. 2022 Aug 10;2022(8):CD015207. doi: 10.1002/14651858.CD015207

Bernabe‐Ortiz 2014.

*Study characteristics*
Methods	Study design: Cluster‐randomised trial Study grouping: Stepped‐wedge Country: Peru Setting: Intervention conducted in semi‐urban villages in Tumbes, northern Peru; outcome measurement conducted at each household Aim of study: To assess the efficacy of a pragmatic salt‐substitution strategy on blood pressure and the incidence of hypertension at population level Unit of allocation: Villages Start date: April 2014 End date: March 2017 Relevant study limitations as reported by study authors: The authors reported absence of dietary assessment of other sources of sodium and potassium, excluding persons with kidney disease and those who were on digoxin, and potential under‐collection of 24‐hour urine at baseline due to lower levels of creatinine at baseline (when compared to follow‐up) as limitations Sample size calculation: Based on an expected difference of 3 mmHg BP between groups (assuming a SD of 20 mmHg of BP within clusters (villages), no. of time periods as 6, a mean cluster size of 300 participants, and an approximation for the ICC of 0.2) using a power of 90% and significance level of 5%
Participants	Baseline Characteristics Overall Age: in years, mean (SD): 43.3 (17.2) [village A 44.5 (16.8); village B 44.8 (18.8); village C 42.6 (16.8); village D 38.9 (14.5); village E 48.8 (18.4); village F 40.0 (15.9)] Gender: Female, % (n/N): 50.4 (1197/2376) [village A 45.7 (245/534); village B 49.4 (221/449); village C 50.8 (167/329); village D 54.1 (224/414); village E 52.1 (171/328); village F 52.5 (169/322)] Ethnicity/race: South American Smoking: NR Body Mass Index (BMI): in kg/m², mean (SD): 27.2 (4.6) [village A 27.4 (4.9); village B 26.4 (4.3); village C 26.8 (4.5); village D 27.5 (4.4); village E 27.2 (4.9); village F 27.8 (4.6)] Blood pressure status: Hypertensive, % (n/N): 18.3 (428/2342) [village A 17.1 (91/534); village B 20.5 (90/449); village C 18.2 (59/329); village D 13.6 (56/414); village E 24.8 (79/328); village F 16.9 (53/322)] Antihypertensive medication used: NR Cardiovascular disease or stroke: NR Diabetes mellitus: Type 2 diabetes, % (n/N): village A 4.3 (23/534); village B 2.2 (10/449); village C 3.3 (11/329); village D 3.1 (13/414); village E 4.6 (15/328); village F 4.7 (15/322) Renal impairment: NR Dietary potassium intake: NR Dietary sodium intake: NR Urinary potassium excretion: Subsample (n = 602), in mmol/24 h, mean (SD): 51 (31) Urinary sodium excretion: Subsample (n = 602), in mmol/24 h, mean (SD): 171 (81) Inclusion criteria: Villages: mid‐sized villages (350 to 700 people living in 130 to 250 households) in the semi‐urban area of the Tumbes region. Individuals: men and women who are full‐time residents of one of the six randomly selected villages; aged 18 years or older; capable of understanding procedures and providing informed consent Exclusion criteria: Households: any with a family member meeting individual exclusion criteria. Individuals: persons with a history of terminal or severe chronic kidney disease (receiving any form of dialysis); taking digoxin or potassium‐sparing diuretics for heart conditions. Participants with mental illness that impaired their ability of providing consent, were excluded. Pretreatment: The study authors reported that there were baseline differences between the clusters (villages) in terms of age, education, wealth index, BMI, SBP, DBP and the proportion of participants with hypertension. Method of recruitment of participants: Potentially eligible individuals from six villages were identified from the latest census in the area at the time (2010). Engagement with authorities and village leaders was initiated first, through a presentation and explanation of the study at village level. Once the research activities were explained, potential participants were contacted through home visits with the intention of enrolling all members of the family in eligible households. Informed consent obtained: Yes, unclear whether written or oral Clusters: Six clusters (villages) were included in the stepped‐wedge design; comprising n = 536 participants in village A, n = 447 in village B, n = 329 in village C, n = 414 in village D, n = 328 in village E, and n = 322 in village F. The clustering of villages were taken into account in the primary analysis, with a random intercept for cluster used in the modelling of SBP and DBP (standard errors allowed