WENBIT - Western Norway B Vitamin Intervention Trial

NCT00354081 | Completed Phase 3 DMC

• 1 other identifier: NSD-14154
• Study Type: interventional
• Target: 3,096
• Locations: 1 country
• Sites: 2

Brief Summary

PURPOSE OF STUDY Observational studies have demonstrated that elevated levels of plasma total homocysteine is a risk factor for cardiovascular disease. The purpose of this trial is to evaluate the clinical effects of homocysteine lowering treatment with B vitamins during 3-5 years follow-up of patients undergoing cardiac catheterization for suspected coronary artery disease (CAD). Special attention will be given to complication rates among patients needing subsequent percutaneous transluminal coronary angioplasty (PCI) or coronary artery by-pass grafting (CABG). HYPOTHESIS The primary hypothesis of this study is that, among patients with CAD, a daily supplement with B vitamins will reduce the risk for cardiovascular mortality and serious cardiovascular events with at least 20%. The secondary hypothesis of this study is that, among patients with CAD, a daily supplement with B vitamins will reduce the risk for total mortality, coronary events, cerebrovascular events and other cardiovascular events. The hypothesis will be tested for an effect of any of the treatments (folic acid / vitamin B12 or B6), and the effect will be evaluated according to initial total homocysteine levels and B vitamin levels as well as to the change in these levels after 1 and 6 months. The sample size has been calculated to 3088 patients using a two-sided chi-square test with significance 0.05 and at an 80% power level, presumed event rate of 22% over 4 years, and event rate reduction of 20%, adjusted for non-compliance/drop-out of 20%. STUDY DESIGN This is a controlled, double-blind two-centre trial with 3090 included men and women who underwent coronary angiography at Haukeland University Hospital or Stavanger University Hospital between April 1999 and April 2004. At baseline about 1300 patients underwent PCI and 600 underwent CABG. The patients were randomized into 4 groups in a 2 x 2 factorial design to receive one of the following four treatments: A, folic acid 0.8 mg plus vitamin B12 0.4 mg and vitamin B6 40 mg per day; B, folic acid 0.8 mg plus vitamin B12 0.4 mg per day; C, vitamin B6 40 mg per day; D, placebo. The active drug and the placebo tablets had identical appearance and taste. Treatment was started as soon as the patients were randomized after the coronary angiography procedure. The patients have been undergoing interviews, clinical examination and blood-sampling at baseline, at follow-up after 1 month and 1 year, and at a final study visit. In addition, information on dietary habits was obtained from 2400 patients at baseline. Among 350 patients that have undergone PCI at baseline, a full clinical examination, blood sampling and repeat coronary angiography to assess re-stenosis has been performed about 9 (6-12) months after the PCI procedure. For these patients, angiograms suitable for quantitative coronary angiography (QCA) analysis have been obtained at the baseline and follow-up invasive procedures. The follow-up was terminated ahead of schedule in October 2005 due to lack of compliance of the participants caused by media reports from the NORVIT study (NCT00266487) on potential increased cancer risk associated by B vitamin supplementation. The patients had then been followed for 1.5 - 5 years. STUDY END POINTS Primary clinical endpoints during follow-up are all cause death, non-fatal acute myocardial infarction, acute hospitalization for unstable angina and non-fatal thromboembolic stroke (infarction). Secondary endpoints are fatal and non-fatal acute myocardial infarction (including procedure related myocardial infarction), acute hospitalization for angina, stable angina with angiographic verified progression, myocardial revascularization, fatal and non-fatal thromboembolic stroke.

