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. 2013 Jul 19;2013(7):CD003285.
doi: 10.1002/14651858.CD003285.pub2.

Homocysteine lowering interventions for peripheral arterial disease and bypass grafts

Affiliations

Homocysteine lowering interventions for peripheral arterial disease and bypass grafts

Alina Andras et al. Cochrane Database Syst Rev. .

Abstract

Background: Elevated plasma levels of the amino acid homocysteine (hyperhomocysteinaemia) are associated with narrowing or blocking of the arteries (atherosclerosis). Treatment to lower homocysteine levels has been shown to be both effective and cheap in healthy volunteers. However, the impact of reducing homocysteine levels on the progression of atherosclerosis and patency of the vessels after treatment for atherosclerosis is still unknown and forms the basis for this review. This is the second update of a review first published in 2002.

Objectives: To assess the effects of plasma homocysteine lowering therapy on the clinical progression of disease in people with peripheral arterial disease (PAD) and hyperhomocysteinaemia including, as a subset, those who have undergone surgical or radiological intervention.

Search methods: For this update, the Cochrane Peripheral Vascular Disease Group Trials Search Co-ordinator (TSC) searched the Specialised Register (last searched January 2013) and CENTRAL (2012, Issue 12). Trial databases were searched by the TSC (January 2013) for details of ongoing and unpublished studies. We also searched the reference lists of relevant articles.

Selection criteria: Randomised trials in which participants with PAD and hyperhomocysteinaemia were allocated to either homocysteine lowering therapy or no treatment, including participants before and after surgical or radiological interventions.

Data collection and analysis: Two review authors independently assessed trial quality and extracted the data. Information on adverse events was collected from the trials.

Main results: Two randomised trials with a total of 161 participants were included in this review. The studies did not report on mortality and rate of limb loss. One randomised trial with a total of 133 participants showed that there was a significant improvement in ankle brachial index (ABI) in participants who received folic acid compared with placebo (mean difference (MD) 0.07, 95% confidence interval (CI) 0.04 to 0.11, P < 0.001) and in participants who received 5-methyltetrahydrofolate (5-MTHF) versus placebo (MD 0.05, 95% CI 0.01 to 0.10, P = 0.009). A second trial with a total of 18 participants showed that there was no difference (P non-significant) in ABI in participants who received a multivitamin B supplement (mean ± SEM: 0.7 ± 01) compared with placebo (mean ± SEM: 0.8 ± 0.1). No major events were reported.

Authors' conclusions: Currently, no recommendation can be made regarding the value of treatment of hyperhomocysteinaemia in peripheral arterial disease. Further, well constructed trials are urgently required.

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Conflict of interest statement

None known

Figures

1
1
Study flow diagram.
2
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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.

Update of

References

References to studies included in this review

Khandanpour 2009 {published data only}
    1. Khandanpour N, Armon MP, Jennings B, Finglas PM, Willis G, Clark A, et al. Randomized clinical trial of folate supplementation in patients with peripheral arterial disease. British Journal of Surgery 2009;96(9):990‐8. - PubMed
    1. Khandanpour N, Armon MP, Jennings B, Willis G, Clark A, Meyer FJ. Folate supplementation improves arterial function in patients with peripheral arterial disease: a randomised double‐blind, placebo‐controlled clinical trial. The Vascular Society of Great Britain & Ireland Yearbook 2008. 2008:81.
Sydow 2003 {published data only}
    1. Sydow K, Schwedhelm E, Arakawa N, Bode‐Böger SM, Tsikas D, Hornig B, et al. ADMA and oxidative stress are responsible for endothelial dysfunction in hyperhomocyst(e)inemia: effects of L‐arginine and B vitamins. Cardiovascular Research 2003;57(1):244‐52. - PubMed

