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. 2017 Aug 17;2017(8):CD006612. doi: 10.1002/14651858.CD006612.pub5

WENBIT 2008.

Study characteristics
Methods Parallel design
Multicentre study
Country: Norway
Follow‐up period: 4 years
Participants 3096 patients randomised (folic acid, vitamins B6 and B12: 772 versus folic acid, vitamin B12: 772 versus vitamin B6: 772 versus placebo: 780)
Gender (% men):

  1. Folic acid, vitamins B6 and B12: 81.2%

  2. Folic acid, vitamin B12: 80.4%

  3. Vitamin B6: 80.2%

  4. Placebo: 76.5%


Age (mean SD, years):

  1. Folic acid, vitamins B6 and B12: 61.7 (10.3)

  2. Folic acid, vitamin B12: 61.3 (10.0)

  3. Vitamin B6: 61.4 ( 9.7)

  4. Placebo: 62.0 (9.9)


Inclusion criteria:

  1. Age: 18 years or older

  2. Undergoing coronary angiography for suspected CAD and/or aortic valve stenosis at the 2 university hospitals in western Norway


Exclusion criteria:

  1. Unavailability for follow‐up

  2. Participation in other trials

  3. History of alcohol abuse, serious mental illness or cancer
Interventions Intervention:

  1. Folic acid (group 1): 0.8 mg; vitamin B12: 0.4 mg; vitamin B6: 40 mg per day

  2. Folic acid (group 2): 0.8 mg; vitamin B12: 0.4 mg per day

  3. Vitamin B6 (group 3): 40 mg per day


Control: placebo
Co‐interventions: statins, insulin, aspirin, clopidogrel, beta‐blockers, ACE inhibitors/ARBs, calcium channel blockers, loop diuretics, oral antidiabetics, medication for chronic obstructive pulmonary disease
Duration of treatment: not described
Outcomes Primary outcome (composite):

  1. All‐cause death, non‐fatal acute MI, acute hospitalisation for unstable angina pectoris and non‐fatal thromboembolic stroke


Secondary outcomes:

  1. Acute MI

  2. Acute hospitalisation for angina pectoris

  3. Stable angina pectoris with angiographically verified progression

  4. Myocardial revascularisation procedures

  5. Stroke

  6. Incident cases of cancer
Notes

  1. Study phase: III, registered (ClinicalTrials.gov number NCT00354081)

  2. A priori sample size estimation: sample of 3088 participants to detect a 20% reduction in the primary endpoint during 4 years of follow‐up with a statistical power of 80% at a 2‐sided significance level of 0.05

  3. Sponsors: the Advanced Research Program and Research Council of Norway, the Norwegian Foundation for Health and Rehabilitation, the Norwegian Heart and Lung Patient Organisation, the Norwegian Ministry of Health and Care Services, the Western Norway Regional Health Authority, the Department of Heart Disease at Haukeland University Hospital, Locus for Homocysteine and Related Vitamins at the University of Bergen, Locus for Cardiac Research at the University of Bergen, the Foundation to Promote Research Into Functional Vitamin B12 Deficiency, Bergen, Norway, and Alpharma Inc, Copenhagen, Denmark

  4. The study medication was provide by Alpharma, which had no access to study data and did not participate in data analysis or interpretation, or in the preparation, review or approval of the manuscript

  5. Other: the first 90 participants were randomised before undergoing angiography in order to ensure no effects on blood indexes from the invasive procedure. Subsequent participants were randomised after baseline angiography

  6. This trial was stopped due to no beneficial effects and a suggested increased risk of cancer from B vitamin treatment
Risk of bias
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Unclear risk 2 x 2 factorial design with block randomisation, with a block size of 20
Allocation concealment (selection bias) Low risk Centralised independently by the manufacturer (Alpharma)
Study nurses received coded boxes provided to participants in numerical order. The codes were kept by the manufacturer until eligibility data were complete
Blinding of participants and personnel (performance bias)
All outcomes Low risk Vitamins were manufactured to be indistinguishable in colour, weight or ability to be dissolved in water. Endpoints adjudicated by an independent committee unaware of patient's assignment
Blinding of outcome assessment (detection bias)
All outcomes Low risk Quote: "end‐points committees were unaware of the treatment allocation"
Incomplete outcome data (attrition bias)
All outcomes High risk 6 patients (0.2% from the sample) withdrew consent to participate in the trial and were excluded from the analysis. Due to the media impact of the NORVIT interim results 692 patients were asked to stop the medication; outcome data available for 86% of patients at the final visit
Selective reporting (reporting bias) Low risk The study protocol is not available but it is clear that the published reports include all expected outcomes, including those that were pre‐specified
Other bias Low risk Other sources of bias not identified

ACE: angiotensin‐converting enzyme
ARB: angiotensin receptor blockers
CAD: coronary artery disease
CHD: coronary heart disease
CK‐MB: creatine kinase‐MB
CVD: cardiovascular disease
ECG: electrocardiogram
HLI: homocysteine‐lowering interventions
IQR: interquartile range
ITT: intention‐to‐treat
IU: international units
MI: myocardial infarction
RCT: randomised controlled trial
SD: standard deviation
t‐Hcy: total homocysteine