WENBIT - Western Norway B Vitamin Intervention Trial

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

Interventions

DRUG

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

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

DRUG

folic acid, vitamin B12 (cyanocobalamin)

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

DRUG

vitamin B6 (pyridoxine)

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

DRUG

placebo

placebo, in a capsule, taken orally once a day

Sponsors & Collaborators

• The Research Council of Norway

  collaborator OTHER

• Norwegian Foundation for Health and Rehabilitation

  collaborator OTHER

• Norwegian Heart and Lung Patient Organisation

  collaborator UNKNOWN

• The Royal Norwegian Ministry of Health

  collaborator OTHER

• Locus for Homocysteine and Related Vitamins, University of Bergen, Norway

  collaborator OTHER

• Locus for Cardiac Research, University of Bergen, Norway

  collaborator OTHER

• Foundation to Promote Research into Functional Vitamin B12 Deficiency, Bergen, Norway

  collaborator OTHER

• Alpharma Pharmaceuticals LLC, a subsidiary of Pfizer Inc.

  collaborator INDUSTRY

• Haukeland University Hospital

  lead OTHER

Principal Investigators

• Ottar Nygård, MD, PhD · Haukeland University Hospital

Study Design

Allocation

RANDOMIZED

Purpose

PREVENTION

Masking

QUADRUPLE

Model

FACTORIAL

Eligibility

Min Age

18 Years

Sex

ALL

Healthy Volunteers

No

Timeline & Regulatory

Start

1999-04-30

Primary Completion

2007-06-30

Completion

2008-02-29

Countries

• Norway

Study Locations