Hypertension is the primary risk factor for stroke. However, none of the previously reported trials compared blood pressure control over the treatment period. Our trial attempted to ensure the comparability of blood pressure levels between the treatment groups both at baseline and throughout follow-up, during which blood pressure control was achieved using a standard protocol of enalapril, 10 mg/d, plus other antihypertensive agents as needed. As such, the CSPPT lends further support that folic acid therapy can lead to an additional 21% risk reduction of first stroke compared with antihypertension treatment alone. A synergy of enalapril (an angiotensin-converting enzyme inhibitor) with folic acid is possible based on the findings of a subanalysis in the WAFACS trial.
Inadequate folate intake is prevalent in most countries without mandatory folic acid fortification, including in Asia and other continents. The MTHFR 677 TT variant, which leads to a 60% reduction in the enzyme function, is present in all populations but with variable frequency (usually 2%-25%). Based on recently published US National Health and Nutrition Examination Survey folate data and our unpublished folate data from the Boston Birth Cohort, there is substantial variability in blood folate levels within the US population and across racial/ethnic groups. We speculate that even in countries with folic acid fortification and widespread use of folic acid supplements such as in the United States and Canada, there may still be room to further reduce stroke incidence using more targeted folic acid therapy—in particular, among those with the TT genotype and low or moderate folate levels.