Folic Acid Supplementation and the Risk of Cardiovascular Diseases: A Meta-Analysis of Randomized Controlled Trials

Journal of the American Heart Association

Volumn 5, Issue 8, 2016, Pages

  Li, Yanping ^a   Huang, Tianyi ^a,c   Zheng, Yan ^a   Muka, Tauland ^b   Troup, Jenna ^b   Hu, Frank B ^a,c  

^a HARVARD SCHOOL OF PUBLIC HEALTH   (United States)

^b ERASMUS MEDICAL CENTER   (Netherlands)

^c HARVARD MEDICAL SCHOOL   (United States)

Author keywords

Cardiovascular disease prevention; Folate; Stroke prevention

Indexed keywords

FOLIC ACID; HOMOCYSTEINE;

AMINO ACID BLOOD LEVEL; ARTICLE; CARDIOVASCULAR DISEASE; CARDIOVASCULAR RISK; CEREBROVASCULAR ACCIDENT; FOLIC ACID BLOOD LEVEL; GENETIC HETEROGENEITY; HEART PROTECTION; HUMAN; ISCHEMIC HEART DISEASE; META ANALYSIS; PRIORITY JOURNAL; RANDOMIZED CONTROLLED TRIAL (TOPIC); THERAPY EFFECT; VITAMIN SUPPLEMENTATION; AGED; CORONARY ARTERY DISEASE; DIETARY SUPPLEMENT; FEMALE; HYPERHOMOCYSTEINEMIA; MALE; MIDDLE AGED; RISK FACTOR;

AGED; CARDIOVASCULAR DISEASES; CORONARY DISEASE; DIETARY SUPPLEMENTS; FEMALE; FOLIC ACID; HUMANS; HYPERHOMOCYSTEINEMIA; MALE; MIDDLE AGED; RANDOMIZED CONTROLLED TRIALS AS TOPIC; RISK FACTORS; STROKE;

EID: 84996576830     PISSN: None     EISSN: 20479980     Source Type: Journal    
DOI: 10.1161/JAHA.116.003768     Document Type: Article

References (68)

