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Original Contribution |

Mortality and Cardiovascular Events in Patients Treated With Homocysteine-Lowering B Vitamins After Coronary Angiography:  A Randomized Controlled Trial FREE

Marta Ebbing, MD; Øyvind Bleie, MD, PhD; Per Magne Ueland, MD, PhD; Jan Erik Nordrehaug, MD, PhD; Dennis W. Nilsen, MD, PhD; Stein Emil Vollset, MD, DrPH; Helga Refsum, MD, PhD; Eva Kristine Ringdal Pedersen, MD; Ottar Nygård, MD, PhD
[+] Author Affiliations

Author Affiliations: Department of Heart Disease, Haukeland University Hospital (Drs Ebbing, Bleie, Nordrehaug, and Nygård), Sections for Pharmacology (Dr Ueland) and Cardiology (Drs Nordrehaug, Nilsen, Ringdal Pedersen, and Nygård), Institute of Medicine, University of Bergen and Haukeland University Hospital, and Department of Public Health and Primary Health Care, University of Bergen (Dr Vollset), Bergen, Norway; Department of Cardiology, Stavanger University Hospital, Stavanger, Norway (Dr Nilsen); Department of Nutrition, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway (Dr Refsum); and Department of Physiology, Anatomy, and Genetics, University of Oxford, Oxford, England (Dr Refsum).


JAMA. 2008;300(7):795-804. doi:10.1001/jama.300.7.795.
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Published online

Context Observational studies have reported associations between circulating total homocysteine concentration and risk of cardiovascular disease. Oral administration of folic acid and vitamin B12 can lower plasma total homocysteine levels.

Objective To assess the effect of treatment with folic acid and vitamin B12 and the effect of treatment with vitamin B6 as secondary prevention in patients with coronary artery disease or aortic valve stenosis.

Design, Setting, and Participants 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.

Interventions Using a 2 × 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, plus vitamin B6, 40 mg (n = 772); folic acid plus vitamin B12 (n = 772); vitamin B6 alone (n = 772); or placebo (n = 780).

Main Outcome Measures 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 B12. 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 B12 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 B6 vs 222 (14.3%) not receiving vitamin B6 (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 B12 or vitamin B6 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.

Trial Registration clinicaltrials.gov Identifier: NCT00354081

Figures in this Article

Observational studies have demonstrated that the concentration of total homocysteine in blood is associated with risk of coronary artery disease (CAD) and stroke.1,2 In prospective cohort studies from western Norway, plasma total homocysteine concentration was found to be a strong predictor of mortality both in patients with CAD3 and those with aortic valve stenosis.4 Because plasma total homocysteine levels can be easily lowered by oral administration of folic acid, trials to investigate whether cardiovascular disease (CVD) could be prevented by such homocysteine-lowering therapy were called for. Furthermore, observational studies have found inverse associations between vitamin B6 intake and risk of future CAD5 and between circulating vitamin B6 concentration and risk of CVD, independent of plasma total homocysteine concentration.6

Since the late 1990s, a series of secondary prevention trials with folic acid, either alone or in combination with vitamin B12 and/or vitamin B6, were initiated in cardiovascular and chronic kidney disease patients.7 So far, none of the larger published trials has reported any effect of homocysteine lowering on risk of cardiovascular disease or total mortality.810 One smaller trial in patients undergoing percutaneous coronary intervention (PCI) found a reduced rate of target lesion revascularization in patients receiving a combination of folic acid, vitamin B12, and vitamin B611 while another similar trial found an increased risk of in-stent restenosis and need for target vessel revascularization following B vitamin treatment.12

In 1998, mandatory folic acid fortification of foods was implemented in the United States and Canada with a primary objective of preventing neural tube defects.13 Circulating folate concentrations substantially increased and plasma total homocysteine concentrations decreased in the North American population following the fortification.13 This change has been linked to an accelerated decline in stroke mortality observed in the United States and Canada from 1998 to 2002 compared with stroke mortality in England and Wales, where folic acid fortification is not mandatory.14

