Effect of B Vitamins Supplementation on Cardiovascular and Cerebrovascular Disease by Lowering Plasma Homocysteine Concentration: A Meta-analysis_Chinese Journal of Evidence-Based Medicine

Authors：

ZHANG Chen ^1,2 ,  ZHU Huilian ¹

1. Faculty of Nutrition, School of Public Health, Sun Yat-sen University, Guangzhou 510080, China;2. Library of Guangzhou Medical College, Guangzhou 510182, China;

Corresponding author：

ZHU Huilian, Email: zhuhl@mail.sysu.edu.cn

Keywords：

B vitamins; Homocysteine; Cardiovascular and cerebrovascular disease; Meta-analysis

DOI：

10.7507/1672-2531.20090013

Video：

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Objective 　To assess the effect of B vitamins supplementation on cardiovascular and cerebrovascular diseases, and also to evaluate the relationship between homocysteine and risk of cardiovascular and cerebrovascular diseases.
Methods 　Using the words ‘homocysteine’, ‘cardiovascular disease’, ‘cerebrovascular disease’, ‘B vitamins’, and ‘randomized controlled trial’, we searched PubMed, Ovid, and Springer. We also hand searched relevant journals and conference proceedings. Randomized controlled trials published between 1998 and July 2008 which evaluated the effect of B vitamins supplementation on vascular diseases were collected. Two reviewers independently screened trials, extracted data, and evaluated the quality of included trials. The Cochrane Collaboration’s RevMan 4.2 software was used for statistical analysis.
Results 　Sixteen trials involving 27,043 patients with vascular disease were included. Results of meta-analyses showed that no significant differences were identified between the B vitamins group and the control group for each of the four endpoints, including the risk of cardiovascular events (RR 0.98, 95%CI 0.94 to 1.03), the risk of coronary heart disease (RR 0.99, 95%CI 0.92 to 1.07), the risk of stroke (RR 0.90, 95%CI 0.80 to 1.02), and the total mortality (RR 0.98, 95%CI 0.92 to 1.05). Sensitivity analyses conducted by a random effect model or with the exclusion of low-quality trials did not change the overall results.
Conclusion 　 The trials currently available cannot confirm the causal relationship between homocysteine and risk of cardiovascular and cerebrovascular diseases. More evidence from large-scale randomized controlled trials is needed to confirm this. There is not sufficient evidence to show that B vitamins supplementation can lower the risk of cardiovascular and cerebrovascular diseases. B vitamins supplementation should not be recommended for the secondary prevention of such diseases.

Citation： ZHANG Chen,ZHU Huilian. Effect of B Vitamins Supplementation on Cardiovascular and Cerebrovascular Disease by Lowering Plasma Homocysteine Concentration: A Meta-analysis. Chinese Journal of Evidence-Based Medicine, 2009, 09(1): 55-62. doi: 10.7507/1672-2531.20090013 Copy