1. McCully KS. Vascular pathology of homocysteinemia: implications for the pathogenesis of arteriosclerosis. Am J Pathol. 1969;56:111-128.
2. Boushey CJ, Beresford SA, 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;274:1049-1057.
3. Homocysteine and risk of ischemic heart disease and stroke: a meta-analysis. JAMA. 2002;288:2015-2022.
4. Wald DS, Law M, Morris JK. Homocysteine and cardiovascular disease: evidence on causality from a meta-analysis. BMJ. 2002;325:1202.
5. Casas JP, Bautista LE, Smeeth L, Sharma P, Hingorani AD. Homocysteine and stroke: evidence on a causal link from Mendelian randomisation. Lancet. 2005;365:224-232.
6. Klerk M, Verhoef P, Clarke R, Blom HJ, Kok FJ, Schouten EG. MTHFR 677C->T polymorphism and risk of coronary heart disease: a meta-analysis. JAMA. 2002;288:2023-2031.
7. Jacques PF, Selhub J, Bostom AG, Wilson PW, Rosenberg IH. The effect of folic acid fortification on plasma folate and total homocysteine concentrations. N Engl J Med. 1999;340:1449-1454.
8. Lowering blood homocysteine with folic acid based supplements: meta-analysis of randomised trials. Homocysteine Lowering Trialists' Collaboration. BMJ. 1998;316:894-898.
9. Crider KS, Bailey LB, Berry RJ. Folic acid food fortification-its history, effect, concerns, and future directions. Nutrients. 2011;3:370-384.
10. Albert CM, Cook NR, Manson JE. Effect of folic acid and B vitamins on cardiovascular disease in women-reply. JAMA. 2008;300:1410.
11. Armitage JM, Bowman L, Clarke RJ, Wallendszus K, Bulbulia R; Study of the Effectiveness of Additional Reductions in C, Homocysteine Collaborative G. 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;303:2486-2494.
12. Bostom AG, Carpenter MA, Kusek JW, Levey AS, Hunsicker L, Pfeffer MA, Selhub J, Jacques PF, Cole E, Gravens-Mueller L, House AA, Kew C, McKenney JL, Pacheco-Silva A, Pesavento T, Pirsch J, Smith S, Solomon S, Weir M. Homocysteine-lowering and cardiovascular disease outcomes in kidney transplant recipients: primary results from the Folic Acid for Vascular Outcome Reduction in Transplantation trial. Circulation. 2011;123:1763-1770.
13. Ebbing M, Bleie Ø, Ueland PM, Nordrehaug JE, Nilsen DW, Vollset SE, Refsum H, Pedersen EK, Nygård O. Mortality and cardiovascular events in patients treated with homocysteine-lowering B vitamins after coronary angiography: a randomized controlled trial. JAMA. 2008;300:795-804.
14. 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. 2010;341:c6273.
15. Hankey GJ, Eikelboom JW, Yi Q, Lees KR, Chen C, Xavier D, Navarro JC, Ranawaka UK, Uddin W, Ricci S, Gommans J, Schmidt R; Group Vts. Antiplatelet therapy and the effects of B vitamins in patients with previous stroke or transient ischaemic attack: a post-hoc subanalysis of VITATOPS, a randomised, placebo-controlled trial. Lancet Neurol. 2012;11:512-520.
16. Jamison RL, Hartigan P, Kaufman JS, Goldfarb DS, Warren SR, Guarino PD, Gaziano JM; Veterans Affairs Site I. 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;298:1163-1170.
17. Lonn E, Yusuf S, Arnold MJ, Sheridan P, Pogue J, Micks M, McQueen MJ, Probstfield J, Fodor G, Held C, Genest J Jr. Homocysteine lowering with folic acid and B vitamins in vascular disease. N Engl J Med. 2006;354:1567-1577.
18. 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;288:973-979.
19. Toole JF, Malinow MR, Chambless LE, Spence JD, Pettigrew LC, Howard VJ, Sides EG, Wang CH, Stampfer M. 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;291:565-575.
20. 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 Nutr. 2015;18:1514-1521.
21. Holmes MV, Newcombe P, Hubacek JA, Sofat R, Ricketts SL, Cooper J, Breteler MM, Bautista LE, Sharma P, Whittaker JC, Smeeth L, Fowkes FG, Algra A, Shmeleva V, Szolnoki Z, Roest M, Linnebank M, Zacho J, Nalls MA, Singleton AB, Ferrucci L, Hardy J, Worrall BB, Rich SS, Matarin M, Norman PE, Flicker L, Almeida OP, van Bockxmeer FM, Shimokata H, Khaw KT, Wareham NJ, Bobak M, Sterne JA, Smith GD, Talmud PJ, van Duijn C, Humphries SE, Price JF, Ebrahim S, Lawlor DA, Hankey GJ, Meschia JF, Sandhu MS, Hingorani AD, Casas JP. 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;378:584-594.
22. Wang X, Qin X, Demirtas H, Li J, Mao G, Huo Y, Sun N, Liu L, Xu X. Efficacy of folic acid supplementation in stroke prevention: a meta-analysis. Lancet. 2007;369:1876-1882.
23. 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. Eur J Intern Med. 2012;23:745-754.
24. Lamas GA, Boineau R, Goertz C, Mark DB, Rosenberg Y, Stylianou M, Rozema T, Nahin RL, Lindblad L, Lewis EF, Drisko J, Lee KL. Oral high-dose multivitamins and minerals after myocardial infarction: a randomized trial. Ann Intern Med. 2013;159:797-804.
