Homocysteine-lowering interventions for preventing cardiovascular events

Cochrane Database of Systematic Reviews

Volumn 2013, Issue 1, 2013, Pages

  Martí Carvajal, Arturo J ^a   Solà, Ivan ^b   Lathyris, Dimitrios ^c   Karakitsiou, Despoina Elvira ^d   Simancas Racines, Daniel ^a  

^a School of Engineering Sciences and Industry   (Ecuador)

^b BIOMEDICAL RESEARCH INSTITUTE SANT PAU IIB SANT PAU   (Spain)

^c General Hospital George Gennimatas   (Greece)

^d UNIVERSITY OF IOANNINA   (Greece)

Author keywords

[No Author keywords available]

Indexed keywords

CYANOCOBALAMIN; FOLIC ACID; HOMOCYSTEINE; PLACEBO; PYRIDOXINE; VITAMIN B COMPLEX;

ALL CAUSE MORTALITY; CARDIOVASCULAR DISEASE; CEREBROVASCULAR ACCIDENT; CLINICAL EFFECTIVENESS; EVIDENCE BASED MEDICINE; FOLLOW UP; HEART INFARCTION; HUMAN; HYPERHOMOCYSTEINEMIA; META ANALYSIS; PRIORITY JOURNAL; RANDOMIZED CONTROLLED TRIAL (TOPIC); REVIEW; SYSTEMATIC REVIEW; VITAMIN SUPPLEMENTATION; ANGINA PECTORIS; RISK FACTOR;

ANGINA PECTORIS; CARDIOVASCULAR DISEASES; HUMANS; HYPERHOMOCYSTEINEMIA; MYOCARDIAL INFARCTION; RANDOMIZED CONTROLLED TRIALS AS TOPIC; RISK FACTORS; STROKE; VITAMIN B COMPLEX;

EID: 84961628731     PISSN: None     EISSN: 1469493X     Source Type: Journal    
DOI: 10.1002/14651858.CD006612.pub3     Document Type: Review

References (179)

