Download PDF
Semin Vasc Med 2005; 5(2): 215-222
DOI: 10.1055/s-2005-872407
Copyright © 2005 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001 USA.

Homocysteine-Lowering Trials for Prevention of Heart Disease and Stroke

Robert Clarke1
  • 1Clinical Trial Service Unit and Epidemiological Studies Unit, University of Oxford, Radcliffe Infirmary, Oxford, England
Further Information

Publication History

Publication Date:
27 July 2005 (online)

    Permissions and Reprints

ABSTRACT

Dietary supplementation with B-vitamins that lower plasma total homocysteine concentrations are expected to lower the risk of cardiovascular disease. Folic acid and vitamin B12 lower blood homocysteine concentrations by about 25-30% in populations without folic acid fortification, but by only 10-15% in populations with fortification. In observational studies, 25% lower homocysteine is associated with about 10% less coronary heart disease (CHD) and about 20% less stroke. This review examines the current status of 12 large-scale randomized trials of B-vitamin supplementation and risk of cardiovascular disease. Seven of these trials are being performed in populations without fortification (five involving participants with prior CHD, two with prior stroke) and five in populations with fortification (two with prior CHD, two with renal disease, and one with prior stroke). Many of these trials may not have included a sufficient number of people or lasted long enough to have adequate power to exclude false-negative results. Taken together, however, these trials involve 32,000 patients with prior vascular disease in unfortified populations and 20,000 (14,000 with vascular disease and 6000 with renal disease) patients in fortified populations. A metaanalysis of these trials should have adequate power to determine whether homocysteine-lowering vitamin supplements can reduce the risk of cardiovascular disease.

