The effect of folic acid therapy has also been studied in patients with chronic renal disease and hyperhomocystein- emia, but the results of these studies are inconsistent.791 793 In the Atherosclerosis and Folic Acid Supplementation Trial, a placebo-controlled study of 315 patients with chronic renal failure, folic acid supplementation did not reduce the compos- ite risk of cardiovascular events, with fewer treated patients having strokes (RR reduction, 0.55; 95% CI, 0.01 0.80).793,794 Similarly, in the HOPE 2 study of patients with established vascular disease or diabetes mellitus, combination therapy with vitamin B6 , vitamin B12 , and folic acid lowered plasma homocysteine levels; did not affect the composite end point of cardiovascular death, MI, or stroke; but did reduce the risk A sub- sequent exploratory analysis found no heterogeneity in the effect on stroke based on whether or not the subjects had a prior history of stroke or TIA (P for interaction=0.88).796 Hyperhomocysteinemia: Summary and Gaps Hyperhomocysteinemia is associated with an increased risk of stroke. Trials that have examined the effect of homocys- teine-lowering therapy with B complex vitamins on the risk of stroke are inconsistent. Stroke reduction generally was found in trials in which the duration of treatment exceeded 3 years, the decrease in plasma homocysteine concentration was >20%, the region where patients were recruited did not fortify diet with folate, and the participants had no prior history of stroke. Better understanding of the mechanisms through which homocysteine causes atherosclerosis may enable identification of more targeted and effective therapies to reduce the risk of stroke in patients with elevated homo- cysteine levels. Hyperhomocysteinemia: Recommendation 1. 