1. Hodis HN, Mack WJ, Dustin L, Mahrer PR, Azen SP, Detrano R, BVAIT Research Group. High-dose B vitamin supplementation and progression of subclinical atherosclerosis: a randomized controlled trial. Stroke 2009;40(3):730-6. [PUBMED: 19118243]
2. Baker F, Picton D, Blackwood S, Hunt J, Erskine M, Dyas M, et al.Blinded comparison of folic acid and placebo in patients with ischaemic heart disease: an outcome trial. Circulation 2002;106(Suppl II):741.
3. Liem AH, van Boven AJ, Veeger NJ, Withagen AJ, Robles de Medina RM, Tijssen JG, et al.Efficacy of folic acid when added to statin therapy in patients with hypercholesterolemia following acute myocardial infarction: a randomised pilot trial. International Journal of Cardiology 2004;93:175-9. [MEDLINE: 14975544]
4. Liem A, Reynierse-Buitenwerf GH, Zwinderman AH, Jukema JW, van Veldhuisen DJ. Secondary prevention with folic acid: effects on clinical outcomes. Journal of the American College of Cardiology 2003;41:2105-13. [MEDLINE: 12821232]
5. Liem A, Reynierse-Buitenwerf GH, Zwinderman AH, Jukema JW, van Veldhuisen DJ. Secondary prevention with folic acid: results of the Goes extension study. Heart 2005;91:1213-4. [MEDLINE: 16103563]
6. Lonn E, Yusuf S, Arnold MJ, Sheridan P, Pogue J, Micks M, et al.Homocysteine lowering with folic acid and B vitamins in vascular disease. New England Journal of Medicine 2006;354:1567-77. [MEDLINE: 16531613]
7. Saposnik G, Ray J, Sheridan P, McQueen M, Lonn E. Homocysteine lowering therapy and stroke risk, severity and disability: Results from the HOPE-2 trial. Stroke 2009;40(4):e131. [DOI: 10.1161]
8. Saposnik G, Ray JG, Sheridan P, McQueen M, Lonn E, Heart Outcomes Prevention Evaluation Investigators. Homocysteine-lowering therapy and stroke risk, severity, and disability: additional findings from the HOPE 2 trial. Stroke 2009; Vol. 40, issue 4:1365-72. [PUBMED: 19228852]
9. Bonaa KH, Njolstad I, Ueland PM, Schirmer H, Tverdal A, Steigen T, et al.Homocysteine lowering and cardiovascular events after acute myocardial infarction. New England Journal of Medicine 2006;354:1578-88. [MEDLINE: 16531614]
10. Armitage JM, Bowman L, Clarke RJ, Wallendszus K, Bulbulia R, Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine (SEARCH) Collaborative Group. Effects of homocysteine-lowering with folic acid plus vitamin B12 vs placebo on mortality and major morbidity in myocardial infarction survivors: a randomized trial. JAMA 2010;303:2486-94. [MEDLINE: 20571015]
11. Clinical Trial Service Unit & Epidemiological Studies Unit. SEARCH Study Protocol. http://www.searchinfo.org/SEARCH_protocol.pdf (accessed 8 February 2012):1-36.
12. Group Search Collaborative. Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine (SEARCH) Collaborative Group. Intensive lowering of LDL cholesterol with 80 mg versus 20 mg simvastatin daily in 12 064 survivors of myocardial infarction: a double-blind randomised. Lancet 2011;377(9760):126.
13. Andreeva VA, Touvier M, Kesse-Guyot E, Julia C, Galan P, Hercberg S. B vitamin and/or ω-3 fatty acid supplementation and cancer: Ancillary findings from the supplementation with folate, vitamins B6 and B12, and/or omega-3 fatty acids (SU.FOL.OM3) randomized trial. Archives of Internal Medicine 2012;172(7):540-7. [PUBMED: 22331983]
14. Blacher J, Czernichow S, Paillard F, Ducimetiere P, Hercberg S, Galan P, on behalf of the SU.FOL.OM3 Study Research Group. Cardiovascular effects of B-vitamins and/or N-3 fatty acids: The Su.Fol.Om3 trial. International Journal of Cardiology 2012;Feb 22:[Epub ahead of print]. [PUBMED: 22365647]
15. Galan P, Briancon S, Blacher J, Czernichow S, Hercberg S. The SU.FOL.OM3 Study: a secondary prevention trial testing the impact of supplementation with folate and B-vitamins and/or Omega-3 PUFA on fatal and non fatal cardiovascular events, design, methods and participants characteristics. Trials 2008;9:35. [PUBMED: 18544171]
16. Galan P, Briancon S, Blacher J, Czernichow S, Hercberg S. The scientific basis of the SU.FOL.OM3 study: a secondary intervention trial of folate, B6 and B12 vitamins and/or omega 3 fatty acid supplements in the prevention of recurrent ischemic events [Bases scientifiques de l'étude SUFOLOM3: essai de prévention secondaire visant à tester l'impact d'une supplémentation en folates, vitamines B6 et B12 et/ou acides gras oméga-3 dans la prévention de la récidive de pathologies ischémiques]. Sang Thrombose Vaisseaux 2009;21(4):207-13. [: ISSN 0999-7385]
17. Galan P, Kesse-Guyot E, Czernichow S, Briancon S, Blacher J, Hercberg S. Effects of B vitamins and omega 3 fatty acids on cardiovascular diseases: A randomised placebo controlled trial. BMJ 2011;342:36. [: ISSN 0959-8146]
18. Galan P, Kesse-Guyot E, Czernichow S, Briancon S, Blacher J, Hercberg S, SU.FOL.OM3 Collaborative Group. Effects of B vitamins and omega 3 fatty acids on cardiovascular diseases: a randomised placebo controlled trial. BMJ 2010;341:1-9. [PUBMED: 21115589]
19. Galan P, de Bree A, Mennen L, Potier de Courcy G, Preziozi P, Bertrais S, et al.Background and rationale of the SU.FOL.OM3 study: double-blind randomized placebo-controlled secondary prevention trial to test the impact of supplementation with folate, vitamin B6 and B12 and/or omega-3 fatty acids on the prevention of recurrent ischemic events in subjects with atherosclerosis in the coronary or cerebral arteries. The Journal of Nutrition, Health & Aging 2003;7(6):428-35. [PUBMED: 14625623]
