intervention or control group at a 1:1 ratio. Participants in the intervention group were provided with enough salt substitute free of charge to replace all household use of regular salt. The salt substitute used for the intervention comprised 75% sodium chloride and 25% potassium chloride. Participants in the control group continued to use regular salt. Central ethics approval was obtained from the ethics committee of The University of Sydney and Peking University Health Science Centre. All participants provided informed content.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003e2.2. Follow-up and Outcomes\u003c/h2\u003e \u003cp\u003eFollow-up for major adverse cardiovascular outcomes was conducted between August 2014 and October 2019 at 6-month intervals through a combination of face-to-face visits to participants and searching routinely collected health data \u0026ndash; New Rural Cooperative Medical Scheme and National Mortality Surveillance System. If a possible event was identified through the face-to-face visits or routinely collected health data, additional information was sought from participants, their family members and any medical facilities that the participant had visited during the illness, whenever possible. All suspected outcomes were ascertained by an independent adjudication committee with any information available.\u003c/p\u003e \u003cp\u003eAs one of the process surveys, blood pressure was measured at 12-month intervals. In the process evaluation survey in the middle follow-up year (in total 6 surveys), the same number of intervention villages and control villages were randomly selected to form sub-samples (at least 12 villages). And approximately 20 participants were invited from each village. Blood pressure was measured using automated blood pressure monitors. However, in this study, the pairwise blood pressure difference between baseline survey and the end of the trial was used as the change of blood pressure. Participants who did not participate in the terminal blood pressure measurement due to illness (such as hospitalization) were replaced by the blood pressure value of their last follow-up visit.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003e2.3. Statistical analysis\u003c/h2\u003e \u003cp\u003eThe primary study endpoints were major adverse cardiovascular events. The secondary outcome of interest in this analysis was the difference between the salt substitute group and the regular salt group in the change of blood pressure from baseline to the end of the trial under different medication subgroups.\u003c/p\u003e \u003cp\u003eTo determine the effect of salt substitute on blood pressure and cardiovascular event risk, we used a linear mixed model and a generalized linear model for data analysis respectively, adjusting for the cluster variables (village) as well as potential confounding variables. After adjusting the potential confounding factors including age, sex(male\u0026thinsp;=\u0026thinsp;1; female\u0026thinsp;=\u0026thinsp;2), BMI(\u0026gt;24.6\u0026thinsp;=\u0026thinsp;1;\u0026le;24.6\u0026thinsp;=\u0026thinsp;2), baseline blood pressure(SBP\u0026gt;141\u0026thinsp;=\u0026thinsp;1;\u0026le;141\u0026thinsp;=\u0026thinsp;2; DBP\u0026gt;79\u0026thinsp;=\u0026thinsp;1;\u0026le;79\u0026thinsp;=\u0026thinsp;2), disease history(stroke or not;hypertension or not) and cardiovascular (use of anti-hypertensive agent or not, use of anti-platelet agent or not, and use of lipid-lowering agent or not), as well as the cluster variable, the incidence of endpoint events and Risk Ratio between the salt substitute group and the regular salt group were analyzed under different anti-hypertensive drugs stratification. The blood pressure changes of each participant from baseline to the end of the trial were set as dependent variable, and the effects of different anti-hypertensive drugs and salt substitute on blood pressure were evaluated by linear mixed model. Taking the incidence of each participant as the dependent variable, the generalized linear mixed model was used to evaluate the effects of different anti-hypertensive drugs and salt substitution on major cardiovascular adverse events.\u003c/p\u003e \u003cp\u003eThe main analysis was based on the intention-to-treat principle. Two-sided p values less than 0.05 were considered statistically significant and we did not adjust for multiple testing. Analyses were performed with the use of SPSS statistical software (IBM SPSS Statistics for Windows, Version 27.0. Armonk, NY, USA) and R version 4.3.2 and R studio version 2022.12.0 Build 353. Packages \u0026ldquo;forestplot\u0026rdquo; were used for statistical analysis and summarizing results.\u003c/p\u003e \u003c/div\u003e"},{"header":"3. Results","content":"\u003ch2\u003e\u003cstrong\u003e\u003cem\u003e3.1 Baseline characteristics\u003c/em\u003e\u003c/strong\u003e\u003c/h2\u003e\n\u003cp\u003eA total of 4211 participants at\u0026nbsp;high\u0026nbsp;cardiovascular\u0026nbsp;risk\u0026nbsp;were included in the analysis (Figure 1). The mean age for all participants was 63.44 years old at baseline, 56.33% were male, 96.96% had a history of stroke, and 90.00% reported having received a diagnosis of hypertension; 87.63% took anti-hypertensive agent, 57.58% took anti-platelet agent, 22.89% took lipid-lowering agent.Among the participants who used at least one blood pressure-lowering medication, 59.27% were using calcium antagonist, 17.62% were using angiotensin-converting to enzyme inhibitor or angiotensin-receptor blocker\u0026nbsp;(ARB/ACEi), 11.90% were using diuretic. Demographic characteristics of\u0026nbsp;salt substitute\u0026nbsp;group and regular salt group are basically balanced (Table 1).\u0026nbsp;Supplementary Table 1 lists the baseline characteristics from the two groups \u0026nbsp;of the participants who took anti-hypertensive drugs or not.\u003c/p\u003e\n\u003ch2\u003e\u003cstrong\u003e\u003cem\u003e3.2 Effect of medication use and salt substitute on the risk of\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cem\u003eadverse\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cem\u003ecardiovascular events\u003c/em\u003e\u003c/strong\u003e\u003c/h2\u003e\n\u003cp\u003eDuring a mean follow-up period of 4.66 years, a total of 660 participants had 731 major adverse cardiovascular events, and 779 participants died. The salt substitute showed a significant role in reducing the risk of adverse cardiovascular events (34.22 events vs. 40.25 events per 1000 person-years; rate ratio, 0.86; 95% CI, 0.74 to 0.99; P = 0.038), after adjusting the confounding factors. The salt substitute reduced risk of adverse cardiovascular events (25.59 vs.32.58; rate ratio 0.82, 95%CI: 0.69 to 0.96, P = 0.016) among the participants who took anti-hypertensive agent, while no significant effect in the participants who did not take any anti-hypertensive drugs.(Table 2).\u003c/p\u003e\n\u003cp\u003eAmong the people taking different anti-hypertensive agent, the significant effect of salt substitute was also observed in the subgroups taking ACEI/ARB (4.57 vs.7.87, rate ratio 0.61, 95%CI: 0.43 to 0.88, p = 0.01) and \u003cem\u003e\u0026alpha;\u003c/em\u003e-blocker (0.20 vs.1.23, rate ratio 0.19, 95%CI: 0.04 to 0.80, p = 0.02). Using diuretic, Calcium antagonist or \u003cem\u003e\u0026beta;\u003c/em\u003e-blocker did not impact the effect of salt substitute on the risk of adverse cardiovascular events of the sample population (P \u0026gt;0.05) (Figure2).\u003c/p\u003e\n\u003ch2\u003e\u003cstrong\u003e\u003cem\u003e3.3 Effect of medication use and salt substitute on blood pressure\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003c/h2\u003e\n\u003cp\u003eUsing anti-hypertensive agent combined salt substitute had a significant effect on lowering systolic blood pressure, with a mean difference of -4.38 mmHg (95% CI: -6.08 to -2.67, p\u0026lt;0.001) between the salt substitute group and the regular salt group. While among participants who did not take any anti-hypertensive agent, the mean SBP change from baseline to the end of trial were not being statistically significant with a mean difference of 0.89mmHg(95%CI:-2.32 to 4.10;P=0.590) between the salt substitute group and the regular salt group (Table 3).