Statistical analysis

Means (SD) and proportions were calculated for population characteristics in accordance with the combined baseline folate and B₁₂ levels (group 1: B₁₂ <280.2 pmol/L [median] and folate <8.1 ng/mL [median]; group 2: B₁₂ <280.2 pmol/L and folate ≥ 8.1 ng/mL; group 3: B₁₂ ≥280.2 pmol/L and folate <8.1 ng/mL; group 4: B₁₂ ≥280.2 pmol/L and folate ≥8.1 ng/mL). The hazard ratios (HRs) and 95% confidence intervals (CIs) for the risk of first ischemic stroke associated with the combined baseline folate and B₁₂ levels were estimated using Cox proportional hazards models in the enalapril-only group without and with adjustment for major covariates. Interactions of B₁₂ and folate subgroups with MTHFR C677T genotypes (CC [wild-type] vs CT or TT) were examined by including interaction terms into the Cox models. We further assessed the effect of folic acid treatment on the total population (participants from the enalapril-only group and the enalapril–folic acid group) on the prevention of first ischemic stroke according to different B₁₂ and folate strata by means of Cox proportional hazards regression both before and after adjustment for the major covariates.

As a post hoc analysis, correction for multiple hypothesis testing was not applied, and a 2-tailed p < 0.05 was considered statistically significant in all analyses. R software, version 3.4.3 (R-project.org/), was used to perform all statistical analyses.