Conditions

Coronary Artery Disease; Myocardial Infarction; Cerebrovascular Stroke

Keywords

Coronary Artery Disease; Myocardial Infarction; Cerebrovascular Stroke; Homocysteine; Folic Acid; Vitamin B 12; Vitamin B 6

Outcome Measures

Primary Outcomes (1)

• Composite of all cause death, non-fatal acute myocardial infarction, acute hospitalization for unstable angina pectoris, and of non-fatal thromboembolic stroke (infarction)

  During follow-up, 1.5-5 years

Secondary Outcomes (6)

• Fatal and non-fatal acute myocardial infarction, including procedure related myocardial infarction

  During follow-up, 1.5-5 years

• Acute hospitalization for angina

  During follow-up, 1.5-5 years

• Stable angina with angiographic verified progression

  During follow-up, 1.5-5 years

• Myocardial revascularization

  During follow-up, 1.5-5 years

• Fatal and non-fatal thromboembolic stroke

  During follow-up, 1.5-5 years

Study Arms (4)

1

ACTIVE COMPARATOR

folic acid (0.8 mg) plus vitamin B12 (0.4 mg) and vitamin B6 (40 mg)

Drug: folic acid, vitamin B12 (cyanocobalamin), vitamin B6 (pyridoxine)

2

ACTIVE COMPARATOR

folic acid (0.8 mg) plus vitamin B12 (0.4 mg)

Drug: folic acid, vitamin B12 (cyanocobalamin)

3

ACTIVE COMPARATOR

vitamin B6 (40 mg)

Drug: vitamin B6 (pyridoxine)

4

PLACEBO COMPARATOR

placebo

Drug: placebo

Interventions

folic acid, vitamin B12 (cyanocobalamin), vitamin B6 (pyridoxine) DRUG

folic acid 0.8 mg plus vitamin B12 0.4 mg and vitamin B6 40 mg, in a capsule, taken orally once a day

1

folic acid, vitamin B12 (cyanocobalamin) DRUG

folic acid 0.8 mg plus vitamin B12 0.4 mg, in a capsule, taken orally once a day

2

vitamin B6 (pyridoxine) DRUG

vitamin B6 40 mg, in a capsule, taken orally once a day

3

placebo DRUG

placebo, in a capsule, taken orally once a day

4

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• adults ≥ 18 years able to give informed consent
• patients prepared to undergo long-term follow-up

You may not qualify if:

• patients who are not available for follow-up
• patients who have previously participated in this study
• patients with known alcohol abuse or serious mental illness
• patients with known active malignant disease
• patients who have undergone coronary angiography for specific reasons, i.e. assessment for cardiac transplantation, kidney donor, heart donor, diagnostic assessment of cardiomyopathy

Sponsors & Collaborators

• Haukeland University Hospital: lead
• The Research Council of Norway: collaborator
• Norwegian Foundation for Health and Rehabilitation: collaborator
• Norwegian Heart and Lung Patient Organisation: collaborator
• The Royal Norwegian Ministry of Health: collaborator
• Locus for Homocysteine and Related Vitamins, University of Bergen, Norway: collaborator
• Locus for Cardiac Research, University of Bergen, Norway: collaborator
• Foundation to Promote Research into Functional Vitamin B12 Deficiency, Bergen, Norway: collaborator
• Alpharma Pharmaceuticals LLC, a subsidiary of Pfizer Inc.: collaborator

Study Sites (2)

Department of Heart Disease, Haukeland University Hospital

Bergen, Bergen, 5021, Norway

Location

Department of Cardiology, Stavanger University Hospital

Stavanger, 4011, Norway

Location

Related Publications (36)

• 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. Am Heart J. 2006 Feb;151(2):282-7. doi: 10.1016/j.ahj.2005.04.025.

  PMID: 16442889 BACKGROUND

• Clarke R, Armitage J, Lewington S, Collins R; B-Vitamin Treatment Trialists' Collaboration. Homocysteine-lowering trials for prevention of vascular disease: protocol for a collaborative meta-analysis. Clin Chem Lab Med. 2007;45(12):1575-81. doi: 10.1515/CCLM.2007.346.

  PMID: 18265450 BACKGROUND

• Nexo E, Hvas AM, Bleie O, Refsum H, Fedosov SN, Vollset SE, Schneede J, Nordrehaug JE, Ueland PM, Nygard OK. Holo-transcobalamin is an early marker of changes in cobalamin homeostasis. A randomized placebo-controlled study. Clin Chem. 2002 Oct;48(10):1768-71.

