A randomized, double‐blind clinical trial to evaluate the blood pressure lowing effect of low‐sodium salt substitution on middle‐aged and elderly hypertensive patients with different plasma renin concentrations

Abstract This study aimed to evaluate the blood pressure (BP) lowing effect of low‐sodium (LS) salt substitution and how the effect influenced by plasma renin concentration (PRC) on middle‐aged and elderly hypertensive patients. Three hundred fifty‐two hypertensives were randomized at a 1:1 ratio into a LS group and a normal salt (NS) group. We compared intergroup changes observed in office blood pressure measurement (OBPM) and home blood pressure measurement (HBPM). Then, all patients in LS group were divided into tertiles according to baseline PRC, aldosterone concentration, and aldosterone/renin ratio (ARR), and changes in OBPM and HBPM were compared across the three tertile subgroups. Follow‐up surveys were completed by 322 patients. The intergroup net reduction in systolic OBPM, systolic HBPM, and diastolic HBPM was −6.6, −4.6, and −2.3 mmHg, respectively (all P < .05), and −1.8 mmHg in diastolic OBPM (P = .068). There was a more significant reduction in OBPM and HBPM among the low baseline PRC subgroup than among the high PRC subgroup. There were no significant differences in the changes in OBPM and HBPM between the three subgroups when grouped according to baseline aldosterone concentration. The reduction in OBPM and HBPM in the high tertile of ARR was larger than that in the low tertile subgroup. LS salt substitution is effective in reducing systolic OBPM, systolic HBPM, and diastolic HBPM in middle‐aged and elderly hypertensive patients. LS salt substitution may offer a non‐pharmaceutical therapy for hypertensive patients. Baseline PRC may be a marker to predict BP response after salt restriction.


INTRODUCTION
High blood pressure (BP) is a major preventable risk factor for heart disease, kidney disease, and cerebral hemorrhage and infarction. Although highly prevalent, the treatment rate (36.9%) and control rate (13.8%) for hypertension are extremely low worldwide. 1 However, high sodium intake is a modifiable risk factor proven to be positively associated with BP, unlike potassium. A study has demonstrated that each one gram increase in 24-hour sodium excretion can increase BP by 4.58/2.25 mmHg, while aleach one gram increase in urinary potassium can decrease systolic blood pressure (SBP) by 3.72 mmHg. 2 Other studies report that reducing sodium intake lowers BP, 3 while potassium depletion leads to an increase in BP. 4 At present, global salt intake is approximately 10 g per day-and 12.5 g per day in China 5 -which exceeds the World Health Organization (WHO) 5 g/day recommendation. 6 Only a few countries meet the daily potassium consumption recommendation proposed by the WHO (upwards of 3510 mg/day). 7 Recent guidelines emphasize lifestyle modification, especially salt reduction and increasing consumption of potassium-rich foods, as one of the first choices of antihypertensive therapy. 8 Several studies have proved salt substitution low in sodium, enriched in potassium and sometimes combined with minerals just like calcium and magnesium may reduce both SBP and diastolic blood pressure (DBP). [9][10][11] Research has proved that compared to office blood pressure measurement (OBPM), home blood pressure measurement (HBPM) can be measured more accurately and it is a stronger predictor of cardiovascular outcome, 12 and should be used in the diagnosis and evaluation of hypertension. 8 While numerous studies have reported the positive effect of low-sodium (LS) salt substitution on BP, most of these studies were performed using OBPM or HBPM alone, with only a few conducted by monitoring OBPM and HBPM simultaneously.
A previous study demonstrated sodium-sensitivity of BP was determined by renin 13 ; therefore, we evaluated BP reduction with different levels of renin respond to the LS salt substitution intervention.
This study evaluates the effect of low-sodium salt substitution on OBPM and HBPM in middle-aged and elderly hypertensive patients, and how the effect influenced by plasma renin concentration (PRC).

Study design
This is a 12-month prospective, multicenter, randomized, double-blind study. Using a computerized randomization program, the study participants were randomly assigned to one of two groups: the normal salt (NS) group or the LS group, in a 1:1 ratio. The NS group consumed 100% sodium chloride, while the substitution consumed by the LS group was 43% sodium chloride, 32% potassium chloride, and 25% other ingredients.
The participants were asked to replace the salt they used for cooking with the salt provided by the study. The questionnaire was achieved to assess the ordinary salt intake of every family, which would guide the quantity of salt distributed. Every participant also got a 5-g spoon to help them control the amount of salt that was informed used during cooking. Telephone follow-up was conducted every 2 weeks to instruct all the participants to reduce salt during cooking and to assess the use of the salt distributed. The recruiting and assigning work was completed by an assistant who was not in charge of the follow-up, and neither the investigators nor the participants were informed of the assignment until the end of the follow-up period.

Blood pressure measurement
The OBPM was performed at the start of the study, and in the 3 rd , 6 th , and 12 th months. The procedure involved the participants sitting and relaxing for 5 minutes before the measurement was taken using a validated electronic upper-arm cuff device (Contec08D, Qinhuangdao, China). The BP in the right arm was measured thrice, with the patient in a seated position, at one-minute interval, and the average of the last two measurements was used as the OBPM.
All patients received free electronic upper-arm cuff devices (Con-tec08D, Qinhuangdao, China) to measure their BP at home. The HBPM was taught by specialists to the participants and was performed at the start of the study, and in the 3 rd , 6 th , 9 th , and 12 th months. Readings were taken in the morning and evening after participants rested for five F I G U R E 1 Flowchart of the study minutes in a quiet environment on three consecutive appointed days.
Two readings were taken with a 1-minute interval between each reading, and the average of all measurements taken during the three days was calculated and used as the HBPM.

