The Western Norway B-Vitamin Intervention Trial (WENBIT)

Ebbing M, Bleie Ø, Ueland PM, et al. Mortality and cardiovascular events in patients treated with homocysteine-lowering B vitamins after

coronary angiography. A randomized controlled trial. JAMA. 2008;300:795-804.

Folic Acid and Birth Defects

• About 2,500 neural tube defects per year in US• Occur at 26-28 days post-conception• 95% are spontaneous with no family history• 1991 UK study showed 71% risk reduction

in recurrences (4mg dose)• In 1999 (Nov NEJM) 85% reduction in risk for

primary prevention (0.4mg dose)• Lifetime costs estimated to be $532.000 (2001,

MOD)

Homocysteine

• Non-protein-forming, sulfur-containing amino acid

• Formed exclusively by demethylation of methionine

• Eliminated through one of two vitamin-dependent pathways, in addition to an alternate vitamin-independent pathway in liver

Hyperhomocystinemia• Independent risk factor for atherosclerotic and

thromboembolic disease• A 5 µM increase in serum level confers a 80% increased risk to

women and a 60% increased risk to men for atherosclerotic vascular disease

• In patients with coronary artery disease, serum homocysteine levels increase with the number of stenosed coronary vessels

• Hyperhomocystinemia may reflect: – Genetic defects– Folate (most common), pyridoxine (vitamin B6), or

cobalamin (vitamin B12) deficiencies– Renal failure

• Serum levels of homocysteine may be lowered by supplementation with folate, vitamin B6, and vitamin B12

DESIGN

• In this randomized, double-blind, controlled trial, 3096 adult participants undergoing coronary angiography (20.5% women; mean age, 61.7 years) were randomly selected.

• With use of 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 B12 (0.4 mg) and vitamin B6 (40 mg; n = 772);

• folic acid plus vitamin B12 (n = 772); • vitamin B6 alone (n = 772);• or placebo (n = 780).

BASELINE

• At baseline, • 59.3% had double- or triple-vessel disease,• 83.7% had stable angina pectoris, • and 14.9% had acute coronary syndromes.

The primary endpoint

• was a composite of all-cause death, nonfatal acute myocardial infarction, acute hospitalization for unstable angina pectoris, and nonfatal thromboembolic stroke.

The trial was terminated early Median follow-up was 38.4 months

NORVIT,• 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.

Mean plasma total homocysteine

• Mean plasma total homocysteine concentration was reduced by 30% after 1 year of treatment in the groups receiving folic acid and vitamin B12 (P < 0.01).

Secondary endpoints

• were fatal and nonfatal acute myocardial infarction, acute hospitalization for angina pectoris, stable angina pectoris with angiographically verified progression, myocardial revascularization procedures, and fatal and nonfatal stroke

Ebbing M et al. JAMA 2008; 300:795-804.

WENBIT: Percentage of patients with cardiovascular events

End point Folic acid+B12+B6 Folic acid+B12 B6 Placebo

Primary end point 12.2 16.3 13.7 12.5All-cause death 4.5 4.9 3.6 3.9Acute MI 7.7 9.9 7.1 7.4Unstable angina 2.9 3.8 3.1 3.5Nonfatal thromboembolic stroke

1.4 2.2 2.6 2.4

Cancer 6.0 5.1 4.9 4.0

There were no differences in treatment response for the separate endpoints of death, total acute myocardial infarction, or unstable angina. The incidence of total stroke was lower in the groups receiving folic acid; however, this observation was not statistically significant. The incidence of acute hospitalization for angina pectoris was lower in the folic acid groups, reaching borderline statistical significance (P = .05).

• The incidence of cancer was higher in the groups receiving folic acid; however, this finding was not statistically significant.

• There were no differences in the rates of adverse effects among the 4 intervention groups and no report of serious adverse events related to study medication.