The Western Norway B Vitamin Intervention Trial (WENBIT) is a prospective, randomized, double-blind, placebo-controlled secondary prevention study of the clinical effects of B vitamin treatment in patients having undergone coronary angiography for suspected CAD or aortic valve stenosis. Our main purpose was to evaluate the effects of homocysteine-lowering treatment with folic acid plus vitamin B12 on mortality and cardiovascular events. The 2 × 2 factorial study design also allowed separate assessment of effects of vitamin B6 treatment.

Participants

Patients eligible for randomization were men and women aged 18 years or older undergoing coronary angiography for suspected CAD and/or aortic valve stenosis at the 2 university hospitals in western Norway. Exclusion criteria were unavailability for follow-up, participation in other trials, known alcohol abuse, serious mental illness, or cancer.

During the main recruitment period at Haukeland University Hospital, Bergen, Norway (January 2000–April 2004), and the recruitment period at Stavanger University Hospital, Stavanger, Norway (September 2000–April 2004), a total of 5630 patients underwent coronary angiography for stable angina pectoris, 4216 for acute coronary syndromes, and 395 for aortic valve stenosis. For capacity reasons, not all of these possibly eligible patients were consecutively screened.

Patients were informed about the trial at the routine clinical interview and examination before baseline coronary angiography. The first 90 participants in the trial, recruited to the WENBIT-90 substudy,15,16 were randomized before undergoing angiography to ensure no effects on blood indexes from the invasive procedure. Subsequent participants were randomized after baseline angiography. Written informed consent was obtained on the day of randomization. The study protocol was in accordance with the principles of the Declaration of Helsinki and the trial was approved by the Regional Committee for Medical and Health Research Ethics, the Norwegian Medicines Agency, and the Data Inspectorate.

Study Intervention

Participants were randomly assigned, using a 2 × 2 factorial design, to 1 of 4 groups receiving a daily oral dose of 1 of the following treatments: (1) folic acid, 0.8 mg, plus vitamin B12 (cyanocobalamin), 0.4 mg, and vitamin B6 (pyridoxine), 40 mg; (2) folic acid, 0.8 mg, plus vitamin B12, 0.4 mg; (3) vitamin B6, 40 mg; or (4) placebo. Treatment with folic acid was expected to lower plasma total homocysteine concentration by 23% to 28%.2 Vitamin B12 was added to folic acid mainly to prevent possible masking of vitamin B12 deficiency by folic acid but also to further lower plasma total homocysteine concentration by 3% to 10%.2 The study medication (Alpharma Inc, Copenhagen, Denmark) was given in a single capsule. For the first 2 weeks after randomization, the groups allocated to receive folic acid were provided with an extra capsule with a loading dose of 5 mg of folic acid per day, while the other groups were provided with an extra capsule of placebo. The randomization sequence was generated in blocks of 20 by Alpharma Inc, and study nurses assigned boxes of study capsules to participants in numerical order. The different capsules were indistinguishable by color, weight, or ability to dissolve in water. Participants, study and laboratory personnel, and the steering and end-points committees were unaware of the treatment allocation, and the randomization code was kept at Alpharma Inc until data entry was completed.

Participants were requested to abstain from taking supplements containing B vitamins. They were given conventional medical treatment and underwent myocardial revascularization procedures and/or valve surgery at the discretion of the treating physician.

Baseline and Follow-up Evaluations

Demographic, clinical, and routine laboratory data were obtained by study personnel. Participants were scheduled for follow-up visits with an interview, a clinical examination, and blood sampling at 1 month, at 1 year, and at a final study visit. Planned median follow-up time was 4 years. If unable or unwilling to attend study visits, participants were interviewed by telephone or by letter.