KEYWORDS

Folic acid - vitamin B12 - trials - cardiovascular disease

REFERENCES

  • 1 McCully K S. Vascular pathology of homocysteinemia: implications for the pathogenesis of arteriosclerosis.  Am J Pathol. 1969;  56(1) 111-128
    Google Scholar
  • 2 Mudd S H, Levy H L, Skovby F. Disorders of transulfuration. In: Scriver CR, Baudet AL, Sly WS, et al., The Metabolic and Molecular Bases of Inherited Disease, 8th ed New York; McGraw-Hill 1995: 1279-1327
    Google Scholar
  • 3 Selhub J, Jacques P F, Wilson P W, Rush D, Rosenberg I H. Vitamin status and intake as primary determinants of homocysteinemia in an elderly population.  JAMA. 1993;  270 2693-2698
    CrossrefPubMedGoogle Scholar
  • 4 Homocysteine Studies Collaboration . Homocysteine and risk of ischemic heart disease and stroke: a meta-analysis.  JAMA. 2002;  288 2015-2222
    CrossrefPubMedGoogle Scholar
  • 5 Homocysteine Lowering Trialists' Collaboration . Lowering blood homocysteine with folic acid based supplements: meta-analysis of randomised trials.  BMJ. 1998;  316 894-898
    PubMedGoogle Scholar
  • 6 Jacques P F, Selhub J, Bostom A G, Wilson P WF, Rosenberg I H. The effect of folic acid fortification on plasma folate and total homocysteine concentrations.  N Engl J Med. 1999;  340 1449-1454
    CrossrefPubMedGoogle Scholar
  • 7 Bostom A G, Liaugaudas G, Jacques P F, Rosenberg I H, Selhub J. Total homocysteine lowering treatment among coronary artery disease patients in the era of folic acid fortified cereal grain flour.  Arterioscler Thromb Vasc Biol. 2002;  22 488-491
    PubMedGoogle Scholar
  • 8 Beaulieu A J, Gohh R Y, Han H et al.. Enhanced reduction of fasting total homocysteine levels with supraphysiological versus standard multivitamin dose folic acid supplementation in renal transplant recipients.  Arterioscler Thromb Vasc Biol. 1999;  19 2918-2921
    PubMedGoogle Scholar
  • 9 Wilcken D E, Wilcken B. The pathogenesis of coronary artery disease. A possible role for methionine metabolism.  J Clin Invest. 1976;  57(4) 1079-1082
    CrossrefPubMedGoogle Scholar
  • 10 Brattstrom L E, Hardebo J E, Hultberg B L. Moderate homocysteinemia-a possible risk factor for arteriosclerotic cerebrovascular disease.  Stroke. 1984;  15(6) 1012-1016
    PubMedGoogle Scholar
  • 11 Boers G H, Smals A G, Trijbels F J et al.. Heterozygosity for homocystinuria in premature peripheral and cerebral occlusive arterial disease.  N Engl J Med. 1985;  313(12) 709-715
    PubMedGoogle Scholar
  • 12 Clarke R, Daly L, Robinson K et al.. Hyperhomocysteinemia: an independent risk factor for vascular disease.  N Engl J Med. 1991;  324(17) 1149-1155
    PubMedGoogle Scholar
  • 13 Genest Jr J J, McNamara J R, Salem D N, Wilson P W, Schaefer E J, Malinow M R. Plasma homocyst(e)ine levels in men with premature coronary artery disease.  J Am Coll Cardiol. 1990;  16(5) 1114-1119
    PubMedGoogle Scholar
  • 14 Pancharuniti N, Lewis C A, Sauberlich H E et al.. Plasma homocyst(e)ine, folate, and vitamin B-12 concentrations and risk for early-onset coronary artery disease.  Am J Clin Nutr. 1994;  59(4) 940-948
    PubMedGoogle Scholar
  • 15 von Eckardstein A, Malinow M R, Upson B et al.. Effects of age, lipoproteins, and hemostatic parameters on the role of homocyst(e)inemia as a cardiovascular risk factor in men.  Arterioscler Thromb. 1994;  14(3) 460-464
    PubMedGoogle Scholar
  • 16 Hopkins P N, Wu L L, Wu J et al.. Higher plasma homocyst(e)ine and increased susceptibility to adverse effects of low folate in early familial coronary artery disease.  Arterioscler Thromb Vasc Biol. 1995;  15(9) 1314-1320
    PubMedGoogle Scholar
  • 17 Lindgren A, Brattstrom L, Norrving B, Hultberg B, Andersson A, Johansson B B. Plasma homocysteine in the acute and convalescent phases after stroke.  Stroke. 1995;  26(5) 795-800
    PubMedGoogle Scholar
  • 18 Malinow M R, Ducimetiere P, Luc G et al.. Plasma homocyst(e)ine levels and graded risk for myocardial infarction: findings in two populations at contrasting risk for coronary heart disease.  Atherosclerosis. 1996;  126(1) 27-34
    CrossrefPubMedGoogle Scholar
  • 19 Graham I M, Daly L E, Refsum H M et al.. Plasma homocysteine as a risk factor for vascular disease. The European Concerted Action Project.  JAMA. 1997;  277(22) 1775-1781
    CrossrefPubMedGoogle Scholar
  • 20 Silberberg J, Crooks R, Fryer J et al.. Gender differences and other determinants of the rise in plasma homocysteine after L-methionine loading.  Atherosclerosis. 1997;  133(1) 105-110
    CrossrefPubMedGoogle Scholar
  • 21 Schwartz S M, Siscovick D S, Malinow M R et al.. Myocardial infarction in young women in relation to plasma total homocysteine, folate, and a common variant in the methylenetetrahydrofolate reductase gene.  Circulation. 1997;  96(2) 412-417
    PubMedGoogle Scholar
