Homocysteine-lowering trials for prevention of cardiovascular events: A review of the design and power of the large randomized trials

Background Dietary supplementation with folic acid and vitamin B-12 lowers blood homocysteine concentrations by about 25% to 30% in populations without routine folic acid fortification of food and by about 10% to 15% in populations with such fortification. In observational studies, 25% lower homocysteine has been associated with about 10% less coronary heart disease (CHID) and about 20% less stroke. Methods We reviewed the design and statistical power of 12 randomized trials assessing the effects of lowering homocysteine with 13-vitamin supplements on risk of cardiovascular disease. Results Seven of these trials are being conducted in populations without fortification (5 involving participants with prior CHID and 2 with prior stroke) and 5 in populations with fortification (2 with prior CHID, 2 with renal disease, and 1 with prior stroke). These trials may not involve sufficient number of vascular events or last long enough to have a good chance on their own to detect reliably plausible effects of homocysteine lowering on cardiovascular risk. But, taken together, these 12 trials involve about 52000 participants: 32000 with prior vascular disease in unfortified populations and 14000 with vascular disease and 6000 with renal disease in fortified populations. Hence, a combined analysis of these trials should have adequate power to determine whether lowering homocysteine reduces the risk of cardiovascular events within just a few years. Conclusion The strength of association of homocysteine with risk of cardiovascular disease may be weaker than had previously been believed. Extending the duration of treatment in these trials would allow any effects associated with prolonged differences in homocysteine concentrations to emerge. Establishing a prospective mete-analysis of the ongoing trials of homocysteine lowering should ensure that reliable information emerges about the effects of such intervention's on cardiovascular disease outcomes.