for intra‐class correlation of SBP and DBP). Subgroups planned/measured: The study authors stated the following: "The analysis will compare the information obtained from different subgroups of participants in order to identify and describe the similarities and divergences between men and women, patients from different age groups, and health workers and stakeholders". Subgroups reported: normotensive vs. hypertensive; age < 40 years vs. 40 to 59 years vs. >= 60 years Participant flow Assessed for eligibility: n = 100 clusters (villages); n = 2605 participants from n = 6 randomly selected clusters (villages) Excluded (number with reasons): n = 94 clusters (n = 80 wrong village size; n = 14 randomly excluded); n = 229 participants from n = 6 clusters (reasons NR) Randomised: n = 6 clusters; n = 2376 participants Allocated to LSSS intervention(s): n = 6 clusters; 3605.3 person‐years (n = 536 for 1366.1 person‐years in village A, n = 447 for 883.1 person‐years in village B, n = 329 for 518.3 person‐years in village C, n = 414 for 460.2 person‐years in village D, n = 328 for 256.3 person‐years in village E, and n = 322 for 121.3 person‐years in village F) Allocated to control: n = 6 clusters; 2547.3 person‐years (n = 536 for 1.7 person‐years in village A, n = 447 for 286.9 person‐years in village B, n = 329 for 329.0 person‐years in village C, n = 414 for 542.1 person‐years in village D, n = 328 for 637.0 person‐years in village E, and n = 322 for 750.6 person‐years in village F) Received allocated LSSS intervention(s): NR Did not receive allocated LSSS intervention(s): NR Lost to follow‐up (LSSS intervention group): Cumulative total: n = 0/6 clusters; n = 950/8987 (10.6%) participants. Step 1: n = 0 clusters; n = 54 in village A. Step 2: n = 76 (n = 0 clusters; n = 46 in village A, and n = 30 in village B). Step 3: n = 0 clusters; n = 115 (n = 56 in village A, n = 51 in village B, and n = 8 in village C). Step 4: n = 0 clusters; n = 116 (n = 44 in village A, n = 34 in village B, n = 27 in village C, and n = 61 in village D). Step 5: n = 0 clusters; n = 224 (n = 57 in village A, n = 43 in village B, n = 27 in village C, n = 68 in village D, and n = 29 in village E). Step 6: n = 0 clusters; n = 315 (n = 77 in village A, n = 62 in village B, n = 29 in village C, n = 84 in village D, n = 28 in village E, and n = 35 in village F). Discontinued intervention (LSSS intervention group): NR Analysed (LSSS intervention group): Step 1: n = 1 clusters; n = 482 in village A. Step 2: n = 2 clusters; n = 907 (n = 490 in village A, and n = 417 in village B). Step 3: n = 3 clusters; n = 1177 (n = 480 in village A, n = 396 in village B, and n = 301 in village C). Step 4: n = 4 clusters; n = 1560 (n = 492 in village A, n = 413 in village B, n = 302 in village C, and n = 353 in village D). Step 5: n = 5 clusters; n = 1830 (n = 479 in village A, n = 404 in village B, n = 302 in village C, n = 346 in village D, and n = 299 in village E). Step 6: n = 6 clusters; n = 2011 (n = 459 in village A, n = 385 in village B, n = 300 in village C, n = 330 in village D, n = 300 in village E, and n = 237 in village F) Excluded from analysis (LSSS intervention group): NR Received allocated control: NR Did not receive allocated control: NR Lost to follow‐up (control group): Cumulative total: n = 0/6 clusters; n = 536/5269 (10.2%) participants. Step 1: n = 0 clusters; n = 183 from five villages (B to F). Step 2: n = 0 clusters; n = 146 from four villages (C to F). Step 3: n = 0 clusters; n = 125 from three villages (D to F). Step 4: n = 0 clusters; n = 52 from two villages (E and F). Step 5: n = 0 clusters; n = 30 from one village (F) Discontinued intervention (control group): NR Analysed (control group): Step 1: n = 5 clusters; n = 1657 from five villages (B to F). Step 2: n = 4 clusters; n = 1247 from four villages (C to F). Step 3: n = 3 clusters; n = 939 from three villages (D to F). Step 4: n = 2 clusters; n = 598 from two villages (E and F). Step 5: n = 1 clusters; n = 292 from one village (F) Excluded from analysis (control group): NR