Biochemistry
Fasting blood specimens were obtained from each participant at the beginning and at the end of the study period, and fasting spot urine specimens were collected at the beginning, and in the 6 th and 12 th months using urine collection cups and storing tubes. We measured serum sodium, potassium, blood urea nitrogen (BUN), serum creatinine (Scr), uric acid (UA), PRC, aldosterone concentration, urine sodium and potassium levels using the collected samples at the DMU (Dalian Medical University) clinical laboratory. ARR was calculated as the ratio of aldosterone to renin. We used the INTERSALT method to evaluate the 24-hour urinary sodium excretion and Tanaka method to evaluate the 24-hour urinary potassium excretion via spot urinary sodium and potassium. 14-16

Outcomes
The primary outcome was the changes of OBPM and HBPM. The secondary outcome was to compare the BP changes across the three tertile subgroups grouped according to baseline PRC, aldosterone concentration, and aldosterone/renin ratio (ARR).

Statistics
On the basis of a prior reference, 17 the difference in mean SBP between groups was 4.9 mmHg in that study, sample size estimation was done using the formula where α was 0.05, and 1 − β was 0.9. The sample size was 160 for each experimental group. Taking

Demographic characteristics
A total of 352 patients were enrolled, and 30 (8.5%) of these participants withdrew during the intervention stage, while 160 participants in the NS group and 162 in the LS group completed all visits.

Comparison of changes in HBPM among the different subgroups according to baseline PRC, aldosterone concentration, and ARR
In the first tertile of the PRC subgroup, changes in BP were −8.9 ± 1.6/−7.4 ± 1.3 mmHg; in the second and third tertile, changes in BP were −5.7 ± 2.0/−3.5 ± 1.6 mmHg and −2.2 ± 1.9/−1.4 ± 1.5 mmHg, respectively. BP reduction was greater among the low PRC group than among the high PRC group (P = .002 for change in SBP, P = .016 for change in DBP).

Safety evaluation of LS salt substitution by monitoring electrolyte concentrations and renal function
At baseline, we observed no significant differences in serum sodium and potassium concentrations between the two groups. At the endpoint of this study, the serum sodium level of the LS group was significantly lower than that of the NS group (P = .030), while the serum potassium level of the LS group was significantly higher than that of the NS group (P < .001). There were no significant differences in the BUN, Scr, and UA of the two groups at baseline and at the endpoint (P > .05) ( Table 2). None of the participants suffered hyperkalemia or severe deterioration of renal function.  Table 3).

DISCUSSION
Our results demonstrate that only systolic OBPM was reduced by lowsodium salt substitution. However, after 12 months of treatment, both systolic and diastolic HBPM were significantly reduced among middleaged and elderly hypertensive patients. Diastolic OBPM was reduced, but not to a significant extent.
A previous clinical trial found that salt substitution significantly reduced office SBP by 8.2 mmHg and DBP by 3.4 mmHg. 18 Another  Salt sensitivity is associated with left-ventricular hypertrophy and cardiovascular events, which has been deemed an independent risk factor for cardiovascular disease 27 and mortality. 28 Identifying salt sensitivity may help guide drug therapy 29 and the implementation of salt restriction as a therapeutic method.
Individuals over 50 years old may have a higher salt intake which is due to age-related taste bud deterioration. 5 Thus, elderly patients were expected to have larger effects of LS salt substitution. Many young individuals prefer to eat at the restaurant or at their workplace, which may influence the effect of LS salt substitution on BP among this group. Therefore, we selected middle-aged and elderly patients who ate at least two meals per day at home.
In our study, serum potassium levels increased among the two groups without chronic conditions such as hyperkalemia. Serum sodium levels also increased among both the NS group and the LS group. This may be attributable to conducting the last interview on a hot summer day, which caused patients to sweat-leading to volume loss. 30 The BUN, Scr, and UA levels all changed without significance.
No deterioration of renal function occurred. Thus, we can infer from this study that LS salt substitution is safe for long-term intervention.
By monitoring urine sodium and potassium levels, at the endpoint of this study, we found that the urine sodium levels among the LS group were lower and the potassium levels were higher than the levels among the NS group, with a statistical significance. Therefore, we confirmed the compliance to LS salt substitution by participants in the intervention group.

LIMITATIONS
First, we evaluated the BP responses to LS salt substitution after intervention according to baseline PRC and ARR in middle-aged and elderly participants but not in young participants. Second, we evaluated compliance to LS salt substitution by measuring fasting spot urine sodium and potassium levels, which may not provide the exact sodium and potassium intake.

CONCLUSIONS
In conclusions, LS salt substitution is effective in reducing systolic OBPM, systolic HBPM, and diastolic HBPM in middle-aged and elderly hypertensive patients. LS salt substitution may offer a nonpharmaceutical therapy for hypertensive patients. Baseline PRC may be a marker to predict BP response after salt restriction.

ACKNOWLEDGEMENT
This study was supported by National Natural Science Foundation of China (Grant Number: 82070427).

CONFLICT OF INTEREST
There are no conflicts of interest.

AUTHOR CONTRIBUTIONS
Yinong Jiang contributed to the conception and design of the study.
Li Che contributed to writing the first draft of the manuscript. Wei Song contributed to the collection of data for the study. Ying Zhang and Yan Lu contributed to data analysis. Yunpeng Cheng contributed to interpretation for the study. All authors revised the manuscript and approved the final version.