1.	孔灵芝, 胡盛寿. 中国心血管病报告. 北京: 中国大百科全书出版社. 2008, 4.
2.	Boushey CJ, Beresford SA, Omenn GS, et al. 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.	The Homocysteine Studies Collaboration. Homocysteine and risk of ischemic heart disease and stroke. JAMA, 2002, 16: 2015-2022.
4.	Sackett DL, Clarke M, Oxman AD, et al. Cochrane Reviewers, Handbook 4.2,In Review Manager.Versions 4.2.Oxford, England: The cochrane collaboration, 2002, 13-36.
5.	Baker F, Picton D, Blackwood S, et al. Blinded comparison of folic acid and placebo in patients with ischemic heart disease: an outcome trial [abstract]. Circulation, 2002, 106(suppl 2): 741S.
6.	Schnyder G, Roffi M, Flammer Y, et al. Effect of homocysteinelowering 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.
7.	Righetti M, Ferrario GM, Milani S, et al. Effects of folic acid treatment on homocysteine levels and vascular disease in hemodialysis patients. Med Sci Monit, 2003, 9: P119-P124.
8.	Lange H, Suryapranata H, De Luca G, et al. Folate therapy and instent restenosis after coronary stenting. N Engl J Med, 2004, 350: 2673-2681.
9.	Toole JF, Mal inow MR, Chambles s LE, e t al . Lower ing 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.
10.	Wrone EM, Hornberger JM, Zehnder JL, et al. Randomized trial of folic acid for prevention of cardiovascular events in end-stage renal disease. J Am Soc Nephrol, 2004, 15: 420-426.
11.	Liem A, Reynierse-Buitenwerf GH, Zwinderman AH, et al. Secondary prevention with folic acid: results of the Goes extension study. Heart, 2005, 91: 1213-1214.
12.	Bonaa KH, Njolstad I, Ueland PM, et al. Homocysteine lowering and cardiovascular events after acute myocardial infarction. N Engl J Med, 2006, 354: 1578-1588.
13.	Lonn E, Yusuf S, Arnold MJ, et al. Homocysteine lowering with folic acid and B vitamins in vascular disease. N Engl J Med, 2006, 354: 1567-1577.
14.	Righetti M, Serbelloni P, Johansson I, et al. Homocysteine-lowering vitamin B treatment decreases cardiovascular events in hemodialysis patients. Blood Purif, 2006, 24: 379-386.
15.	Zoungas S, McGrath BP, Branley P, et al. 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.
16.	Haijer M, Willems HP, Blom HJ, et al. Homocysteine lowering by B vitamins and the secondary prevention of deep vein thrombosis and pulmonary embolism:a randomized, placebo-controlled, doubleblind trial. Blood, 2007, 109: 139-144.
17.	Jamison RL, Hartigan P, Kaufman JS, 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): 1163-1170.
18.	Ebbing Marta. the European Society of Cardiology Congress 2007.
19.	Albert CM, Cook NR, Gaziano JM, 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): 2027-2036.
20.	Mann JF, Sheridan P, McQueen MJ, et al. 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(2): 645-653.
21.	Wald NJ. Folic acid and the prevention of neural-tube defects. N Engl J Med, 2004, 350: 101-103．.
22.	Bor MV, Refsum H, Bisp MR, et al. Plasma vitamin B6 vitamers before and after oral vitamin B6 treatment:a randomized placebocontrolled study. Clin Chem, 2003, 49: 155-161.
23.	Matsubara K, Mori M, Matsuura Y, et al. Pyridoxal 5-phosphate and pyridoxal inhibit angiogenesis in serum-free rat aortic ring assay. Int J Mol Med, 2001, 8: 505-508.
24.	Ulrich CM, Potter JD. Folate and cancer--timing is everything. JAMA, 2007, 297(21): 2408-2409.
25.	Moat SJ, Doshi SN, Lang D, et al. Treatment of coronary heart disease with folic acid: Is there a future? Am J Physiol Heart Circ Physiol, 2004, 287: H1-H7.
26.	Kothekar MA. Homocysteine in cardiovascular disease: A culprit or an innocent bystander? Indian J Med Sci, 2007, 61(6): 361-371.
27.	Bostom AG, Carpenter MA, Kusek Jw, et al. Rationale and design of the Folic Acid for Vascular Outcome Reduction In Transplantation(FAVORIT) trial. Am Heart J, 2006, 152: 448.e1-7.
28.	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. Am Heart J, 2007, 154: 815-823.
29.	VITATOPS Trial Study Group. 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. Int J Stroke, 2007, 2(2): 144-150.