References to studies excluded from this review

Carrero 2005 {published data only}
    1. Carrero JJ, López‐Huertas E, Salmerón LM, Baró L, Ros E. Daily supplementation with (n‐3) PUFAs, oleic acid, folic acid, and vitamins B‐6 and E increases pain‐free walking distance and improves risk factors in men with peripheral vascular disease. The Journal of Nutrition 2005;135(6):1393‐9. - PubMed
Constans 1999 {published data only}
    1. Constans J, Blann AD, Resplandy F, Parrot F, Renard M, Seigneur M, et al. Three months supplementation of hyperhomocysteinaemic patients with folic acid and vitamin B6 improves biological markers of endothelial dysfunction. British Journal of Haematology 1999;107(4):776‐8. - PubMed
De Jong 1999 {published data only}
    1. Jong SC, Stehouwer CD, Berg M, Geurts TW, Bouter LM, Rauwerda JA. Normohomocysteinaemia and vitamin‐treated hyperhomocysteinaemia are associated with similar risks of cardiovascular events in patients with premature peripheral arterial occlusive disease. A prospective cohort study. Journal of Internal Medicine 1999;246(1):87‐96. - PubMed
Garg 1999 {published data only}
    1. Garg R, Malinow M, Pettinger M, Upson B, Hunninghake D. Niacin treatment increases plasma homocyst(e)ine levels. American Heart Journal 1999;138(6 Part 1):1082‐7. - PubMed
Lonn 2006 {published data only}
    1. Lonn E, Yusuf S, Arnold MJ, Sheridan P, Pogue J, Micks M, et al. Heart Outcomes Prevention Evaluation (HOPE) 2 Investigators. Homocysteine lowering with folic acid and B vitamins in vascular disease. New England Journal of Medicine 2006;354(15):1567‐77. - PubMed
Taylor 1999 {published and unpublished data}
    1. Anonymous. Homocysteine and progression of atherosclerosis. http://clinicaltrials.gov/ct2/show/NCT00005338 (accessed 1 May 2013). [ClinicalTrials.gov Identifier: NCT00005338]
    1. Musicant SE, Taylor LM Jr, Peters D, Schuff RA, Urankar R, Landry GJ, et al. Prospective evaluation of the relationship of between C‐reactive protein, D‐dimer and progression of peripheral arterial disease. Journal of Vascular Surgery 2006;43(4):772‐80, discussion 780. - PubMed
    1. Nicoloff AD, Taylor JM Jr, Sexton GJ, Schuff RA, Edwards JMM, Yeager RA, et al. Homocysteine and Progression of Atherosclerosis Study Investigators. Relationship between site of initial symptoms and subsequent progression of disease in a prospective study of atherosclerosis progression in patients receiving long‐term treatment for symptomatic peripheral arterial disease. Journal of Vascular Surgery 2002;35(1):38‐46, discussion 46‐7. - PubMed
    1. Taylor LM Jr, Moneta GL, Sexton GJ, Schuff RA, Porter JM. Prospective blinded study of the relationship between plasma homocysteine and progression of symptomatic peripheral arterial disease. Journal of Vascular Surgery 1999;29(1):8‐19, discussion 19‐21. - PubMed