20. Vesin C, Galan P, Gautier B, Czernichow S, Hercberg S, Blacher J. Control of baseline cardiovascular risk factors in the SU-FOL-OM3 study cohort: does the localization of the arterial event matter?. European Journal of Cardiovascular Prevention and Rehabilitation 2010; Vol. 17, issue 5:541-8. [PUBMED: 20216318]
21. Elias GA, Patel RK, Chen WM, Mychaleckyj JC, Hsu FC, Worrall B B, et al.Association of a transcobalamin 2 (TCN2) variant located in the 3UTR with post-stroke homocysteine level in subjects from the vitamin intervention for stroke prevention trial. Stroke. 2010; Vol. 41(4):e335. [: ISSN 0039-2499]
22. Elkhatib SD, Hsu FC, Pemberton BL, Sale MM, Worrall BB. Sex differences in genetic associations with homocysteine in the vitamin intervention for stroke prevention (VISP) trial. Stroke. 2011; Vol. 42 (3):e187. [: ISSN 0039-2499]
23. Sale MM, Hsu FC, Mychaleckyj JC, Rich SS, Furie KL, Worrall BB. A variant in the adenosine 2B receptor gene is associated with homocysteine levels and stroke severity in african american subjects from the vitamin intervention for stroke prevention (VISP) trial. Stroke. 2010; Vol. 41(4):e334. [PUBMED: ISSN: 0039-2499]
24. Spence JD, Bang H, Chambless LE, Stampfer MJ. Vitamin Intervention For Stroke Prevention trial: an efficacy analysis. Stroke 2005;36:2404-9.
25. Toole JF, Malinow MR, Chambless LE, Spence JD, Pettigrew LC, Howard VJ, et al.Lowering homocysteine in patients with ischemic stroke to prevent recurrent stroke, myocardial infarction, and death: the Vitamin Intervention for Stroke Prevention (VISP) randomized controlled trial. JAMA 2004;291:565-75. [PUBMED: 14762035]
26. Dusitanond P, Eikelboom JW, Hankey GJ, Thom J, Gilmore G, Loh K, et al.Homocysteine-lowering treatment with folic acid, cobalamin, and pyridoxine does not reduce blood markers of inflammation, endothelial dysfunction, or hypercoagulability in patients with previous transient ischemic attack or stroke: a randomized substudy of the VITATOPS trial. Stroke 2005;36(1):144-6. [PUBMED: 15569860]
27. Dusitanond P, Eikelboom JW, Hankey GJ, Thom J, Gilmore G, Loh K, et al.Homocysteine-lowering treatment with folic acid, cobalamin, and pyridoxine does not reduce blood markers of inflammation, endothelial dysfunction, or hypercoagulability in patients with previous transient ischemic attack or stroke: a randomized substudy of the VITATOPS trial. Stroke 2005;36:144-6. [MEDLINE: 15569860]
28. Group Vitatops Study. The VITATOPS (VITAmins TO Prevent Stroke) trial: rationale, design and progress of an international, large simple, randomised trial of homocysteine-lowering multivitamin therapy in patients with recent transient attack or stroke [Abstract]. Internal Medicine Journal. 2007; Vol. Suppl 4:A110.
29. Hankey GJ. The vitamins to prevent stroke (VITATOPS) trial: results of a double-blind, placebo-controlled, randomised trial of B-vitamin therapy in 8, 164 patients with recent transient ischaemic attack or stroke. Cerebrovascular Diseases. 2010; Vol. 29:11. [DOI: 10.1159/000321266]
30. Potter K, Hankey GJ, Green DJ, Eikelboom J, Jamrozik K, Arnolda LF. The effect of long-term homocysteine-lowering on carotid intima-media thickness and flow-mediated vasodilation in stroke patients: a randomized controlled trial and meta-analysis. BMC Cardiovascular Disorders 2008;8:24. [PUBMED: 18803866]
31. Potter K, Lenzo N, Eikelboom JW, Arnolda LF, Beer C, Hankey GJ. Effect of long-term homocysteine reduction with B vitamins on arterial wall inflammation assessed by fluorodeoxyglucose positron emission tomography: a randomised double-blind, placebo-controlled trial. Cerebrovascular Diseases 2009;27(3):259-65. [PUBMED: 19202330]
32. Saposnik G. The role of vitamin B in stroke prevention: a journey from observational studies to clinical trials and critique of the VITAmins TO Prevent Stroke (VITATOPS). Stroke 2011;42(3):838-42. [PUBMED: 21273566]
33. The VITATOPS Trial Study Group. B vitamins in patients with recent transient ischaemic attack or stroke in the VITAmins TO Prevent Stroke (VITATOPS) trial:a randomised, double-blind, parallel, placebo-controlled trial. Lancet Neurology 2010;9(9):855-65. [PUBMED: 20688574]
34. VITATOPS Trial Study Group, Hankey GJ, Algra A, Chen C, Wong MC, Cheung R, et al.VITATOPS, the VITAmins TO prevent stroke trial: rationale and design of a randomised trial of B-vitamin therapy in patients with recent transient ischaemic attack or stroke (NCT00097669) (ISRCTN74743444). International Journal of Stroke 2007;2(2):144-50. [PUBMED: 18705976]
35. Albert CM, Cook NR, Gaziano JM, Zaharris E, MacFadyen J, Danielson E, et al.Effect of folic acid and B vitamins on risk of cardiovascular events and total mortality among women at high risk for cardiovascular disease: a randomized trial. JAMA 2008;299(17):2027-36. [MEDLINE: 18460663]
36. Glynn RJ, Manson JE, Women's Antioxidant and Folic Acid CardiovascularStudy Group. Effect of folic acid and B vitamins on the occurrence of venous thromboembolism: a randomized trial in women at high cardiovascular risk. Circulation 2008;118:S1137.
37. Redbeg RF, Block PC. A randomized trial of folic acid and B-vitamins in the secondary prevention of cardiovascular events in women: Results from the Women's Antioxidant and Folic Acid Cardiovascular Study (WAFACS). ACC Cardiosource Review Journal 2006;16(7):52-8.
