The study protocol and methods have been described previously29, and a summary is provided below. The CONSORT statement for randomized cluster trials30 and recent literature on reporting results of stepped-wedge cluster trials31,32 were utilized.

Study design

A stepped-wedge, cluster, randomized controlled trial was conducted, in which the six participating villages (clusters) crossed over from the control to the intervention phase during the study33. The order of switchover for each cluster was determined by randomization, and all villages received the salt substitute by the end of the study. The structure of the stepped wedge is provided in Fig. 3, where the intervention periods (village implementation phases, shown in gray) lasted 4 months, and blood pressure measurements were made every 5 months after the baseline period. The study was undertaken between April 2014 (start of baseline assessment) and March 2017 (last measurement and assessment).

Study setting

Tumbes, a coastal region in northern Peru, bordering Ecuador, was the setting selected for the present study because hypertension prevalence and incidence rates are above the national average34,35. According to official estimates of the Tumbes population36, in 2017 there were 243,362 inhabitants with a life expectancy of 75 years; 20% of the population did not have any health insurance and 12% were below the poverty line. The semi-urban area of the region, with approximately 100 villages of varying sizes and approximately 80,000 inhabitants, was the area chosen for the study. Mid-sized villages with 350–700 individuals (~130–250 households) were initially selected for the study. Of the 20 villages available with these characteristics, 6 were randomly selected. Sufficient distance between them was also ensured (that is, a median of 14 km (interquartile range 7.1–17.1) between them) to avoid contamination by verifying the selection of villages on the map.

Participants and recruitment

Potentially eligible subjects were identified from the most updated census in the area (2010, updated in 2014). All men and women aged ≥18 years from the six selected villages, who were capable of understanding procedures and of providing informed consent, and full-time residents in the area, were eligible. Individuals with a self-reported history of chronic kidney disease or of heart disease treated with digoxin were excluded from the study.

Participant recruitment, as well as the initial assessment, was performed during the first 4 months of the study (April to July 2014). Individuals were contacted through home visits aiming to enroll all members of households in the villages who met the selection criteria.

Randomization and blinding

The selected villages were randomly assigned to one of the six sequences (one village = one cluster) for time crossover from control to intervention. For this, a computer-generated list of random numbers was used and information was kept in a password-protected computer. The order of the villages to be implemented was revealed one by one as required, according to the nature of the study. Due to the pragmatic nature of the intervention, the participants were not blinded; however, the primary study outcome was objectively measured using standardized techniques. A team of fieldworkers, not involved with the implementation of the intervention, was responsible for periodic assessments of participants using automated devices to reduce observer bias.

Intervention

Through the application of social marketing strategies37, a campaign was developed to target women responsible for food preparation at home. The purpose of the marketing campaign was to introduce the salt substitute as a new product in the intervention villages, and enhance its acceptance. Thus, common salt (NaCl) used in the enrolled households was retrieved and replaced, free of charge, with a salt substitute, using a combination of 75% NaCl and 25% KCl, based on previous research19. Iodine, in addition to fluorine, was also part of the salt substitute following Peruvian regulations38. As the usual cost of a bag of 1 kg of common salt in the region was between $US0.15 and $US0.17 (about 0.50 PEN), we provided the salt substitute free of charge to the participants in their respective homes.

The time for provision of a salt replacement was planned to happen over a period of 5 months in each village; however, there was a delay in salt-substitute delivery of, on average, 15 d. The intervention considered making the salt delivery to families, as well as to owners of small shops, bakeries and community kitchens28, and food vendors including street vendors and restaurants. This approach was used to guarantee full replacement of salt in the entire village. Additional salt-substitute packs were also made freely available during the study period in case any household required additional salt.

Outcomes and data collection

The primary outcomes were SBP and DBP, assessed as continuous variables (in mm Hg) evaluated in the period between the end of each wedge and the start of the next one. Blood pressure assessments were performed with the participants seated, after a 5-min resting period, using an automated device (OMRON HEM-780) that had been previously validated in adult populations39. 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.

The secondary outcomes included progression toward hypertension (incidence) and, in a random subsample of participants, changes in levels of sodium and potassium excretion in the 24-h urine. Hypertension at baseline was defined as SBP ≥ 140 mm Hg, DBP ≥ 90 mm Hg, a self-reported physician diagnosis or current treatment for hypertension40. During follow-up, hypertension was defined in two ways: considering only the study measurements (average of the second and third measurements, with the participant in seated position, after resting 5 min, and at least 1 min between measurements) or taking advantage of the repeated assessments conducted every 5 months, as well as using the same definition as in the baseline.

