This Article  • Full text  • PDF  • Send to a friend  • Save in My Folder  • Save to citation manager  • Permissions  Citing Articles  • Citation map  • Citing articles on HighWire  • Citing articles on ISI (363)  • Contact me when this article is cited  Related Content  • Related letters  • Related articles  • Similar articles in JAMA  Topic Collections  • Neurology  • Cerebrovascular Disease  • Randomized Controlled Trial  • Stroke  • Alert me on articles by topic

The Vitamin Intervention for Stroke Prevention (VISP) Randomized Controlled Trial

James F. Toole, MD; M. René Malinow, MD; Lloyd E. Chambless, PhD; J. David Spence, MD; L. Creed Pettigrew, MD, MPH; Virginia J. Howard, MSPH; Elizabeth G. Sides, MEd; Chin-Hua Wang, PhD; Meir Stampfer, MD, DrPH

JAMA. 2004;291:565-575.

Context  In observational studies, elevated plasma total homocysteine levels have been positively associated with ischemic stroke risk. However the utility of homocysteine-lowering therapy to reduce that risk has not been confirmed by randomized trials.

Objective  To determine whether high doses of folic acid, pyridoxine (vitamin B₆), and cobalamin (vitamin B₁₂), given to lower total homocysteine levels, reduce the risk of recurrent stroke over a 2-year period compared with low doses of these vitamins.

Design  Double-blind randomized controlled trial (September 1996–May 2003).

Setting and Participants  3680 adults with nondisabling cerebral infarction at 56 university-affiliated hospitals, community hospitals, private neurology practices, and Veterans Affairs medical centers across the United States, Canada, and Scotland.

Interventions  All participants received best medical and surgical care plus a daily multivitamin containing the US Food and Drug Administration's reference daily intakes of other vitamins; patients were randomly assigned to receive once-daily doses of the high-dose formulation (n = 1827), containing 25 mg of pyridoxine, 0.4 mg of cobalamin, and 2.5 mg of folic acid; or the low-dose formulation (n = 1853), containing 200 µg of pyridoxine, 6 µg of cobalamin_,and 20 µg of folic acid.

Main Outcome Measures  Recurrent cerebral infarction (primary outcome); coronary heart disease (CHD) events and death (secondary outcomes).

Results  Mean reduction of total homocysteine was 2 µmol/L greater in the high-dose group than in the low-dose group, but there was no treatment effect on any end point. The unadjusted risk ratio for any stroke, CHD event, or death was 1.0 (95% confidence interval [CI], 0.8-1.1), with chances of an event within 2 years of 18.0% in the high-dose group and 18.6% in the low-dose group. The risk of ischemic stroke within 2 years was 9.2% for the high-dose and 8.8% for the low-dose groups (risk ratio, 1.0; 95% CI, 0.8-1.3) (P = .80 by log-rank test of the primary hypothesis of difference in ischemic stroke between treatment groups). There was a persistent and graded association between baseline total homocysteine level and outcomes. A 3-µmol/L lower total homocysteine level was associated with a 10% lower risk of stroke (P = .05), a 26% lower risk of CHD events (P<.001), and a 16% lower risk of death (P = .001) in the low-dose group and a nonsignificantly lower risk in the high-dose group by 2% for stroke, 7% for CHD events, and 7% for death.

Conclusions  In this trial, moderate reduction of total homocysteine after nondisabling cerebral infarction had no effect on vascular outcomes during the 2 years of follow-up. However, the consistent findings of an association of total homocysteine with vascular risk suggests that further exploration of the hypothesis is warranted and longer trials in different populations with elevated total homocysteine may be necessary.

Author Affiliations: Stroke Research Center, Department of Neurology, Wake Forest University School of Medicine, Winston-Salem, NC (Dr Toole and Ms Sides); Laboratory of Cardiovascular Disease, Oregon National Primate Research Center, Beaverton (Dr Malinow); Department of Biostatistics, Collaborative Studies Coordinating Center, University of North Carolina at Chapel Hill (Drs Chambless and Wang); Stroke Prevention and Atherosclerosis Research Centre, Robarts Research Institute, London, Ontario (Dr Spence); Stroke Program/Sanders-Brown Center on Aging, University of Kentucky, Lexington (Dr Pettigrew); Department of Epidemiology and International Health, University of Alabama, Birmingham (Ms Howard); and Department of Epidemiology, Harvard School of Public Health, Boston, Mass (Dr Stampfer).