38. Song Y, Cook NR, Albert CM, Van Denburgh M, Manson JE. Effect of homocysteine-lowering treatment with folic acid and B vitamins on risk of type 2 Diabetes Mellitus in women: a randomized controlled trial. Circulation. 2009; Vol. 119:E273. [: ISSN 0009-7322]
39. Song Y, Cook NR, Albert CM, Van Denburgh M, Manson JE. Effect of homocysteine-lowering treatment with folic acid and B vitamins on risk of type 2 diabetes in women: a randomized, controlled trial. Diabetes 2009; Vol. 58, issue 8:1921-8. [PUBMED: 19491213]
40. Zhang SM, Cook NR, Albert CM, Gaziano JM, Buring JE, Manson JE. Effect of combined folic acid, vitamin B6, and vitamin B12 on cancer risk in women: a randomized trial. JAMA 2008; Vol. 300, issue 17:2012-21. [PUBMED: 18984888]
41. Bleie Ø, Strand E, Ueland PM, Vollset SE, Refsum H, Igland J, et al.Coronary blood flow in patients with stable coronary artery disease treated long term with folic acid and vitamin B12. Coronary Artery Disease 2011; Vol. 22, issue 4:270-8. [PUBMED: 21389855]
42. Ebbing M, Bleie Ø, Ueland PM, Nordrehaug JE, Nilsen DW, Vollset SE, et al.Mortality and cardiovascular events in patients treated with homocysteine-lowering B vitamins after coronary angiography: a randomized controlled trial. JAMA 2008;300:795-804. [PUBMED: 18714059]
43. Loland KH, Bleie O, Blix AJ, Strand E, Ueland PM, Refsum H, et al.Effect of homocysteine-lowering B vitamin treatment on angiographic progression of coronary artery disease: a Western Norway B Vitamin Intervention Trial (WENBIT) substudy. American Journal of Cardiology 2010;105(11):1577-84. [PUBMED: 20494665]
44. Bazzano LA, Reynolds K, Holder KN, He J. Effect of folic acid supplementation on risk of cardiovascular diseases: a meta-analysis of randomized controlled trials. JAMA 2006;296:2720-6.
45. Clarke R, Halsey J, Lewington S, Lonn E, Armitage J, Manson JAE, for the B-Vitamin Treatment Trialists' Collaboration. Effects of lowering homocysteine levels with B vitamins on cardiovascular disease, cancer, and cause-specific mortality: Meta-analysis of 8 randomized trials Involving 37 485 individuals. Archives of Internal Medicine 2010;170(18):1622-31. [PUBMED: 20937919]
46. Cui R, Iso H, Date C, Kikuchi S, Tamakoshi A. Dietary folate and vitamin b6 and B12 intake in relation to mortality from cardiovascular diseases: Japan collaborative cohort study. Stroke 2010;41(6):1285-9. [PUBMED: 20395608]
47. Deshmukh US, Joglekar CV, Lubree HG, Ramdas LV, Bhat DS, Naik SS, et al.Effect of physiological doses of oral vitamin B12 on plasma homocysteine: a randomized, placebo-controlled, double-blind trial in India. European Journal of Clinical Nutrition 2010;64(5):495-502. [PUBMED: 20216560]
48. 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. [PUBMED: 21430116]
49. Ebbing M, Bonaa KH, Nordrehaug JE, Ueland PM, Arnesen E, Refsum H, et al.Combined results and long-term follow-up in NORVIT and WENBIT with 6837 coronary artery disease patients: Homocysteine-lowering B-vitamin treatment does not prevent major cardiovascular events. Journal of Internal Medicine 2009;30(4):184. [PUBMED: 20698927]
50. Ebbing M, Bonaa KH, Nygard O, Arnesen E, Ueland PM, Nordrehaug JE, et al.Cancer incidence and mortality after treatment with folic acid and vitamin B12. JAMA 2009;302(19):2119-26. [PUBMED: 19920236]
51. Nevado J. Folate Intervention in Non-ST elevation myocardial infarction and unstable angina: a randomised placebo-controlled trial [2006]. http://controlled-trials.com/ISRCTN30249553/homocysteine (accessed Oct 12th 2007).
52. Green TJ, Skeaff CM, McMahon JA, Venn BJ, Williams SM, Devlin AM, et al.Homocysteine-lowering vitamins do not lower plasma S-adenosylhomocysteine in older people with elevated homocysteine concentrations. British Journal of Nutrition 2010; Vol. 103, issue 11:1629-34. [PUBMED: 20089204]
53. 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. [PUBMED: 21803414]
54. Imasa MS, Gomez NT, Nevado JB. Folic acid-based intervention in non-ST elevation acute coronary syndromes. Asian Cardiovascular & Thoracic Annals 2009; Vol. 17, issue 1:13-21. [PUBMED: 19515873]
55. 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. [PUBMED: 22695899]
56. 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. [MEDLINE: 15215483]
57. Lee M, Hong KS, Chang SC, Saver JL. Efficacy of homocysteine lowering therapy with folic acid in stroke prevention: A meta-analysis of randomized controlled trials. Stroke. 2010; Vol. 41:e291. [: ISSN: 0039-2499]
58. Lee M, Hong KS, Chang SC, Saver JL. Efficacy of homocysteine-lowering therapy with folic acid in stroke prevention: a meta-analysis. Stroke 2010;41(6):1205-12. [PUBMED: 20413740]
59. Lonn E. Homocysteine in the prevention of ischemic heart disease, stroke and venous thromboembolism: therapeutic target or just another distraction?. Current Opinion in Hematology. 2007;14:481-7. [MEDLINE: 17934354]
60. Mager A, Orvin K, Koren-Morag N, Lev IE, Assali A, Kornowski R, et al.Impact of homocysteine-lowering vitamin therapy on long-term outcome of patients with coronary artery disease. American Journal of Cardiology 2009;104(6):745-9. [PUBMED: 19733705]
61. Manolescu BN, Oprea E, Farcasanu IC, Berteanu M, Cercasov C. Homocysteine and vitamin therapy in stroke prevention and treatment: a review. Acta Biochimica Polonica 2010;57(4):467-77. [PUBMED: 21140003]
