Western Norway B-Vitamin Intervention Trial - WENBIT

Oct 09, 2008
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Trial Sponsor:
Several non-profit organizations, and Alpharma Inc., Copenhagen, Denmark.
Date Presented:
01/01/2007
Date Published:
01/01/2008
Date Updated:
10/09/2008
Original Posted Date:
10/09/2008
References

Description:

Data from observational studies suggest a link between serum homocysteine concentration and coronary artery disease (CAD). The goal of the trial was to evaluate the long-term clinical effects of homocysteine-lowering treatment with folic acid and B vitamins among patients undergoing cardiac catheterization for suspected CAD.

Hypothesis:

Homocysteine-lowering with folic acid and B vitamins will be associated with a reduction in mortality and cardiovascular events in patients undergoing coronary angiography for suspected CAD or aortic valve stenosis.

Study Design

Study Design:

Patients Enrolled: 3,090
Mean Follow Up: Median: 38.4 months
Mean Patient Age: 62 years
Female: 21

Patient Populations:

Patients with and without significant CAD who have undergone coronary angiography immediately prior to inclusion

Exclusions:

  • Patients who have undergone coronary angiography for specific reasons (i.e., assessment for cardiac transplantation, kidney donor, heart donor, diagnostic assessment of cardiomyopathy)
  • Known active malignant disease
  • Known alcohol abuse or serious mental illness
  • Not available for follow-up

Primary Endpoints:

  • All-cause death
  • Nonfatal acute MI
  • Acute hospitalization for unstable angina
  • Nonfatal thromboembolic stroke

Secondary Endpoints:

  • Fatal and nonfatal acute MI
  • Acute hospitalization for angina
  • Stable angina with angiographic verified progression
  • Myocardial revascularization
  • Fatal and nonfatal thromboembolic stroke

Drug/Procedures Used:

Patients were randomized in a double-blind manner with a 2 x 2 factorial design to receive one of the following four treatments: 1) folic acid 0.8 mg plus vitamin B12 0.4 mg and vitamin B6 40 mg per day (n = 771), 2) folic acid 0.8 mg plus vitamin B12 0.4 mg per day (n = 769), 3) vitamin B6 40 mg per day (n = 771), or 4) placebo (n = 779).

Concomitant Medications:

Aspirin (90%), statins (89%), and beta-blockers (77%)

Principal Findings:

Baseline characteristics were fairly similar between the four groups. The majority (83.7%) of patients in the trial had stable angina, with 14.9% enrolled having an acute coronary syndrome and 1.4% having aortic valve stenosis. Single-vessel disease was present in 30% of patients, whereas three-vessel disease was noted in about 33% of the patients. Percutaneous coronary intervention was performed in 44% of patients and coronary artery bypass grafting in 24%.

Mean plasma total homocysteine levels decreased from 10.8 mmol/L at baseline to 7.6 mmol/L at the end of 1 year (30% decrease) in the folic acid groups, but did not change in the groups not treated with folic acid. The study drop-out rate was 18%. Follow-up was discontinued early after media reports raised concerns for patients following the release of the Norwegian Vitamin Trial (NORVIT), which showed no benefit with folic acid and vitamin B therapy in patients with ST-elevation myocardial infarction (MI), but a possible cancer risk.

There was no difference in the primary composite endpoint of death, MI, hospitalization for unstable angina, or stroke between the folic acid group and non-folic acid group (14.2% vs. 13.1%, p = 0.36), or the vitamin B6 group and the non-vitamin B6 group (13.0% vs. 14.3%, p = 0.28). All the other endpoints, including death, acute MI, unstable angina, and stroke were similar between the four groups, except acute hospitalization, which occurred less frequently in the folic acid group compared with the non-folic acid groups (hazard ratio 0.82; 95% confidence interval 0.67-1.00, p = 0.05).

The incidence of cancer was similar between the four groups.

Interpretation:

Among patients undergoing cardiac catheterization for suspected CAD, supplementation with homocysteine-lowering vitamin B and/or folic acid was not associated with a reduction in the composite of death, MI, hospitalization for unstable angina, or stroke at 3-year follow-up.

Findings in the WENBIT trial are similar to those of the NORVIT trial, which showed no benefit of vitamin B and folic acid in ST-elevation MI patients, and to those of the HOPE 2 trial, which showed no benefit of vitamin B and folic acid in patients with cardiovascular disease or diabetes. As with these other trials, homocysteine levels were reduced from baseline within the active treatment groups. However, the reduction in homocysteine levels did not translate into a change in clinical events, suggesting that while it is known from observational studies that elevated homocysteine is a marker for increased risk of cardiovascular events, it may not have a causal impact on the occurrence of such events.

Unlike NORVIT, there was no suggestion that cancer may be increased in the folic acid groups. Based on the totality of the randomized trial data to date, homocysteine lowering with vitamin B and folic acid supplementation does not appear to be an effective secondary prevention strategy for patients with coronary heart disease.

References:

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.

Presented by Dr. Marta Ebbing at the European Society of Cardiology Congress, September 2007, Vienna, Austria.

Keywords: Coronary Artery Disease, Myocardial Infarction, Stroke, Neoplasms, Acute Coronary Syndrome, Follow-Up Studies, Angina, Stable, Cardiac Catheterization, Vitamin B 12, Percutaneous Coronary Intervention, Homocysteine, Vitamin B 6, Secondary Prevention, Coronary Angiography, Folic Acid, Confidence Intervals, Coronary Artery Bypass, Diabetes Mellitus


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