  PMID: 12324494 RESULT

• Bor MV, Refsum H, Bisp MR, Bleie O, Schneede J, Nordrehaug JE, Ueland PM, Nygard OK, Nexo E. Plasma vitamin B6 vitamers before and after oral vitamin B6 treatment: a randomized placebo-controlled study. Clin Chem. 2003 Jan;49(1):155-61. doi: 10.1373/49.1.155.

  PMID: 12507972 RESULT

• Holm PI, Bleie O, Ueland PM, Lien EA, Refsum H, Nordrehaug JE, Nygard O. Betaine as a determinant of postmethionine load total plasma homocysteine before and after B-vitamin supplementation. Arterioscler Thromb Vasc Biol. 2004 Feb;24(2):301-7. doi: 10.1161/01.ATV.0000114569.54976.31. Epub 2003 Dec 29.

  PMID: 14699020 RESULT

• Bleie O, Refsum H, Ueland PM, Vollset SE, Guttormsen AB, Nexo E, Schneede J, Nordrehaug JE, Nygard O. Changes in basal and postmethionine load concentrations of total homocysteine and cystathionine after B vitamin intervention. Am J Clin Nutr. 2004 Sep;80(3):641-8. doi: 10.1093/ajcn/80.3.641.

  PMID: 15321804 RESULT

• Gavasso S, Nygard O, Pedersen ER, Aarseth JH, Bleie O, Myhr KM, Vedeler CA. Fcgamma receptor IIIA polymorphism as a risk-factor for coronary artery disease. Atherosclerosis. 2005 Jun;180(2):277-82. doi: 10.1016/j.atherosclerosis.2004.12.011. Epub 2005 Jan 25.

  PMID: 15910853 RESULT

• Morkbak AL, Hvas AM, Lloyd-Wright Z, Sanders TA, Bleie O, Refsum H, Nygaard OK, Nexo E. Effect of vitamin B12 treatment on haptocorrin. Clin Chem. 2006 Jun;52(6):1104-11. doi: 10.1373/clinchem.2005.061549. Epub 2006 Apr 13.

  PMID: 16613998 RESULT

• Ulvik B, Wentzel-Larsen T, Hanestad BR, Omenaas E, Nygard OK. Relationship between provider-based measures of physical function and self-reported health-related quality of life in patients admitted for elective coronary angiography. Heart Lung. 2006 Mar-Apr;35(2):90-100. doi: 10.1016/j.hrtlng.2005.07.003.

  PMID: 16543037 RESULT

• Bleie O, Semb AG, Grundt H, Nordrehaug JE, Vollset SE, Ueland PM, Nilsen DW, Bakken AM, Refsum H, Nygard OK. Homocysteine-lowering therapy does not affect inflammatory markers of atherosclerosis in patients with stable coronary artery disease. J Intern Med. 2007 Aug;262(2):244-53. doi: 10.1111/j.1365-2796.2007.01810.x.

  PMID: 17645592 RESULT

• Ulvik B, Nygard O, Hanestad BR, Wentzel-Larsen T, Wahl AK. Associations between disease severity, coping and dimensions of health-related quality of life in patients admitted for elective coronary angiography - a cross sectional study. Health Qual Life Outcomes. 2008 May 29;6:38. doi: 10.1186/1477-7525-6-38.

  PMID: 18510727 RESULT

• Ulvik B, Bjelland I, Hanestad BR, Omenaas E, Wentzel-Larsen T, Nygard O. Comparison of the Short Form 36 and the Hospital Anxiety and Depression Scale measuring emotional distress in patients admitted for elective coronary angiography. Heart Lung. 2008 Jul-Aug;37(4):286-95. doi: 10.1016/j.hrtlng.2007.08.001.

  PMID: 18620104 RESULT

• Ebbing M, Bleie O, Ueland PM, Nordrehaug JE, Nilsen DW, Vollset SE, Refsum H, Pedersen EK, Nygard O. Mortality and cardiovascular events in patients treated with homocysteine-lowering B vitamins after coronary angiography: a randomized controlled trial. JAMA. 2008 Aug 20;300(7):795-804. doi: 10.1001/jama.300.7.795.