25. Sharma M, Mittal N. Prevalence of hyperhomocysteinaemia in chronic kidney disease and effect of supplementation of folic acid and vitamin B12 on cardiovascular mortality. J Indian Acad Clin Med. 2013;14:33-36.
26. Huo Y, Li J, Qin X, Huang Y, Wang X, Gottesman RF, Tang G, Wang B, Chen D, He M, Fu J, Cai Y, Shi X, Zhang Y, Cui Y, Sun N, Li X, Cheng X, Wang J, Yang X, Yang T, Xiao C, Zhao G, Dong Q, Zhu D, Ge J, Zhao L, Hu D, Liu L, Hou FF. Efficacy of folic acid therapy in primary prevention of stroke among adults with hypertension in China: the CSPPT randomized clinical trial. JAMA. 2015;313:1325-1335.
27. Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gotzsche PC, Ioannidis JP, Clarke M, Devereaux PJ, Kleijnen J, Moher D. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: explanation and elaboration. BMJ. 2009;339:b2700.
28. Hutton B, Salanti G, Caldwell DM, Chaimani A, Schmid CH, Cameron C, Ioannidis JP, Straus S, Thorlund K, Jansen JP, Mulrow C, Catala-Lopez F, Gotzsche PC, Dickersin K, Boutron I, Altman DG, Moher D. The PRISMA extension statement for reporting of systematic reviews incorporating network meta-analyses of health care interventions: checklist and explanations. Ann Intern Med. 2015;162:777-784.
29. Higgins JP, Altman DG, Gøtzsche PC, Jüni P, Moher D, Oxman AD, Savovic J, Schulz KF, Weeks L, Sterne JA. The Cochrane Collaboration's tool for assessing risk of bias in randomised trials. BMJ. 2011;343:d5928.
30. Vianna ACA, Mocelin AJ, Matsuo T, Morais-Filho D, Largura A, Delfino VA, Soares AE, Matni AM. Uremic hyperhomocysteinemia: a randomized trial of folate treatment for the prevention of cardiovascular events. Hemodial Int. 2007;11:210-216.
31. Bonaa KH, Njolstad I, Ueland PM, Schirmer H, Tverdal A, Steigen T, Wang H, Nordrehaug JE, Arnesen E, Rasmussen K. Homocysteine lowering and cardiovascular events after acute myocardial infarction. N Engl J Med. 2006;354:1578-1588.
32. Liem A, Reynierse-Buitenwerf GH, Zwinderman AH, Jukema JW, van Veldhuisen DJ. Secondary prevention with folic acid: effects on clinical outcomes. J Am Coll Cardiol. 2003;41:2105-2113.
33. 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;91:1213-1214.
34. Mann JF, Sheridan P, McQueen MJ, Held C, Arnold JM, Fodor G, Yusuf S, Lonn EM. Homocysteine lowering with folic acid and B vitamins in people with chronic kidney disease-results of the renal HOPE-2 study. Nephrol Dial Transplant. 2008;23:645-653.
35. Higgins JPT, Green S. Cochrane Handbook for Systematic Reviews of Interventions. Version 5.1.0. [updated March 2011]. The Cochrane Collaboration, 2011. Available from http://handbook.cochrane.org. Accessed August 10, 2016.
36. Egger M, Davey Smith G, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ. 1997;315:629-634.
37. 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 Neurol. 2010;9:855-865.
38. Mark SD, Wang W, Fraumeni JF Jr, Li JY, Taylor PR, Wang GQ, Guo W, Dawsey SM, Li B, Blot WJ. Lowered risks of hypertension and cerebrovascular disease after vitamin/mineral supplementation: the Linxian Nutrition Intervention Trial. Am J Epidemiol. 1996;143:658-664.
39. Baker F, Picton D, Blackwood S, Hunt J, Erskine M, Dyas M, Ashby M, Siva A, Brown MJ. Blinded comparison of folic acid and placebo in patients with ischaemic heart disease: an outcome trial. Circulation. 2002;106(suppl II):741.
40. Righetti M, Ferrario GM, Milani S, Serbelloni P, La Rosa L, Uccellini M, Sessa A. Effects of folic acid treatment on homocysteine levels and vascular disease in hemodialysis patients. Med Sci Monit. 2003;9:PI19-PI24.
41. Lange H, Suryapranata H, De Luca G, Borner C, Dille J, Kallmayer K, Pasalary MN, Scherer E, Dambrink JH. Folate therapy and in-stent restenosis after coronary stenting. N Engl J Med. 2004;350:2673-2681.
42. Liem AH, van Boven AJ, Veeger NJ, Withagen AJ, Robles de Medina RM, Tijssen JG, van Veldhuisen DJ. Efficacy of folic acid when added to statin therapy in patients with hypercholesterolemia following acute myocardial infarction: a randomised pilot trial. Int J Cardiol. 2004;93:175-179.
43. Wrone EM, Hornberger JM, Zehnder JL, McCann LM, Coplon NS, Fortmann SP. Randomized trial of folic acid for prevention of cardiovascular events in end-stage renal disease. J Am Soc Nephrol. 2004;15:420-426.
44. Righetti M, Serbelloni P, Milani S, Ferrario G. Homocysteine-lowering vitamin B treatment decreases cardiovascular events in hemodialysis patients. Blood Purif. 2006;24:379-386.
45. Zoungas S, McGrath BP, Branley P, Kerr PG, Muske C, Wolfe R, Atkins RC, Nicholls K, Fraenkel M, Hutchison BG, Walker R, McNeil JJ. Cardiovascular morbidity and mortality in the atherosclerosis and folic acid supplementation trial (ASFAST) in chronic renal failure: a multicenter, randomized, controlled trial. J Am Coll Cardiol. 2006;47:1108-1116.
