Cited by 1,729Folate and B Vitamins ResearchLipoproteins and Cardiovascular HealthMenopause: Health Impacts and Treatments

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Homocysteine Lowering with Folic Acid and B Vitamins in Vascular Disease

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The Heart Outcomes Prevention Evaluation (HOPE) 2 Investigators·2006·New England Journal of Medicine

DOI 10.1056/nejmoa060900

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Abstract

BACKGROUND: In observational studies, lower homocysteine levels are associated with lower rates of coronary heart disease and stroke. Folic acid and vitamins B6 and B12 lower homocysteine levels. We assessed whether supplementation reduced the risk of major cardiovascular events in patients with vascular disease. METHODS: We randomly assigned 5522 patients 55 years of age or older who had vascular disease or diabetes to daily treatment either with the combination of 2.5 mg of folic acid, 50 mg of vitamin B6, and 1 mg of vitamin B12 or with placebo for an average of five years. The primary outcome was a composite of death from cardiovascular causes, myocardial infarction, and stroke. RESULTS: Mean plasma homocysteine levels decreased by 2.4 micromol per liter (0.3 mg per liter) in the active-treatment group and increased by 0.8 micromol per liter (0.1 mg per liter) in the placebo group. Primary outcome events occurred in 519 patients (18.8 percent) assigned to active therapy and 547 (19.8 percent) assigned to placebo (relative risk, 0.95; 95 percent confidence interval, 0.84 to 1.07; P=0.41). As compared with placebo, active treatment did not significantly decrease the risk of death from cardiovascular causes (relative risk, 0.96; 95 percent confidence interval, 0.81 to 1.13), myocardial infarction (relative risk, 0.98; 95 percent confidence interval, 0.85 to 1.14), or any of the secondary outcomes. Fewer patients assigned to active treatment than to placebo had a stroke (relative risk, 0.75; 95 percent confidence interval, 0.59 to 0.97). More patients in the active-treatment group were hospitalized for unstable angina (relative risk, 1.24; 95 percent confidence interval, 1.04 to 1.49). CONCLUSIONS: Supplements combining folic acid and vitamins B6 and B12 did not reduce the risk of major cardiovascular events in patients with vascular disease. (ClinicalTrials.gov number, NCT00106886; Current Controlled Trials number, ISRCTN14017017.).