RELATED LETTERS

Vitamin Supplementation and Risk of Stroke
Ciriaco Aguirre, Guillermo Ruiz-Irastorza, Maria-Victoria Egurbide, and Agustin Martinez-Berriotxoa
JAMA. 2004;291(18):2191.
EXTRACT | FULL TEXT  

Vitamin Supplementation and Risk of Stroke
David S. Wald
JAMA. 2004;291(18):2191.
EXTRACT | FULL TEXT  

Vitamin Supplementation and Risk of Stroke—Reply
J. David Spence, James F. Toole, Lloyd E. Chambless, Chin-Hua Wang, Meir Stampfer, L. Creed Pettigrew, Virginia J. Howard, and Elizabeth G. Sides
JAMA. 2004;291(18):2191-2192.
EXTRACT | FULL TEXT  

RELATED ARTICLES

Antiphospholipid Antibodies and Subsequent Thrombo-occlusive Events in Patients With Ischemic Stroke
APASS Investigators
JAMA. 2004;291(5):576-584.
ABSTRACT | FULL TEXT  

The Challenge of Stroke Prevention
Daniel F. Hanley
JAMA. 2004;291(5):621-622.
EXTRACT | FULL TEXT  

THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES

Traffic-related Particles Are Associated with Elevated Homocysteine: The VA Normative Aging Study
Park et al.
Am. J. Respir. Crit. Care Med. 2008;178:283-289.
ABSTRACT | FULL TEXT  

Prevalence and effects of gene-gene and gene-nutrient interactions on serum folate and serum total homocysteine concentrations in the United States: findings from the third National Health and Nutrition Examination Survey DNA Bank
Yang et al.
Am. J. Clin. Nutr. 2008;88:232-246.
ABSTRACT | FULL TEXT  

Plasma total homocysteine: instigator or indicator of cardiovascular disease?
Moat
Ann Clin Biochem 2008;45:345-348.
ABSTRACT | FULL TEXT  

Effects of L-Isoleucine and L-Valine on Hot Flushes and Serum Homocysteine: A Randomized Controlled Trial
Guttuso et al.
Obstet Gynecol 2008;112:109-115.
ABSTRACT | FULL TEXT  

Mesna for Treatment of Hyperhomocysteinemia in Hemodialysis Patients: A Placebo-Controlled, Double-Blind, Randomized Trial
Urquhart et al.
CJASN 2008;3:1041-1047.
ABSTRACT | FULL TEXT  

Circulating homocysteine levels in patients with radiofrequency catheter ablation for atrial fibrillation
Shimano et al.
Europace 2008;0:eun140v1-6.
ABSTRACT | FULL TEXT  

The Homocysteine Paradox
Rodionov and Lentz
Arterioscler. Thromb. Vasc. Bio. 2008;28:1031-1033.
FULL TEXT  

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
Albert et al.
JAMA 2008;299:2027-2036.
ABSTRACT | FULL TEXT  

Homocysteine-Lowering B Vitamin Therapy in Cardiovascular Prevention--Wrong Again?
Lonn
JAMA 2008;299:2086-2087.
FULL TEXT  

Homocysteine Inhibits Arterial Endothelial Cell Growth Through Transcriptional Downregulation of Fibroblast Growth Factor-2 Involving G Protein and DNA Methylation
Chang et al.
Circ. Res. 2008;102:933-941.
ABSTRACT | FULL TEXT  

Is folic acid good for everyone?
Smith et al.
Am. J. Clin. Nutr. 2008;87:517-533.
ABSTRACT | FULL TEXT  

Homocysteine lowering with folic acid and B vitamins in people with chronic kidney disease--results of the renal Hope-2 study
Mann et al.
Nephrol Dial Transplant 2008;23:645-653.
ABSTRACT | FULL TEXT  

Intake of Folate, Vitamin B6 and Vitamin B12 and the Risk of CHD: The Japan Public Health Center-Based Prospective Study Cohort I
Ishihara et al.
J. Am. Coll. Nutr. 2008;27:127-136.
ABSTRACT | FULL TEXT  

NINDS Clinical Trials in Stroke: Lessons Learned and Future Directions
Marler
Stroke 2007;38:3302-3307.
ABSTRACT | FULL TEXT  