62. Mei W, Rong Y, Jinming L, Yongjun L, Hui Z. Effect of homocysteine interventions on risk of cardiocerebrovascular events: A meta-analysis of randomized controlled trials. Circulation. 2010; Vol. 122 (2):e140-1.
63. Mei W, Rong Y, Jinming L, Yongjun L, Hui Z. Effect of homocysteine interventions on the risk of cardiocerebrovascular events: a meta-analysis of randomised controlled trials. International Journal of Clinical Practice 2010;64(2):208-15. [PUBMED: 19912385]
64. Mendez-Gonzalez J, Rodriguez-Millan 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 Neurología 2010;50(4):235-44. [PUBMED: 20198596]
65. 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. [PUBMED: 20691310]
66. Moghaddasi M, Mamarabad M. Homocysteine, vitamin B12 and folic acid levels in cerebrovascular accident: a case-control study. Journal of Neurology. 2009; Vol. 256 (Suppl 2):S171.
67. 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. [PUBMED: 20433777]
68. 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. [PUBMED: 19963194]
69. 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. [PUBMED: 19201496]
70. 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: 12395803]
71. Rautiainen S, Akesson A, Levitan EB, Morgenstern R, Mittleman MA, Wolk A. Multivitamin use and the risk of myocardial infarction: a population-based cohort of Swedish women. American Journal of Clinical Nutrition 2010;Sep 22:Epub ahead of print. [MEDLINE: 20861174]
72. 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.
73. 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; Vol. 40, issue 5:380-6. [PUBMED: 19766902]
74. 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. [MEDLINE: 12190367]
75. 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; Vol. 93, issue 1:11-8. [PUBMED: 20980493]
76. 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]. Medecine des Maladies Metaboliques 2007;1:50-2. [EMBASE: 2007490543]
77. 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. [MEDLINE: 17544768]
78. Wierzbicki AS. Homocysteine and cardiovascular disease: a review of the evidence. Diabetes & Vascular Disease Research 2007;4:143-50. [MEDLINE: 17654449]
79. Zhang C, Zhu HL. Effect of B vitamins supplementation on cardiovascular and cerebrovascular disease by lowering plasma homocysteine concentration: A meta-analysis. [Chinese]. Chinese Journal of Evidence-Based Medicine 2009;1:55-62. [: ISSN: 1672-2531]
80. 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. [PUBMED: 21980387]
81. Balshem H, Helfand M, Schunemann HJ, Oxman AD, Kunz R, Brozek J, et al.GRADE guidelines: 3. Rating the quality of evidence. Journal of Clinical Epidemiology 2011;64(4):401-6. [PUBMED: 21208779]
82. Blom HJ, Smulders Y. Overview of homocysteine and folate metabolism. With special references to cardiovascular disease and neural tube defects. Journal of Inherited Metabolic Disease 2011;34(1):75-81. [PUBMED: 20814827]
83. Boushey CJ, Beresford SAA, Omenn GS, Motulsky AG. A quantitative assessment of plasma homocysteine as a risk factor for vascular disease. Probable benefits of increasing folic acid intakes. JAMA 1995;274:1049-57.
84. Bowman L, Armitage J, Bulbulia R, Parish S, Collins R, SEARCH Study Collaborative Group. Study of the effectiveness of additional reductions in cholesterol and homocysteine (SEARCH): characteristics of a randomized trial among 12064 myocardial infarction survivors. American Heart Journal 2007;154(5):815-23, 823.e1-6. [PUBMED: 17967584]
85. Brok J, Thorlund K, Gluud C, Wetterslev J. Trial sequential analysis reveals insufficient information size and potentially false positive results in many meta-analyses. Journal of Clinical Epidemiology 2008;61(8):763-9. [PUBMED: 18411040]
86. Brok J, Thorlund K, Wetterslev J, Gluud C. Apparently conclusive meta-analyses may be inconclusive--Trial sequential analysis adjustment of random error risk due to repetitive testing of accumulating data in apparently conclusive neonatal meta-analyses. International journal of epidemiology 2009;38(1):287-98. [PUBMED: 18824466]
87. Brozek JL, Akl EA, Compalati E, Kreis J, Terracciano L, Fiocchi A, et al.Grading quality of evidence and strength of recommendations in clinical practice guidelines part 3 of 3. The GRADE approach to developing recommendations. Allergy 2011;66(5):588-95. [PUBMED: 21241318]
88. Brustolin S, Giugliani R, Félix TM. Genetics of homocysteine metabolism and associated disorders. Brazilian Journal of Medical & Biological Research 2010;43(1):1-7. [PUBMED: 19967264]
89. No authors listed. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). CAPRIE Steering Committee. Lancet 1996;348(9038):1329-39. [PUBMED: 8918275]
90. Casas JP, Bautista LE, Smeeth L, Sharma, P, Hingorani AD. Homocysteine and stroke: evidence on a causal link from mendelian randomisation. Lancet 2005;365:224-32.
91. Castro R, Rivera I, Blom HJ, Jakobs C, Tavares de Almeida I. Homocysteine metabolism, hyperhomocysteinaemia and vascular disease: an overview. Journal of Inherited Metabolic Disease 2006;29:3-20.
92. Clarke R, Lewington S, Sherliker P, Armitage J. Effects of B-vitamins on plasma homocysteine concentrations and on risk of cardiovascular disease and dementia. Current Opinion in Clinical Nutrition and Metabolic Care 2007;10:32-9. [MEDLINE: 17143052]
