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Review
. 2017 Aug 17;8(8):CD006612.
doi: 10.1002/14651858.CD006612.pub5.

Homocysteine-lowering interventions for preventing cardiovascular events

Arturo J Martí-Carvajal  1 , Ivan Solà, Dimitrios Lathyris, Mark Dayer
Affiliations
Review

Homocysteine-lowering interventions for preventing cardiovascular events

Arturo J Martí-Carvajal et al. Cochrane Database Syst Rev. .

Abstract

Background: Cardiovascular disease, which includes coronary artery disease, stroke and peripheral vascular disease, is a leading cause of death worldwide. Homocysteine is an amino acid with biological functions in methionine metabolism. A postulated risk factor for cardiovascular disease is an elevated circulating total homocysteine level. The impact of homocysteine-lowering interventions, given to patients in the form of vitamins B6, B9 or B12 supplements, on cardiovascular events has been investigated. This is an update of a review previously published in 2009, 2013, and 2015.

Objectives: To determine whether homocysteine-lowering interventions, provided to patients with and without pre-existing cardiovascular disease are effective in preventing cardiovascular events, as well as reducing all-cause mortality, and to evaluate their safety.

Search methods: We searched the Cochrane Central Register of Controlled Trials (CENTRAL 2017, Issue 5), MEDLINE (1946 to 1 June 2017), Embase (1980 to 2017 week 22) and LILACS (1986 to 1 June 2017). We also searched Web of Science (1970 to 1 June 2017). We handsearched the reference lists of included papers. We also contacted researchers in the field. There was no language restriction in the search.

Selection criteria: We included randomised controlled trials assessing the effects of homocysteine-lowering interventions for preventing cardiovascular events with a follow-up period of one year or longer. We considered myocardial infarction and stroke as the primary outcomes. We excluded studies in patients with end-stage renal disease.

Data collection and analysis: We performed study selection, 'Risk of bias' assessment and data extraction in duplicate. We estimated risk ratios (RR) for dichotomous outcomes. We calculated the number needed to treat for an additional beneficial outcome (NNTB). We measured statistical heterogeneity using the I2 statistic. We used a random-effects model. We conducted trial sequential analyses, Bayes factor, and fragility indices where appropriate.

Main results: In this third update, we identified three new randomised controlled trials, for a total of 15 randomised controlled trials involving 71,422 participants. Nine trials (60%) had low risk of bias, length of follow-up ranged from one to 7.3 years. Compared with placebo, there were no differences in effects of homocysteine-lowering interventions on myocardial infarction (homocysteine-lowering = 7.1% versus placebo = 6.0%; RR 1.02, 95% confidence interval (CI) 0.95 to 1.10, I2 = 0%, 12 trials; N = 46,699; Bayes factor 1.04, high-quality evidence), death from any cause (homocysteine-lowering = 11.7% versus placebo = 12.3%, RR 1.01, 95% CI 0.96 to 1.06, I2 = 0%, 11 trials, N = 44,817; Bayes factor = 1.05, high-quality evidence), or serious adverse events (homocysteine-lowering = 8.3% versus comparator = 8.5%, RR 1.07, 95% CI 1.00 to 1.14, I2 = 0%, eight trials, N = 35,788; high-quality evidence). Compared with placebo, homocysteine-lowering interventions were associated with reduced stroke outcome (homocysteine-lowering = 4.3% versus comparator = 5.1%, RR 0.90, 95% CI 0.82 to 0.99, I2 = 8%, 10 trials, N = 44,224; high-quality evidence). Compared with low doses, there were uncertain effects of high doses of homocysteine-lowering interventions on stroke (high = 10.8% versus low = 11.2%, RR 0.90, 95% CI 0.66 to 1.22, I2 = 72%, two trials, N = 3929; very low-quality evidence).We found no evidence of publication bias.