  PMID: 18714059 RESULT

• Lonnebakken MT, Bleie O, Strand E, Staal EM, Nygard OK, Gerdts E. Myocardial contrast echocardiography in assessment of stable coronary artery disease at intermediate dobutamine-induced stress level. Echocardiography. 2009 Jan;26(1):52-60. doi: 10.1111/j.1540-8175.2008.00738.x.

  PMID: 19125808 RESULT

• Lonnebakken MT, Staal EM, Bleie O, Strand E, Nygard OK, Gerdts E. Quantitative contrast stress echocardiography in assessment of restenosis after percutaneous coronary intervention in stable coronary artery disease. Eur J Echocardiogr. 2009 Oct;10(7):858-64. doi: 10.1093/ejechocard/jep090. Epub 2009 Jun 23.

  PMID: 19549699 RESULT

• Manger MS, Strand E, Ebbing M, Seifert R, Refsum H, Nordrehaug JE, Nilsen DW, Drevon CA, Tell GS, Bleie O, Vollset SE, Pedersen ER, Nygard O. Dietary intake of n-3 long-chain polyunsaturated fatty acids and coronary events in Norwegian patients with coronary artery disease. Am J Clin Nutr. 2010 Jul;92(1):244-51. doi: 10.3945/ajcn.2010.29175. Epub 2010 May 19.

  PMID: 20484456 RESULT

• Loland KH, Bleie O, Blix AJ, Strand E, Ueland PM, Refsum H, Ebbing M, Nordrehaug JE, Nygard O. Effect of homocysteine-lowering B vitamin treatment on angiographic progression of coronary artery disease: a Western Norway B Vitamin Intervention Trial (WENBIT) substudy. Am J Cardiol. 2010 Jun 1;105(11):1577-84. doi: 10.1016/j.amjcard.2010.01.019. Epub 2010 Apr 10.

  PMID: 20494665 RESULT

• Dhar I, Svingen GF, Ulvik A, Bjornestad EO, Sagen JV, Nygard OK. Serum Vitamin A Is Associated with Variations in the Relationship between Plasma B6 Vitamers and Cardiovascular Disease Risk. J Nutr. 2026 Jan;156(1):101223. doi: 10.1016/j.tjnut.2025.10.036. Epub 2025 Oct 30.

  PMID: 41176280 DERIVED

• Sikora M, Skrzydlewski P, Perla-Kajan J, Jakubowski H. Homocysteine thiolactone contributes to the prognostic value of fibrin clot structure/function in coronary artery disease. PLoS One. 2022 Oct 27;17(10):e0275956. doi: 10.1371/journal.pone.0275956. eCollection 2022.

  PMID: 36301961 DERIVED

• Dhar I, Lysne V, Svingen GFT, Ueland PM, Gregory JF, Bonaa KH, Nygard OK. Elevated plasma cystathionine is associated with increased risk of mortality among patients with suspected or established coronary heart disease. Am J Clin Nutr. 2019 Jun 1;109(6):1546-1554. doi: 10.1093/ajcn/nqy391.

  PMID: 31005968 DERIVED

• Borowczyk K, Piechocka J, Glowacki R, Dhar I, Midtun O, Tell GS, Ueland PM, Nygard O, Jakubowski H. Urinary excretion of homocysteine thiolactone and the risk of acute myocardial infarction in coronary artery disease patients: the WENBIT trial. J Intern Med. 2019 Feb;285(2):232-244. doi: 10.1111/joim.12834. Epub 2018 Sep 23.

  PMID: 30193001 DERIVED

• Puaschitz NG, Assmus J, Strand E, Karlsson T, Vinknes KJ, Lysne V, Drevon CA, Tell GS, Dierkes J, Nygard O. Adherence to the Healthy Nordic Food Index and the incidence of acute myocardial infarction and mortality among patients with stable angina pectoris. J Hum Nutr Diet. 2019 Feb;32(1):86-97. doi: 10.1111/jhn.12592. Epub 2018 Aug 8.