\u003c/p\u003e\n\u003cp\u003eAmong participants who took different anti-hypertensive drugs, the systolic blood pressure of participants taking calcium antagonists, ACEI/ARB or diuretics was significantly lower in the salt substitute group than that in the regular salt group, but there was no significant difference in the diastolic blood pressure group (Table 4). \u003c/p\u003e"},{"header":"4. Discussion","content":"\u003cp\u003eThrough the five-year follow-up intervention in high cardiovascular risk patients with a history of stroke or hypertension from 120 villages of Shanxi Province, the results emphasized that combining salt substitute with anti-hypertensive drug therapy significantly decrease blood pressure and the incidence of major cardiovascular adverse events. Prior studies which focused on the relationship between sodium reduction and salt substitution had demonstrated that salt reduction was additive to anti-hypertensive treatments\u003csup\u003e\u003cspan additionalcitationids=\"CR21\" citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e. However, a meta-analysis showed that use of anti-hypertensive agent had little effect on the BP effects of sodium reduction\u003csup\u003e\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u003c/sup\u003e. There were two reasons for this result: all the studies included in the meta-analysis were experimental studies, not population studies and the subjects included involved both hypertensive patients and non-hypertensive patients. In the present trial, combining anti-hypertensive agent with salt substitute reducing systolic blood pressure by 4.38 mmHg (P\u0026thinsp;\u0026lt;\u0026thinsp;0.001) and diastolic blood pressure for 1.31 mmHg (P for interaction\u0026thinsp;=\u0026thinsp;0.020) than with regular salt, which was consistent with the result of a pilot study in hypertension patients that salt substitute showed potential in reducing blood pressure and reducing use of anti-hypertensive agents\u003csup\u003e\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eMaintaining long-term stability of blood pressure is also conducive to reducing the risk of cardiovascular adverse events\u003csup\u003e\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e\u003c/sup\u003e. All kinds of anti-hypertensive drugs could reduce the risk of cardiovascular events in high-risk population to varying degrees. However prior study have emphasized that the protective effect of risk reduction came from the reduction of blood pressure itself, rather than the specificity of any certain anti-hypertensive drugs\u003csup\u003e\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e\u003c/sup\u003e. The results of this study showed that salt substitute reduced the risk of adverse cardiovascular events in participants taking ACEI/ARB (RR: 0.61; 95%CI: 0.43\u0026thinsp;~\u0026thinsp;0.88; P\u0026thinsp;=\u0026thinsp;0.008) is particularly effective. Whether the combination of salt substitute and specific anti-hypertensive drugs could offer more significant protective effect needs to be verified in a wider range of people.\u003c/p\u003e \u003cp\u003e In terms of cardiovascular endpoint events, a significant risk reduction was observed in salt substitute group among the participants who took anti-hypertensive agents, especially for subgroup in use of only one kind of anti-hypertensive drugs. On the one hand, it might be related to the size of sample population: the proportion of participants taking one kind of anti-hypertensive drug(42.06%) was slightly larger than that taking two kind of anti-hypertensive drugs(36.55%) and those taking more two kind of anti-hypertensive drugs (9.02%). The larger the sample population, the more endpoint events can be observed. On the other hand, it might be related to the risk of cardiovascular events: participants who take kinds of anti-hypertensive drugs represent their own high risk of uncontrolled blood pressure to a certain extent\u003csup\u003e\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e\u003c/sup\u003e, thus the protective effect of salt substitute might be limited in such patients.\u003c/p\u003e \u003cp\u003eNevertheless, to the best of our knowledge, the study represented the pioneering investigation into the combined effects between salt substitutes and various medications. This study also has some limitations. First, our sample population was derived solely from the SSASS trial conducted in Shanxi province. The relatively small sample size might restrict the extrapolation of the result. More interaction between different medications and salt substitute need to be studied in a wider population. Second, diseases often required an extended period for their occurrence and progression, while both medication treatment and salt substitution necessitate the preventive effect of also needs a long period. Prolonged utilization of salt substitution is likely to yield superior outcomes in terms of blood pressure control as well as disease prevention compared to short-term use alone. Regrettably, this study only encompassed a five-year follow-up period with limited incidence rates that might have constrained the evaluation of such interactions. Consequently, future research endeavors will focus on conducting longer post-intervention follow-ups to comprehensively observe the interplay between salt substitute usage and medication use.\u003c/p\u003e \u003cp\u003eIn conclusion, our study found combining salt substitute with anti-hypertensive agent could be significantly conducive to blood pressure control and the risk reduction of major adverse cardiovascular events among high cardiovascular risk patients with a history of stroke or hypertension.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e This study was a sub-study supported by the National Health and Medical Research Council of Australia (NHMRC) Project Grant (APP1049417), NHMRC Program Grant (APP1052555), and NHMRC Centre for Research Excellence Grant (APP1117300).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflicts of interests\u003c/strong\u003e The authors declare no conflict of interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval\u0026nbsp;\u003c/strong\u003eThe ethic of this study has been approved by according to the guidelines of the Declaration of Helsinki and was approved by the Center for Health Sciences at Peking University in China (Peking University Institutional Review Board, IRB00001052-13069, September 2013) and the Institutional Review Board at the University of Sydney, Australia (University of Sydney Ethics Committee, 2013/888, June 2013).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eInformed consent\u003c/strong\u003e Informed consent was obtained from all subjects involved in the study.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eContributors\u0026nbsp;\u003c/strong\u003eConceptualization, Z.Q., S.T.\u0026nbsp;and Z.L; methodology, L.H., M.T., X.F. and Z.L; software, Z.Q., S.T.; validation, Y.H., Y.L., T.H., H.Y. and Y.S; formal analysis, Y.H., Y.L., T.H., H.Y. and Y.S; investigation, Y.H., Y.L., T.H., H.Y. and Y.S.; resources, T.H., H.Y.; data curation, Y.L.; writing\u0026mdash;original draft preparation, Z.Q. and S.T.; writing\u0026mdash;review and editing, Z.Q., S.T., Y.H., L.H., M.T., X.F. and Z.L.; visualization, T.H., H.Y. and Y.S.; supervision, L.H.,M.T., X.F. and Z.L.; project administration, X.F. and Z.L.; funding acquisition, Z.L. All authors have read and agreed to the published version of the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability\u0026nbsp;\u003c/strong\u003eThe data that support the findings of this study are available from the corresponding author, upon reasonable request.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eMensah, G. A., Roth, G. A. \u0026amp; Fuster, V. The Global Burden of Cardiovascular Diseases and Risk Factors: 2020 and Beyond. Journal of the American College of Cardiology 74, 2529\u0026ndash;2532, doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.jacc.2019.10.009\u003c/span\u003e\u003cspan address=\"10.1016/j.jacc.2019.10.009\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2019).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRoth, G. A. \u003cem\u003eet al.