Adherence was judged by capsule counts and interviews. Participants were asked about hospital admissions, and copies of hospital records were retrieved by mail. In addition, archives of the hospitals in western Norway were searched for information on all participants' hospital admissions, and copies of records on possible events were collected. Data on deaths were obtained from the Cause of Death Registry and on incident cancer from the Cancer Registry in Norway, using the Norwegian unique 11-digit person number for each participant.

Trial Outcomes

The primary clinical end point was a composite of all-cause death, nonfatal acute myocardial infarction (AMI), acute hospitalization for unstable angina pectoris, and nonfatal thromboembolic stroke (infarction). Secondary end points were fatal and nonfatal AMI, acute hospitalization for angina pectoris, stable angina pectoris with angiographically verified progression, myocardial revascularization procedures, and fatal and nonfatal stroke. Incident cases of newly diagnosed cancer, except basal cell carcinoma, were recorded as a measure of safety.

If death occurred within 28 days after the onset of an event, the event was classified as fatal. Acute MIs were classified according to the diagnostic criteria of the revised definition of MI published in 200017 and strokes according to definitions published in 2001.18 Procedure-related nonfatal AMIs within 24 hours after coronary angiography, after PCI, or after coronary artery bypass grafting (CABG) were not included in the primary end point but were in the secondary end point. Events of unstable angina pectoris were classified as primary end points if patients were urgently admitted to the hospital because of acute onset of typical ischemic symptoms accompanied by electrocardiographic ST-T findings of myocardial ischemia at rest and/or accompanied by coronary angiography during the same hospital stay verifying significant progression of CAD.18 Events of worsened but not unstable angina pectoris with angiographically verified significant progression of CAD were classified as secondary end points. Nonfatal hemorrhagic strokes were not included in the primary end point but were in the secondary end point. Myocardial revascularization procedures as determined by baseline angiography were not included in the secondary end point. All events were adjudicated by members of the end-points committee.

Laboratory Analysis

Blood samples obtained at baseline and during follow-up were collected and processed by study personnel. Routine blood analyses were performed by the hospital laboratories. Glomerular filtration rates were estimated by the 4-variable Modification of Diet in Renal Disease equations.19 Low-density lipoprotein cholesterol was calculated using the Friedewald formula. Blood samples for assessment of B vitamins and total homocysteine were stored at –80°C until analyzed in the laboratory of Bevital AS, Bergen, Norway, by published methods.2023 Results from follow-up measurements of B vitamins and total homocysteine were not disclosed to study personnel or the end-points committee until the randomization code was broken.

Statistical Analysis

The 2 × 2 factorial design allowed separate assessments of effects from the folic acid plus vitamin B12 and the vitamin B6 interventions. Because we anticipated no effect modification by vitamin B6 on the effect of folic acid plus vitamin B12, we ignored the secondary factor (vitamin B6) in the sample size calculations. Using data from a cohort of patients with CAD in western Norway in 1991-19923 and accounting for the effects of more widespread use of lipid-lowering treatment since the mid-1990s, we estimated a 4-year mortality rate of 7.5% and a total 4-year event rate (fatal and nonfatal events) of 22% in the placebo group. We expected that a 30% reduction in plasma total homocysteine concentration in the groups allocated to folic acid plus vitamin B12 would give an event rate reduction of 20% in these groups compared with the groups allocated to no treatment with folic acid/vitamin B12. Furthermore, we assumed a combined withdrawal and nonadherence rate of 20%. Thus, we calculated that a sample size of 3088 participants would be needed to detect a 20% reduction in the primary end point during 4 years of follow-up with a statistical power of 80% at a 2-sided significance level of .05.