Interventions	Intervention Characteristics LSSS intervention Theoretical basis: Population level LSSS intervention may reduce BP and the incidence of hypertension. Description: Salt substitute (75% NaCl; 25% KCl) LSSS category: < 30% KCl Contains fortificant: NR Delivery: discretionary use Duration of run‐in period: none Duration of active intervention: ranged from 5 to 30 months (median duration of 15 months); 3605.3 person‐years (median 489.25 person‐years) Duration of follow‐up (as reported): none Total duration of study (as reported): 30 months Timing: Daily use throughout the intervention period Implementation: Replacement of 'ordinary' salt with LSSS via the salt supply chain at the population level: in households, food vendors, bakeries, community kitchens and restaurants in each village. Social marketing strategy in each village aimed at women responsible for food preparation at home. Additional salt substitute packs were also made freely available during the study period in case any household required additional salt. Providers: Manufacturer of LSSS and details of persons providing the LSSS not reported Co‐interventions: NR Resource requirements: Cost of LSSS was 14 Peruvian Sol (PEN; ~4 USD) at scaled price reduction for study (usually 35 PEN; ~10 USD). LSSS provided free of charge to participants. Other costs specified but not reported were costs associated with marketing campaign, training, administration, production, and delivery. Integrity of delivery: The assessments of salt consumption were carried out using questionnaires and weighing of salt containers at randomly selected households over time, and also by evaluating supply chain management indicators such as rate of delivery of the salt substitute to each family or to food vendors. There was a delay in salt substitute delivery of, on average, 15 d. Control Theoretical basis: To enable comparison of LSSS intervention with standard practice Description: 'ordinary' salt (100% NaCl) Contains fortificant: NR Delivery: discretionary use Duration of run‐in period: none Duration of active intervention: ranged from 5 to 25 months (median duration of 12.5 months); 2547.3 (median 435.55) person‐years Duration of follow‐up (as reported): none Total duration of study (as reported): 30 months Timing: Daily use throughout the control period Implementation: 'Ordinary' salt used in households, food vendors, bakeries, community kitchens and restaurants in each village. Providers: Normal salt supply chain Co‐interventions: NR Resource requirements: Cost of 1 kg of common salt: from $US0.15 to $US0.17 (about 0.50 PEN) Integrity of delivery: n/a
Outcomes	Primary outcomes: Diastolic Blood Pressure (DBP): Outcome measurement: performed with the participants seated, after a 5‐min resting period, using an automated device, validated in adults. Three different measurements, at least 1 min apart, were carried out, and the average of the second and third measurements was used for the analyses; time points: time and cluster regression for all time points Systolic Blood Pressure (SBP): Outcome measurement: performed with the participants seated, after a 5‐min resting period, using an automated device, validated in adults. Three different measurements, at least 1 min apart, were carried out, and the average of the second and third measurements was used for the analyses; time points: time and cluster regression for all time points Hypertension (as reported, or SBP > 140 mmHg or DBP > 85 mmHg): Outcome measurement: at baseline defined as SBP >= 140 mm Hg, DBP >= 90 mm Hg for the average of the second and third measurements, or self‐reported physician diagnosis, or current antihypertensive treatment. At follow‐up, visit defined as SBP >= 140 mmHg, DBP >= 90 mmHg or using repeated assessments every five months of these cut‐offs; time points: duration of study period Blood pressure control (achieving blood pressure threshold or 'control' as prespecified): NR Cardiovascular events‐stroke: NR Cardiovascular events‐myocardial infarction: NR Cardiovascular events‐other: NR Cardiovascular mortality: NR Blood potassium: NR Hyperkalaemia: NR Hypokalaemia: NR Secondary outcomes: All‐cause mortality: NR Adverse events: NR Antihypertensive medication use: Outcome measurement: participant‐reported medication use obtained through questionnaire. Time points: duration of the study Body Mass index (BMI): NR Serum creatinine: NR Albuminuria: NR Urinary albumin‐to‐creatinine ratio (uACR): NR Fasting blood glucose: NR Blood triglycerides: NR Total blood cholesterol: NR 24‐h urinary sodium excretion: 24‐hour urine sample. Time points: 30 months 24‐h urinary potassium excretion: 24‐hour urine sample. Time points: 30 months