1. 孔灵芝, 胡盛寿. 中国心血管病报告. 北京: 中国大百科全书出版社. 2008, 4.
2. Boushey CJ, Beresford SA, Omenn GS, et al. 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. The Homocysteine Studies Collaboration. Homocysteine and risk of ischemic heart disease and stroke. JAMA, 2002, 16: 2015-2022.
4. Sackett DL, Clarke M, Oxman AD, et al. Cochrane Reviewers, Handbook 4.2,In Review Manager.Versions 4.2.Oxford, England: The cochrane collaboration, 2002, 13-36.
5. Baker F, Picton D, Blackwood S, et al. Blinded comparison of folic acid and placebo in patients with ischemic heart disease: an outcome trial [abstract]. Circulation, 2002, 106(suppl 2): 741S.
6. Schnyder G, Roffi M, Flammer Y, et al. Effect of homocysteinelowering 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.
7. Righetti M, Ferrario GM, Milani S, et al. Effects of folic acid treatment on homocysteine levels and vascular disease in hemodialysis patients. Med Sci Monit, 2003, 9: P119-P124.
8. Lange H, Suryapranata H, De Luca G, et al. Folate therapy and instent restenosis after coronary stenting. N Engl J Med, 2004, 350: 2673-2681.
9. Toole JF, Mal inow MR, Chambles s LE, e t al . Lower ing 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.
10. Wrone EM, Hornberger JM, Zehnder JL, et al. Randomized trial of folic acid for prevention of cardiovascular events in end-stage renal disease. J Am Soc Nephrol, 2004, 15: 420-426.
11. Liem A, Reynierse-Buitenwerf GH, Zwinderman AH, et al. Secondary prevention with folic acid: results of the Goes extension study. Heart, 2005, 91: 1213-1214.
12. Bonaa KH, Njolstad I, Ueland PM, et al. Homocysteine lowering and cardiovascular events after acute myocardial infarction. N Engl J Med, 2006, 354: 1578-1588.
13. Lonn E, Yusuf S, Arnold MJ, et al. Homocysteine lowering with folic acid and B vitamins in vascular disease. N Engl J Med, 2006, 354: 1567-1577.
14. Righetti M, Serbelloni P, Johansson I, et al. Homocysteine-lowering vitamin B treatment decreases cardiovascular events in hemodialysis patients. Blood Purif, 2006, 24: 379-386.
15. Zoungas S, McGrath BP, Branley P, et al. 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.
16. Haijer M, Willems HP, Blom HJ, et al. Homocysteine lowering by B vitamins and the secondary prevention of deep vein thrombosis and pulmonary embolism:a randomized, placebo-controlled, doubleblind trial. Blood, 2007, 109: 139-144.
17. Jamison RL, Hartigan P, Kaufman JS, 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): 1163-1170.
18. Ebbing Marta. the European Society of Cardiology Congress 2007.
19. Albert CM, Cook NR, Gaziano JM, 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): 2027-2036.
20. Mann JF, Sheridan P, McQueen MJ, et al. 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(2): 645-653.
21. Wald NJ. Folic acid and the prevention of neural-tube defects. N Engl J Med, 2004, 350: 101-103．.
22. Bor MV, Refsum H, Bisp MR, et al. Plasma vitamin B6 vitamers before and after oral vitamin B6 treatment:a randomized placebocontrolled study. Clin Chem, 2003, 49: 155-161.
23. Matsubara K, Mori M, Matsuura Y, et al. Pyridoxal 5-phosphate and pyridoxal inhibit angiogenesis in serum-free rat aortic ring assay. Int J Mol Med, 2001, 8: 505-508.
24. Ulrich CM, Potter JD. Folate and cancer--timing is everything. JAMA, 2007, 297(21): 2408-2409.
25. Moat SJ, Doshi SN, Lang D, et al. Treatment of coronary heart disease with folic acid: Is there a future? Am J Physiol Heart Circ Physiol, 2004, 287: H1-H7.
26. Kothekar MA. Homocysteine in cardiovascular disease: A culprit or an innocent bystander? Indian J Med Sci, 2007, 61(6): 361-371.
27. Bostom AG, Carpenter MA, Kusek Jw, et al. Rationale and design of the Folic Acid for Vascular Outcome Reduction In Transplantation(FAVORIT) trial. Am Heart J, 2006, 152: 448.e1-7.
28. 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. Am Heart J, 2007, 154: 815-823.
29. VITATOPS Trial Study Group. 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. Int J Stroke, 2007, 2(2): 144-150.

Chinese Journal of Evidence-Based Medicine

Effect of B Vitamins Supplementation on Cardiovascular and Cerebrovascular Disease by Lowering Plasma Homocysteine Concentration: A Meta-analysis

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