Association of diabetes, homocysteine, and HDL with cognition and disability after stroke
Newman et al.
Neurology 2007;69:2054-2062.
ABSTRACT | FULL TEXT  

Effect of a voluntary food fortification policy on folate, related B vitamin status, and homocysteine in healthy adults
Hoey et al.
Am. J. Clin. Nutr. 2007;86:1405-1413.
ABSTRACT | FULL TEXT  

Homocysteine, vitamins, and vascular disease prevention
McCully
Am. J. Clin. Nutr. 2007;86:1563S-1568S.
ABSTRACT | FULL TEXT  

Hyperhomocysteinemia: a cardiovascular risk factor in autoimmune diseases?
Lazzerini et al.
Lupus 2007;16:852-862.
ABSTRACT  

Mild Parkinsonian Signs and Plasma Homocysteine Concentration in Community-Dwelling Elderly Individuals
Louis et al.
Arch Neurol 2007;64:1646-1651.
ABSTRACT | FULL TEXT  

B Vitamin Plasma Levels and the Risk of Ischemic Stroke and Transient Ischemic Attack in a German Cohort
Weikert et al.
Stroke 2007;38:2912-2918.
ABSTRACT | FULL TEXT  

Homocysteine induces VCAM-1 gene expression through NF-{kappa}B and NAD(P)H oxidase activation: protective role of Mediterranean diet polyphenolic antioxidants
Carluccio et al.
Am. J. Physiol. Heart Circ. Physiol. 2007;293:H2344-H2354.
ABSTRACT | FULL TEXT  

Methylenetetrahydrofolate Reductase C677T Polymorphism and Cognitive Function in Older Women
Elkins et al.
Am J Epidemiol 2007;166:672-678.
ABSTRACT | FULL TEXT  

Effect of Homocysteine Lowering on Mortality and Vascular Disease in Advanced Chronic Kidney Disease and End-stage Renal Disease: A Randomized Controlled Trial
Jamison et al.
JAMA 2007;298:1163-1170.
ABSTRACT | FULL TEXT  

B Vitamins for the Prevention of Vascular Disease: Insufficient Evidence to Justify Treatment
Baigent and Clarke
JAMA 2007;298:1212-1214.
FULL TEXT  

Folic acid improves vascular reactivity in humans: a meta-analysis of randomized controlled trials
de Bree et al.
Am. J. Clin. Nutr. 2007;86:610-617.
ABSTRACT | FULL TEXT  

Low vitamin B6 levels and the risk of recurrent venous thromboembolism
Hron et al.
haematol 2007;92:1250-1253.
ABSTRACT | FULL TEXT  

Aortic Arch Atheroma Progression and Recurrent Vascular Events in Patients With Stroke or Transient Ischemic Attack
Sen et al.
Circulation 2007;116:928-935.
ABSTRACT | FULL TEXT  

Mesna as a Nonvitamin Intervention to Lower Plasma Total Homocysteine Concentration: Implications for Assessment of the Homocysteine Theory of Atherosclerosis
Urquhart et al.
J Clin Pharmacol 2007;47:991-997.
ABSTRACT | FULL TEXT  

Vitamin supplementation in the secondary prevention of venous thromboembolism: about the VITRO study
Marcucci et al.
Blood 2007;109:5520-5520.
FULL TEXT  

The Homocysteine Hypothesis of Depression
Folstein et al.
Am. J. Psychiatry 2007;164:861-867.
ABSTRACT | FULL TEXT  

Race-ethnicity differences in folic acid intake in women of childbearing age in the United States after folic acid fortification: findings from the National Health and Nutrition Examination Survey, 2001-2002
Yang et al.
Am. J. Clin. Nutr. 2007;85:1409-1416.
ABSTRACT | FULL TEXT  

Homocysteine and Cardiovascular Risk: Considering the Evidence in the Context of Study Design, Folate Fortification, and Statistical Power
Ueland and Clarke
Clin. Chem. 2007;53:807-809.
FULL TEXT  

Lowering Homocysteine with B Vitamins Has No Effect on Blood Pressure in Older Adults
McMahon et al.
J. Nutr. 2007;137:1183-1187.
ABSTRACT | FULL TEXT  

Homocysteine, 5,10-Methylenetetrahydrofolate Reductase 677C>T Polymorphism, Nutrient Intake, and Incident Cardiovascular Disease in 24 968 Initially Healthy Women
Zee et al.
Clin. Chem. 2007;53:845-851.
ABSTRACT | FULL TEXT  