Additional references

Adam 2005
    1. Adam DJ, Beard JD, Cleveland T, Bell J, Bradbury AW, Forbes JF, et al. Bypass versus angioplasty in severe ischaemia of the leg (BASIL): multicentre, randomised controlled trial.. Lancet 2005;366(9501):1925‐34. - PubMed
Anonymous 1998
    1. Anonymous. Lowering blood homocysteine with folic acid based supplements: meta‐analysis of randomised trials. Homocysteine Lowering Trialists' Collaboration. BMJ 1998;316(7135):894‐8. - PMC - PubMed
Anonymous 2006
    1. B‐Vitamin Treatment Trialists' Collaboration. Homocysteine‐lowering trials for prevention of cardiovascular events: a review of the design and power of the large randomized trials. American Heart Journal 2006;151(2):282‐7. - PubMed
Bainton 1994
    1. Bainton D, Sweetnam P, Baker I, Elwood P. Peripheral vascular disease: consequence for survival and association with risk factors in the Speedwell prospective heart disease study. British Heart Journal 1994;72(2):128‐32. - PMC - PubMed
Boushey 1995
    1. 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(13):1049‐57. - PubMed
Carmody 1999
    1. Carmody BJ, Arora S, Avena R, Cosby K, Sidawy AN. Folic acid inhibits homocysteine‐induced proliferation of human arterial smooth muscle cells. Journal of Vascular Surgery 1999;30(6):1121‐8. - PubMed
Cattaneo 1999
    1. Cattaneo M. Hyperhomocysteinemia, atherosclerosis and thrombosis. Thrombosis and Haemostasis 1999;81(2):165‐76. - PubMed
Chao 1999
    1. Chao CL, Chien KL, Lee YT. Effect of short‐term vitamin (folic acid, vitamins B6 and B12) administration on endothelial dysfunction induced by post‐methionine load hyperhomocysteinemia. American Journal of Cardiology 1999;84(11):1359‐61, A8. - PubMed
Clarke 1991
    1. Clarke R, Daly L, Robinson K, Naughten E, Cahalane S, Fowler B, et al. Hyperhomocysteinemia: an independent risk factor for vascular disease. New England Journal of Medicine 1991;324(17):1149‐55. - PubMed
Clarke 1998
    1. Clarke R, Smith AD, Jobst KA, Refsum H, Sutton L, Ueland PM. Folate, vitamin B12, and serum total homocysteine levels in confirmed Alzheimer disease. Archives of Neurology 1998;55(11):1449‐55. - PubMed
Collins 1987
    1. Collins R, Gray R, Godwin J, Peto R. Avoidance of large biases and large random errors in the assessment of moderate treatment effects: the need for systematic overviews. Statistics in Medicine 1987;6(3):245‐54. - PubMed
Coni 1992
    1. Coni N, Tennison B, Troup M. Prevalence of lower extremity arterial disease among elderly people in the community. British Journal of General Practice 1992;42(357):149‐52. - PMC - PubMed
Criqui 1997
    1. Criqui MH, Denenberg JO, Langer RD, Fronek A. The epidemiology of peripheral arterial disease: importance of identifying the population at risk. Vascular Medicine 1997;2(3):221‐6. - PubMed
Currie 1996
    1. Currie IC, Wilson YG, Scott J, Day A, Stansbie D, Baird RN, et al. Homocysteine:an independant risk factor for the failure of vascular intervention. British Journal of Surgery 1996;83(9):1238‐41. - PubMed
den Heijer 1998
    1. Heijer M, Rosendaal FR, Blom HJ, Gerrits WB, Bos GM. Hyperhomocysteinemia and venous thrombosis: a meta‐analysis. Thrombosis and Haemostasis 1998;80(6):874‐7. - PubMed
Diehm 2004
    1. Diehm C, Schuster A, Allenberg JR, Darius H, Haberl R, Lange S, et al. High prevalence of peripheral arterial disease and co‐morbidity in 6880 primary care patients: cross‐sectional study. Atherosclerosis 2004;172(1):95‐105. - PubMed
Dormandy 1991
    1. Dormandy JA, Murray GD. The fate of the claudicant ‐‐ a prospective study of 1969 claudicants. European Journal of Vascular Surgery 1991;5(2):131‐3. - PubMed
Franken 1994
    1. Franken DG, Boers GH, Blom HJ, Trijbels FJ, Kloppenborg PW. Treatment of mild hyperhomocysteinemia in vascular disease patients. Arteriosclerosis and Thrombosis 1994;14(3):465‐70. - PubMed
Hermans 1992
    1. Hermans WR, Rensing BJ, Foley DP, Deckers JW, Rutsch W, Emanuelsson H, et al. Therapeutic dissection after successful coronary balloon angioplasty: no influence on restenosis or clinical outcome in 693 patients. The MERCATOR Study Group (Multicenter European Research Trial with Cilazapril after Angioplasty to prevent Transluminal Coronary Obstruction and Restenosis). Journal of the American College of Cardiology 1992;20(4):767‐80. - PubMed
