Mortality and Cardiovascular Events in Patients Treated With Homocysteine-Lowering B Vitamins After Coronary Angiography

Department of Heart Disease, Haukeland University Hospital, Jonas Liesvei 65, 5021 Bergen, Norway.
JAMA The Journal of the American Medical Association (Impact Factor: 35.29). 09/2008; 300(7):795-804. DOI: 10.1001/jama.300.7.795
Source: PubMed


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.
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.
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.
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).
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.
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).
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. Identifier: NCT00354081.

Download full-text


Available from: Per M Ueland,
  • Source
    • "Of these patients, 2573 (62.0%) were enrolled in the Western Norway B Vitamin Intervention Trial (WENBIT) which studied the prognostic impact of B-vitamin supplementation upon incident CV events and mortality ( Identifier: NCT00354081) [11]. Patients for whom there was no BMI data (n = 3) were excluded from the study, as were underweight patients (BMI < 18.5 kg/m2) (n = 30).This left a total of 4131 subjects eligible for the analyses. "
    [Show abstract] [Hide abstract]
    ABSTRACT: BackgroundA number of previous studies have suggested that overweight or obese patients with coronary artery disease (CAD) may have lower morbidity and mortality than their leaner counterparts. Few studies have addressed possible gender differences, and the results are conflicting. We examined the association between body mass index (BMI) and risk of acute myocardial infarction (AMI), cardiovascular (CV) death and all-cause mortality in men and women with suspected stable angina pectoris.MethodThe cohort included 4164 patients with suspected stable angina undergoing elective coronary angiography between 2000 and 2004. Events were registered until the end of 2006. Hazard ratios (HR) (95% confidence intervals) were estimated using Cox regression by comparing normal weight (18.5-24.9 kg/m2) with overweight (25–29.9 kg/m2) and obese (≥30 kg/m2) patients. Underweight (<18.5 kg/m2) patients were excluded from the study.ResultsOf 4131 patients with complete data, 72% were males and 75% were diagnosed with significant CAD. The mean (standard deviation (SD)) age in the total population was 62 (10) years. Mean (SD) BMI was 26.8 (3.9) kg/m2, 34% was normal weight, 48% overweight and 19% obese. During follow up, a total of 337 (8.2%) experienced an AMI and 302 (7.3%) patients died, of whom 165 (4.0%) died from cardiovascular causes. We observed a significant interaction between BMI groups and gender with regards to risk of AMI (p = 0.011) and CV death (p = 0.031), but not to risk of all-cause mortality; obese men had a multivariate adjusted increased risk of AMI (HR 1.80 (1.28, 2.52)) and CV death (HR 1.60 (1.00, 2.55)) compared to normal weight men. By contrast, overweight women had a decreased risk of AMI (HR 0.56 (0.33, 0.98)) compared to normal weight women. The risk of all-cause mortality did not differ between BMI categories.ConclusionCompared with normal weight subjects, obese men had an increased risk of AMI and CV death, while overweight women had a decreased risk of AMI. These findings may potentially explain some of the result variation in previous studies reporting on the obesity paradox.Trial Identifier: NCT00354081
    BMC Cardiovascular Disorders 05/2014; 14(1):68. DOI:10.1186/1471-2261-14-68 · 1.88 Impact Factor
  • Source
    • "Similarly, apoe 2/2 mice fed methionine-rich, folate-deficient diet presented with an increased atherosclerotic lesion area [63]. However, supplementation with folate and other B vitamins failed to reduce the CVD risk in several large scale randomized controlled intervention trials in humans, despite successfully lowering plasma homocysteine levels [67] [68] [69] [70] [71]. It is worthwhile noting that these trials have been secondary prevention trials in patients that had a prior CVD history. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Folate is an essential B vitamin required for the maintenance of AdoMet-dependent methylation. The liver is responsible for many methylation reactions that are used for post-translational modification of proteins, methylation of DNA, and the synthesis of hormones, creatine, carnitine, and phosphatidylcholine. Conditions where methylation capacity is compromised, including folate deficiency, are associated with impaired phosphatidylcholine synthesis resulting in non-alcoholic fatty liver disease and steatohepatitis. In addition, folate intake and folate status have been associated with changes in the expression of genes involved in lipid metabolism, obesity, and metabolic syndrome. In this review, we provide insight on the relationship between folate and lipid metabolism, and an outlook for the future of lipid-related folate research. © 2013 BioFactors, 2013.
    BioFactors 05/2014; 40(3). DOI:10.1002/biof.1154 · 4.59 Impact Factor
  • Source
    • "These studies led to speculations that high homocysteine levels could contribute to atherosclerosis in at least three ways: (a) a direct toxic effect that damages the cells lining the inside of the arteries, (b) interference with clotting factors, and (c) oxidation of low-density lipoproteins (LDL). Without clinical trials, however, it was impossible to know whether abnormal homocysteine levels among the general population cause atherosclerosis or is merely a "marker"—a non-causative finding that often occurs in people with atherosclerosis (Toole et al., 2004; Bønaa et al., 2006; Albert et al., 2008; Ebbing et al., 2008; SEARCH Collaborative Group 2010). Plasma tHcy status and its determinants have been studied extensively in developed countries but seldom in developing countries (Selhub et al., 1999; Kim et al., 2003; Must et al., 2003; Jacques et al., 1999). "

Show more