Authors' conclusions: In this third update of the Cochrane review, there were no differences in effects of homocysteine-lowering interventions in the form of supplements of vitamins B6, B9 or B12 given alone or in combination comparing with placebo on myocardial infarction, death from any cause or adverse events. In terms of stroke, this review found a small difference in effect favouring to homocysteine-lowering interventions in the form of supplements of vitamins B6, B9 or B12 given alone or in combination comparing with placebo.There were uncertain effects of enalapril plus folic acid compared with enalapril on stroke; approximately 143 (95% CI 85 to 428) people would need to be treated for 5.4 years to prevent 1 stroke, this evidence emerged from one mega-trial.Trial sequential analyses showed that additional trials are unlikely to increase the certainty about the findings of this issue regarding homocysteine-lowering interventions versus placebo. There is a need for additional trials comparing homocysteine-lowering interventions combined with antihypertensive medication versus antihypertensive medication, and homocysteine-lowering interventions at high doses versus homocysteine-lowering interventions at low doses. Potential trials should be large and co-operative.

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Conflict of interest statement

Arturo Marti‐Carvajal: In 2004, Arturo Martí‐Carvajal was employed by Eli Lilly to run a four‐hour workshop on 'How to critically appraise clinical trials on osteoporosis and how to teach this'. This activity was not related to his work with Cochrane or any Cochrane review. In 2007, Arturo Martí‐Carvajal was employed by Merck to run a four‐hour workshop 'How to critically appraise clinical trials and how to teach this'. This activity was not related to his work with Cochrane or any Cochrane review. Ivan Solà: none known. Dimitris Lathyris: none known. Mark Dayer: none known.