\u003c/em\u003e Global Burden of Cardiovascular Diseases and Risk Factors, 1990\u0026ndash;2019: Update From the GBD 2019 Study. Journal of the American College of Cardiology 76, 2982\u0026ndash;3021, doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.jacc.2020.11.010\u003c/span\u003e\u003cspan address=\"10.1016/j.jacc.2020.11.010\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2020).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZhao, D., Liu, J., Wang, M., Zhang, X. \u0026amp; Zhou, M. J. N. R. C. Epidemiology of cardiovascular disease in China: current features and implications. 16, 203\u0026ndash;212 (2019).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eReport on Cardiovascular Health and Diseases in China 2021: An Updated Summary. Biomedical and environmental sciences: BES 35, 573\u0026ndash;603, doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.3967/bes2022.079\u003c/span\u003e\u003cspan address=\"10.3967/bes2022.079\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2022).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePharmacological blood pressure lowering for primary and secondary prevention of cardiovascular disease across different levels of blood pressure: an individual participant-level data meta-analysis. Lancet (London, England) 397, 1625\u0026ndash;1636, doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/s0140-6736(21)00590-0\u003c/span\u003e\u003cspan address=\"10.1016/s0140-6736(21)00590-0\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2021).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKarunathilake, S. P. \u0026amp; Ganegoda, G. U. Secondary Prevention of Cardiovascular Diseases and Application of Technology for Early Diagnosis. \u003cem\u003eBioMed research international\u003c/em\u003e 2018, 5767864, doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1155/2018/5767864\u003c/span\u003e\u003cspan address=\"10.1155/2018/5767864\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2018).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFrancula-Zaninovic, S. \u0026amp; Nola, I. A. Management of Measurable Variable Cardiovascular Disease' Risk Factors. Current cardiology reviews 14, 153\u0026ndash;163, doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.2174/1573403x14666180222102312\u003c/span\u003e\u003cspan address=\"10.2174/1573403x14666180222102312\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2018).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLeong, D. P. \u003cem\u003eet al.\u003c/em\u003e Reducing the Global Burden of Cardiovascular Disease, Part 2: Prevention and Treatment of Cardiovascular Disease. Circulation research 121, 695\u0026ndash;710, doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1161/circresaha.117.311849\u003c/span\u003e\u003cspan address=\"10.1161/circresaha.117.311849\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2017).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMehta, S. \u003cem\u003eet al.\u003c/em\u003e Cardiovascular preventive pharmacotherapy stratified by predicted cardiovascular risk: a national data linkage study. European journal of preventive cardiology 28, 1905\u0026ndash;1913, doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1093/eurjpc/zwaa168\u003c/span\u003e\u003cspan address=\"10.1093/eurjpc/zwaa168\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2022).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCarey, R. M., Wright, J. T., Jr., Taler, S. J. \u0026amp; Whelton, P. K. Guideline-Driven Management of Hypertension: An Evidence-Based Update. Circulation research 128, 827\u0026ndash;846, doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1161/circresaha.121.318083\u003c/span\u003e\u003cspan address=\"10.1161/circresaha.121.318083\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2021).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAtar, D. \u003cem\u003eet al.\u003c/em\u003e New cardiovascular prevention guidelines: How to optimally manage dyslipidaemia and cardiovascular risk in 2021 in patients needing secondary prevention? \u003cem\u003eAtherosclerosis\u003c/em\u003e 319, 51\u0026ndash;61, doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.atherosclerosis.2020.12.013\u003c/span\u003e\u003cspan address=\"10.1016/j.atherosclerosis.2020.12.013\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2021).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGasperi, V., Catani, M. V. \u0026amp; Savini, I. Platelet Responses in Cardiovascular Disease: Sex-Related Differences in Nutritional and Pharmacological Interventions. \u003cem\u003eCardiovascular therapeutics\u003c/em\u003e 2020, 2342837, doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1155/2020/2342837\u003c/span\u003e\u003cspan address=\"10.1155/2020/2342837\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2020).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKorhonen, M. J. \u003cem\u003eet al.\u003c/em\u003e Lifestyle Changes in Relation to Initiation of Antihypertensive and Lipid-Lowering Medication: A Cohort Study. Journal of the American Heart Association 9, e014168, doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1161/jaha.119.014168\u003c/span\u003e\u003cspan address=\"10.1161/jaha.119.014168\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2020).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYuan, Y. \u003cem\u003eet al.\u003c/em\u003e Salt substitution and salt-supply restriction for lowering blood pressure in elderly care facilities: a cluster-randomized trial. Nature medicine 29, 973\u0026ndash;981, doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1038/s41591-023-02286-8\u003c/span\u003e\u003cspan address=\"10.1038/s41591-023-02286-8\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2023).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYu, J. \u003cem\u003eet al.\u003c/em\u003e Effects of a reduced-sodium added-potassium salt substitute on blood pressure in rural Indian hypertensive patients: a randomized, double-blind, controlled trial. The American journal of clinical nutrition 114, 185\u0026ndash;193, doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1093/ajcn/nqab054\u003c/span\u003e\u003cspan address=\"10.1093/ajcn/nqab054\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2021).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSun, H., Ma, B., Wu, X., Wang, H. \u0026amp; Zhou, B. Long-Term Effect of Salt Substitute on All-Cause and Cardiovascular Disease Mortality: An Exploratory Follow-Up of a Randomized Controlled Trial. Frontiers in cardiovascular medicine 8, 645902, doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.3389/fcvm.2021.645902\u003c/span\u003e\u003cspan address=\"10.3389/fcvm.2021.645902\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2021).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNeal, B. \u003cem\u003eet al.\u003c/em\u003e Effect of Salt Substitution on Cardiovascular Events and Death. The New England journal of medicine 385, 1067\u0026ndash;1077, doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1056/NEJMoa2105675\u003c/span\u003e\u003cspan address=\"10.1056/NEJMoa2105675\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2021).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZhou, B. \u003cem\u003eet al.\u003c/em\u003e Intake of low sodium salt substitute for 3years attenuates the increase in blood pressure in a rural population of North China - A randomized controlled trial. International journal of cardiology 215, 377\u0026ndash;382, doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.ijcard.2016.04.073\u003c/span\u003e\u003cspan address=\"10.1016/j.ijcard.2016.04.073\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2016).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNeal, B. \u003cem\u003eet al.\u003c/em\u003e Rationale, design, and baseline characteristics of the Salt Substitute and Stroke Study (SSaSS)-A large-scale cluster randomized controlled trial. American heart journal 188, 109\u0026ndash;117, doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.ahj.2017.02.033\u003c/span\u003e\u003cspan address=\"10.1016/j.ahj.2017.02.033\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2017).