After providing consent, each participant was given a unique code. At baseline, detailed information about sociodemographics (for example, age, sex, education and wealth index), lifestyle behaviors (smoking, alcohol consumption and physical activity), self-reported personal medical history and medication (hypertension and type 2 diabetes mellitus), anthropometric measurements (height, weight and blood pressure), and healthcare utilization and expenditure was collected using paper-based formats. Follow-up assessments were conducted in all participants and included some lifestyle behaviors (smoking and alcohol consumption), anthropometric measurements (weight and blood pressure), and healthcare utilization and expenditure.

Urine samples were retrieved in a random subsample of 600 participants after baseline and in another randomly selected subsample of 600 participants at the end of the study. Only one participant per household was included in the urine assessments. Urine samples were collected over a 24-h period, and all samples were assessed in a central laboratory facility. These samples were used to extract information about levels of creatinine, sodium and potassium. Sodium and potassium were assessed using the ion-selective electrode method, whereas creatinine was assessed using the compensated kinetic Jaffe method.

Statistical methods

All statistical procedures were conducted using Stata for Windows v.15.0 (StataCorp) and R statistical software41, and a per-protocol, intent-to-treat analysis was performed. A pre-specified linear mixed effects regression analysis was performed to model SBP and DBP using an identity link, an unstructured working correlation, including covariates for intervention status and time period, which was considered as a factor, and random effects for village, family and repeated observations of the same individual over time42,43, and robust variances were computed. Thus, the following model was used:

$$Y_{ijkl} = \mu + \alpha _i + \gamma _j + \varphi _k + \beta _l + \theta X_{kl} + \varepsilon _{ijkl}$$

where Y ijkl is the SBP (or DBP) measured for individual i, in family j, at cluster k, in time l; μ is the mean outcome in the control group at baseline; α i is a random intercept of individual i; γ j is a random intercept for family j; φ k is a random intercept for cluster k; β is the effect of time l; X kl is an indicator of the treatment mode in village k at time l; θ is the overall effect of the intervention; and ε ijkl is the random error for the measurement of individual i, in family j, at cluster k, at time l.

We also evaluated, as a sensitivity analysis, whether there was evidence of a delayed effect, that is, an interaction between duration of exposure and intervention42, and estimated the effect of the intervention on SBP and DBP, controlling for assumed defined possible confounders: age, sex, education, wealth index and BMI at baseline. Furthermore, we conducted exploratory subgroup analyses by hypertension status and age group defined at baseline.

For incidence calculations, Cox’s proportional hazard modeling on a calendar time axis, to account for time trends with random effects that follow gamma distribution for village-level (shared) frailty, was considered to compare the instantaneous risk of hypertension for both the intervention and the control groups44. The Schoenfeld residuals were used to test for the non-proportional hazard without considering the frailty term45. Time- and cluster-adjusted Cox’s models were constructed for the primary analysis, and fully adjusted models were generated to account for confounding variables such as age, sex, education, wealth index and BMI at baseline. Calculations (that is, HRs) were estimated taking into account the clustering of villages; in addition, a time-varying binary covariate tracking intervention status was fit, using definitions of times at risk in each of the periods described above.

Finally, changes in the 24-h urine concentrations of sodium and potassium were also evaluated (at the end of the study and after baseline). For the analysis, we included only individuals with a complete 24-h urine sample, defined as (1) at least 500 ml and (2) creatinine <4 mmol dl−1 in women or <6 mmol dl−1 in men46,47. Comparisons were conducted using the Student’s t-test for independent samples.

Ethics

This project was registered in ClinicalTrials.gov (no. NCT01960972). The protocol and informed consent forms used in this project were reviewed and approved by the institutional review boards of Universidad Peruana Cayetano Heredia, Lima, Peru, and Johns Hopkins University, Baltimore, MD, USA. Given that the intervention was implemented at the village level, but the outcome was measured at the individual level, we involved all the members of the recruited families in the study. For this, we initially engaged with the authorities and leaders from the villages, and an initial presentation and explanation of the study at the village level were conducted before starting the research activities. Then, family members aged ≥18 years were contacted for individual informed consent. As hypertension is not common among children, we did not include children and adolescents, that is any family member aged <18 years, in the study. Participants with a history of terminal or severe chronic kidney disease (any form of dialysis) or those taking digoxin or potassium-sparing diuretics (for heart disease), together with their families, were excluded from this study.

Reporting summary

Further information on research design is available in the Nature Research Reporting Summary linked to this article.