WENBIT - Western Norway B Vitamin Intervention Trial
WENBIT - Western Norway B Vitamin Intervention Trial
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.
BACKGROUND Coronary artery disease (CAD) is one of our common diseases, and despite the
 decline in mortality from acute coronary syndromes in the Western world, CAD remains the most
 important cause of death in Norway.

 HOMOCYSTEINE Homocysteine (Hcy) is an amino acid and total homocysteine (tHcy) is the sum of
 several different forms of Hcy that is present in blood, usually measured in serum or plasma.
 A population-based study of plasma tHcy in 18,043 individuals in Hordaland, Norway
 demonstrated that plasma tHcy usually is between 5 and 15 micromol/L, is higher in men than
 in women and increases with age [Nygård, et al., 1995].

 FOLIC ACID The most common cause of elevated tHcy is low intake of folic acid (a B vitamin)
 that occurs in many fruits, vegetables, liver products, milk, and bread. Vitamin supplements
 that are sold without prescription commonly contain folic acid (0.1 or 0.2 mg in Norway, 0.4
 or 0.8 mg in other countries). In the United States and United Kingdom many food products are
 fortified with folic acid. The Food and Drug administration in the United States has made
 fortification with folic acid mandatory for some products from 1998. The rationale for this
 policy is to reduce the occurrence of neural tube defects, a class of serious congenital
 malformations. Several studies have also shown a direct relation between serum folic acid and
 coronary heart disease.

 MODERATELY ELEVATED tHcy AND CARDIOVASCULAR DISEASE More than twenty retrospective and three
 prospective studies, including two Norwegian [Nygård, et al., 1997], over the past twenty
 years have demonstrated a relation between tHcy measured in serum or plasma and coronary
 heart disease, peripheral artery disease or stroke [Boushey, et al., 1995, Ueland, et al.,
 1992]. The meta-analysis performed by Boushey et al [Boushey, et al., 1995] estimated that a
 5 micromol/L difference in tHcy increase the risk of coronary artery disease with 60%. Common
 causes of moderately elevated tHcy include nutritional deficiency of folic acid, vitamin B6
 and B12, genetic variation in genes coding key enzymes of the Hcy metabolism (e.g.,
 thermolabile MTHFR) and, as demonstrated in the Hordaland Homocysteine Study [Nygård, et al.,
 1995], life-style factors as smoking, coffee drinking and exercise.

 VITAMIN THERAPY A common feature of most individuals with elevated tHcy is responsiveness to
 folic acid therapy. One exception is vitamin B12 deficiency that needs to be corrected with
 appropriate therapy. A recent meta-analysis shows that the mean tHcy lowering effect of folic
 acid at doses 0.5-5.0 mg/day is 25% at tHcy levels of 12 micromol/L [Homocysteine Lowering
 Trialists' Collaboration, 1998 #1892]. The study further shows that the absolute and
 percentage reduction in tHcy is higher in subjects with higher tHcy levels and particular low
 folic acid concentrations. Moreover, additional daily oral therapy with 0,5 mg B12 seems to
 have a small but significant additional tHcy lowering effect whereas vitamin B6 at a mean
 dose of 16,5 mg daily has no effect on basal tHcy levels.

 RANDOMIZED TRIALS WITH FOLIC ACID There is solid evidence that tHcy is associated with
 cardiovascular disease. We know that tHcy is easily lowered by folic acid in most patients,
 but we cannot know that folic acid will prevent cardiovascular disease or complications of
 such disease until randomized double-blind trials are carried out. The only possible problem
 with folic acid is that it may correct the anemia, but not the neuropathy, of vitamin B12
 deficiency. This necessitates careful screening for B12 deficiency or combining folic acid
 with B12 in a sufficient oral dose to treat an occasional pernicious anemia.

 RANDOMIZED TRIALS WITH VITAMIN B6 Data from several studies show that inappropriate vitamin
 B6 status is a strong risk factor for cardiovascular disease and that this increased risk
 probably is independent of tHcy levels. Thus, commonly applied tHcy lowering regimens
 combining folic acid and vitamin B6 can not be applied to test the homocysteine theory of
 atherosclerosis.

 HOMOCYSTEINE AND VITAMIN MEASUREMENTS Determination of tHcy and associated amino acids and B
 vitamins will be performed at the Department of Pharmacology of the University of Bergen.
 These analyses will be done on all patients at randomization and at follow-up after 1 month
 and 1 year, and will both serve as monitoring of compliance and also give the possibility to
 relate clinical events to, for example, the amount of reduction in plasma tHcy.

 STEERING COMITTEE

 -  Professor Jan Erik Nordrehaug, Chief of the Department of Heart Disease, Haukeland
 University Hospital.

 -  Professors Helga Refsum, Per Magne Ueland and Stein Emil Vollset at Locus of
 Homocysteine and Related B vitamins, University of Bergen.

 -  Professor Ottar Nygård, Department of Heart Disease, Haukeland University Hospital, and
 Locus of Homocysteine and Related B vitamins.

 -  Professor Dennis W Nilsen, Section of Heart Disease, Stavanger University Hospital

 DATA OWNERSHIP AND PUBLICATION OF RESULTS All data collected specifically for the study are
 owned by WENBIT. Data that are already recorded according to routine procedures at the
 participating centers, are owned by the center or department delivering the data and by
 WENBIT. The WENBIT Steering Committee has the disposal of all data registered in the WENBIT
 database, and any use of these data including the preparation and publication of scientific
 reports must be approved by The Steering Committee. Scientific articles will be published by
 WENBIT or by authors mentioned by name. The author sequence should be approved by the
 Steering Committee and based upon contribution. Incentives to involve articles as part of
 doctoral thesis should be encouraged. All collaborators of the study will be mentioned by
 name in an Appendix section of the main article from the study. The results will be published
 in peer-reviewed scientific journals and in magazines for the general public.

 LITERATURE

 -  Boushey CJ, Beresford SAA, Omenn GS, Motulsky AG. A quantitative assessment of plasma
 homocysteine as a risk factor for vascular disease: Probable benefits of increasing
 folic acid intakes. JAMA 1995;274:1049-1057.

 -  NORVIT Protocol September 1998, Institute of Community Medicine, University of Tromsø,
 Norway

 -  Nygård O, Nordrehaug JE, Refsum H, Farstad M, Ueland PM, Vollset SE. Plasma homocysteine
 levels and mortality in patients with coronary artery disease. N Engl J Med
 1997;337:230-236.

 -  Nygård O, Vollset SE, Refsum H, Stensvold I, Tverdal A, Nordrehaug JE, et al. Total
 plasma homocysteine and cardiovascular risk profile. The Hordaland Homocysteine Study.
 JAMA 1995;274:1526-1533.

 -  Ueland PM, Refsum H, Brattström L. Plasma homocysteine and cardiovascular disease. In:
 Francis RBJ, ed. Atherosclerotic Cardiovascular Disease, Hemostasis, and Endothelial
 Function. New York: Marcel Dekker, inc.; 1992:183-236.
Inclusion Criteria:

 -  adults ≥ 18 years able to give informed consent

 -  patients prepared to undergo long-term follow-up

 -  patients with and without significant coronary artery disease (CAD) who have undergone
 coronary angiography just before inclusion

 Exclusion Criteria:

 -  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