Differences between intervention groups were tested using the χ2 test for categorical variables and the t test or analysis of variance for continuous variables. The prespecified analyses were comparison of treatment effect of folic acid plus vitamin B12 (groups 1 and 2) with control (groups 3 and 4) and comparison of treatment effect of vitamin B6 (groups 1 and 3) with control (groups 2 and 4), according to the 2 × 2 factorial study design. We also performed a post hoc overall comparison of treatment effect of the 3 different vitamin interventions with that of placebo. For each participant, only the first of events in the composite primary or secondary end points was included in the survival analyses. Survival curves were constructed using the Kaplan-Meier method, and the differences in survival between groups were analyzed by the log-rank test. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox proportional hazard regression with separate assessment for the folic acid plus vitamin B12 groups vs control and the vitamin B6 groups vs control. All analyses were performed according to the intention-to-treat principle. We also conducted a per-protocol analysis for the primary end point. Reported P values are 2-sided and unadjusted for multiple comparisons, and P<.05 was regarded as statistically significant. We used the statistical software packages SPSS for Windows, version 15.0 (SPSS Inc, Chicago, Illinois), and S-PLUS, version 7.0 (Insightful Corp, Seattle, Washington).

From April 1999 to April 2004, a total of 3096 patients were randomized (Figure 1). In 1999, recruitment was limited to 90 patients for the WENBIT-90 substudy.15,16 Six participants withdrew consent immediately after randomization without having started study medication and were excluded from further analyses. Thus, the study population consisted of 3090 patients, of which 2121 (68.6%) were randomized at Haukeland University Hospital and 969 (31.4%) at Stavanger University Hospital. Reasons for referral to baseline angiography were stable angina pectoris (n = 2585 [83.7%]), acute coronary syndromes (n = 461 [14.9%]), and aortic valve stenosis (n = 44 [1.4%]).

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Figure 1. Flow of Participants Through the Trial
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Media reports on preliminary results from the Norwegian Vitamin Trial (NORVIT),24 presented in September 2005, stating no beneficial effects and suggesting increased risk of cancer by B vitamin treatment, made numerous WENBIT participants worried. Although the interim analysis on total mortality did not give any reason for concern, the steering committee was advised by the safety committee to stop the intervention because adherence could be severely compromised. The remaining participants by October 2005 (n = 692) were therefore asked by letter to discontinue study medication and were subsequently called for their final study visit, the last of which was carried out in April 2006.

Median follow-up was 38.4 (5th-95th percentile, 19.3-55.0) months. A total of 131 participants (4.2%) died, and 2557 participants (86.4% of participants alive) attended the final study visit. Of the participants who had premature termination of study intervention, 650 (94%) attended the final study visit. Three patients had incomplete follow-up because of emigration and were censored by the time of last contact. Data entry was completed by June 2007.

Baseline Characteristics

The randomization procedure resulted in well-balanced intervention groups with no differences in baseline demographics or clinical characteristics. The study population included 20.5% women, 9.6% of participants were older than 75 years, and 59.3% had double- or triple-vessel disease (Table 1). Regular use of over-the-counter supplements containing B vitamins was reported by 329 participants (10.8%) prior to randomization. Following baseline angiography, 92% of participants used antiplatelet drugs, 88.4% used statins, and 78.2% used β-blockers. A total of 2072 patients (67.1%) underwent PCI and/or CABG, among whom 55 (1.8% of all) also had valve surgery, whereas 46 (1.5% of all) had only valve surgery (Table 2). Median time from baseline angiography to planned procedures was 21 (5th-95th percentile, 0-84) days.

Table Graphic Jump LocationTable 1. Baseline Participant Characteristics
Table Graphic Jump LocationTable 2. Conventional Treatments Following Baseline Angiography
Adherence and Adverse Events

A total of 102 participants (3.3%) never started study medication, and 456 (14.8%) stopped taking it during follow-up; among these, 46 (1.5% of all) reported adverse effects as the reason for stopping. There was no difference in adverse effect rates among the 4 intervention groups and no report of serious adverse events related to study medication. A total of 2532 (81.9% of all) took 50% to 100% of their study medication throughout follow-up. The proportion of patients adhering to study medication was somewhat higher in the folic acid plus vitamin B12 groups than in the non–folic acid groups (83.9% vs 80.0%; P = .005).

