Total Homocysteine Lowering Treatment Among Coronary Artery Disease Patients in the Era of Folic Acid Fortified Cereal Grain Flour
Background: The prevalence of both deficient plasma folate status, and elevated total (t) plasma levels of the putatively atherothrombotic amino acid homocysteine (Hcy), have been dramatically reduced since the recent advent of fortification of all enriched cereal grain flour products with physiological amounts (i.e., 140 μg/ 100 g flour) of folic acid. Against this new background fortification, we evaluated the tHcy-lowering efficacy of pharmacological dose, folic acid based B-vitamin supplementation among stable coronary artery disease (CAD) patients. Methods and Results: Using a 2x2 factorial design, we randomly assigned 131 stable CAD patients (mean age 60.1 years; 29.8 % women) to folic acid 2.5 mg/d, riboflavin 5 mg/d, + B12 0.4 mg/d [ FA group] or FA placebo [PL] , ± B6 [ B6 group] 50 mg/d or B6 placebo[PL], for 12 weeks of treatment. All pre-treatment and final on-treatment analyte values were based on the average of two blood collections performed within 1-week. Geometric mean pre-treatment, on-treatment, and pre-treatment minus on-treatment change in (Δ) tHcy levels (μmol/L), were- FA, B6 (n=31): 8.7 (pre-), 7.4 (on-), Δ= -1.3; B6, PL (n=32): 8.7 (pre-), 9.1 (on-), Δ= + 0.4; FA, PL (n=34): 9.0 (pre-), 8.0 (on-), Δ= - 1.0; PL, PL (n=34): 8.4 (pre-), 8.5 (on-), Δ= + 0.1. ANCOVA adjusted for baseline tHcy levels revealed that the very modest (i.e., ∼ 1.0 μmol/L) reductions in fasting values afforded by the FA containing treatments were statistically significant (p <0.05). Conclusions: In the era of cereal grain flour products fortified with physiological amounts of folic acid, stable CAD patients supplemented with high dose, folic acid containing B-vitamin regimens experience only very modest reductions in their mean plasma tHcy levels. These findings have important implications for the statistical power of clinical trials testing the hypothesis that tHcy-lowering treatment may reduce recurrent atherothrombotic event rates.