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Clinical Chemistry and Laboratory Medicine (CCLM)

Published in Association with the European Federation of Clinical Chemistry and Laboratory Medicine (EFLM)

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Homocysteine-lowering trials for prevention of vascular disease: protocol for a collaborative meta-analysis

1Clinical Trial Service Unit, University of Oxford, Oxford, UK and Collaborators are listed at the end of this article.

Corresponding author: Robert Clarke, Clinical Trial Service Unit, University of Oxford, Richard Doll Building, Old Road Campus, Roosevelt Drive, Oxford, OX3 7LF, UK Phone: +44-1865-743743, Fax: +44-1865-743985,

Citation Information: Clinical Chemical Laboratory Medicine. Volume 45, Issue 12, Pages 1575–1581, ISSN (Online) 14374331, ISSN (Print) 14346621, DOI: 10.1515/CCLM.2007.346, December 2007

Publication History

Published Online:


Background: Elevated plasma total homocysteine is a risk factor for cardiovascular disease (CVD), but the randomized trials of dietary supplementation with B-vitamins to lower homocysteine have not yet provided clear evidence of benefit on vascular risk.

Methods: Cumulative meta-analysis of all randomized trials assessing the effects of lowering homocysteine levels with B-vitamins on risk of CVD.

Results: An individual patient data meta-analysis of all randomized trials of the effects on vascular risk of lowering homocysteine with B-vitamins will maximize the power to assess the epidemiologically predicted differences in risk. Among the 12 randomized homocysteine-lowering trials for prevention of CVD, involving more than 1000 participants, data should be available on approximately 52,000 participants (32,000 with prior CVD in unfortified populations; and 14,000 with prior CVD and 6000 with renal disease in fortified populations). To minimize bias, the design and primary analyses to be carried out have been pre-specified. The analyses will include assessment of effects on major vascular events (MVE), stroke, major coronary events (MCE), in addition to venous thrombosis, cancer and fractures. Additional analyses will assess effects on vascular outcomes in sub-groups defined by population, prior disease, per 3 μmol/L difference in homocysteine levels achieved by treatment, pre-treatment vitamin status, duration, age, sex and vascular events excluding revascularizations and, separately, excluding vascular events occurring during the first year of treatment.

Conclusions: A cumulative meta-analysis of the homocysteine-lowering trials should ensure that reliable evidence emerges about the effects of lowering homocysteine on risk of vascular and non-vascular outcomes.

Clin Chem Lab Med 2007;45:1575–81.

Keywords: folic acid; homocysteine; meta-analysis; trials; vitamin B12

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