Folic Acid in Stroke Prevention in Countries without Mandatory Folic Acid Food Fortification: A Meta-Analysis of Randomized Controlled Trials

Abstract

Background and PurposeAdditional folic acid (FA) treatment appears to have a neutral effect on reducing vascular risk in countries that mandate FA fortification of food (e.g., USA and Canada). However, it is uncertain whether FA therapy reduces stroke risk in countries without FA food fortification. The purpose of this study was to comprehensively evaluate the efficacy of FA therapy on stroke prevention in countries without FA food fortification. MethodsPubMed, EMBASE, and clinicaltrials.gov from January 1966 to August 2016 were searched to identify relevant studies. Relative risk (RR) with 95% confidence interval (CI) was used as a measure of the association between FA supplementation and risk of stroke, after pooling data across trials in a random-effects model. ResultsThe search identified 13 randomized controlled trials (RCTs) involving treatment with FA that had enrolled 65,812 participants, all of which stroke was reported as an outcome measure. After all 13 RCTs were pooled, FA therapy versus control was associated with a lower risk of any future stroke (RR, 0.85; 95% CI, 0.77 to 0.95). FA alone or combination of FA and minimal cyanocobalamin (≤0.05 mg/day) was associated with a lower risk of future stroke (RR, 0.75; 95% CI, 0.66 to 0.86) whereas combination of FA and cyanocobalamin (≥0.4 mg/day) was not associated with a lower risk of future stroke (RR, 0.95; 95% CI, 0.86 to 1.05). ConclusionsFA supplement reduced stroke in countries without mandatory FA food fortification. The benefit was found mostly in patients receiving FA alone or combination of FA and minimal cyanocobalamin.

B vitamins for stroke prevention

“…A recent systematic review identified 13 RCTs of folic acid therapy in which stroke was reported as an outcome and most participants (>50%) in a trial resided in countries without mandatory fortification of food with folic acid. 27 At total of 65 812 participants were enrolled in 13 trials; 12 trials included individuals with pre-existing conditions: stroke (one trial), coronary heart disease (five trials), cardiovascular disease (one trial), end-stage renal disease or advanced chronic kidney disease (three trials), hypertension (one trial) and oesophageal dysplasia (one trial), while one trial included individuals living in high altitude. Folic acid alone or the combination of folic acid and minimal cyanocobalamin (≤0.05 mg/day) was used in an active treatment group in eight trials, whereas the combination of folic acid and cyanocobalamin (≥0.4 mg/day) was used in an active treatment group in five trials.…”

“…A meta-analysis of these trials among people who were living in countries without mandatory folic acid fortification in food found that folic acid therapy was associated with a lower risk of any future stroke compared with control (RR 0.85, 95% CI 0.77 to 0.95; p=0.004; 3–8 fewer events per 1000 patients). 27 …”

“…A subsequent subgroup analysis of the meta-analysis of RCTs 27 of folic acid therapy among 65 812 participants who were mainly living in countries without mandatory folic acid fortification (referred to in the above section on folic acid fortification of food) found that folic acid alone or the combination of folic acid and minimal cyanocobalamin (≤0.05 mg/day) was associated with a lower risk of future stroke (RR 0.75, 95% CI 0.66 to 0.86), whereas the combination of folic acid and a higher dose of cyanocobalamin (≥0.4 mg/day) was not associated with a lower risk of future stroke (RR 0.95, 95% CI 0.86 to 1.05). 27 The lack of benefit of folic acid plus higher doses of cyanocobalamin (≥0.4 mg/day) was observed in trials which all included some participants with chronic kidney disease. 27 In patients with diabetic nephropathy who were enrolled in the Diabetic Intervention with Vitamins to Improve Nephropathy (DIVINe) trial, B vitamins, which included cyanocobalamin in a dose of 1000 μg daily, accelerated the decline in renal function and doubled the risk of stroke and other cardiovascular events compared with placebo (HR 2.0, 95% CI 1.0 to 4.0).…”

“… 27 The lack of benefit of folic acid plus higher doses of cyanocobalamin (≥0.4 mg/day) was observed in trials which all included some participants with chronic kidney disease. 27 In patients with diabetic nephropathy who were enrolled in the Diabetic Intervention with Vitamins to Improve Nephropathy (DIVINe) trial, B vitamins, which included cyanocobalamin in a dose of 1000 μg daily, accelerated the decline in renal function and doubled the risk of stroke and other cardiovascular events compared with placebo (HR 2.0, 95% CI 1.0 to 4.0). 34 All the events occurred among participants with eGFR <50 mL/min/1.73 m 2 .…”

Genes and genetics in hyperhomocysteinemia and the “1-carbon metabolism”: implications for retinal structure and eye functions

“…Higher levels of Hcy (i.e., HHcy) have been shown to affect methylation potential and DNA methylation, while in vitro acute treatment of lymphocytes from healthy male donors with HHcy (i.e., >20 mol/L for 8 h) failed to cause any noticeable change(s) in the methylation or DNA hypomethylation, indicating that HHcyinduced toxicity is most likely the result of a chronic, rather than acute, response (Fux et al 2005). Recent studies have shown that folate supplementation alone does not reduce the risk(s) of coronary artery disease and stroke (Banerjee et al 2007;Gao et al 2012;Hsu et al 2018;Yu et al 2011). Several clinical studies revealed that Hcy levels to be significantly higher in multiple sclerosis patients than in control individuals without B 12 and (or) folate deficiency, in the absence of MTHFR mutation (Ho et al 2002;Kararizou et al 2013;Kruman et al 2000;Teunissen et al 2008).…”