Figures

1
1
Study flow diagram.
2
2
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
3
3
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
4
4
Trial Sequential Analysis for homocysteine‐lowering interventions versus placebo on myocardial infarction. The diversity‐adjusted required information size (DARIS) was calculated based on an expected relative risk reduction (RRR) of 10% from proportion event in control (Pc) group of 5.95% with an alpha of 5% and beta of 20%. Cumulative Z‐curve (blue line) reached futility area which means that no more trials are needed.
5
5
Funnel plot of comparison: 1 Homocysteine‐lowering interventions versus placebo, outcome: 1.1 Myocardial infarction.
6
6
Contour‐enhanced funnel plot of comparison: 1 Homocysteine‐lowering interventions versus placebo, outcome: 1.1 Myocardial infarction.
7
7
Trial Sequential Analysis for homocysteine‐lowering interventions versus placebo on stroke. The diversity‐adjusted required information size (DARIS) was calculated based on an expected relative risk reduction (RRR) of 10% from proportion event in control (Pc) group of 5% with an alpha of 5% and beta of 20%.
8
8
Funnel plot of comparison: 1 Homocysteine‐lowering interventions versus placebo, outcome: 1.2 Stroke.
9
9
Contour‐enhanced funnel plot of comparison: 1 Homocysteine‐lowering interventions versus placebo, outcome: 1.2 Stroke.
10
10
Trial Sequential Analysis for homocysteine‐lowering interventions versus placebo on death from any cause. The diversity‐adjusted required information size (DARIS) was calculated based on an expected relative risk reduction (RRR) of 12% from proportion event in control (Pc) group of 11.7% with an alpha of 5% and beta of 20%. Cumulative Z‐curve (blue line) reached futility area which means that no more trials are needed.
11
11
Funnel plot of comparison: 1 Homocysteine‐lowering interventions versus placebo, outcome: 1.4 Death from any cause.
12
12
Contour‐enhanced funnel plot of comparison: 1 Homocysteine‐lowering interventions versus placebo, outcome: 1.4 Death from any cause.
13
13
Trial Sequential Analysis for homocysteine‐lowering interventions versus placebo on adverse events (cancer). The diversity‐adjusted required information size (DARIS) was calculated based on an expected relative risk reduction (RRR) of 10% from proportion event in control (Pc) group of 8.49% with an alpha of 5% and beta of 20%. Cumulative Z‐curve (blue line) reached futility area which means that no more trials are needed.
1.1
1.1. Analysis
Comparison 1: Homocysteine‐lowering treatment versus other (any comparisons), Outcome 1: Myocardial infarction
1.2
1.2. Analysis
Comparison 1: Homocysteine‐lowering treatment versus other (any comparisons), Outcome 2: Stroke
1.3
1.3. Analysis
Comparison 1: Homocysteine‐lowering treatment versus other (any comparisons), Outcome 3: First unstable angina pectoris episode requiring hospitalisation
1.4
1.4. Analysis
Comparison 1: Homocysteine‐lowering treatment versus other (any comparisons), Outcome 4: Death from any cause
1.5
1.5. Analysis
Comparison 1: Homocysteine‐lowering treatment versus other (any comparisons), Outcome 5: Serious adverse events (cancer)
1.6
1.6. Analysis
Comparison 1: Homocysteine‐lowering treatment versus other (any comparisons), Outcome 6: Adverse events (serious and non‐serious) excluding cancer
2.1
2.1. Analysis
Comparison 2: Homocysteine‐lowering treatment versus placebo or standard care (Sensitivity analysis), Outcome 1: Myocardial infarction
2.2
2.2. Analysis
Comparison 2: Homocysteine‐lowering treatment versus placebo or standard care (Sensitivity analysis), Outcome 2: Stroke
2.3
2.3. Analysis
Comparison 2: Homocysteine‐lowering treatment versus placebo or standard care (Sensitivity analysis), Outcome 3: Death from any cause
3.1
3.1. Analysis
Comparison 3: Homocysteine‐lowering treatment versus placebo (Subgoup analysis), Outcome 1: Myocardial Infarction
3.2
3.2. Analysis
Comparison 3: Homocysteine‐lowering treatment versus placebo (Subgoup analysis), Outcome 2: Stroke
3.3
3.3. Analysis
Comparison 3: Homocysteine‐lowering treatment versus placebo (Subgoup analysis), Outcome 3: Death
4.1
4.1. Analysis
Comparison 4: Homocysteine‐lowering treatment (folic acid) plus antihypertensive therapy (enalapril) versus antihypertensive therapy (enalapril) (Sensitivity analysis), Outcome 1: Myocardial infarction
4.2
4.2. Analysis
Comparison 4: Homocysteine‐lowering treatment (folic acid) plus antihypertensive therapy (enalapril) versus antihypertensive therapy (enalapril) (Sensitivity analysis), Outcome 2: Stroke
4.3
4.3. Analysis
Comparison 4: Homocysteine‐lowering treatment (folic acid) plus antihypertensive therapy (enalapril) versus antihypertensive therapy (enalapril) (Sensitivity analysis), Outcome 3: Death from any cause
5.1
5.1. Analysis
Comparison 5: Homocysteine‐lowering treatment at high dose versus low dose (Subgoup analysis), Outcome 1: Stroke
6.1
6.1. Analysis
Comparison 6: Homocysteine‐lowering treatment (high dose) versus Homocysteine‐lowering treatment (low dose) (Sensitivity analysis), Outcome 1: Stroke
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References