Effect of Intervention on Circulating B Vitamins and Homocysteine Levels

Figure 2 shows circulating B vitamin and total homocysteine levels in the 4 treatment groups at baseline, at follow-up visits, and at the final study visit. At baseline, plasma total homocysteine levels were similar in the 4 groups (P = .72). None of the participants had severe hyperhomocysteinemia (total homocysteine >100 μmol/L), 25 (0.8%) had intermediate (total homocysteine 30-100 μmol/L), and 271 (8.8%) had mild hyperhomocysteinemia (total homocysteine 15-30 μmol/L) as currently defined.2

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Figure 2. Mean Circulating B Vitamin and Total Homocysteine Levels at Baseline and During Follow-up
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Mean concentration of B vitamins and total homocysteine in serum or plasma. Error bars represent 95% confidence intervals. Data for the final study visit (median, 38.4 months) are the final data points shown in each graph. Samples for determination of serum folate, serum cobalamin, and plasma total homocysteine were available for 3083 participants at baseline, 2765 participants at 1 month, 2704 participants at 12 months, and 2557 participants at the end of the intervention. Samples for determination of plasma pyridoxal phosphate were available for 3054 participants at baseline, 2726 participants at 1 month, 2665 participants at 12 months, and 2533 participants at the end of the intervention.

After 1 year of intervention, mean serum folate concentration increased 7-fold and mean serum cobalamin concentration increased by 65% in the groups receiving folic acid plus vitamin B12. At the same time, mean plasma pyridoxal phosphate concentration increased 9-fold in the groups receiving vitamin B6.

Mean plasma total homocysteine level was decreased by 30%, from 10.8 (SD, 4.5) μmol/L at baseline to 7.6 (SD, 2.2) μmol/L after 1 year of intervention in the groups receiving folic acid and vitamin B12 (P < .001). Plasma total homocysteine concentration remained unaltered in the groups receiving vitamin B6 alone or placebo. At the final study visit, mean plasma total homocysteine level was 2.8 μmol/L lower in the folic acid plus B12 groups than in the non–folic acid groups (a difference of 26%; P < .001).

Clinical End Points

Figure 3 shows the Kaplan-Meier curves for the event rates of the prespecified primary composite end point comparing groups receiving folic acid or no folic acid and comparing groups receiving vitamin B6 or no vitamin B6. Table 3 shows the number and rates of events in the composite primary as well as secondary end points in the 4 intervention groups and the HRs for the prespecified comparisons.

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Figure 3. Kaplan-Meier Curves for the Composite Primary End Point in the Folic Acid vs Non–Folic Acid Groups and the Vitamin B6 vs Non–Vitamin B6 Groups
Graphic Jump Location

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

Table Graphic Jump LocationTable 3. Primary and Secondary End-Point Events and Cox Proportional Hazards for End Points

During follow-up, 422 participants (13.7% of all) experienced an event in the composite primary end point of death, AMI, unstable angina pectoris, or thromboembolic stroke. A total of 219 participants (14.2%) in the groups receiving folic acid vs 203 participants (13.1%) in the groups not receiving folic acid experienced the primary end point (HR, 1.09; 95% CI, 0.90-1.32; P = .36). In the groups receiving vitamin B6, 200 participants (13.0%) experienced the primary end point compared with 222 (14.3%) in the groups not receiving vitamin B6 (HR, 0.90; 95% CI, 0.74-1.09; P = .28).

In the prespecified per-protocol analysis performed among patients adhering to the study medication throughout follow-up, 157 participants (12.2%) in the groups receiving folic acid groups vs 146 (11.8%) of those not receiving folic acid experienced the primary end point (HR, 1.04; 95% CI, 0.83-1.30; P = .75). In the groups receiving vitamin B6, 139 participants (11.0%) who adhered to study medication experienced the primary end point vs 164 (12.9%) of those not receiving vitamin B6 (HR, 0.85; 95% CI, 0.68-1.06; P = .15).