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHe, F. J., Tan, M., Ma, Y. \u0026amp; MacGregor, G. A. Salt Reduction to Prevent Hypertension and Cardiovascular Disease: JACC State-of-the-Art Review. Journal of the American College of Cardiology 75, 632\u0026ndash;647, doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.jacc.2019.11.055\u003c/span\u003e\u003cspan address=\"10.1016/j.jacc.2019.11.055\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2020).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGreer, R. C. \u003cem\u003eet al.\u003c/em\u003e Potassium-Enriched Salt Substitutes as a Means to Lower Blood Pressure: Benefits and Risks. \u003cem\u003eHypertension (Dallas, Tex.\u003c/em\u003e: 1979) 75, 266\u0026ndash;274, doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1161/hypertensionaha.119.13241\u003c/span\u003e\u003cspan address=\"10.1161/hypertensionaha.119.13241\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2020).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSudano, I., Osto, E. \u0026amp; Ruschitzka, F. Blood Pressure-Lowering Therapy. Handbook of experimental pharmacology 270, 25\u0026ndash;45, doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1007/164_2020_372\u003c/span\u003e\u003cspan address=\"10.1007/164_2020_372\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2022).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFilippini, T. \u003cem\u003eet al.\u003c/em\u003e Blood Pressure Effects of Sodium Reduction: Dose-Response Meta-Analysis of Experimental Studies. Circulation 143, 1542\u0026ndash;1567, doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1161/circulationaha.120.050371\u003c/span\u003e\u003cspan address=\"10.1161/circulationaha.120.050371\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2021).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMu, L. \u003cem\u003eet al.\u003c/em\u003e A pilot study on efficacy and safety of a new salt substitute with very low sodium among hypertension patients on regular treatment. Medicine 99, e19263, doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1097/md.0000000000019263\u003c/span\u003e\u003cspan address=\"10.1097/md.0000000000019263\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2020).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLu, J. \u003cem\u003eet al.\u003c/em\u003e Secondary prevention of cardiovascular disease in China. Heart (British Cardiac Society) 106, 1349\u0026ndash;1356, doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1136/heartjnl-2019-315884\u003c/span\u003e\u003cspan address=\"10.1136/heartjnl-2019-315884\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2020).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eThomopoulos, C., Parati, G. \u0026amp; Zanchetti, A. Effects of blood pressure lowering on outcome incidence in hypertension: 4. Effects of various classes of antihypertensive drugs \u0026ndash; Overview and meta-analyses. 33, 195\u0026ndash;211, doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1097/hjh.0000000000000447\u003c/span\u003e\u003cspan address=\"10.1097/hjh.0000000000000447\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2015).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCherfane, M. \u003cem\u003eet al.\u003c/em\u003e Risk factors for uncontrolled blood pressure among individuals with hypertension on treatment: the CONSTANCES population-based study. Int J Epidemiol 53, doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1093/ije/dyae027\u003c/span\u003e\u003cspan address=\"10.1093/ije/dyae027\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2024).\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003e\u003cstrong\u003eTable 1.\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eBas\u003c/strong\u003e\u003cstrong\u003eic\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;characteristics of\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eoverall\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;participants\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;in the\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003etrial\u003c/strong\u003e\u003cstrong\u003e.\u003c/strong\u003e\u003c/p\u003e\n\u003cdiv align=\"\"\u003e\n \u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"664\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"35.24096385542169%\"\u003e\n \u003cp\u003e\u003cstrong\u003eBaseline characteristics\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.52409638554217%\"\u003e\n \u003cp\u003e\u003cstrong\u003eTotal\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(n=4211)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.879518072289155%\"\u003e\n \u003cp\u003e\u003cstrong\u003eSalt substitute\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(n=2106)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.018072289156628%\"\u003e\n \u003cp\u003e\u003cstrong\u003eRegular salt\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(n=2105)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.337349397590362%\"\u003e\n \u003cp\u003e\u003cstrong\u003eP\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"35.24096385542169%\"\u003e\n \u003cp\u003e\u003cstrong\u003eSex\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.52409638554217%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.879518072289155%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.018072289156628%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.337349397590362%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"35.24096385542169%\"\u003e\n \u003cp\u003eMale, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.52409638554217%\"\u003e\n \u003cp\u003e2372 (56.33)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.879518072289155%\"\u003e\n \u003cp\u003e1184 (56.22)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.018072289156628%\"\u003e\n \u003cp\u003e1188 (56.44)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.337349397590362%\"\u003e\n \u003cp\u003e0.925\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"35.24096385542169%\"\u003e\n \u003cp\u003eFemale, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.52409638554217%\"\u003e\n \u003cp\u003e1839 (43.67)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.879518072289155%\"\u003e\n \u003cp\u003e922 (43.78)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.018072289156628%\"\u003e\n \u003cp\u003e917 (43.56)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.337349397590362%\"\u003e\n \u003cp\u003e0.915\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"35.24096385542169%\"\u003e\n \u003cp\u003e\u003cstrong\u003eAge, years\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.52409638554217%\"\u003e\n \u003cp\u003e63.44 \u0026plusmn; 8.43\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.879518072289155%\"\u003e\n \u003cp\u003e63.72 \u0026plusmn; 8.29\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.018072289156628%\"\u003e\n \u003cp\u003e63.16 \u0026plusmn; 8.43\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.337349397590362%\"\u003e\n \u003cp\u003e0.030\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"35.24096385542169%\"\u003e\n \u003cp\u003e\u0026le; 64, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.52409638554217%\"\u003e\n \u003cp\u003e2284\u0026nbsp;(54.24)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.879518072289155%\"\u003e\n \u003cp\u003e1102\u0026nbsp;(52.33)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.018072289156628%\"\u003e\n \u003cp\u003e1182\u0026nbsp;(56.15)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.337349397590362%\"\u003e\n \u003cp\u003e0.092\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"35.24096385542169%\"\u003e\n \u003cp\u003e\u0026gt; 64, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.52409638554217%\"\u003e\n \u003cp\u003e1927\u0026nbsp;(45.76)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.879518072289155%\"\u003e\n \u003cp\u003e1004\u0026nbsp;(47.67)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.018072289156628%\"\u003e\n \u003cp\u003e923\u0026nbsp;(43.85)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.337349397590362%\"\u003e\n \u003cp\u003e0.067\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"35.24096385542169%\"\u003e\n \u003cp\u003e\u003cstrong\u003eBMI, kg/m\u003csup\u003e2\u003c/sup\u003e\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.52409638554217%\"\u003e\n \u003cp\u003e24.62 \u0026plusmn; 3.71\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.879518072289155%\"\u003e\n \u003cp\u003e24.49 \u0026plusmn; 3.82\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.018072289156628%\"\u003e\n \u003cp\u003e24.76 \u0026plusmn; 3.59\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.337349397590362%\"\u003e\n \u003cp\u003e0.018\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"35.24096385542169%\"\u003e\n \u003cp\u003e\u0026le; 24.60, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.52409638554217%\"\u003e\n \u003cp\u003e2235 (53.08)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.879518072289155%\"\u003e\n \u003cp\u003e1147 (54.46)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.018072289156628%\"\u003e\n \u003cp\u003e1088 (51.69)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.337349397590362%\"\u003e\n \u003cp\u003e0.216\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"35.24096385542169%\"\u003e\n \u003cp\u003e\u0026gt; 24.60, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.52409638554217%\"\u003e\n \u003cp\u003e1976 (46.92)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.879518072289155%\"\u003e\n \u003cp\u003e959 (45.54)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.018072289156628%\"\u003e\n \u003cp\u003e1017 (48.31)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.337349397590362%\"\u003e\n \u003cp\u003e0.188\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"35.24096385542169%\"\u003e\n \u003cp\u003e\u003cstrong\u003eSBP, mm Hg\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.52409638554217%\"\u003e\n \u003cp\u003e140.57 \u0026plusmn; 21.21\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.879518072289155%\"\u003e\n \u003cp\u003e140.91 \u0026plusmn; 21.02\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.018072289156628%\"\u003e\n \u003cp\u003e140.22 \u0026plusmn; 21.40\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.337349397590362%\"\u003e\n \u003cp\u003e0.291\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"35.24096385542169%\"\u003e\n \u003cp\u003e\u0026lt;140 mmHg, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.52409638554217%\"\u003e\n \u003cp\u003e2215 (52.60)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.879518072289155%\"\u003e\n \u003cp\u003e1109 (52.66)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.018072289156628%\"\u003e\n \u003cp\u003e1106 (52.54)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.337349397590362%\"\u003e\n \u003cp\u003e0.957\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"35.24096385542169%\"\u003e\n \u003cp\u003e\u0026ge;140 and \u0026lt;160 mmHg, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.52409638554217%\"\u003e\n \u003cp\u003e1258 (29.87)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.879518072289155%\"\u003e\n \u003cp\u003e618 (29.34)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.018072289156628%\"\u003e\n \u003cp\u003e640 (30.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.337349397590362%\"\u003e\n \u003cp\u003e0.530\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"35.24096385542169%\"\u003e\n \u003cp\u003e\u0026ge;160 mmHg, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.52409638554217%\"\u003e\n \u003cp\u003e738 (17.53)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.879518072289155%\"\u003e\n \u003cp\u003e379 (18.00)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.018072289156628%\"\u003e\n \u003cp\u003e359 (17.06)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.337349397590362%\"\u003e\n \u003cp\u003e0.466\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"35.24096385542169%\"\u003e\n \u003cp\u003e\u003cstrong\u003eDBP, mm Hg\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.52409638554217%\"\u003e\n \u003cp\u003e78.88 \u0026plusmn; 11.15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.879518072289155%\"\u003e\n \u003cp\u003e78.90 \u0026plusmn; 11.25\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.018072289156628%\"\u003e\n \u003cp\u003e78.86 \u0026plusmn; 11.07\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.337349397590362%\"\u003e\n \u003cp\u003e0.907\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"35.24096385542169%\"\u003e\n \u003cp\u003e\u0026lt;90 mmHg, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.52409638554217%\"\u003e\n \u003cp\u003e3554 (84.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.879518072289155%\"\u003e\n \u003cp\u003e1763 (83.71)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.018072289156628%\"\u003e\n \u003cp\u003e1791 (85.08)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.337349397590362%\"\u003e\n \u003cp\u003e0.628\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"35.24096385542169%\"\u003e\n \u003cp\u003e\u0026ge;90 and \u0026lt;100 mmHg, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.52409638554217%\"\u003e\n \u003cp\u003e488 (11.59)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.879518072289155%\"\u003e\n \u003cp\u003e254 (12.06)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.018072289156628%\"\u003e\n \u003cp\u003e234 (11.12)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.337349397590362%\"\u003e\n \u003cp\u003e0.370\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"35.24096385542169%\"\u003e\n \u003cp\u003e\u0026ge;100 mmHg, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.52409638554217%\"\u003e\n \u003cp\u003e169 (4.01)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.879518072289155%\"\u003e\n \u003cp\u003e89 (4.23)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.018072289156628%\"\u003e\n \u003cp\u003e80 (3.80)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.337349397590362%\"\u003e\n \u003cp\u003e0.492\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"35.24096385542169%\"\u003e\n \u003cp\u003e\u003cstrong\u003eSmoke history\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.52409638554217%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.879518072289155%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.018072289156628%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.337349397590362%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"35.24096385542169%\"\u003e\n \u003cp\u003eEver smoked, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.52409638554217%\"\u003e\n \u003cp\u003e1723 (40.92)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.879518072289155%\"\u003e\n \u003cp\u003e868 (41.22)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.018072289156628%\"\u003e\n \u003cp\u003e855 (40.62)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.337349397590362%\"\u003e\n \u003cp\u003e0.761\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"35.24096385542169%\"\u003e\n \u003cp\u003eCurrent smoker, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.52409638554217%\"\u003e\n \u003cp\u003e714 (16.96)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.879518072289155%\"\u003e\n \u003cp\u003e348 (16.52)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.018072289156628%\"\u003e\n \u003cp\u003e366 (17.39)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.337349397590362%\"\u003e\n \u003cp\u003e0.497\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"35.24096385542169%\"\u003e\n \u003cp\u003e\u003cstrong\u003eDisease history\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.52409638554217%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.879518072289155%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.018072289156628%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.337349397590362%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"35.24096385542169%\"\u003e\n \u003cp\u003eStroke, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.52409638554217%\"\u003e\n \u003cp\u003e4083 (96.96)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.879518072289155%\"\u003e\n \u003cp\u003e2048 (97.25)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.018072289156628%\"\u003e\n \u003cp\u003e2035 (96.67)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.337349397590362%\"\u003e\n \u003cp\u003e0.850\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"35.24096385542169%\"\u003e\n \u003cp\u003eHypertension, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.52409638554217%\"\u003e\n \u003cp\u003e3790 (90.00)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.879518072289155%\"\u003e\n \u003cp\u003e1872 (88.89)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.018072289156628%\"\u003e\n \u003cp\u003e1918 (91.12)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.337349397590362%\"\u003e\n \u003cp\u003e0.446\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"35.24096385542169%\"\u003e\n \u003cp\u003e\u003cstrong\u003eMedication use\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.52409638554217%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.879518072289155%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.018072289156628%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.337349397590362%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"35.24096385542169%\"\u003e\n \u003cp\u003eAnti-hypertensive agent, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.52409638554217%\"\u003e\n \u003cp\u003e3690 (87.63)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.879518072289155%\"\u003e\n \u003cp\u003e1805 (85.71)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.018072289156628%\"\u003e\n \u003cp\u003e1885 (89.55)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.337349397590362%\"\u003e\n \u003cp\u003e0.183\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"35.24096385542169%\"\u003e\n \u003cp\u003e\u003cem\u003eCalcium antagonist\u0026nbsp;\u003c/em\u003e\u003cem\u003e,\u003c/em\u003e\u003cem\u003e\u0026nbsp;n (%)\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.52409638554217%\"\u003e\n \u003cp\u003e2496 (59.27)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.879518072289155%\"\u003e\n \u003cp\u003e1214 (57.64)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.018072289156628%\"\u003e\n \u003cp\u003e1282 (60.90)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.337349397590362%\"\u003e\n \u003cp\u003e0.170\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"35.24096385542169%\"\u003e\n \u003cp\u003e\u003cem\u003eACEI/ARB, n (%)\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.52409638554217%\"\u003e\n \u003cp\u003e742 (17.62)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.879518072289155%\"\u003e\n \u003cp\u003e367 (17.43)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.018072289156628%\"\u003e\n \u003cp\u003e375 (17.81)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.337349397590362%\"\u003e\n \u003cp\u003e0.764\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"35.24096385542169%\"\u003e\n \u003cp\u003e\u003cem\u003eDiuretic, n (%)\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.52409638554217%\"\u003e\n \u003cp\u003e501 (11.90)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.879518072289155%\"\u003e\n \u003cp\u003e266 (12.63)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.018072289156628%\"\u003e\n \u003cp\u003e235 (11.16)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.337349397590362%\"\u003e\n \u003cp\u003e0.168\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"35.24096385542169%\"\u003e\n \u003cp\u003e\u003cem\u003e\u0026beta;-blocker, n (%)\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.52409638554217%\"\u003e\n \u003cp\u003e177 (4.20)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.879518072289155%\"\u003e\n \u003cp\u003e65 (3.09)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.018072289156628%\"\u003e\n \u003cp\u003e112 (5.32)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.337349397590362%\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"35.24096385542169%\"\u003e\n \u003cp\u003e\u003cem\u003e\u0026alpha;-blocker\u003c/em\u003e\u003cem\u003e,\u003c/em\u003e\u003cem\u003e\u0026nbsp;n (%)\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.52409638554217%\"\u003e\n \u003cp\u003e57 (1.35)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.879518072289155%\"\u003e\n \u003cp\u003e19 (0.90)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.018072289156628%\"\u003e\n \u003cp\u003e38 (1.81)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.337349397590362%\"\u003e\n \u003cp\u003e0.012\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"35.24096385542169%\"\u003e\n \u003cp\u003eAnti-platelet agent, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.52409638554217%\"\u003e\n \u003cp\u003e2425 (57.58)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.879518072289155%\"\u003e\n \u003cp\u003e1199 (59.63)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.018072289156628%\"\u003e\n \u003cp\u003e1226 (58.24)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.337349397590362%\"\u003e\n \u003cp\u003e0.575\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"35.24096385542169%\"\u003e\n \u003cp\u003eLipid-lowering agent, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.52409638554217%\"\u003e\n \u003cp\u003e964 (22.89)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.879518072289155%\"\u003e\n \u003cp\u003e488 (23.17)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.018072289156628%\"\u003e\n \u003cp\u003e476 (22.61)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.337349397590362%\"\u003e\n \u003cp\u003e0.704\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003eWhere not specified, values are mean \u0026plusmn; SD\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003e2. Effect of\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003esalt substitute on\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;major adverse cardiovascular events under different Anti-hypertensive\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003emedication subgroups\u003c/strong\u003e\u003cstrong\u003e.\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\"\u003e\n \u003cp\u003e\u003cstrong\u003eSubgroup\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\"\u003e\n \u003cp\u003e\u003cstrong\u003eN\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\"\u003e\n \u003cp\u003e\u003cstrong\u003eno. of events per 1000 person-years\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\"\u003e\n \u003cp\u003e\u003cstrong\u003eRate Ratio (95%CI)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\"\u003e\n \u003cp\u003e\u003cstrong\u003eP\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eSalt substitute\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eRegular salt\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eSalt substitute\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eRegular salt\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eUse of anti-hypertensive agent(n=3690)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1805\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1885\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e28.63\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e35.96\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.82(0.69,0.96)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.016\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eOne kind of anti-hypertensive drugs(n=1771)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e897\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e874\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e14.21\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e18.08\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.75(0.59,0.95)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.019\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eTwo kind of anti-hypertensive drugs(n=1539)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e703\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e836\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e10.66\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e13.79\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.88(0.66,1.17)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.379\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eMore than two kind of anti-hypertensive drugs(n=380)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e205\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e175\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e3.76\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e4.09\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.80(0.47,1.35)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.399\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eNo use of anti-hypertensive agent(n=521)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e301\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e220\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e5.58\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e4.29\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.90(0.61,1.32)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.594\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eAll the participants\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e2106\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e2105\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e34.22\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e40.25\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.86(0.74,0.99)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.038\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003e3. Effect of\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003esalt substitute on blood pressure changes\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;under different Anti-hypertensive\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003emedication subgroups\u003c/strong\u003e\u003cstrong\u003e.