Higgins 2011
    1. Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [updated March 2011]. The Cochrane Collaboration, 2011. Available from www.cochrane‐handbook.org.
Hooi 2001
    1. Hooi JD, Kester ADM, Stoffers HE, Overdijk MM, Ree JW, Knottnerus JA. Incidence of and risk factors for asymptomatic peripheral arterial occlusive disease: a longitudinal study. American Journal of Epidemiology 2001;153(7):666‐72. - PubMed
Inglis 2013
    1. Inglis SC, Hermis A, Shehab S, Newton PJ, Lal S, Davidson PM. Peripheral arterial disease and chronic heart failure: a dangerous mix. Heart Failure Reviews 2013;18(4):457‐64. - PubMed
Irvine 1996
    1. Irvine C, Wilson YG, Currie IC, McGrath C, Scott J, Day A, et al. Hyperhomocysteinaemia is a risk factor for vein graft stenosis. European Journal of Vascular and Endovascular Surgery 1996;12(3):304‐9. - PubMed
Iwama 1998
    1. Iwama Y, Mokuno H, Yokoi H, Daida H, Yamaguchi H, Hosoda Y. [Elevated levels of plasma homocysteine related to saphenous vein graft disease after coronary artery bypass graft surgery]. Journal of Cardiology 1998 Dec;32(6):357‐62. - PubMed
Khandanpour 2009a
    1. Khandanpour N, Willis G, Meyer FJ, Armon MP, Loke YK, Wright AJ, et al. Peripheral arterial disease and methylenetetrahydrofolate reductase (MTHFR) C677T mutations: A case‐control study and meta‐analysis. Journal of Vascular Surgery 2009;49(3):711‐8. - PubMed
Khandanpour 2009b
    1. Khandanpour N, Loke YK, Meyer FJ, Jennings B, Armon MP. Homocysteine and peripheral arterial disease: systematic review and meta‐analysis. European Journal of Vascular and Endovascular Surgery 2009;38(3):316‐22. - PubMed
Leng 1996
    1. Leng GC, Lee AJ, Fowkes FG, Whiteman M, Dunbar J, Housley E, et al. Incidence, natural history and cardiovascular events in symptomatic and asymptomatic peripheral arterial disease in the general population. International Journal of Epidemiology 1996;25(6):1172‐81. - PubMed
Malinow 1996
    1. Malinow MR. Plasma homocyst(e)ine: a risk factor for arterial occlusive diseases. Journal of Nutrition 1996;126(4 Suppl):1238S‐43S. - PubMed
Malinow 1998
    1. Malinow MR, Duell PB, Hess DL, Anderson PH, Kruger WD, Phillipson BE, et al. Reduction of plasma homocyst(e)ine levels by breakfast cereal fortified with folic acid in patients with coronary heart disease. New England Journal of Medicine 1998;338(15):1009‐15. - PubMed
Mantel 1959
    1. Mantel N, Haenszel W. Statistical aspects of the analysis of data from retrospective studies of disease. Journal of the National Cancer Institute 1959;22(4):719‐48. - PubMed
Marti‐Carvajal 2013
    1. Marti‐Carvajal AJ, Solà I, Lathyris D, Karakitsiou DE, Simancas‐Racines D. Homocysteine‐lowering interventions for preventing cardiovascular events. Cochrane Database of Systematic Reviews 2013, Issue 1. [DOI: 10.1002/14651858.CD006612.pub3] - DOI - PubMed
McCully 1969
    1. McCully KS. Vascular pathology of homocysteinemia: implications for the pathogenesis of arteriosclerosis. American Journal of Pathology 1969;56(1):111‐28. - PMC - PubMed
McCully 1996
    1. McCully KS. Homocysteine and vascular disease. Nature Medicine 1996;2(4):386‐9. - PubMed
Mei 2010
    1. 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 Clinincal Practice 2010;64(2):208‐15. - PubMed
Meijer 1998
    1. Meijer WT, Hoes AW, Rutgers D, Bots ML, Hofman A, Grobbee DE. Peripheral arterial disease in the elderly: The Rotterdam Study. Arteriosclerosis, Thrombosis, and Vascular Biology 1998;18(2):185‐92. - PubMed
Mireskandari 1998
    1. Mireskandari M, Schachter M, Timms IGO, Sever P, Wolfe JHN. Plasma homocysteine is an independent risk factor for vein graft stenosis. British Journal of Surgery 1998;85 Suppl(Supp 1):27.
NICE 2012
    1. National Institute for Health and Clinical Excellence. Lower limb peripheral arterial disease: diagnosis and management. http://guidance.nice.org.uk/CG147/NICEGuidance/pdf/English August 2012 (accessed 4 July 2013).
Pell 1994
    1. Pell JP, Whyman MR, Fowkes FG, Gillespie I, Ruckley CV. Trends in vascular surgery since the introduction of percutaneous transluminal angioplasty. British Journal of Surgery 1994;81(6):832‐5. - PubMed