  PMID: 30091209 DERIVED

• Midttun O, Ulvik A, Nygard O, Ueland PM. Performance of plasma trigonelline as a marker of coffee consumption in an epidemiologic setting. Am J Clin Nutr. 2018 Jun 1;107(6):941-947. doi: 10.1093/ajcn/nqy059.

  PMID: 29771289 DERIVED

• Degerud E, Nygard O, de Vogel S, Hoff R, Svingen GFT, Pedersen ER, Nilsen DWT, Nordrehaug JE, Midttun O, Ueland PM, Dierkes J. Plasma 25-Hydroxyvitamin D and Mortality in Patients With Suspected Stable Angina Pectoris. J Clin Endocrinol Metab. 2018 Mar 1;103(3):1161-1170. doi: 10.1210/jc.2017-02328.

  PMID: 29325121 DERIVED

• Strand E, Rebnord EW, Flygel MR, Lysne V, Svingen GFT, Tell GS, Loland KH, Berge RK, Svardal A, Nygard O, Pedersen ER. Serum Carnitine Metabolites and Incident Type 2 Diabetes Mellitus in Patients With Suspected Stable Angina Pectoris. J Clin Endocrinol Metab. 2018 Mar 1;103(3):1033-1041. doi: 10.1210/jc.2017-02139.

  PMID: 29325058 DERIVED

• Strand E, Pedersen ER, Svingen GF, Olsen T, Bjorndal B, Karlsson T, Dierkes J, Njolstad PR, Mellgren G, Tell GS, Berge RK, Svardal A, Nygard O. Serum Acylcarnitines and Risk of Cardiovascular Death and Acute Myocardial Infarction in Patients With Stable Angina Pectoris. J Am Heart Assoc. 2017 Feb 3;6(2):e003620. doi: 10.1161/JAHA.116.003620.

  PMID: 28159823 DERIVED

• Ding Y, Pedersen ER, Svingen GF, Helgeland O, Gregory JF, Loland KH, Meyer K, Tell GS, Ueland PM, Nygard OK. Methylenetetrahydrofolate Dehydrogenase 1 Polymorphisms Modify the Associations of Plasma Glycine and Serine With Risk of Acute Myocardial Infarction in Patients With Stable Angina Pectoris in WENBIT (Western Norway B Vitamin Intervention Trial). Circ Cardiovasc Genet. 2016 Dec;9(6):541-547. doi: 10.1161/CIRCGENETICS.116.001483. Epub 2016 Nov 21.

  PMID: 27872106 DERIVED

• Borgeraas H, Hertel JK, Seifert R, Berge RK, Bohov P, Ueland PM, Nygard O, Hjelmesaeth J. Serum trans fatty acids, asymmetric dimethylarginine and risk of acute myocardial infarction and mortality in patients with suspected coronary heart disease: a prospective cohort study. Lipids Health Dis. 2016 Feb 27;15:38. doi: 10.1186/s12944-016-0204-9.

  PMID: 26920731 DERIVED

• Ding Y, Svingen GF, Pedersen ER, Gregory JF, Ueland PM, Tell GS, Nygard OK. Plasma Glycine and Risk of Acute Myocardial Infarction in Patients With Suspected Stable Angina Pectoris. J Am Heart Assoc. 2015 Dec 31;5(1):e002621. doi: 10.1161/JAHA.115.002621.

  PMID: 26722126 DERIVED

• Rebnord EW, Pedersen ER, Strand E, Svingen GF, Meyer K, Schartum-Hansen H, Loland KH, Seifert R, Ueland PM, Nilsen DW, Nordrehaug JE, Nygard O. Glycated hemoglobin and long-term prognosis in patients with suspected stable angina pectoris without diabetes mellitus: a prospective cohort study. Atherosclerosis. 2015 May;240(1):115-20. doi: 10.1016/j.atherosclerosis.2015.02.053. Epub 2015 Feb 28.