Genetic and Environmental Influences on Plasma Homocysteine: Results from a Danish Twin Study
Bathum et al.
Clin. Chem. 2007;53:971-979.
ABSTRACT | FULL TEXT  

Reply
Kaul et al.
J Am Coll Cardiol 2007;49:1371-1371.
FULL TEXT  

No Association Between the Common MTHFR 677C->T Polymorphism and Venous Thrombosis: Results From the MEGA Study
Bezemer et al.
Arch Intern Med 2007;167:497-501.
ABSTRACT | FULL TEXT  

Both vitamin B6 and total homocysteine plasma levels predict long-term atherothrombotic events in healthy subjects
Vanuzzo et al.
Eur Heart J 2007;28:484-491.
ABSTRACT | FULL TEXT  

Homocysteine, B vitamins, and the risk of dementia
Clarke
Am. J. Clin. Nutr. 2007;85:329-330.
FULL TEXT  

High Prevalence of Hyperhomocysteinemia in Chinese Adults Is Associated with Low Folate, Vitamin B-12, and Vitamin B-6 Status
Hao et al.
J. Nutr. 2007;137:407-413.
ABSTRACT | FULL TEXT  

Levels of homocysteine are increased in metabolic syndrome patients but are not associated with an increased cardiovascular risk, in contrast to patients without the metabolic syndrome
Hajer et al.
Heart 2007;93:216-220.
ABSTRACT | FULL TEXT  

Primary Prevention and Health Services Delivery
Goldstein and Rothwell
Stroke 2007;38:222-224.
FULL TEXT  

Risk Factors for Early Myocardial Infarction in South Asians Compared With Individuals in Other Countries
Joshi et al.
JAMA 2007;297:286-294.
ABSTRACT | FULL TEXT  

Elevated Homocysteine Is Associated With Reduced Regional Left Ventricular Function: The Multi-Ethnic Study of Atherosclerosis
Nasir et al.
Circulation 2007;115:180-187.
ABSTRACT | FULL TEXT  

The reverse epidemiology of plasma total homocysteine as a mortality risk factor is related to the impact of wasting and inflammation
Suliman et al.
Nephrol Dial Transplant 2007;22:209-217.
ABSTRACT | FULL TEXT  

Relation of Higher Folate Intake to Lower Risk of Alzheimer Disease in the Elderly
Luchsinger et al.
Arch Neurol 2007;64:86-92.
ABSTRACT | FULL TEXT  

Using Genetic Variation to Optimize Nutritional Preemption
Gillies and Krul
J. Nutr. 2007;137:270S-274S.
ABSTRACT | FULL TEXT  

Homocysteine lowering by B vitamins and the secondary prevention of deep vein thrombosis and pulmonary embolism: a randomized, placebo-controlled, double-blind trial
den Heijer et al.
Blood 2007;109:139-144.
ABSTRACT | FULL TEXT  

Effect of Folic Acid Supplementation on Risk of Cardiovascular Diseases: A Meta-analysis of Randomized Controlled Trials
Bazzano et al.
JAMA 2006;296:2720-2726.
ABSTRACT | FULL TEXT  

Folic acid, homocysteine, and cardiovascular disease: judging causality in the face of inconclusive trial evidence
Wald et al.
BMJ 2006;333:1114-1117.
FULL TEXT  

Homocysteine and Carotid Intima-Media Thickness in a German Population: Lack of Clinical Relevance
Linnebank et al.
Stroke 2006;37:2840-2842.
ABSTRACT | FULL TEXT  

Summary of American Heart Association Diet and Lifestyle Recommendations Revision 2006
Lichtenstein et al.
Arterioscler. Thromb. Vasc. Bio. 2006;26:2186-2191.
FULL TEXT  

Homocysteine and Cardiovascular Disease: Is HDL the Link?
Barter and Rye
Circ. Res. 2006;99:565-566.
FULL TEXT  

5-Methyltetrahydrofolate Rapidly Improves Endothelial Function and Decreases Superoxide Production in Human Vessels: Effects on Vascular Tetrahydrobiopterin Availability and Endothelial Nitric Oxide Synthase Coupling
Antoniades et al.
Circulation 2006;114:1193-1201.
ABSTRACT | FULL TEXT  