93. Borenstein M, Hedges L, Higgins J, Rothstein H. Comprehensive Meta-analysis. 2. Englewood NJ: Biostat, 2005.
94. Crider KS, Bailey LB, Berry RJ. Folic acid food fortification-its history, effect, concerns, and future directions. Nutrients 2011;3(3):370-84. [PUBMED: 22254102]
95. Copenhagen Trial Unit. TSA - Trial Sequential Analysis. http://ctu.dk/tsa/ (accessed 29 September 2011), 2011.
96. Danesh J, Lewington S. Plasma homocysteine and coronary heart disease: systematic review of published epidemiological studies. Journal of Cardiovascular Risk 1998;5:229-32. [MEDLINE: 9919470]
97. di Salvo ML, Contestabile R, Safo MK. Vitamin B(6) salvage enzymes: mechanism, structure and regulation. Biochimica et Biophysica Acta 2011;1814(11):1597-608. [PUBMED: 21182989]
98. di Salvo ML, Safo MK, Contestabile R. Biomedical aspects of pyridoxal 5'-phosphate availability. Frontiers in Bioscience 2012;4:897-913. [PUBMED: 22201923]
99. Eikelboom JW, Lonn E, Genest J Jr, Hankey G, Yusuf S. Homocyst(e)ine and cardiovascular disease: a critical review of the epidemiologic evidence. Annals of Internal Medicine 1999;131:363-75.
100. Epstein FH. Cardiovascular disease epidemiology: a journey from the past into the future. Circulation 1996;93:1755-64.
101. Fedosov SN. Physiological and molecular aspects of cobalamin transport. Sub-cellular Biochemistry 2012;56:347-67. [PUBMED: 22116708]
102. Ferretti G, Bacchetti T, Negre-Salvayre A, Salvayre R, Dousset N, Curatola G. Structural modifications of HDL and functional consequences. Atherosclerosis 2006;184:1-7.
103. Ford ES, Smith SJ, Stroup DF, Steinberg KK, Mueller PW, Thacker SB. Homocyst(e)ine and cardiovascular disease: a systematic review of the evidence with special emphasis on case-control studies and nested case-control studies. International Journal of Epidemiology 2002;31:59-70. [MEDLINE: 11914295]
104. Fowler B. Homocysteine: overview of biochemistry, molecular biology, and role in disease processes. Seminars in Vascular Medicine 2005;5:77-86. [MEDLINE: 16047261]
105. Friso S, Lotto V, Corrocher R, Choi SW. Vitamin B6 and cardiovascular disease. Sub-cellular Biochemistry 2012;56:265-90. [PUBMED: 22116704]
106. Gaziano T, Reddy KS, Paccaud F, Horton S, Chaturvedi V. Cardiovascular Disease. In: Jamison DT, et al. editor(s). Disease Control Priorities in Developing Countries. 2nd Edition. Washington DC; New York: The World Bank and Oxford University Press, 2006.
107. Gori AM, Sofi F, Marcucci R, Giusti B, Franco Gensini G, Abbate R. Association between homocysteine, vitamin B(6) concentrations and inflammation. Clinical Chemistry and Laboratory Medicine 2007;45:1728-36. [MEDLINE: 17990948]
108. Brozek J, Oxman A, Schünemann H. GRADEpro [Computer program]. 3.2 for Windows. The GRADE Working Group, 2008.
109. Guthikonda S, Haynes WG. Homocysteine: role and implications in atherosclerosis. Current Atherosclerosis Reports 2006;8:100-6.
110. Guyatt GH, Oxman AD, Kunz R, Atkins D, Brozek J, Vist G, et al.GRADE guidelines: 2. Framing the question and deciding on important outcomes. Journal of Clinical Epidemiology 2011;64(4):395-400. [PUBMED: 21194891]
111. Guyatt G, Oxman AD, Akl EA, Kunz R, Vist G, Brozek J, et al.GRADE guidelines: 1. Introduction-GRADE evidence profiles and summary of findings tables. Journal of Clinical Epidemiology 2011;64(4):383-94. [PUBMED: 21195583]
112. Guyatt GH, Oxman AD, Vist G, Kunz R, Brozek J, Alonso-Coello P, et al.GRADE guidelines: 4. Rating the quality of evidence--study limitations (risk of bias). Journal of Clinical Epidemiology 2011;64(4):407-15. [PUBMED: 21247734]
113. Guyatt GH, Oxman AD, Sultan S, Glasziou P, Akl EA, Alonso-Coello P, et al.GRADE guidelines: 9. Rating up the quality of evidence. Journal of Clinical Epidemiology 2011;64(12):1311-6. [PUBMED: 21802902]
114. Guyatt GH, Oxman AD, Kunz R, Woodcock J, Brozek J, Helfand M, et al.GRADE guidelines: 8. Rating the quality of evidence--indirectness. Journal of Clinical Epidemiology 2011;64(12):1303-10. [PUBMED: 21802903]
115. Guyatt GH, Oxman AD, Kunz R, Woodcock J, Brozek J, Helfand M, et al.GRADE guidelines: 7. Rating the quality of evidence--inconsistency. Journal of Clinical Epidemiology 2011;64(12):1294-302. [PUBMED: 21803546]
116. Guyatt GH, Oxman AD, Kunz R, Brozek J, Alonso-Coello P, Rind D, et al.GRADE guidelines 6. Rating the quality of evidence--imprecision. Journal of Clinical Epidemiology 2011;64(12):1283-93. [PUBMED: 21839614]
117. Guyatt GH, Oxman AD, Montori V, Vist G, Kunz R, Brozek J, et al.GRADE guidelines: 5. Rating the quality of evidence--publication bias. Journal of Clinical Epidemiology 2011;64(12):1277-82. [PUBMED: 21802904]
118. Guyatt G, Oxman AD, Sultan S, Brozek J, Glasziou P, Alonso-Coello P, et al.GRADE guidelines 11-making an overall rating of confidence in effect estimates for a single outcome and for all outcomes. Journal of Clinical Epidemiology 2012;Apr 27:Epub ahead of print. [PUBMED: 22542023]
119. Guyatt GH, Oxman AD, Santesso N, Helfand M, Vist G, Kunz R, et al.GRADE guidelines 12. Preparing Summary of Findings tables-binary outcomes. Journal of Clinical Epidemiology 2012; Vol. May 18:Epub ahead of print. [PUBMED: 22609141]
120. Hackam DG, Anand SS. Emerging risk factors for atherosclerotic vascular disease: a critical review of the evidence. JAMA 2003;290:932-40.
121. Herrmann W, Obeid R. Cobalamin deficiency. Sub-cellular Biochemistry 2012;56:301-22. [PUBMED: 22116706]
122. Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analysis. BMJ 2003;327:557-60.
123. Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions Version 5.0.1. The Cochrane Collaboration. Available from www.cochrane-handbook.org, 2011.
124. Homocysteine Lowering Trialists' Collaboration. Dose-dependent effects of folic acid on blood concentrations of homocysteine: a meta-analysis of the randomized trials. American Journal of Clinical Nutrition 2005;82:806-12.
125. Homocysteine Studies Collaboration. Homocysteine and risk of ischemic heart disease and stroke: a meta-analysis. JAMA 2002;288:2015-22.
126. Humphrey LL, Fu R, Rogers K, Freeman M, Helfand M. Homocysteine level and coronary heart disease incidence: a systematic review and meta-analysis. Mayo Clinic Proceedings 2008;83:1203-12.
127. International Committee on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use. Code of Federal Regulations & International Conference on Harmonisation Guidelines. Philadelphia, US: Barnett International/PAREXEL, 1997.
128. Ioannidis JP. Meta-research: The art of getting it wrong. Research Synthesis Methods 2010;10(3-4):169-84.
129. Jacobsen DW, Catanescu O, Dibello PM, Barbato JC. Molecular targeting by homocysteine: a mechanism for vascular pathogenesis. Clinical Chemistry & Laboratory Medicine 2005;43:1076-83.
130. Jacobsen DW. Homocysteine targeting of plasma proteins in hemodialysis patients. Kidney International 2006;69:787-9.
131. Jakubowski H. Homocysteine thiolactone: metabolic origin and protein homocysteinylation in humans. Journal of Nutrition 2000;130(2S Suppl):377S-81S.
132. Jakubowski H. Molecular basis of homocysteine toxicity in humans. Cellular and Molecular Life Sciences 2004;61:470-87.
133. Jakubowski H. The pathophysiological hypothesis of homocysteine thiolactone-mediated vascular disease. Journal of Physiology and Pharmacology 2008;59 (Suppl 9):155-67. [MEDLINE: 19261978]
134. Jamison DT, Breman JG, Measham AR, Alleyne G, Claeson M, Evans DB, et al.Priorities in Health. Washington DC: The World Bank, 2006.
135. Jamison RL, Hartigan P, Kaufman JS, Goldfarb DS, Warren SR, Guarino PD, et al.Effect of homocysteine lowering on mortality and vascular disease in advanced chronic kidney disease and end-stage renal disease: a randomized controlled trial. JAMA 2007;298(10):1163-70. [PUBMED: 17848650]
136. Kahn R, Robertson RM, Smith R, Eddy D. The impact of prevention on reducing the burden of cardiovascular disease. Circulation 2008;118:576-85.
137. Kardesoglu E, Uz O, Isilak Z, Cebeci BS. Homocysteine as a new risk factor for cardiovascular events in heart failure. International Journal of Cardiology 2011;146(1):126-7. [PUBMED: 21074871]
138. Kräutler B. Biochemistry of B12-cofactors in human metabolism. Sub-cellular Biochemistry 2012;56:323-46. [PUBMED: 22116707]
139. Lefebvre C, Manheimer E, Glanville J. Chapter 6: Searching for Studies. In: Higgins JPT, Green S, editor(s). Cochrane Handbook for Systematic Reviews of Interventions. Version 5.1.0. [updated March 2011]. The Cochrane Collaboration, 2011.
140. Maron BA, Loscalzo J. Homocysteine. Clinics in Laboratory Medicine 2006;26:591-609. [MEDLINE: 16938586]
141. Maron BA, Loscalzo J. The treatment of hyperhomocysteinemia. Annual Review of Medicine 2009;60:39-54. [PUBMED: 18729731]
142. Math MV, Balasubramaniam P. Steps to control the burden of cardiovascular disease in the Indian Subcontinent. The Indian Journal of Medical Research 2007;125:590-1.
143. McCully KS. Hyperhomocysteinemia and arteriosclerosis: historical perspectives. Clinical Chemistry & Laboratory Medicine 2005;43:980-6.
144. Molloy AM. Genetic aspects of folate metabolism. Sub-cellular Biochemistry 2012;56:105-30. [PUBMED: 22116697]
145. Mudd SH, Finkelstein JD, Refsum H, Ueland PM, Malinow MR, Lentz SR, et al.Homocysteine and its disulfide derivatives: a suggested consensus terminology. Arteriosclerosis, Thrombosis, and Vascular Biology 2000;20:704-6. [MEDLINE: 10894806]
146. Mukherjee T, Hanes J, Tews I, Ealick SE, Begley TP. Pyridoxal phosphate: biosynthesis and catabolism. Biochimica et Biophysica Acta 2011;1814(11):1585-96. [PUBMED: 21767669]
147. Myers GL, Christenson RH, Cushman M, Ballantyne CM, Cooper GR, Pfeiffer CM, et al.National Academy of Clinical Biochemistry Laboratory Medicine Practice guidelines: emerging biomarkers for primary prevention of cardiovascular disease. Clinical Chemistry 2009;55:378-84. [MEDLINE: 19106185]
148. Narayan KMV, Zhang P, Kanaya AM, Williams DE, Engelgau MM, Imperatore G, et al.Diabetes: the pandemic and potential solutions. In: Jameson DT editor(s). Disease Control Priorities in Developing Countries. 2nd Edition. Washington, Oxford: The World Bank and Oxford University Press, 2006.
149. Obeid R, Herrmann W. Homocysteine and lipids: S-adenosyl methionine as a key intermediate. FEBS Letters 2009;583:1215-25. [MEDLINE: 19324042]
150. Ohrvik VE, Witthoft CM. Human folate bioavailability. Nutrients 2011;3(4):475-90. [PUBMED: 22254106]
151. Perła-Kaján J, Twardowski T, Jakubowski H. Mechanisms of homocysteine toxicity in humans. Amino Acids 2007;32:561-72. [MEDLINE: 17285228]
152. Ramakrishnan S, Sulochana KN, Lakshmi S, Selvi R, Angayarkanni N. Biochemistry of homocysteine in health and diseases. Indian Journal of Biochemistry & Biophysics 2006;43:275-83. [MEDLINE: 17133733]