There were no differences in treatment response for the separate end points of death, total AMI (fatal and nonfatal, including procedure-related), or unstable angina pectoris (Table 3). The incidence of total stroke (fatal and nonfatal, including hemorrhagic) was lower in the groups receiving folic acid, but this observation was not statistically significant. The incidence of acute hospitalization due to angina pectoris was lower in the folic acid groups reaching borderline statistical significance (HR, 0.82; 95% CI, 0.67-1.00; P = .05). There was no difference in the incidence of stable angina pectoris with angiographically verified progression of CAD or in the incidence of PCI or CABG. The incidence of cancer was higher, but not statistically significantly so, in the groups receiving folic acid.

Figure 4 shows the Kaplan-Meier curves for the composite primary end point in the 4 different intervention groups. In the post hoc overall survival analysis, there were no differences between the groups (P = .07) but there was an increased risk of the composite primary end point in the group receiving folic acid plus vitamin B12 (HR, 1.34; 95% CI, 1.03-1.75; P = .03) compared with placebo.

Place holder to copy figure label and caption
Figure 4. Kaplan-Meier Curves for the Composite Primary End Point in the 4 Intervention Groups
Graphic Jump Location

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

The baseline level of total homocysteine in plasma was a significant predictor of the primary end point (HR associated with a 3-μmol/L difference in total homocysteine level, 1.07; 95% CI, 1.02-1.13; P = .01) after adjustment for age, sex, smoking status (never, ex-, or current smoker), and serum creatinine concentration.

In this randomized, double-blind, placebo-controlled trial, we could not detect any preventive effect of intervention with folic acid plus vitamin B12 or with vitamin B6 on mortality or major cardiovascular events among patients with mainly stable CAD undergoing intensive conventional treatment. We found a numerically lower incidence of stroke and higher incidence of cancer in the groups receiving folic acid, but these observations were not statistically significant. Our results are in concordance with findings in other large secondary prevention trials with homocysteine-lowering B vitamins in patients surviving an AMI24 and in patients with established or at high risk of CVD.10,25

WENBIT is one of the larger randomized, placebo-controlled trials to evaluate the clinical effects of homocysteine-lowering treatment with B vitamins in patients with established CVD. Inclusion criteria were wide, and the extent of CAD was precisely ascertained by coronary angiography at baseline. Adherence to study medication was greater than 80% and was corroborated by assessment of B vitamin concentrations in serum and plasma. There is no mandatory folic acid fortification of foods in Norway, and the self-reported use of over-the-counter B vitamin supplements was modest in this study population. Thus, the homocysteine-lowering effect of the intervention was substantial. Follow-up for clinical end points was complete in all but 3 participants.

There are several limitations to this trial. The insufficient capacity to consecutively screen all possible eligible participants made the inclusion process nontransparent. However, we find no reason to believe that this biased the randomization. Ultimately, 3006 (29.4%) of all possible eligible participants (N = 10 241) were randomized from January 2000 to April 2004, and our study population was quite similar to contemporary populations who had undergone invasive evaluation for angina pectoris or acute coronary syndromes and who had verified CAD in other European hospitals.26,27 Hence, our findings should be generalizable to other CAD populations, primarily to patients with stable CAD. The power of the trial was less than planned because of lower event rates than anticipated and shorter follow-up than planned, the latter due to premature study termination of 692 participants (22%). Thus, WENBIT had a power of 80% to detect a 24% reduction in risk of the primary end point and a power of 62% to detect the prespecified, hypothesized 20% reduction in risk of the primary end point by the homocysteine-lowering therapy. Limited statistical power has also been a problem in several other homocysteine-lowering clinical trials.7