\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\"\u003e\n \u003cp\u003e\u003cstrong\u003eSubgroup\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"4\"\u003e\n \u003cp\u003e\u003cstrong\u003eSBP change from baseline\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"4\"\u003e\n \u003cp\u003e\u003cstrong\u003eDBP change from baseline\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eSalt substitute\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eRegular salt\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eMean Difference\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(95%CI)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eP\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eSalt substitute\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eRegular salt\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eMean Difference\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(95%CI)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eP\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eUse of anti-hypertensive agent(n=3690)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e-2.10\u0026plusmn;1.73\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e2.27\u0026plusmn;2.27\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e-4.38(-6.08,-2.67)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e2.48\u0026plusmn;0.82\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e2.27\u0026plusmn;2.27\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e-1.31(-2.42,-0.21)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.020\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eOne kind of anti-hypertensive drugs(n=1771)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e-6.38\u0026plusmn;4.14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e-1.70\u0026plusmn;4.13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e-4.68(-6.66,-2.69)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1.33\u0026plusmn;2.42\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e2.69\u0026plusmn;2.41\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e-1.37(-2.55,-0.18)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.025\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eTwo kind of anti-hypertensive drugs(n=1539)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e-1.70\u0026plusmn;3.01\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e2.05\u0026plusmn;2.95\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e-3.75(-6.02,-1.48)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1.90\u0026plusmn;1.83\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e3.23\u0026plusmn;1.79\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e-1.33(-2.84,0.17)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.082\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eMore than two kind of anti-hypertensive drugs(n=380)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e-1.41\u0026plusmn;5.76\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e4.94\u0026plusmn;5.60\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e-6.35(-10.49,-2.21)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.003\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.96\u0026plusmn;3.09\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e2.07\u0026plusmn;3.01\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e-1.11(-3.46,1.23)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.352\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eNo use of anti-hypertensive agent(n=521)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e-1.78\u0026plusmn;3.27\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e-2.67\u0026plusmn;3.24\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.89(-2.32,4.10)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.590\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e4..01\u0026plusmn;1.88\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e2.66\u0026plusmn;1.86\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1.35(-0.43,3.12)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.136\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cstrong\u003e\u003csup\u003e\u0026nbsp;\u003c/sup\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003e4. Effect of\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003esalt substitute on blood pressure (BP) changes\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;under different Anti-hypertensive\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003emedication subgroups\u003c/strong\u003e\u003cstrong\u003e.\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"17.130620985010708%\" rowspan=\"2\"\u003e\n \u003cp\u003e\u003cstrong\u003eSubgroup\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"42.82655246252676%\" colspan=\"4\"\u003e\n \u003cp\u003e\u003cstrong\u003eSBP change from baseline\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"40.04282655246253%\" colspan=\"4\"\u003e\n \u003cp\u003e\u003cstrong\u003eDBP change from baseline\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"14.470284237726098%\"\u003e\n \u003cp\u003e\u003cstrong\u003eSalt substitute\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.4031007751938%\"\u003e\n \u003cp\u003e\u003cstrong\u003eRegular salt\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.27906976744186%\"\u003e\n \u003cp\u003e\u003cstrong\u003eMean Difference\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(95%CI)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.527131782945736%\"\u003e\n \u003cp\u003e\u003cstrong\u003eP\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.627906976744185%\"\u003e\n \u003cp\u003e\u003cstrong\u003eSalt substitute\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.695090439276486%\"\u003e\n \u003cp\u003e\u003cstrong\u003eRegular salt\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.633074935400517%\"\u003e\n \u003cp\u003e\u003cstrong\u003eMean Difference\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(95%CI)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.364341085271318%\"\u003e\n \u003cp\u003e\u003cstrong\u003eP\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"17.130620985010708%\"\u003e\n \u003cp\u003eUse of\u0026nbsp;Calcium antagonist\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.991434689507495%\"\u003e\n \u003cp\u003e-0.13\u0026plusmn;2.74\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.278372591006423%\"\u003e\n \u003cp\u003e3.79\u0026plusmn;2.71\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.490364025695932%\"\u003e\n \u003cp\u003e-3.92(-5.84,-2.01)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.0663811563169165%\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.635974304068522%\"\u003e\n \u003cp\u003e3.31\u0026plusmn;1.61\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.349036402569594%\"\u003e\n \u003cp\u003e4.24\u0026plusmn;1.59\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.955032119914346%\"\u003e\n \u003cp\u003e-0.94(-2.12,0.25)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.102783725910064%\"\u003e\n \u003cp\u003e0.123\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"17.130620985010708%\"\u003e\n \u003cp\u003eUse of\u0026nbsp;ACEI/ARB\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.991434689507495%\"\u003e\n \u003cp\u003e-4.80\u0026plusmn;4.48\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.278372591006423%\"\u003e\n \u003cp\u003e0.99\u0026plusmn;4.38\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.490364025695932%\"\u003e\n \u003cp\u003e-5.79(-9.10,-2.48)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.0663811563169165%\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.635974304068522%\"\u003e\n \u003cp\u003e1.04\u0026plusmn;2.65\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.349036402569594%\"\u003e\n \u003cp\u003e2.56\u0026plusmn;2.58\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.955032119914346%\"\u003e\n \u003cp\u003e-1.52(-3.51,0.47)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.102783725910064%\"\u003e\n \u003cp\u003e0.130\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"17.130620985010708%\"\u003e\n \u003cp\u003eUse of\u0026nbsp;Diuretic\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.991434689507495%\"\u003e\n \u003cp\u003e2.14\u0026plusmn;5.89\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.278372591006423%\"\u003e\n \u003cp\u003e8.21\u0026plusmn;5.93\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.490364025695932%\"\u003e\n \u003cp\u003e-6.07(-9.27,-2.87)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.0663811563169165%\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.635974304068522%\"\u003e\n \u003cp\u003e0.37\u0026plusmn;3.26\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.349036402569594%\"\u003e\n \u003cp\u003e2.18\u0026plusmn;3.28\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.955032119914346%\"\u003e\n \u003cp\u003e-1.81(-3.82,0.19)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.102783725910064%\"\u003e\n \u003cp\u003e0.077\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"17.130620985010708%\"\u003e\n \u003cp\u003eUse of\u0026nbsp;\u0026beta;-blocker\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.991434689507495%\"\u003e\n \u003cp\u003e15.88\u0026plusmn;7.13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.278372591006423%\"\u003e\n \u003cp\u003e15.63\u0026plusmn;7.23\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.490364025695932%\"\u003e\n \u003cp\u003e0.25(-5.69,6.19)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.0663811563169165%\"\u003e\n \u003cp\u003e0.933\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.635974304068522%\"\u003e\n \u003cp\u003e7.02\u0026plusmn;3.87\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.349036402569594%\"\u003e\n \u003cp\u003e5.62\u0026plusmn;3.92\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.955032119914346%\"\u003e\n \u003cp\u003e1.39(-1.74,4.52)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.102783725910064%\"\u003e\n \u003cp\u003e0.380\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"17.130620985010708%\"\u003e\n \u003cp\u003eUse of\u0026nbsp;\u0026alpha;-blocker\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.991434689507495%\"\u003e\n \u003cp\u003e13.05\u0026plusmn;12.23\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.278372591006423%\"\u003e\n \u003cp\u003e20.48\u0026plusmn;11.91\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.490364025695932%\"\u003e\n \u003cp\u003e-7.43(-19.20,4.34)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.0663811563169165%\"\u003e\n \u003cp\u003e0.209\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.635974304068522%\"\u003e\n \u003cp\u003e13.03\u0026plusmn;6.92\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.349036402569594%\"\u003e\n \u003cp\u003e17.68\u0026plusmn;6.66\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.955032119914346%\"\u003e\n \u003cp\u003e-4.65(-11.48,2.19)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.102783725910064%\"\u003e\n \u003cp\u003e0.177\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003csup\u003eb\u0026nbsp;\u003c/sup\u003eAccounting for clustering effects (village), the combined effect of medication use and salt substitute on BP was tested using linear mixed models with the difference of BP from baseline to the latest follow-up for each participant included in the dependent variable, baseline measurement of blood pressure, group allocation (intervention vs. control), use of medication (use of anti-hypertensive medication vs. no use of anti-hypertensive medication, use of anti-platelet medication vs. no use of anti-platelet medication, and use of lipid-lowering medication vs. no use of lipid-lowering medication), the interaction between group allocation and anti-hypertensive medication use as well as the interaction between group allocation and different kind of anti-hypertensive medication use included in the fixed effect.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"salt substitute, medication, blood pressure, cardiovascular events","lastPublishedDoi":"10.21203/rs.3.rs-4333779/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4333779/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eIntroduction:\u003c/strong\u003e Previous studies have shown that the protective effect of salt substitute varied between the hypertensive population and the normotensive population, but it was not clear whether it was related to cardiovascular drugs. The purpose of this study is to explore the effect of salt substitutes and anti-hypertensive drugs on blood pressure and adverse cardiovascular events.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods:\u003c/strong\u003e 4211 people with a history of stroke or hypertension from 120 villages in Shanxi Province who participated in an open-label cluster randomized controlled trial (SSaSS) were included in this study. Generalized linear mixed models and linear mixed models were used to explore the effect of salt substitute on blood pressure and adverse cardiovascular events in different group of population respectively, adjusting for the stratification variables at randomization (village) as well as potential confounding variables.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults: \u003c/strong\u003eSalt \u0026nbsp;\u0026nbsp;substitute reduced the risk of \u0026nbsp;\u0026nbsp;adverse cardiovascular events in participants who took anti-hypertensive drugs(28.63 events vs. 35.96 events per 1000 person-years; rate \u0026nbsp;\u0026nbsp;ratio, 0.75, 95% CI, 0.59 to 0.95; P=0.016) while no significant \u0026nbsp;effect among the participants who did not take any \u0026nbsp;\u0026nbsp;anti-hypertensive drugs.\u003cstrong\u003e \u003c/strong\u003eSalt substitute \u0026nbsp;reduced the blood pressure in participants who took anti-hypertensive drugs with a \u0026nbsp;\u0026nbsp;mean SBP difference of -4.38mmHg (95% \u0026nbsp;\u0026nbsp;CI: -6.08 to -2.67, P\u0026lt;0.001) and a mean DBP \u0026nbsp;\u0026nbsp;difference of -1.31mmHg (95% CI: \u0026nbsp;\u0026nbsp;-2.42 to -0.21, P=0.020), while \u0026nbsp;\u0026nbsp;no significant blood pressure difference among \u0026nbsp;\u0026nbsp;the participants who did not take any anti-hypertensive drugs.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions:\u003c/strong\u003e Combining salt \u0026nbsp;substitute with anti-hypertensive drugs could reduce blood pressure and the \u0026nbsp;risk of cardiovascular events.\u003c/p\u003e","manuscriptTitle":"Effect of salt substitute and medication use among high cardiovascular risk patients","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-05-09 18:07:58","doi":"10.21203/rs.3.rs-4333779/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"ae7c4270-162c-4c77-be56-2b22e1e93a62","owner":[],"postedDate":"May 9th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":31595342,"name":"Health sciences/Diseases/Cardiovascular diseases"},{"id":31595343,"name":"Health sciences/Medical research/Epidemiology"}],"tags":[],"updatedAt":"2025-08-12T10:23:50+00:00","versionOfRecord":[],"versionCreatedAt":"2024-05-09 18:07:58","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4333779","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4333779","identity":"rs-4333779","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}