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Bahmani 2014 {published data only}
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    1. Durga J, Bots ML, Schouten EG, Grobbee DE, Kok FJ, Verhoef P. Effect of 3 y of folic acid supplementation on the progression of carotid intima-media thickness and carotid arterial stiffness in older adults. American Journal of Clinical Nutrition 2011;93(5):941-9. [PMID: 21430116] - PubMed
Earnest 2012 {published data only}
    1. Earnest CP, Kupper JS, Thompson AM, Guo W, Church T. Complementary effects of multivitamin and omega-3 fatty acid supplementation on indices of cardiovascular health in individuals with elevated homocysteine. International Journal for Vitamin and Nutrition Research 2012;82(1):41-52. [PMID: ] - PubMed
Ebbing 2009 {published data only}
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Ebbing 2009a {published data only}
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Goel 2015 {published data only}
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Holmes 2011 {published data only}
    1. Holmes MV, Newcombe P, Hubacek JA, Sofat R, Ricketts SL, Cooper J, et al. Effect modification by population dietary folate on the association between MTHFR genotype, homocysteine, and stroke risk: a meta-analysis of genetic studies and randomised trials. Lancet 2011;378(9791):584-94. [PMID: ] - PMC - PubMed
Huang 2012 {published data only}
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Huang 2015 {published data only}
    1. Huang T, Li K, Asimi S, Chen Q, Li D. Effect of vitamin B-12 and n-3 polyunsaturated fatty acids on plasma homocysteine, ferritin, C-reaction protein, and other cardiovascular risk factors: a randomized controlled trial. Asia Pacific Journal of Clinical Nutrition 2015;24(3):403-11. [PMID: ] - PubMed
Huo 2012 {published data only}
    1. Huo Y, Qin X, Wang J, Sun N, Zeng Q, Xu X, et al. Efficacy of folic acid supplementation in stroke prevention: new insight from a meta-analysis. International Journal of Clinical Practice 2012;66(6):544-51. [PMID: ] - PubMed
Imasa 2009 {published data only}
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Jardine 2012 {published data only}
    1. Jardine MJ, Kang A, Zoungas S, Navaneethan SD, Ninomiya T, Nigwekar SU, et al. The effect of folic acid based homocysteine lowering on cardiovascular events in people with kidney disease: systematic review and meta-analysis. BMJ 2012;344:e3533. [PMID: ] - PMC - PubMed
Ji 2013 {published data only}
    1. Ji Y, Tan S, Xu Y, Chandra A, Shi C, Song B, et al. Vitamin B supplementation, homocysteine levels, and the risk of cerebrovascular disease: a meta-analysis. Neurology 2013;81(15):1298-307. [PMID: ] - PubMed
Lange 2004 {published data only}
    1. Lange H, Suryapranata H, De Luca G, Börner C, Dille J, Kallmayer K, et al. Folate therapy and in-stent restenosis after coronary stenting. New England Journal of Medicine 2004;350:2673-81. [PMID: ] - PubMed
Lee 2010 {published data only}
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Li 2014 {published data only}
    1. Li WF, Zhang DD, Xia JT, Wen SF, Guo J, Li ZC. The association between B vitamins supplementation and adverse cardiovascular events: a meta-analysis. International Journal of Clinical and Experimental Medicine 2014;7(8):1923-30. [PMID: ] - PMC - PubMed
Li 2015 {published data only}
    1. Li J, Li B, Qi J, Shen B. [Meta-analysis of clinical trials of folic acid, vitamin B12 and B6 supplementation on plasma homocysteine level and risk of cardiovascular disease]. Zhonghua Xin Xue guan Bing Za Zhi 2015;43(6):554-61. [PMID: ] - PubMed
Liu 2014 {published data only}
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Lonn 2007 {published data only}
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Mager 2009 {published data only}
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Manolescu 2010 {published data only}
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Mei 2010 {published data only}
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Méndez‐González 2010 {published data only}