Notes	Funding source: The study, its authors and the CRONICAS Center of Excellence in Chronic Diseases were supported by the National Heart, Lung, and Blood Institute: the study under the Global Alliance for Chronic Diseases (GACD) programme; the authors and their affiliate centre under the contract Global Health Activities in Developing Countries to Combat Non‐Communicable Chronic Diseases. Investigators were supported by grants from the Wellcome Trust Research Training Fellowship in Public Health and Tropical Medicine and the Dirección de Gestión de la Investigación at the Pontifica Universidad Católica del Perú. Authors name: Antonio Bernabe‐Ortiz; J. Jaime Miranda Institution: CRONICAS Center of Excellence in Chronic Diseases, Universidad Peruana Cayetano Heredia and Department of Medicine, School of Medicine, Universidad Peruana Cayetano Heredia (both in Lima, Peru) Email: Antonio.Bernabe@upch. pe; [email protected] Possible conflicts of interest (for study authors): "The authors declare no competing interests." Sources used for data extraction: Journal article with results of the trial; trial protocol (published; trial registry) Trial registration details: NCT01960972
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Use of a computer‐generated list of random numbers to obtain randomisation sequence of the six villages (clusters)
Allocation concealment (selection bias)	Low risk	The allocation of all the villages or clusters was performed by a statistician at the beginning of the study according to the randomisation sequence.
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Inhabitants were not blinded to the intervention, but were only informed of the allocation at the moment of implementation in their village (which included a social marketing campaign). The research team were aware of treatment assignment. It was not clear how the lack of blinding may have introduced performance bias.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Outcomes were assessed by a separate team of fieldworkers who were blinded to treatment assignment. Primary study outcomes were assessed objectively by standardised techniques.
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Cumulative loss to follow‐up was n = 950/8987 (10.6%) participants in the intervention and n = 536/5269 (10.2%) participants in the control group. Attrition in the intervention group ranged from 7.7% to 10% at the different time points or steps; with 13.3% at the last time point. For the control group, it ranged between 8% and 10% at the different time points, with 11.7% at the third time point. Reasons for attrition not reported. The study authors stated that a "per‐protocol intention to treat" analysis was conducted. However, no imputation of any data were reported.
Selective reporting (reporting bias)	Low risk	The primary outcomes were reported according to those prespecified in the study protocol (SBP, DBP).
Other bias	Unclear risk	In some clusters (villages), a reduction in blood pressure was observed before the intervention, and potential explanations for this could be a community‐like white coat effect, which, in the case of rural or semi‐urban areas with limited access to healthcare, can also be present.
Recruitment bias (cluster‐RCTs)	Low risk	Recruitment of participants in all selected villages (clusters) conducted before the start of the intervention in the first village (cluster)
Comparability with individually randomised trials (cluster‐RCTs)	Low risk	Results comparable with findings reported by a meta‐analysis of individually randomised RCTs (Peng 2014). "Salt substitutes have been previously tested, mostly in China and mainly on patients with established hypertension, and they show reductions in blood pressure, with a larger effect observed among individuals with hypertension. Similar results have been obtained using home blood pressure measurements."
Loss of clusters (cluster‐RCTs)	Low risk	No loss of clusters
Baseline imbalance (cluster‐RCTs)	Low risk	Differences were observed between villages for age, education, wealth index, BMI, SBP, DBP and hypertension. Models were adjusted for baseline sex, age, years of education, wealth index and BMI.
Incorrect analysis (cluster‐RCTs)	Low risk	The study authors used generalised estimating equations (GEEs) which uses within‐cluster and between‐cluster information to estimate the treatment effect. In addition, they also adjusted the estimates for time (due to the stepped‐wedge design).
Overall risk of bias	Unclear risk	Unclear risk of bias for incomplete outcome data; low risk for baseline imbalance, recruitment bias and loss of clusters