46. Cole BF, Baron JA, Sandler RS, Haile RW, Ahnen DJ, Bresalier RS, McKeown-Eyssen G, Summers RW, Rothstein RI, Burke CA, Snover DC, Church TR, Allen JI, Robertson DJ, Beck GJ, Bond JH, Byers T, Mandel JS, Mott LA, Pearson LH, Barry EL, Rees JR, Marcon N, Saibil F, Ueland PM, Greenberg ER. Folic acid for the prevention of colorectal adenomas: a randomized clinical trial. JAMA. 2007;297:2351-2359.
47. Potena L, Grigioni F, Masetti M, Magnani G, Coccolo F, Fallani F, Russo A, Pizzuti M, Scalone A, Bianchi IG, Branzi A. Long-term effect of folic acid therapy in heart transplant recipients: follow-up analysis of a randomized study. Transplantation. 2008;85:1146-1150.
48. Hodis HN, Mack WJ, Dustin L, Mahrer PR, Azen SP, Detrano R, Selhub J, Alaupovic P, Liu CR, Liu CH, Hwang J, Wilcox AG, Selzer RH. High-dose B vitamin supplementation and progression of subclinical atherosclerosis: a randomized controlled trial. Stroke. 2009;40:730-736.
49. Imasa MS, Gomez NT, Nevado JB Jr. Folic acid-based intervention in non-ST elevation acute coronary syndromes. Asian Cardiovasc Thorac Ann. 2009;17:13-21.
50. Heinz J, Kropf S, Domrose U, Westphal S, Borucki K, Luley C, Neumann KH, Dierkes J. B vitamins and the risk of total mortality and cardiovascular disease in end-stage renal disease: results of a randomized controlled trial. Circulation. 2010;121:1432-1438.
51. House AA, Eliasziw M, Cattran DC, Churchill DN, Oliver MJ, Fine A, Dresser GK, Spence JD. Effect of B-vitamin therapy on progression of diabetic nephropathy: a randomized controlled trial. JAMA. 2010;303:1603-1609.
52. Dong H, Pi F, Ding Z, Chen W, Pang S, Dong W, Zhang Q. Efficacy of supplementation with B vitamins for stroke prevention: a network meta-analysis of randomized controlled trials. PLoS One. 2015;10:e0137533.
53. Clarke R, Halsey J, Lewington S, Lonn E, Armitage J, Manson JE, Bønaa KH, Spence JD, Nygård O, Jamison R, Gaziano JM, Guarino P, Bennett D, Mir F, Peto R, Collins R. 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. Arch Intern Med. 2010;170:1622-1631.
54. Huo Y, Qin X, Wang J, Sun N, Zeng Q, Xu X, Liu L, Wang X. Efficacy of folic acid supplementation in stroke prevention: new insight from a meta-analysis. Int J Clin Pract. 2012;66:544-551.
55. Lee M, Hong KS, Chang SC, Saver JL. Efficacy of homocysteine-lowering therapy with folic acid in stroke prevention: a meta-analysis. Stroke. 2010;41:1205-1212.
56. Martí-Carvajal AJ, Solà I, Lathyris D, Salanti G. Homocysteine lowering interventions for preventing cardiovascular events. Cochrane Database Syst Rev. 2009;4:CD006612.
57. 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. Int J Clin Pract. 2010;64:208-215.
58. Miller IER, 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. Am J Cardiol. 2010;106:517-527.
59. Zhou YH, Tang JY, Wu MJ, Lu J, Wei X, Qin YY, Wang C, Xu JF, He J. Effect of folic acid supplementation on cardiovascular outcomes: a systematic review and meta-analysis. PLoS One. 2011;6:e25142.
60. 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;296:2720-2726.
61. 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:e107060.
62. Undas A, Stepien E, Plicner D, Zielinski L, Tracz W. Elevated total homocysteine is associated with increased platelet activation at the site of microvascular injury: effects of folic acid administration. J Thromb Haemost. 2007;5:1070-1072.
63. Qin X, Huo Y, Langman CB, Hou F, Chen Y, Matossian D, Xu X, Wang X. Folic acid therapy and cardiovascular disease in ESRD or advanced chronic kidney disease: a meta-analysis. Clin J Am Soc Nephrol. 2011;6:482-488.
64. Ji Y, Tan S, Xu Y, Chandra A, Shi C, Song B, Qin J, Gao Y. Vitamin B supplementation, homocysteine levels, and the risk of cerebrovascular disease: a meta-analysis. Neurology. 2013;81:1298-1307.
65. Humphrey LL, Fu R, Rogers K, Freeman M, Helfand M. Homocysteine level and coronary heart disease incidence: a systematic review and meta-analysis. Mayo Clin Proc. 2008;83:1203-1212.
66. Saposnik G, Ray JG, Sheridan P, McQueen M, Lonn E. Homocysteine-lowering therapy and stroke risk, severity, and disability: additional findings from the HOPE 2 trial. Stroke. 2009;40:1365-1372.
67. Ebbing M, Bonaa KH, Arnesen E, Ueland PM, Nordrehaug JE, Rasmussen K, Njolstad I, Nilsen DW, Refsum H, Tverdal A, Vollset SE, Schirmer H, Bleie O, Steigen T, Midttun O, Fredriksen A, Pedersen ER, Nygard O. Combined analyses and extended follow-up of two randomized controlled homocysteine-lowering B-vitamin trials. J Intern Med. 2010;268:367-382.
68. Bots ML, Launer LJ, Lindemans J, Hoes AW, Hofman A, Witteman JC, Koudstaal PJ, Grobbee DE. Homocysteine and short-term risk of myocardial infarction and stroke in the elderly: the Rotterdam Study. Arch Intern Med. 1999;159:38-44.