    1. Méndez-González J, Rodríguez-Millán E, Julve J, Blanco-Vaca F. Vitamin treatments that lower homocysteine concentration: can they decrease cerebrovascular disease in primary prevention? [Tratamientos vitamínicos para disminuir la concentración de homocisteína: reducen el riesgo de enfermedad cerebrovascular en prevención primaria?]. Revista de Neurologia 2010;50(4):235-44. [PMID: ] - PubMed
Miller 2010 {published data only}
    1. Miller ER 3rd, Juraschek S, Pastor-Barriuso R, Bazzano LA, Appel LJ, Guallar E. Meta-analysis of folic acid supplementation trials on risk of cardiovascular disease and risk interaction with baseline homocysteine levels. American Journal of Cardiology 2010;106:517-27. [PMID: ] - PubMed
Mishchenko 2015 {published data only}
    1. Mishchenko O, Iakovlieva L, Kyrychenko O, Gerasymova O, Bezditko N, Tkachova O. Pharmacoeconomic analysis of the combined homocysteine-lowering and standard therapy versus standard therapy of patients with CHD, postpercutaneous coronary intervention (Pci) and B12 deficiency. Value in Health 2015;18(7):A404. [PMID: ] - PubMed
Moghaddasi 2010 {published data only}
    1. Moghaddasi M, Mamarabadi M, Mirzadeh S, Freydoonnejad AA, Razjouyan H. Homocysteine, vitamin B12 and folate levels in Iranian patients with ischemic stroke. Neurological Research 2010;32(9):953-6. [PMID: ] - PubMed
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Ntaios 2009 {published data only}
    1. Ntaios G, Savopoulos C, Grekas D, Hatzitolios A. The controversial role of B-vitamins in cardiovascular risk: an update. Archives of Cardiovascular Diseases 2009;102(12):847-54. [PMID: ] - PubMed
Ntaios 2010 {published data only}
    1. Ntaios G, Savopoulos C, Karamitsos D, Economou I, Destanis E, Chryssogonidis I, et al. The effect of folic acid supplementation on carotid intima-media thickness in patients with cardiovascular risk: a randomized, placebo-controlled trial. International Journal of Cardiology 2010;143(1):16-9. [PMID: ] - PubMed
PACIFIC 2002 {published data only}
    1. Neal B, MacMahon S, Ohkubo T, Tonkin A, Wilcken D, PACIFIC Study Group. Dose-dependent effects of folic acid on plasma homocysteine in a randomized trial conducted among 723 individuals with coronary heart disease. European Heart Journal 2002;23:1509-15. [MEDLINE: ] - PubMed
Pan 2012 {published data only}
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Park 2016 {published data only}
    1. Park JH, Saposnik G, Ovbiagele B, Markovic D, Towfighi A. Effect of B-vitamins on stroke risk among individuals with vascular disease who are not on antiplatelets: A meta-analysis. International Journal of Stroke 2016;11(2):206-11. [PMID: ] - PubMed
Qin 2014 {published data only}
    1. Qin X, Fan F, Cui Y, Chen F, Chen Y, Cheng X, et al. Folic acid supplementation with and without vitamin B6 and revascularization risk: a meta-analysis of randomized controlled trials. Clinical Nutrition 2014;33(4):603-12. [PMID: ] - PubMed
Rautiainen 2010 {published data only}
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Sharifi 2010 {published data only}
    1. Sharifi F, Fakhrzadeh H, Mirarefin M, Pourebrahim R, Nouri M, Forouzanfar MH, et al. The effects of high-dose folic acid on blood pressure of hypertensive adults with hyperhomocysteinemia: a randomized double-blind placebo controlled clinical trial (Tehran homocysteine survey). Iranian Journal of Diabetes and Lipid Disorders 2010;9:13-20.
Shidfar 2009 {published data only}
    1. Shidfar F, Homayounfar R, Fereshtehnejad SM, Kalani A. Effect of folate supplementation on serum homocysteine and plasma total antioxidant capacity in hypercholesterolemic adults under lovastatin treatment: a double-blind randomized controlled clinical trial. Archives of Medical Research 2009;40(5):380-6. [PMID: ] - PubMed
Sudchada 2012 {published data only}
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Swiss 2002 {published data only}
    1. Schnyder G, Roffi M, Flammer Y, Pin R, Hess OM. Effect of homocysteine-lowering therapy with folic acid, vitamin B12, and vitamin B6 on clinical outcome after percutaneous coronary intervention: the Swiss Heart study: a randomized controlled trial. JAMA 2002;288:973-9. [PMID: ] - PubMed
Tighe 2011 {published data only}