  • 22 Joubran R, Asmi M, Busjahn A, Vergopoulos A, Luft F C, Jouma M. Homocysteine levels and coronary heart disease in Syria.  J Cardiovasc Risk. 1998;  5(4) 257-261
    PubMedGoogle Scholar
  • 23 Chambers J C, Obeid O A, Refsum H et al.. Plasma homocysteine concentrations and risk of coronary heart disease in UK Indian Asian and European men.  Lancet. 2000;  355(9203) 523-527
    CrossrefPubMedGoogle Scholar
  • 24 Coull B M, Malinow M R, Beamer N, Sexton G, Nordt F, de Garmo P. Elevated plasma homocyst(e)ine concentration as a possible independent risk factor for stroke.  Stroke. 1990;  21(4) 572-576
    Google Scholar
  • 25 Dalery K, Lussier Cacan S, Selhub J, Davignon J, Latour Y, Genest Jr J. Homocysteine and coronary artery disease in French Canadian subjects: relation with vitamins B12, B6, pyridoxal phosphate, and folate.  Am J Cardiol. 1995;  75(16) 1107-1111
    CrossrefPubMedGoogle Scholar
  • 26 Robinson K, Mayer E L, Miller D P et al.. Hyperhomocysteinemia and low pyridoxal phosphate. Common and independent reversible risk factors for coronary artery disease.  Circulation. 1995;  92(10) 2825-2830
    PubMedGoogle Scholar
  • 27 Lolin Y I, Sanderson J E, Cheng S K et al.. Hyperhomocysteinaemia and premature coronary artery disease in the Chinese.  Heart. 1996;  76(2) 117-122
    PubMedGoogle Scholar
  • 28 Evers S, Koch H G, Grotemeyer K H, Lange B, Deufel T, Ringelstein E B. Features, symptoms, and neurophysiological findings in stroke associated with hyperhomocysteinemia.  Arch Neurol. 1997;  54(10) 1276-1282
    PubMedGoogle Scholar
  • 29 Boushey C J, Beresford S A, Omenn G S, Motulsky A G. A quantitative assessment of plasma homocysteine as a risk factor for vascular disease. Probable benefits of increasing folic acid intakes.  JAMA. 1995;  274(13) 1049-1057
    Google Scholar
  • 30 Danesh J, Lewington S. Plasma homocysteine and coronary heart disease: systematic review of published epidemiological studies.  J Cardiovasc Risk. 1998;  5(4) 229-232
    PubMedGoogle Scholar
  • 31 Verhoef P, Hennekens C H, Malinow M R, Kok F J, Willett W C, Stampfer M J. A prospective study of plasma homocyst(e)ine and risk of ischemic stroke.  Stroke. 1994;  25 1924-1930
    CrossrefPubMedGoogle Scholar
  • 32 Verhoef P, Stampfer M J, Buring J E et al.. Homocysteine metabolism and risk of myocardial infarction: relation with vitamins B6, B12, and folate.  Am J Epidemiol. 1996;  143(9) 845-859
    PubMedGoogle Scholar
  • 33 Verhoef P, Kok F J, Kruyssen D A et al.. Plasma total homocysteine, B vitamins, and risk of coronary atherosclerosis.  Arterioscler Thromb Vasc Biol. 1997;  17(5) 989-995
    PubMedGoogle Scholar
  • 34 Alfthan G, Pekkanen J, Jauhiainen M et al.. Relation of serum homocysteine and lipoprotein(a) concentrations to atherosclerotic disease in a prospective Finnish population based study.  Atherosclerosis. 1994;  106(1) 9-19
    CrossrefPubMedGoogle Scholar
  • 35 Arnesen E, Refsum H, Bonaa K H, Ueland P M, Forde O H, Nordrehaug J E. Serum total homocysteine and coronary heart disease.  Int J Epidemiol. 1995;  24(4) 704-709
    CrossrefPubMedGoogle Scholar
  • 36 Perry I J, Refsum H, Morris R W, Ebrahim S B, Ueland P M, Shaper A G. Prospective study of serum total homocysteine concentration and risk of stroke in middle-aged British men.  Lancet. 1995;  346(8987) 1395-1398
    CrossrefPubMedGoogle Scholar
  • 37 Evans R W, Shaten B J, Hempel J D, Cutler J A, Kuller L H. Homocyst(e)ine and risk of cardiovascular disease in the Multiple Risk Factor Intervention Trial.  Arterioscler Thromb Vasc Biol. 1997;  17(10) 1947-1953
    PubMedGoogle Scholar
  • 38 Ubbink J B, Fehily A M, Pickering J, Elwood P C, Vermaak W J. Homocysteine and ischaemic heart disease in the Caerphilly cohort.  Atherosclerosis. 1998;  140(2) 349-356
    CrossrefPubMedGoogle Scholar
  • 39 Stehouwer C D, Weijenberg M P, van den Berg M, Jakobs C, Feskens E J, Kromhout D. Serum homocysteine and risk of coronary heart disease and cerebrovascular disease in elderly men: a 10-year follow-up.  Arterioscler Thromb Vasc Biol. 1998;  18(12) 1895-1901
    PubMedGoogle Scholar
  • 40 Folsom A R, Nieto F J, McGovern P G et al.. Prospective study of coronary heart disease incidence in relation to fasting total homocysteine, related genetic polymorphisms, and B vitamins: the Atherosclerosis Risk in Communities (ARIC) study.  Circulation. 1998;  98(3) 204-210
    PubMedGoogle Scholar
  • 41 Wald N J, Watt H C, Law M R, Weir D G, McPartlin J, Scott J M. Homocysteine and ischemic heart disease: results of a prospective study with implications regarding prevention.  Arch Intern Med. 1998;  158(8) 862-867
    CrossrefPubMedGoogle Scholar
  • 42 Bots M L, Launer L J, Lindemans J et al.. Homocysteine and short-term risk of myocardial infarction and stroke in the elderly: the Rotterdam Study.  Arch Intern Med. 1999;  159(1) 38-44
    CrossrefPubMedGoogle Scholar
