A Randomised Double Blind Study of the Effects of Homocysteine Lowering Therapy on Mortality and Cardiac Events in Patients Undergoing Coronary Angiography
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
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.
- Professor Jan Erik Nordrehaug, Chief of the Department of Heart Disease, Haukeland
- 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.
- 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,
- 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
- 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.
- 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.
Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Factorial Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Prevention
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
Ottar Nygård, MD, PhD
Haukeland University Hospital
Norway: Norwegian Medicines Agency