  PMID: 25770690 DERIVED

• Borgeraas H, Hertel JK, Svingen GF, Seifert R, Pedersen EK, Schartum-Hansen H, Hjelmesaeth J, Nygard O. Association of body mass index with risk of acute myocardial infarction and mortality in Norwegian male and female patients with suspected stable angina pectoris: a prospective cohort study. BMC Cardiovasc Disord. 2014 May 21;14:68. doi: 10.1186/1471-2261-14-68.

  PMID: 24885137 DERIVED

• Midttun O, Townsend MK, Nygard O, Tworoger SS, Brennan P, Johansson M, Ueland PM. Most blood biomarkers related to vitamin status, one-carbon metabolism, and the kynurenine pathway show adequate preanalytical stability and within-person reproducibility to allow assessment of exposure or nutritional status in healthy women and cardiovascular patients. J Nutr. 2014 May;144(5):784-90. doi: 10.3945/jn.113.189738. Epub 2014 Mar 19.

  PMID: 24647388 DERIVED

• Strand E, Pedersen ER, Svingen GF, Schartum-Hansen H, Rebnord EW, Bjorndal B, Seifert R, Bohov P, Meyer K, Hiltunen JK, Nordrehaug JE, Nilsen DW, Berge RK, Nygard O. Dietary intake of n-3 long-chain polyunsaturated fatty acids and risk of myocardial infarction in coronary artery disease patients with or without diabetes mellitus: a prospective cohort study. BMC Med. 2013 Oct 8;11:216. doi: 10.1186/1741-7015-11-216.

  PMID: 24103380 DERIVED

• Loland KH, Bleie O, Strand E, Ueland PM, Nordrehaug JE, Garcia-Garcia HM, Serruys PW, Nygard O. Effect of folic acid supplementation on levels of circulating Monocyte Chemoattractant Protein-1 and the presence of intravascular ultrasound derived virtual histology thin-cap fibroatheromas in patients with stable angina pectoris. PLoS One. 2013 Jul 25;8(7):e70101. doi: 10.1371/journal.pone.0070101. Print 2013.

  PMID: 23936148 DERIVED

• Loland KH, Bleie O, Borgeraas H, Strand E, Ueland PM, Svardal A, Nordrehaug JE, Nygard O. The association between progression of atherosclerosis and the methylated amino acids asymmetric dimethylarginine and trimethyllysine. PLoS One. 2013 May 29;8(5):e64774. doi: 10.1371/journal.pone.0064774. Print 2013.

  PMID: 23734218 DERIVED

• Midttun O, Ulvik A, Ringdal Pedersen E, Ebbing M, Bleie O, Schartum-Hansen H, Nilsen RM, Nygard O, Ueland PM. Low plasma vitamin B-6 status affects metabolism through the kynurenine pathway in cardiovascular patients with systemic inflammation. J Nutr. 2011 Apr 1;141(4):611-7. doi: 10.3945/jn.110.133082. Epub 2011 Feb 10.

  PMID: 21310866 DERIVED

MeSH Terms

Conditions

Coronary Artery Disease; Myocardial Infarction; Stroke

Interventions

Folic Acid; Vitamin B 12; Vitamin B 6; Pyridoxine

Condition Hierarchy (Ancestors)

Coronary Disease; Myocardial Ischemia; Heart Diseases; Cardiovascular Diseases; Arteriosclerosis; Arterial Occlusive Diseases; Vascular Diseases; Infarction; Ischemia; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Necrosis; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases

Intervention Hierarchy (Ancestors)

Pterins; Pteridines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Corrinoids; Tetrapyrroles; Pyrroles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds, 4 or More Rings; Macrocyclic Compounds; Polycyclic Compounds; Picolines; Pyridines

Study Officials

• Ottar Nygård, MD, PhD

  Haukeland University Hospital

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: PREVENTION
• Intervention Model: FACTORIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 19, 2006
• First Posted: July 20, 2006
• Study Start: April 1, 1999
• Primary Completion: June 1, 2007
• Study Completion: February 1, 2008
• Last Updated: July 12, 2013

Record last verified: 2010-05

Locations

NO (2)