    1. Tighe P, Ward M, McNulty H, Finnegan O, Dunne A, Strain J, et al. A dose-finding trial of the effect of long-term folic acid intervention: implications for food fortification policy. American Journal of Clinical Nutrition 2011;93(1):11-8. [PMID: ] - PubMed
Vesin 2007 {published data only}
    1. Vesin C, Mairesse S, Iaria P, Blacher J. Efficacy of folic acid in prevention of cerebrovascular disease [Efficacite de l’acide folique dans la prevention cerebrovasculaire]. Medecinedes Maladies Metaboliques 2007;1:50-2. [EMBASE: 2007490543]
Wang 2007 {published data only}
    1. Wang X, Qin X, Demirtas H, Li J, Mao G, Huo Y, et al. Efficacy of folic acid supplementation in stroke prevention: a meta-analysis. Lancet 2007;369:876-82. [PMID: ] - PubMed
Wang 2012 {published data only}
    1. Wang ZM, Zhou B, Nie ZL, Gao W, Wang YS, Zhao H, et al. Folate and risk of coronary heart disease: a meta-analysis of prospective studies. Nutrition, Metabolism, and Cardiovascular Diseases 2012;22(10):890-9. [PMID: ] - PubMed
Wang 2015a {published data only}
    1. Wang L, Li H, Zhou Y, Jin L, Liu J. Low-dose B vitamins supplementation ameliorates cardiovascular risk: a double-blind randomized controlled trial in healthy Chinese elderly. European Journal of Nutrition 2015;54(3):455-64. [PMID: ] - PubMed
Wang 2015b {published data only}
    1. Wang LP, Cui WW, Nan GX, Yu Y. Meta-analysis reveals protective effects of vitamin B on stroke patients. Translational Neuroscience 2015;6(1):150-6. - PMC - PubMed
Wierzbicki 2007 {published data only}
    1. Wierzbicki AS. Homocysteine and cardiovascular disease: a review of the evidence. Diabetes & Vascular Disease Research 2007;4(2):143-50. [PMID: ] - PubMed
Wise 2015 {published data only}
    1. Wise J. Folic acid significantly reduces risk of first stroke, large Chinese study finds. BMJ 2015;350:h1461. [PMID: ] - PubMed
Yang 2012 {published data only}
    1. Yang HT, Lee M, Hong KS, Ovbiagele B, Saver JL. Efficacy of folic acid supplementation in cardiovascular disease prevention: an updated meta-analysis of randomized controlled trials. European Journal of Internal Medicine 2012;23(8):745-54. [PMID: ] - PubMed
Yi 2014 {published data only}
    1. Yi X, Zhou Y, Jiang D, Li X, Guo Y, Jiang X. Efficacy of folic acid supplementation on endothelial function and plasma homocysteine concentration in coronary artery disease: A meta-analysis of randomized controlled trials. Experimental and Therapeutic Medicine 2014;7(5):1100-10. [PMID: ] - PMC - PubMed
Zappacosta 2013 {published data only}
    1. Zappacosta B, Mastroiacovo P, Persichilli S, Pounis G, Ruggeri S, Minucci A, et al. Homocysteine lowering by folate-rich diet or pharmacological supplementations in subjects with moderate hyperhomocysteinemia. Nutrients 2013;5(5):1531-43. [PMID: ] - PMC - PubMed
Zeng 2015 {published data only}
    1. Zeng R, Xu CH, Xu YN, Wang YL, Wang M. The effect of folate fortification on folic acid-based homocysteine-lowering intervention and stroke risk: a meta-analysis. Public Health Nutrition 2015;18(8):1514-21. [PMID: ] - PMC - PubMed
Zhang 2009 {published data only}
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Zhang 2013 {published data only}
    1. Zhang C, Chi FL, Xie TH, Zhou YH. Effect of B-vitamin supplementation on stroke: a meta-analysis of randomized controlled trials. PLOS One 2013;8(11):e81577. [PMID: ] - PMC - PubMed
Zhang 2014 {published data only}
    1. Zhang C, Wang ZY, Qin YY, Yu FF, Zhou YH. Association between B vitamins supplementation and risk of cardiovascular outcomes: a cumulative meta-analysis of randomized controlled trials. PLOS One 2014;9(9):e107060. [PMID: ] - PMC - PubMed
Zhou 2011 {published data only}
    1. Zhou YH, Tang JY, Wu MJ, Lu J, Wei X, Qin YY, et al. Effect of folic acid supplementation on cardiovascular outcomes: a systematic review and meta-analysis. PLOS One 2011;6(9):e25142. [PMID: ] - PMC - PubMed

References to ongoing studies

NCT01956786 {published data only}
    1. Efficacy of amlodipine-folic acid tablets on reduction of blood pressure and plasma homocysteine. Ongoing study. September 2013.. Contact author for more information.

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