It remains unclear whether the effectiveness of B vitamin treatment within the no-antiplatelet subgroup represents biological modification of the effects of homocysteine by antiplatelet drugs, intergroup differences between patients on and off antiplatelet therapy (such as the greater proportion of patients with hemorrhagic or cardioembolic strokes among those not taking antiplatelets), or a spurious result of secondary analysis. A meta-analysis of folic acid supplementation in 26 randomized, controlled tri- found no effect on the risk of CVD (RR, 0.98; 95% CI, 0.95 1.02) but a trend toward reduced stroke risk (RR, 0.93; 95% CI, 0.86 1.00). A some- what stronger reduction in stroke (RR, 0.89; 95% CI, 0.79 0.99) was noted in a different subgroup analysis790 restricted to 35325 participants who did not have stroke as a qualifying event for inclusion in the trial. 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. 