Effects and individual response of salt substitute intervention on blood pressure in a high-risk stroke population: findings from 4200 participants of the China Salt Substitute and Stroke Study

: The protective effects of salt substitutes on blood pressure are well established, yet the individual variations in response to salt substitutes remain unclear. Our study aims to identify the individuals who derive the greatest benefit from salt substitute interventions. : Our study involved 4200 participants at high-risk of stroke from 120 villages in Liaoning Province, as a sub-study of the Salt Substitute and Stroke Study (SSaSS) trial, with 60 villages receiving a 5-year salt substitute intervention and other 60 villages using regular salt. The baseline and endpoint data on basic demographics, anthropometric measurements, and blood pressures were collected. General linear regressions were applied to assess the hypotensive effect of salt substitute intervention on both systolic blood pressure (SBP) and diastolic blood pressure (DBP), with adjustments for potential confounders using both regression adjustment and inverse probability of treatment weighting (IPTW). Individual treatment effects (ITEs) of the salt substitute were estimated using causal forest and causal tree methods, and a treatment-by-subgroup interaction analysis was conducted to validate the robustness of our findings. : During the 5-year follow-up, the salt substitute group exhibited a significant SBP reduction compared to the regular salt intervention group ( = -1.86 mmHg, 95% CI: -3.56 to -0.15 mmHg). This reduction remained significant after adjusting for potential confounders ( = -2.82 mmHg, 95% CI: -4.26 to -1.37 mmHg) and the usage status of antihypertensive medications ( = -2.60 mmHg, 95% CI: -4.95 to -1.15 mmHg). However, no significant reduction was observed in DBP levels. Moreover, baseline SBP, body mass index (BMI) and age were identified as the top three modifiers of the salt substitute intervention's efficacy on SBP levels. Specifically, individuals with a baseline SBP ≤ 142 mmHg and age ≤ 65 years old (ITE = -3.02 mmHg, 95% CI = -5.97 to -0.07 mmHg) or those with a baseline SBP >142 mmHg and BMI ≤ 28.2 kg m (ITE = -4.36 mmHg, 95% CI = -6.58 to -2.14 mmHg) received greater benefits from salt substitute supplementations in reducing SBP levels, and the treatment-by-subgroup interaction analysis further corroborated these findings ( = 0.03 and = 0.01). : Salt substitutes may effectively lower blood pressure in individuals at high-risk of stroke, with the hypotensive effect varying according to individual characteristics. Notably, middle-aged individuals with normotension and