Mortality and cardiovascular events in patients treated with homocysteine-lowering B vitamins after coronary angiography: a randomized controlled trial.
BACKGROUND
Observational studies have reported associations between circulating total homocysteine concentration and risk of cardiovascular disease. Oral administration of folic acid and vitamin B(12) can lower plasma total homocysteine levels.


OBJECTIVE
To assess the effect of treatment with folic acid and vitamin B(12) and the effect of treatment with vitamin B(6) as secondary prevention in patients with coronary artery disease or aortic valve stenosis.


METHODS
Randomized, double-blind controlled trial conducted in the 2 university hospitals in western Norway in 1999-2006. A total of 3096 adult participants undergoing coronary angiography (20.5% female; mean age, 61.7 years) were randomized. At baseline, 59.3% had double- or triple-vessel disease, 83.7% had stable angina pectoris, and 14.9% had acute coronary syndromes.


METHODS
Using a 2 x 2 factorial design, participants were randomly assigned to 1 of 4 groups receiving daily oral treatment with folic acid, 0.8 mg, plus vitamin B(12), 0.4 mg, plus vitamin B(6), 40 mg (n = 772); folic acid plus vitamin B(12) (n = 772); vitamin B(6) alone (n = 772); or placebo (n = 780).


METHODS
The primary end point was a composite of all-cause death, nonfatal acute myocardial infarction, acute hospitalization for unstable angina pectoris, and nonfatal thromboembolic stroke.


RESULTS
Mean plasma total homocysteine concentration was reduced by 30% after 1 year of treatment in the groups receiving folic acid and vitamin B(12). The trial was terminated early because of concern among participants due to preliminary results from a contemporaneous Norwegian trial suggesting adverse effects from the intervention. During a median 38 months of follow-up, the primary end point was experienced by a total of 422 participants (13.7%): 219 participants (14.2%) receiving folic acid/vitamin B(12) vs 203 (13.1%) not receiving such treatment (hazard ratio, 1.09; 95% confidence interval, 0.90-1.32; P = .36) and 200 participants (13.0%) receiving vitamin B(6) vs 222 (14.3%) not receiving vitamin B(6) (hazard ratio, 0.90; 95% confidence interval, 0.74-1.09; P = .28).


CONCLUSIONS
This trial did not find an effect of treatment with folic acid/vitamin B(12) or vitamin B(6) on total mortality or cardiovascular events. Our findings do not support the use of B vitamins as secondary prevention in patients with coronary artery disease.


BACKGROUND
clinicaltrials.gov Identifier: NCT00354081.
Ebbing
Marta
M
Department of Heart Disease, Haukeland University Hospital, Jonas Liesvei 65, 5021 Bergen, Norway. marta.ebbing@helse-bergen.no
Bleie
Øyvind
Ø
Ueland
Per Magne
PM
Nordrehaug
Jan Erik
JE
Nilsen
Dennis W
DW
Vollset
Stein Emil
SE
Refsum
Helga
H
Pedersen
Eva Kristine Ringdal
EK
Nygård
Ottar
O
D000368:Aged; D001024:Aortic Valve Stenosis / Q000097:blood* / Q000517:prevention & control*; D002318:Cardiovascular Diseases / Q000097:blood / Q000401:mortality; D017023:Coronary Angiography; D003324:Coronary Artery Disease / Q000097:blood* / Q000517:prevention & control*; D004311:Double-Blind Method; D005260:Female; D005492:Folic Acid / Q000097:blood / Q000627:therapeutic use*; D006710:Homocysteine / Q000097:blood*; D006801:Humans; D008297:Male; D008875:Middle Aged; D012306:Risk; D014805:Vitamin B 12 / Q000097:blood / Q000627:therapeutic use*; D025101:Vitamin B 6 / Q000097:blood / Q000627:therapeutic use*; D014803:Vitamin B Complex / Q000097:blood / Q000627:therapeutic use*
D006710:Homocysteine; D014803:Vitamin B Complex; D025101:Vitamin B 6; D005492:Folic Acid; D014805:Vitamin B 12