Our finding of a modestly lowered risk of being urgently hospitalized for angina pectoris when treated with folic acid plus vitamin B12 is not consistent with the nonappearance of beneficial effects on other cardiovascular outcomes in our trial. In particular, we found no difference in the risk of unstable angina between the groups receiving and not receiving folic acid (HR, 1.00; 95% CI, 0.68-1.48; P = .99) (Table 3). That we did not adjust for multiple comparisons adds further support to the notion that the reduced risk of hospitalization for angina might be a spurious observation. The apparent elevated risk of the composite primary end point in the group receiving folic acid plus vitamin B12 compared with the group receiving placebo could also be a chance finding due to multiple comparisons.

The null results in this and other homocysteine-lowering B vitamin intervention trials suggest that homocysteine is not a modifiable cause but rather a biological marker of CVD risk. The homocysteine hypothesis of vascular disease emerged from results of mainly retrospective observational studies.1,2 However, more recent prospective observational studies have demonstrated that plasma total homocysteine concentration is at most a modest risk factor of CVD.7 Mendelian randomization studies, which cannot be subject to confounding or reverse causality, have yielded some evidence that an elevated total homocysteine level could cause CVD, especially stroke,28 but a meta-analysis found only a weak overall association between the methylenetetrahydrofolate reductase (MTHFR) 677C→T polymorphism and CAD in populations in Europe, North America, and Australia.29 A recent large study in white American women found no association between the variant genotype and future risk of CVD.30

The focus of our trial was an intervention to prevent or delay occurrence of occlusive vascular disease in patients with mainly stable CAD. Inflammation plays a key role in CAD and other manifestations of atherosclerosis.31 Intervention with B vitamins in WENBIT16 and in other trials in populations with established CVD32 or elevated plasma total homocysteine levels33 has not led to significant reduction in circulating concentrations of inflammatory markers involved in atherogenesis. Thus, the failure to reverse inflammatory processes could explain the lack of effect of the B vitamin intervention on cardiovascular events in our trial.

We could not demonstrate any separate effect of the vitamin B6 intervention on clinical outcomes. Observational studies from the late 1990s demonstrated an association between vitamin B6 status and risk of CAD and other CVD,5,6 whereas more recent studies have shown that circulating concentrations of vitamin B6 are strongly and inversely associated with C-reactive protein.34,35 In a large prospective study, the association between plasma pyridoxal phosphate concentration and risk of future AMI was abolished after adjustment for low-grade inflammation and smoking.36 Hence, low circulating levels of vitamin B6 might be a consequence of low-grade inflammation accompanying CAD and/or smoking rather than a cause of CAD itself.

Conceivably, B vitamins in pharmacological doses may exert some deleterious effect in patients with established CVD that could counteract their potential benefits.37 Harmful effects of high serum folate concentration could be mediated through mechanisms involving direct effects on vascular smooth muscle cell proliferation and matrix formation in coronary arteries.12,37 During the last few years, the assumption that folate prevents cancer has been challenged. One randomized trial with folic acid to prevent colorectal adenomas found increased risk of cancer in the group receiving folic acid,38 but another similar trial found no such increased risk.39 In both WENBIT and NORVIT, the incidence of cancer was higher in the groups receiving folic acid, but in none of these trials was this of statistical significance. Furthermore, it has been postulated that folic acid fortification of foods may have been wholly or partly responsible for the observed increase in colorectal cancer rates in the United States and Canada in the late 1990s.40 The view prevails that folate may prevent early stages of carcinogenesis but may enhance the growth of established cancer cells.41

In conclusion, we could not demonstrate an effect of homocysteine-lowering therapy with B vitamins on mortality or major cardiovascular events in patients with CAD during 38 months of follow-up. These results are essentially in agreement with published results from similar larger secondary intervention trials.10,24,25 B vitamin interventions might have a different influence on cerebrovascular disorders, as suggested by meta- and reanalyses of published trials42,43 and by accelerated decline in stroke mortality in populations supplied with folic acid fortified foods.14 More fulfilling answers on the role of B vitamins in secondary prevention of CVD must await the results of ongoing trials and meta-analyses of pooled data.7 Future studies should also evaluate the possible adverse effects from folic acid supplementation and fortification of foods and especially on the risk of cancer. At this stage, use of B vitamin supplements to improve prognosis in patients with CAD is not justified.