Refsum 1998
    1. Refsum H, Ueland PM, Nygard O, Vollset SE. Homocysteine and cardiovascular disease. Annual Review of Medicine 1998;49:31‐62. - PubMed
Sakura 1998
    1. Sakura N, Ono H, Nomura S, Ueda H, Fujita N. Betaine dose and treatment intervals in therapy for homocystinuria due to 5,10‐methylenetetrahydrofolate reductase deficiency. Journal of Inherited Metabolic Disease 1998;21(1):84‐5. - PubMed
Shammas 2007
    1. Shammas NW. Epidemiology, classification, and modifiable risk factors of peripheral arterial disease. Vascular Health and Risk Management 2007;3(2):229‐34. - PMC - PubMed
Southern 1998
    1. Southern FN, Cruz N, Fink LM, Cooney CA, Barone GW, Eidt JF, et al. Hyperhomocysteinemia increases intimal hyperplasia in a rat carotid endarterectomy model. Journal of Vascular Surgery 1998;28(5):909‐18. - PubMed
Spark 2003
    1. Spark JI, Laws P, Fitridge R. The incidence of hyperhomocysteinaemia in vascular patients. European Journal of Vascular and Endovascular Surgery 2003;26(5):558‐61. - PubMed
Stoffers 1996
    1. Stoffers HE, Rinkens PE, Kester AD, Kaiser V, Knottnerus JA. The prevalence of asymptomatic and unrecognized peripheral arterial occlusive disease. International Journal of Epidemiology 1996;25(2):282‐90. - PubMed
Stoyioglou 2004
    1. Stoyioglou A, Jaff MR. Medical treatment of peripheral arterial disease: a comprehensive review. Journal of Vascular and Interventional Radiology 2004;15(11):1197‐207. - PubMed
Taylor 1999a
    1. Taylor LM Jr, Moneta GL, Sexton GJ, Schuff RA, Porter JM. Prospective blinded study of the relationship between plasma homocysteine and progression of symptomatic peripheral arterial disease. Journal of Vascular Surgery 1999;29(1):8‐19, discussion 19‐21. - PubMed
Thompson 1994
    1. Thompson MM, Budd JS, Eady SL, Underwood MJ, James RFL, Bell PRF. The effect of transluminal endothelial seeding on myointimal hyperplasia following angioplasty. European Journal of Vascular Surgery 1994;8(4):423‐34. - PubMed
Tierney 2000
    1. Tierney S, Fennessy F, Hayes DB. ABC of arterial and vascular disease. Secondary prevention of peripheral vascular disease. BMJ 2000;320(7244):1262‐5. - PMC - PubMed
Verin 1995
    1. Verin V, Popowski Y, Urban P, Belenger J, Redard M, Costa M, et al. Intra‐arterial beta irradiation prevents neointimal hyperplasia in a hypercholesterolemic rabbit restenosis model. Circulation 1995;92(8):2284‐90. - PubMed
Vermeulen 2000
    1. Vermeulen EG, Stehouwer CD, Twisk JW, Berg M, Jong SC, Mackaay AJ, et al. Effect of homocysteine‐lowering treatment with folic acid plus vitamin B6 on progression of subclinical atherosclerosis: a randomised, placebo‐controlled trial. Lancet 2000;355(9203):517‐22. - PubMed
Voller 2002
    1. Voller H. Peripheral arterial disease (PAD): secondary prevention. Deutsche Medizinische Wochenschrift 2002;127(37):1870‐2. - PubMed
White 2007
    1. White CJ, Gray WA. Endovascular therapies for peripheral arterial disease: an evidence‐based review. Circulation 2007;116(19):2203‐15. - PubMed
Wilcken 1983
    1. Wilcken DE, Wilcken B, Dudman NP, Tyrrell PA. Homocystinuria ‐ the effects of betaine in the treatment of patients not responsive to pyridoxine. New England Journal of Medicine 1983;309(8):448‐53. - PubMed
Wilcken 1985
    1. Wilcken DE, Dudman NP, Tyrrell PA. Homocystinuria due to cystathionine beta‐synthase deficiency‐‐the effects of betaine treatment in pyridoxine‐responsive patients. Metabolism 1985;34(12):1115‐21. - PubMed
Woo 1999
    1. Woo KS, Chook P, Lolin YI, Sanderson JE, Metreweli C, Celermajer DS. Folic acid improves arterial endothelial function in adults with hyperhomocystinemia. Journal of the American College of Cardiology 1999;34(7):2002‐6. - PubMed
Yla‐Herttuala 2000
    1. Yla‐Herttuala S, Martin JF. Cardiovascular gene therapy. Lancet 2000;355(9199):213‐22. - PubMed

References to other published versions of this review

Hansrani 2002
    1. Hansrani M, Stansby GP. Homocysteine lowering interventions for peripheral arterial disease and bypass grafts. Cochrane Database of Systematic Reviews 2002, Issue 3. [DOI: 10.1002/14651858.CD003285] - DOI - PubMed

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