Homocysteine Hypothesis for Atherothrombotic Cardiovascular Disease: Not Validated
Kaul et al.
J Am Coll Cardiol 2006;48:914-923.
ABSTRACT | FULL TEXT  

Nutrition and Stroke Prevention
Fisher et al.
Stroke 2006;37:2430-2435.
ABSTRACT | FULL TEXT  

Lowering homocysteine with folic acid and B vitamins did not prevent vascular events in vascular disease
Shekelle
Evid. Based Med. 2006;11:104-104.
FULL TEXT  

Lowering homocysteine with folic acid and B vitamins did not prevent vascular events after myocardial infarction
Shekelle
Evid. Based Med. 2006;11:105-105.
FULL TEXT  

Trials that matter: should we routinely measure homocysteine levels and "treat" mild hyperhomocysteinemia?
Rosenberg and Mulrow
ANN INTERN MED 2006;145:226-227.
FULL TEXT  

Homocysteine, B vitamins, and cardiovascular disease.
de Craen et al.
NEJM 2006;355:205-206.
FULL TEXT  

Diet and Lifestyle Recommendations Revision 2006: A Scientific Statement From the American Heart Association Nutrition Committee
Lichtenstein et al.
Circulation 2006;114:82-96.
ABSTRACT | FULL TEXT  

Effects of folinic acid on forearm blood flow in patients with end-stage renal disease
Anderson et al.
Nephrol Dial Transplant 2006;21:1927-1933.
ABSTRACT | FULL TEXT  

Folate and Vitamin B6 Rapidly Normalize Endothelial Dysfunction In Children With Type 1 Diabetes Mellitus
MacKenzie et al.
Pediatrics 2006;118:242-253.
ABSTRACT | FULL TEXT  

Primary Prevention of Ischemic Stroke: A Guideline From the American Heart Association/American Stroke Association Stroke Council: Cosponsored by the Atherosclerotic Peripheral Vascular Disease Interdisciplinary Working Group; Cardiovascular Nursing Council; Clinical Cardiology Council; Nutrition, Physical Activity, and Metabolism Council; and the Quality of Care and Outcomes Research Interdisciplinary Working Group: The American Academy of Neurology affirms the value of this guideline.
Goldstein et al.
Circulation 2006;113:e873-e923.
ABSTRACT | FULL TEXT  

Folic Acid, Vitamin B12, MTHFR Genotypes, and Plasma Homocysteine.
Golledge et al.
Clin. Chem. 2006;52:1205-1206.
FULL TEXT  

The Many Facets of Hyperhomocysteinemia: Studies from the Framingham Cohorts
Selhub
J. Nutr. 2006;136:1726S-1730S.
ABSTRACT | FULL TEXT  

The Hordaland Homocysteine Study: A Community-Based Study of Homocysteine, Its Determinants, and Associations with Disease
Refsum et al.
J. Nutr. 2006;136:1731S-1740S.
ABSTRACT | FULL TEXT  

Primary Prevention of Ischemic Stroke: A Guideline From the American Heart Association/American Stroke Association Stroke Council: Cosponsored by the Atherosclerotic Peripheral Vascular Disease Interdisciplinary Working Group; Cardiovascular Nursing Council; Clinical Cardiology Council; Nutrition, Physical Activity, and Metabolism Council; and the Quality of Care and Outcomes Research Interdisciplinary Working Group: The American Academy of Neurology affirms the value of this guideline.
Goldstein et al.
Stroke 2006;37:1583-1633.
ABSTRACT | FULL TEXT  

Statin treatment and adherence to national cholesterol guidelines after ischemic stroke
Ovbiagele et al.
Neurology 2006;66:1164-1170.
ABSTRACT | FULL TEXT  

Confounding of the Relation between Homocysteine and Peripheral Arterial Disease by Lead, Cadmium, and Renal Function
Guallar et al.
Am J Epidemiol 2006;163:700-708.
ABSTRACT | FULL TEXT  

Homocysteine Trials -- Clear Outcomes for Complex Reasons
Loscalzo
NEJM 2006;354:1629-1632.
FULL TEXT  

Homocysteine Lowering and Cardiovascular Events after Acute Myocardial Infarction
Bonaa et al.
NEJM 2006;354:1578-1588.
ABSTRACT | FULL TEXT  

