Elsevier

American Heart Journal

Volume 151, Issue 2, February 2006, Pages 282-287
American Heart Journal

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

https://doi.org/10.1016/j.ahj.2005.04.025Get rights and content

Background

Dietary supplementation with folic acid and vitamin B12 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 (CHD) and about 20% less stroke.

Methods

We reviewed the design and statistical power of 12 randomized trials assessing the effects of lowering homocysteine with B-vitamin supplements on risk of cardiovascular disease.

Results

Seven of these trials are being conducted in populations without fortification (5 involving participants with prior CHD and 2 with prior stroke) and 5 in populations with fortification (2 with prior CHD, 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 52 000 participants: 32 000 with prior vascular disease in unfortified populations and 14 000 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 meta-analysis of the ongoing trials of homocysteine lowering should ensure that reliable information emerges about the effects of such interventions on cardiovascular disease outcomes.

Section snippets

Data from ongoing or completed trials

We aimed to identify all randomized trials involving >1000 participants that were assessing the effects of folic acid supplements (with or without the addition of vitamins B12 or B6) versus control without such supplementation on the incidence of vascular events.13, 14, 15, 16, 17, 18, 19 Trials were identified by MEDLINE searches and by personal contact with relevant investigators. Investigators were asked to provide information about the number of people to be randomized, the details of the

Trials in patients with prior CHD

Table I provides selected details of the number randomized, treatment duration, vitamin regimen, plasma homocysteine reductions, and vascular event rates in each trial involving >1000 people. Among the 7 large randomized trials in people with prior CHD, 5 involve 22 694 people in European populations without systematic fortification of food with folic acid and 2 involve 11 022 people predominantly recruited in North America with mandatory folic acid fortification. All trials use daily doses of

Discussion

Combined analyses of previous observational epidemiologic studies suggest that a 25% lowering in homocysteine levels is associated with about 10% lower risk of CHD and 20% lower risk of stroke.4 If these epidemiologically predicted differences in risk of 10% to 20% are reversible at least within a few years, then the implications for public health of decreasing population homocysteine concentrations could be substantial. Several large-scale randomized trials are assessing whether lowering

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  • Cited by (0)

    The study was supported in part by grants from the British Heart Foundation, London, England, and the Medical Research Council, London, England, and the European Union BIOMED Program (BMH4-98-3549), Brussels, Belgium.

    1

    Authors members and collaborators are listed at Appendix A.

    Reprint requests: Robert Joseph Clarke, MD, MRCP, Clinical Trial Service Unit and Epidemiological Studies Unit, Nuffield Department of Clinical Medicine, Radcliffe Infirmary, OX2 6HE Oxford, UK. E-mail: [email protected]

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