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Review
. 2012 Jun 13:344:e3533.
doi: 10.1136/bmj.e3533.

The effect of folic acid based homocysteine lowering on cardiovascular events in people with kidney disease: systematic review and meta-analysis

Meg J Jardine  1 , Amy Kang, Sophia Zoungas, Sankar D Navaneethan, Toshiharu Ninomiya, Sagar U Nigwekar, Martin P Gallagher, Alan Cass, Giovanni Strippoli, Vlado Perkovic
Affiliations
Review

The effect of folic acid based homocysteine lowering on cardiovascular events in people with kidney disease: systematic review and meta-analysis

Meg J Jardine et al. BMJ. .

Abstract

Objective: To systematically review the effect of folic acid based homocysteine lowering on cardiovascular outcomes in people with kidney disease.

Design: Systematic review and meta-analysis.

Data sources: Medline, Embase, the Cochrane Library, and ClinicalTrials.gov to June 2011.

Study selection: Randomised trials in people with non-dialysis dependent chronic kidney disease or end stage kidney disease or with a functioning kidney transplant reporting at least 100 patient years of follow-up and assessing the effect of folic acid based homocysteine lowering therapy. No language restrictions were applied.

Data extraction: Two reviewers independently extracted data on study setting, design, and outcomes using a standardised form. The primary endpoint was cardiovascular events (myocardial infarction, stroke, and cardiovascular mortality, or as defined by study author). Secondary endpoints included the individual composite components, all cause mortality, access thrombosis, requirement for renal replacement therapy, and reported adverse events, including haematological and neurological events. The effect of folic acid based homocysteine lowering on outcomes was assessed with meta-analysis using random effects models.

Results: 11 trials were identified that reported on 4389 people with chronic kidney disease, 2452 with end stage kidney disease, and 4110 with functioning kidney transplants (10,951 participants in total). Folic acid based homocysteine therapy did not prevent cardiovascular events (relative risk 0.97, 95% confidence interval 0.92 to 1.03, P = 0.326) or any of the secondary outcomes. There was no evidence of heterogeneity in subgroup analyses, including those of kidney disease category, background fortification, rates of pre-existing disease, or baseline homocysteine level. The definitions of chronic kidney disease varied widely between the studies. Non-cardiovascular events could not be analysed as few studies reported these outcomes.

Conclusions: Folic acid based homocysteine lowering does not reduce cardiovascular events in people with kidney disease. Folic acid based regimens should not be used for the prevention of cardiovascular events in people with kidney disease.

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Conflict of interest statement

Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declare that : no support from any organisation for the submitted work; SZ is a member of the advisory boards for MSD, Novo Nordisk, and Boehringer Ingelheim, and has received consultancies from Novo Nordisk and Johnson and Johnson, speakers fees from MSD, Novo Nordisk, Astra Zeneca/BMS, Novartis, Sanofi Aventis, and Servier International, and payment for the development of educational presentations from Medi Mark; MG has received payment for lectures from Roche Pharmaceuticals; SDN has received a KL2 grant from the National Institutes of Health; AC has received payment for lectures from Roche, Servier, AMGEN, and MSD; MJ has received an unrestricted grant from CSL; Concord Hospital has received an educational grant from Shire; VP is a member of the Abbot advisory board, has grants or grants pending from Roche, Johnson and Johnson, Baxter, and Servier and has received payment for lectures from Roche, Servier, and Astra Zeneca; MJ, AK, SZ, TN, MG, AC, and VP are affiliated with the George Institute, which receives funding from various pharmaceutical companies to support parts of its research activities, which companies might have an interest in the submitted work in the previous three years; and no other relationships or activities that could appear to have influenced the submitted work.

Figures

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Fig 1 Identification process for eligible studies
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Fig 2 Effect of folic acid based homocysteine lowering therapy on composite cardiovascular events
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Fig 3 Subgroup analyses for effect of homocysteine lowering on cardiovascular events. Data reported as ‘”not available” applied to chronic kidney disease subgroups of relevant studies
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