Homocysteine Lowering with Folic Acid and B Vitamins in Vascular Disease
The Heart Outcomes Prevention Evaluation (HOPE) 2
NEJM 2006;354:1567-1577.
ABSTRACT | FULL TEXT  

Prevalence of Neural Tube Defects, Folate Status, and Folate Fortification of Enriched Cereal-Grain Products in the United States
Rader and Schneeman
Pediatrics 2006;117:1394-1399.
FULL TEXT  

Cardiovascular Morbidity and Mortality in the Atherosclerosis and Folic Acid Supplementation Trial (ASFAST) in Chronic Renal Failure: A Multicenter, Randomized, Controlled Trial
Zoungas et al.
J Am Coll Cardiol 2006;47:1108-1116.
ABSTRACT | FULL TEXT  

Improvement in Stroke Mortality in Canada and the United States, 1990 to 2002
Yang et al.
Circulation 2006;113:1335-1343.
ABSTRACT | FULL TEXT  

Guidelines for Prevention of Stroke in Patients With Ischemic Stroke or Transient Ischemic Attack: A Statement for Healthcare Professionals From the American Heart Association/American Stroke Association Council on Stroke: Co-Sponsored by the Council on Cardiovascular Radiology and Intervention: The American Academy of Neurology affirms the value of this guideline.
Sacco et al.
Circulation 2006;113:e409-e449.
ABSTRACT | FULL TEXT  

Guidelines for Prevention of Stroke in Patients With Ischemic Stroke or Transient Ischemic Attack: A Statement for Healthcare Professionals From the American Heart Association/American Stroke Association Council on Stroke: Co-Sponsored by the Council on Cardiovascular Radiology and Intervention: The American Academy of Neurology affirms the value of this guideline.
Sacco et al.
Stroke 2006;37:577-617.
ABSTRACT | FULL TEXT  

Homocysteine: Call Off the Funeral
Spence
Stroke 2006;37:282-283.
FULL TEXT  

Methylenetetrahydrofolate Reductase Polymorphisms and Homocysteine-Lowering Effect of Vitamin Therapy in Singaporean Stroke Patients
Ho et al.
Stroke 2006;37:456-460.
ABSTRACT | FULL TEXT  

Soluble Vascular Cell Adhesion Molecule 1 and N-terminal Pro-B-Type Natriuretic Peptide in Predicting Ischemic Stroke in Patients With Cerebrovascular Disease
Campbell et al.
Arch Neurol 2006;63:60-65.
ABSTRACT | FULL TEXT  

Randomized controlled trial of homocysteine-lowering vitamin treatment in elderly patients with vascular disease
Stott et al.
Am. J. Clin. Nutr. 2005;82:1320-1326.
ABSTRACT | FULL TEXT  

Risk of Myocardial Infarction and Vascular Death After Transient Ischemic Attack and Ischemic Stroke: A Systematic Review and Meta-Analysis
Touze et al.
Stroke 2005;36:2748-2755.
ABSTRACT | FULL TEXT  

Meta-analysis of MTHFR 677C->T polymorphism and coronary heart disease: does totality of evidence support causal role for homocysteine and preventive potential of folate?
Lewis et al.
BMJ 2005;331:1053.
ABSTRACT | FULL TEXT  

Total Plasma Homocysteine and Arteriosclerotic Outcomes in Type 2 Diabetes with Nephropathy
Friedman et al.
J. Am. Soc. Nephrol. 2005;16:3397-3402.
ABSTRACT | FULL TEXT  

Vitamin Intervention for Stroke Prevention Trial: An Efficacy Analysis
Spence et al.
Stroke 2005;36:2404-2409.
ABSTRACT | FULL TEXT  

Do low doses of folic acid result in maximum lowering of homocysteine?
Bailey
Am. J. Clin. Nutr. 2005;82:717-718.
FULL TEXT  

Dose-dependent effects of folic acid on blood concentrations of homocysteine: a meta-analysis of the randomized trials
Homocysteine Lowering Trialists' Collaboration
Am. J. Clin. Nutr. 2005;82:806-812.
ABSTRACT | FULL TEXT  

Assessment of Hemostatic Risk Factors in Predicting Arterial Thrombotic Events
Feinbloom and Bauer
Arterioscler. Thromb. Vasc. Bio. 2005;25:2043-2053.
ABSTRACT | FULL TEXT