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Background
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Prognostic Value of Free Plasma Homocysteine Levels in Patients Hospitalized With Acute Coronary Syndrome
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“In HOPE-2[59] (younger healthier population with better renal function than in NORVIT and VISP), B vitamins reduced the risk of stroke by 23%.”
Background
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Azarpazhooh, M. R., Andalibi, M. S. S., Hackam, D. G., & Spence, J. D. (2020) · Nutrition · doi:10.1016/j.nut.2020.110874 · Cited by 22
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BackgroundInfluential
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Iglesia, I., Huybrechts, I., González‐Gross, M., Mouratidou, T., Santabárbara, J., Chajès, V., González‐Gil, E. M., Park, J. Y., Bel‐Serrat, S., Cuenca‐García, M., et al. (2017) · British Journal Of Nutrition · doi:10.1017/s0007114516004414 · Cited by 22
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Dietary Supplement Intake and Fecundability in a Singapore Preconception Cohort Study
Ku, C. W., Ku, C. O., Tay, L. P. C., Xing, H. K., Cheung, Y. B., Godfrey, K. M., Colega, M., Teo, C., Tan, K. M. L., Chong, Y. S., et al. (2022) · Nutrients · doi:10.3390/nu14235110 · Cited by 21
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Plasma Total Homocysteine Level in Association With Folate, Pyridoxine, and Cobalamin Status Among Iranian Primary Breast Cancer Patients
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Identification of N -homocysteinylated apolipoprotein AI in normal human serum
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Homocysteine as a Diagnostic and Etiopathogenic Factor in Children with Autism Spectrum Disorder
Józefczuk, J., Kasprzycka, W., Czarnecki, R., Graczyk, A., Józefczuk, P., Magda, K., & Lampart, U. (2017) · Journal of Medicinal Food · doi:10.1089/jmf.2016.0150 · Cited by 21
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Defects in homocysteine metabolism: diversity among hyperhomocyst(e)inemias
Matthews, R. G., & Elmore, C. L. (2007) · Clinical Chemistry and Laboratory Medicine (CCLM) · doi:10.1515/cclm.2007.324 · Cited by 20
Should hyperhomocysteinemia be treated in patients with atherosclerotic disease?
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Polypill: the evidence and the promise
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Association of heme oxygenase-1 gene rs2071746 polymorphism with vascular outcomes in patients with atherosclerotic stroke
Cao, L., Zhang, Z., Cai, B., Bai, W., Zhang, Y., Sun, W., Xie, X., Sun, W., Cai, Q., Li, Z., et al. (2014) · Journal of the Neurological Sciences · doi:10.1016/j.jns.2014.06.046 · Cited by 21
Effects of pyridoxal-5′-phosphate (MC-1) in patients undergoing high-risk coronary artery bypass surgery: Results of the MEND-CABG randomized study
Tardif, J., Carrier, M., Kandzari, D. E., Emery, R., Côté, R., Heinonen, T. M., Zettler, M. E., Hasselblad, V., Guertin, M., & Harrington, R. A. (2007) · Journal of Thoracic and Cardiovascular Surgery · doi:10.1016/j.jtcvs.2007.01.049 · Cited by 21
Vascular oxidative stress increases dendritic cell adhesion and transmigration induced by homocysteine
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Higher gastric parietal cell antibody titer significantly increases the frequencies of macrocytosis, serum vitamin B12 deficiency, and hyperhomocysteinemia in patients with burning mouth syndrome
Jin, Y., Wu, Y.-H., Wu, Y., Chang, J. Y., Chiang, C., & Sun, A. (2021) · Journal of Dental Sciences · doi:10.1016/j.jds.2021.08.004 · Cited by 20
“Supplement therapy with folic acid, vitamin B12, and vitamin B6 can reduce blood homocysteine levels.(27) Our previous studies also demonstrated that supplementations with vitamin BC capsules plus corresponding deficient vitamin B12 and/or folic acid can reduce the abnormally high serum homocysteine level to significa…”
Background
Anemia, hematinic deficiencies, hyperhomocysteinemia, and gastric parietal cell antibody positivity in burning mouth syndrome patients with normocytosis
Wu, Y., Jin, Y., Wu, Y., Chang, J. Y., Chiang, C., & Sun, A. (2021) · Journal of Dental Sciences · doi:10.1016/j.jds.2021.09.025 · Cited by 20
“Deficiencies of vitamin B6, folic acid, and vitamin B12 can lead to high serum homocysteine levels (hyperhomocysteinemia).(35) However, in our hospital routine blood examination does not include the measurement of serum vitamin B6 level; thus, we did not know whether our patients had vitamin B6 deficiency or not.”
Background
Anemia, hematinic deficiencies, and hyperhomocysteinemia in younger and older burning mouth syndrome patients
Wu, Y., Wu, Y., Chang, J. Y., Lang, M.-J., Chiang, C., & Sun, A. (2022) · Journal of Dental Sciences · doi:10.1016/j.jds.2022.02.005 · Cited by 20
“A previous study has shown that a supplementation with folic acid and vitamins B12 and B6 can reduce blood homocysteine levels.(41) Our previous studies also demonstrated that supplementations with vitamin BC capsules plus corresponding deficient vitamin B12 and/or folic acid can reduce the abnormally high serum homoc…”
Result
Homocisteína e polimorfismos dos genes MTHFR e VEGF: impacto na doença arterial coronariana
Guerzoni, A. R., Biselli-Chicote, P. M., de Godoy, M. F., Souza, D. R. S., Haddad, R., Eberlin, M. N., Pavarino, É. C., & Goloni‐Bertollo, E. M. (2009) · Arquivos Brasileiros de Cardiologia · doi:10.1590/s0066-782x2009000400003 · Cited by 22

Authors: The Heart Outcomes Prevention Evaluation (HOPE) 2 Investigators
Affiliations: Hamilton General Hospital (CA)
Corresponding author: The Heart Outcomes Prevention Evaluation (HOPE) 2 Investigators
Venue: New England Journal of Medicine
Publisher: Massachusetts Medical Society
Published: 2006-04-13
Volume: 354
Issue: 15
Pages: 1567-1577
ISSN: 0028-4793 (ISSN-L)
1533-4406
DOI: 10.1056/nejmoa060900
OpenAlex: W2109544293
Cited by: 1,729
References: 20
Citations by year: 2026: 43 · 2025: 46 · 2024: 33 · 2023: 30 · 2022: 43 · 2021: 37 · 2020: 52 · 2019: 46 · 2018: 46 · 2017: 70 · 2016: 81 · 2015: 77 · 2014: 84 · 2013: 85 · 2012: 104
FWCI: 136.11
Type: journal article
Language: en
Open access: bronze
doi.org
Locations: New England Journal of Medicine (publishedVersion)
PubMed (publishedVersion)
Funders: University of Pittsburgh
Massachusetts Medical Society
Topics: Health Sciences › Nursing › Nutrition and Dietetics › Folate and B Vitamins Research
Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipoproteins and Cardiovascular Health
Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Menopause: Health Impacts and Treatments
Keywords: homocysteine lowering, folic acid, vitamin B6, vitamin B12, vascular disease, cardiovascular events, stroke, myocardial infarction, cardiovascular mortality, unstable angina, diabetes mellitus, older adults
MeSH terms: Aged, Cardiovascular Diseases, Diabetes Mellitus, Double-Blind Method, Drug Therapy, Combination, Female, Folic Acid, Follow-Up Studies, Humans, Male, Middle Aged, Myocardial Infarction, Risk Factors, Vascular Diseases, Vitamin B 12, Hyperhomocysteinemia, Stroke, Vitamin B 6

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Homocysteine Lowering with Folic Acid and B Vitamins in Vascular Disease

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