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Combined Analyses and Long-term Follow-up in the Two Norwegian Homocysteine-Lowering B-Vitamin Trials NORVIT and WENBIT

27 Years
86 Years
Open (Enrolling)
Cancer, Myocardial Infarction, Cerebrovascular Stroke

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Trial Information

Combined Analyses and Long-term Follow-up in the Two Norwegian Homocysteine-Lowering B-Vitamin Trials NORVIT and WENBIT

The "homocysteine-hypothesis" of vascular disease has attracted considerable interest, as
total plasma homocysteine levels can be easily lowered by folic acid and vitamin B12,
raising the prospect that cardiovascular disease could be lowered by such B-vitamin

Two large B-vitamin intervention trials have been performed in Norway during the period 1998
to 2005, NORVIT and WENBIT, both registered at, identifiers NCT00266487
and NCT00354081, respectively. The main objective in these trials was to study the effects
of homocysteine-lowering therapy with folic acid and vitamin B12 to reduce the risk of
cardiovascular events in patients with established coronary artery disease. The B-vitamin
intervention, which included vitamin B6 in a 2x2 factorial design, was identical in the two
trials. Follow-up was terminated for NORVIT on March 31st 2004 and for WENBIT October 5th
2005. Results from the NORVIT trial was published April 2006 {Bonaa, 2006} and preliminary
results from the WENBIT trial were presented at the annual congress of the European Society
of Cardiology September 4th 2007 {Zegers, 2007}. The WENBIT trial is completed and submitted
for publication early in year 2008.

So far, none of the B-vitamin intervention trials have shown any statistically significant
favourable effect of homocysteine-lowering therapy with folic acid with or without
concomitant vitamin B12 on cardiovascular events {Bazzano, 2006}. In NORVIT there was even a
trend towards an increased risk of cardiovascular events (myocardial infarctions) in
patients receiving the combination of folic acid, vitamin B12 and vitamin B6. This trend was
not observed in WENBIT. Thus, the "homocysteine-hypothesis" of vascular disease has been
attenuated through the emergence of these negative trial results. There is still some
evidence that folic acid might prevent strokes, and there has been a call for meta-analyses
when several large ongoing trials are completed {Clarke, 2007}.

There is so far no data on possible long-term effects following years of B-vitamin
supplementation. By combining analyses and follow-up in the NORVIT and WENBIT cohorts, we
will probably have some more answers both considering possible subgroup and long-term
effects of the B-vitamin intervention.

Current data indicate that folate prevents cancer, especially breast and colorectal cancer.
However, during the last few years several reports have challenged this assumption. Swedish
observational studies found increased risk of colorectal cancer at high blood folate levels
{Van Guelpen, 2006} and increased risk of prostate cancer at high levels of folate and
vitamin B12 {Hultdin, 2005}. In a randomised trial with folic acid versus placebo to prevent
colorectal adenomas, one found increased risk of cancer in the group receiving folic acid,
especially of prostate cancer {Cole, 2007}. In a long-term follow-up of women taking high
doses of folic acid throughout pregnancy one found a doubled risk of deaths attributable to
breast cancer {Charles, 2004}. Recently it has been hypothesized that the implementation of
folic acid fortification of foods may have been wholly or partly responsible for the
observed increase in colorectal cancer rates in the USA and Canada in the mid to late 1990s
{Mason, 2007}. This has led to new hypotheses that folate may prevent carcinogenesis but may
enhance the growth of established cancer cells {Ulrich, 2007}. The question of possible
adverse effects of folic acid supplementation will be of major importance when public health
administrations decide whether to implement or enhance programs folic acid fortification of

Inclusion Criteria:

- Randomised in the Norwegian Vitamin Trial (NORVIT) or in the Western Norway B-Vitamin
Intervention Trial (WENBIT)

Exclusion Criteria:

- Withdrawn consent to participate in study cohort for post-trial observational

Type of Study:


Study Design:

Observational Model: Cohort, Time Perspective: Prospective

Outcome Measure:

Possible effects of B-vitamin treatment on risk of developing cancer during the trial periods (completed by 2004 and 2005) and during post-trial follow-up.

Outcome Time Frame:


Safety Issue:


Principal Investigator

Marta Ebbing, MD, PhD

Investigator Role:

Study Chair

Investigator Affiliation:

Department of Heart Disease, Haukeland University Hospital


Norway: Norwegian Social Science Data Services (NSD)

Study ID:




Start Date:

December 1998

Completion Date:

January 2015

Related Keywords:

  • Cancer
  • Myocardial Infarction
  • Cerebrovascular Stroke
  • Cancer
  • Coronary artery disease
  • Myocardial infarction
  • Cerebrovascular stroke
  • Homocysteine
  • Vitamin B Complex
  • Folic acid
  • Vitamin B12
  • Vitamin B6
  • Pyridoxal phosphate
  • Infarction
  • Myocardial Infarction
  • Stroke
  • Cerebral Infarction