153. Refsum H, Ueland PM, Nygard O, Vollset SE. Homocysteine and cardiovascular disease. Annual Review of Medicine 1998;49:31-62.
154. The Nordic Cochrane Centre: The Cochrane Collaboration. Review Manager (RevMan). 5.1. Copenhagen: The Nordic Cochrane Centre: The Cochrane Collaboration, 2011.
155. Riksen NP, Rongen GA, Boers GH, Blom HJ, van den Broek PH, Smits P. Enhanced cellular adenosine uptake limits adenosine receptor stimulation in patients with hyperhomocysteinemia. Arteriosclerosis, Thrombosis & Vascular Biology 2005;25:109-14.
156. Rodgers A, Lawes CMM, Gaziano TA, Vos T. The growing burden of risk from high blood pressure, cholesterol, and bodyweight. In: Jameson DT editor(s). Disease Control Priorities in Developing Countries. 2nd Edition. Washington, New York: The World Bank and Oxford University Press, 2006.
157. Selhub J, Jacques PF, Wilson PWF, Rush D, Rosenberg IH. Vitamin status and intake as primary determinants of homocysteinemia in an elderly population. JAMA 1993;270:2693-8.
158. Selhub J. The many facets of hyperhomocysteinemia: studies from the Framingham cohorts. Journal of Nutrition 2006;136(6 Suppl):1726S-30S.
159. Shelhub J. Public health significance of elevated homocysteine. Food and Nutrition Bulletin 2008;29 (Suppl 2):116-25. [MEDLINE: 18709886]
160. Sofi F, Marcucci R, Bolli P, Giambene B, Sodi A, Fedi S, et al.Low vitamin B6 and folic acid levels are associated with retinal vein occlusion independently of homocysteine levels. Atherosclerosis 2008;198:223-7. [MEDLINE: 17945240]
161. Splaver A, Lamas GA, Hennekens CH. Homocysteine and cardiovascular disease: biological mechanism, observational epidemiology, and the need for randomised trials. American Heart Journal 2004;148:34-40.
162. No authors listed. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet 1994;344(8934):1383-9. [PUBMED: 7968073]
163. Stampfer MJ, Malinow MR, Willett WC, Newcomer LM, Upson B, Ullmann D, et al.prospective study of plasma homocyst(e)ine and risk of myocardial infarction in US physicians. JAMA 1992;268:877-81.
164. Thorlund K, Devereaux PJ, Wetterslev J, Guyatt G, Ioannidis JP, Thabane L, et al.Can trial sequential monitoring boundaries reduce spurious inferences from meta-analyses?. International Journal of Epidemiology 2009;38(1):276-86. [PUBMED: 18824467]
165. Thorlund K, Anema A, Mills E. Interpreting meta-analysis according to the adequacy of sample size. An example using isoniazid chemoprophylaxis for tuberculosis in purified protein derivative negative HIV-infected individuals. Clinical Epidemiology 2010;2:57-66. [PUBMED: 20865104]
166. Thorlund K, Engstrøm J, Wetterslev J, Brok J, Imberger G, Gluud C. User manual for Trial Sequential Analysis (TSA). http://ctu.dk/tsa/files/tsa_manual.pdf 2011 (accessed 30 April 2012). 2011.
167. Vianna AC, Mocelin AJ, Matsuo T, Morais-Filho D, Largura A, Delfino VA, et al.Uremic hyperhomocysteinemia: a randomized trial of folate treatment for the prevention of cardiovascular events. Hemodialysis International 2007;11:210-6.
168. Wald DS, Law M, Morris JK. Homocysteine and cardiovascular disease: evidence on causality from a meta-analysis. BMJ 2002;325:1202-6.
169. Wang H, Tan H, Yang F. Mechanisms in homocysteine-induced vascular disease. Drug Discovery Today: Disease Mechanisms 2005;2:25-31.
170. Wetterslev J, Thorlund K, Brok J, Gluud C. Trial sequential analysis may establish when firm evidence is reached in cumulative meta-analysis. Journal of Clinical Epidemiology 2008;61(1):64-75. [PUBMED: 18083463]
171. Wetterslev J, Thorlund K, Brok J, Gluud C. Estimating required information size by quantifying diversity in random-effects model meta-analyses. BMC Medical Research Methodology 2009;9:86. [PUBMED: 20042080]
172. World Health Organization. The world health report: reducing risks, promoting healthy life. Available at http://www.who.int/whr/2002/en/whr02_en.pdf [accessed 01 01 2007]. Geneva: World Health Organization, 2002.
173. Willett WC, Koplan JP, Nugent R, Dusenbury C, Puska P, Gaziano TA. Prevention of chronic disease by means of diet and lifestyle changes. In: Jameson DT editor(s). Disease Control Priorities in Developing Countries. 2nd Edition. New York, Oxford: The World Bank and Oxford University Press, 2006.
174. Williams KT, Schalinske KL. Homocysteine metabolism and its relation to health and disease. Bifactors 2010;36(1):19-24. [PUBMED: 20091801]
175. Wirakartakusumah MA, Hariyadi P. Technical aspects of food fortification. Food and Nutrition Bulletin. Vol. 19, United Nations University Press, Tokyo, Japan, 1998.
176. Yetley EA, Johnson CL. Folate and vitamin B-12 biomarkers in NHANES: history of their measurement and use. The American Journal of Clinical Nutrition 2011;94(1):322S-31S. [PUBMED: 21593508]
177. Yusuf S, Sleight P, Pogue J, Bosch J, Davies R, Dagenais G. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators. New England Journal of Medicine 2000;342(3):145-53. [PUBMED: 10639539]
178. Zhou J, Austin RC. Contributions of hyperhomocysteinemia to atherosclerosis: Causal relationship and potential mechanisms. Biofactors 2009;35:120-9. [MEDLINE: 19449439]
179. Marti-Carvajal AJ, Sola I, Lathyris D, Salanti G. Homocysteine lowering interventions for preventing cardiovascular events. Cochrane Database of Systematic Reviews 2009, Issue 4. [DOI: 10.1002/14651858.CD006612.pub2]