Combined analyses and extended follow-up of two randomized controlled homocysteine-lowering B-vitamin trials.
OBJECTIVE
In the Norwegian Vitamin Trial and the Western Norway B Vitamin Intervention Trial, patients were randomly assigned to homocysteine-lowering B-vitamins or no such treatment. We investigated their effects on cardiovascular outcomes in the trial populations combined, during the trials and during an extended follow-up, and performed exploratory analyses to determine the usefulness of homocysteine as a predictor of cardiovascular outcomes.


METHODS
Pooling of data from two randomized controlled trials (1998-2005) with extended post-trial observational follow-up until 1 January 2008.


METHODS
Thirty-six hospitals in Norway.


METHODS
6837 patients with ischaemic heart disease.


METHODS
One capsule per day containing folic acid (0.8 mg) plus vitamin B12 (0.4 mg) and vitamin B6 (40 mg), or folic acid plus vitamin B12, or vitamin B6 alone or placebo.


METHODS
Major adverse cardiovascular events (MACEs; cardiovascular death, acute myocardial infarction or stroke) during the trials and cardiovascular mortality during the extended follow-up.


RESULTS
Folic acid plus vitamin B12 treatment lowered homocysteine levels by 25% but did not influence MACE incidence (hazard ratio, 1.07; 95% CI, 0.95-1.21) during 39 months of follow-up, or cardiovascular mortality (hazard ratio, 1.12; 95% CI, 0.95-1.31) during 78 months of follow-up, when compared to no such treatment. Baseline homocysteine level was not independently associated with study outcomes. However, homocysteine concentration measured after 1-2 months of folic acid plus vitamin B12 treatment was a strong predictor of MACEs.


CONCLUSIONS
We found no short- or long-term benefit of folic acid plus vitamin B12 on cardiovascular outcomes in patients with ischaemic heart disease. Our data suggest that cardiovascular risk prediction by plasma total homocysteine concentration may be confined to the homocysteine fraction that does not respond to B-vitamins.
Ebbing
M
M
Department of Heart Disease, Haukeland University Hospital, Bergen, Norway. marta.ebbing@helse-bergen.no
Bønaa
K H
KH
Arnesen
E
E
Ueland
P M
PM
Nordrehaug
J E
JE
Rasmussen
K
K
Njølstad
I
I
Nilsen
D W
DW
Refsum
H
H
Tverdal
A
A
Vollset
S E
SE
Schirmer
H
H
Bleie
Ø
Ø
Steigen
T
T
Midttun
Ø
Ø
Fredriksen
A
A
Pedersen
E R
ER
Nygård
O
O
D002214:Capsules; D004311:Double-Blind Method; D004338:Drug Combinations; D005260:Female; D005492:Folic Acid / Q000627:therapeutic use*; D006710:Homocysteine / Q000187:drug effects*; D006801:Humans; D008297:Male; D008875:Middle Aged; D015337:Multicenter Studies as Topic; D009203:Myocardial Infarction / Q000209:etiology; D017202:Myocardial Ischemia / Q000097:blood / Q000401:mortality / Q000517:prevention & control*; D010349:Patient Compliance; D016032:Randomized Controlled Trials as Topic; D012307:Risk Factors; D020521:Stroke / Q000209:etiology; D016896:Treatment Outcome; D014805:Vitamin B 12 / Q000627:therapeutic use*; D025101:Vitamin B 6 / Q000627:therapeutic use*; D014803:Vitamin B Complex / Q000627:therapeutic use*
D002214:Capsules; D004338:Drug Combinations; D006710:Homocysteine; D014803:Vitamin B Complex; D025101:Vitamin B 6; D005492:Folic Acid; D014805:Vitamin B 12