  • 43 Whincup P H, Refsum H, Perry I J et al.. Serum total homocysteine and coronary heart disease: Prospective study in middle aged men.  Heart. 1999;  82(4) 448-454
    PubMedGoogle Scholar
  • 44 Clarke R, Lewington S, Donald A et al.. Underestimation of the importance of homocysteine as a risk factor for cardiovascular disease in epidemiological studies.  J Cardiovasc Risk. 2001;  8 363-369
    CrossrefPubMedGoogle Scholar
  • 45 Clarke R, Shipley M, Lewington S et al.. Underestimation of risk associations due to regression dilution in long-term follow-up of prospective studies.  Am J Epidemiol. 1999;  150 341-353
    CrossrefPubMedGoogle Scholar
  • 46 Bostom A G, Silbershatz H, Rosenberg I H et al.. Nonfasting plasma total homocysteine levels and all-cause and cardiovascular disease mortality in elderly Framingham men and women.  Arch Intern Med. 1999;  159(10) 1077-1080
    CrossrefPubMedGoogle Scholar
  • 47 Kark J D, Selhub J, Adler B et al.. Nonfasting plasma total homocysteine level and mortality in middle-aged and elderly men and women in Jerusalem.  Ann Intern Med. 1999;  131 321-330
    PubMedGoogle Scholar
  • 48 Voutilainen S, Lakka T A, Hamelahti P, Lehtimaki T, Poulsen H E, Salonen J T. Plasma total homocysteine concentration and the risk of acute coronary events: the Kuopio Ischaemic Heart Disease Risk Factor Study.  J Intern Med. 2000;  248 217-222
    CrossrefPubMedGoogle Scholar
  • 49 Vollset S E, Refsum H, Tverdal A et al.. Plasma total homocysteine and cardiovascular disease and noncardiovascular mortality: the Hordaland Homocysteine Study.  Am J Clin Nutr. 2001;  74 130-136
    PubMedGoogle Scholar
  • 50 Knekt P, Reunanen A, Alfthan G et al.. Hyperhomocysteinemia: a risk factor or consequence of coronary heart disease?.  Arch Intern Med. 2001;  161 1589-1594
    CrossrefPubMedGoogle Scholar
  • 51 Ridker P M, Manson J E, Buring J E, Shih J, Matias M, Hennekens C H. Homocysteine and risk of cardiovascular disease among post-menopausal women.  JAMA. 1999;  281 1817-1821
    CrossrefPubMedGoogle Scholar
  • 52 Davey Smith G. “Mendelian randomization”: can genetic epidemiology contribute to understanding environmental determinants of disease?.  Int J Epidemiol. 2003;  32 1-22
    CrossrefPubMedGoogle Scholar
  • 53 Klerk M, Verhoef P, Clarke R et al.. MTHFR 677TC→t polymorphism and risk of coronary heart disease: a meta-analysis.  JAMA. 2002;  288 2023-2031
    CrossrefPubMedGoogle Scholar
  • 54 Jacques P F, Bostom A G, Williams R R et al.. Relation between folate status, a common mutation between methylenetetrahydrofolate reductase, and plasma homocysteine concentrations.  Circulation. 1996;  93 7-9
    CrossrefPubMedGoogle Scholar
  • 55 Wald D S, Law M, Morris J K. Homocysteine and cardiovascular disease: evidence on causality from a meta-analysis.  BMJ. 2002;  325 1202-1206
    CrossrefPubMedGoogle Scholar
  • 56 Casas J, Bautista L, Smeeth L, Sharma P, Hingorani A. Homocysteine and stroke: evidence on a causal link from mendelian randomization.  Lancet. 2005;  365 224-232
    PubMedGoogle Scholar
  • 57 Thambyrajah J, Landray M J, McGlynn F J, Jones H J, Wheeler D C, Townend J N. Does folic acid decrease plasma homocysteine and improve endothelial function in patients with predialysis renal failure?.  Circulation. 2000;  102 871-875
    PubMedGoogle Scholar
  • 58 Schnyder G, Roffi M, Flammer Y, Pin R, Hess O M. Effect of homocysteine-lowering therapy with folic acid, vitamin B(12) and vitamin B(6) on clinical outcome after percutaneous coronary intervention: The Swiss Heart Study: a randomized controlled trial.  JAMA. 2002;  288 973-979
    CrossrefPubMedGoogle Scholar
  • 59 Schnyder G, Roffi M, Pin R et al.. Decreased rate of coronary restenosis after lowering of plasma homocysyteine levels.  N Engl J Med. 2001;  345 1593-1600
    PubMedGoogle Scholar
  • 60 Baker F, Picton D, Blackwood S et al.. Blinded comparison of folic acid and placebo in patients with ischemic heart disease: an outcome trial.  Circulation. 2002;  106 A3642
    PubMedGoogle Scholar
  • 61 The VITATOPS Study Group . The VITATOPS (Vitamins to Prevent Stroke) Trial: Rationale and design of an international large, simple, randomised trial of homocysteine-lowering multivitamin therapy in patients with recent transient ischaemic attack or stroke.  Cerebrovasc Dis. 2002;  13 120-126
    PubMedGoogle Scholar
  • 62 Toole J F, Malinow M R, Chambless L E et al.. Lowering homocysteine in patients with ischemic stroke to prevent recrurrent stroke, myocardial infarction, and death: The Vitamin Intervention for Stroke Prevention (VISP) randomized controlled trial.  JAMA. 2004;  291 565-575
    CrossrefPubMedGoogle Scholar

 Dr.
Robert Clarke

Clinical Trial Service Unit and Epidemiological Studies Unit

Nuffield Department of Clinical Medicine, Radcliffe Infirmary

Oxford OX2 6HE, United Kingdom

      >