Corresponding Author: Marta Ebbing, MD, Department of Heart Disease, Haukeland University Hospital, Jonas Liesvei 65, 5021 Bergen, Norway (marta.ebbing@helse-bergen.no).

Author Contributions: Dr Ebbing had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Ueland, Nordrehaug, Nilsen, Vollset, Refsum, Nygård.

Acquisition of data: Ebbing, Bleie, Ueland, Ringdal Pedersen, Nygård.

Analysis and interpretation of data: Ebbing, Bleie, Ueland, Nordrehaug, Vollset, Refsum, Nygård.

Drafting the manuscript: Ebbing.

Critical revision of the manuscript for important intellectual content: Ebbing, Bleie, Ueland, Nordrehaug, Nilsen, Vollset, Refsum, Ringdal Pedersen, Nygård.

Statistical analysis: Ebbing, Vollset, Nygård.

Obtained funding: Ueland, Nordrehaug, Nilsen, Vollset, Refsum, Nygård.

Administrative, technical or material support: Bleie, Ueland, Nordrehaug, Nilsen, Vollset, Ringdal Pedersen, Nygård.

Study supervision: Ueland, Nordrehaug, Nilsen, Vollset, Refsum, Nygård.

Financial Disclosures: Dr Ueland reports that he is a member of the steering board of the nonprofit Foundation to Promote Research Into Functional Vitamin B12 Deficiency. Drs Ueland and Nygård report that they have received consulting fees from Nycomed. No other disclosures were reported.

WENBIT Investigators:Department of Heart Disease, Haukeland University Hospital: Øyvind Bleie, Elfrid Blomdal, Carmen Dybdal, Janne Dyngeland, Tove Sell Dyngeland, Britt Gjellefall, Marie Husa, Vivi Lill Johannessen, Liv Johanne Karstensen, Sarita Kvamme, Svein Erik Laukli, Ove Netland, Janne Nilsen, Ottar Nygård, Elisabeth Norheim, Elin Strand, Linda Træet, Britt Jeanette Ulvatn, Marie Vik, Ove Årseth; Department of Cardiology, Stavanger University Hospital: Reidun Meling, Dennis W. Nilsen, Selma Ramstrøm, Hellen Svalestad; Steering Committee: Ottar Nygård (chair), Per Magne Ueland, Jan Erik Nordrehaug, Dennis W. Nilsen, Stein Emil Vollset, Helga Refsum; End-Points Committee: Per Lund-Johansen, MD, PhD (chair), Section for Cardiology, Institute of Medicine, University of Bergen and Haukeland University Hospital; Leik Woie, MD (consultant cardiologist), Department of Cardiology, Stavanger University Hospital; Marta Ebbing, MD, Department of Heart Disease, Haukeland University Hospital; Safety Committee: Rolv T. Lie, PhD (chair), Section for Epidemiology and Medical Statistics, Department of Public Health and Primary Health Care, University of Bergen; Terje R. Pedersen, MD, PhD, Centre for Preventive Medicine, Ullevål University Hospital, Oslo, Norway.

Funding/Support: This trial was funded by the Advanced Research Program and Research Council of Norway, the Norwegian Foundation for Health and Rehabilitation, the Norwegian Heart and Lung Patient Organisation, the Norwegian Ministry of Health and Care Services, the Western Norway Regional Health Authority, the Department of Heart Disease at Haukeland University Hospital, Locus for Homocysteine and Related Vitamins at the University of Bergen, Locus for Cardiac Research at the University of Bergen, the Foundation to Promote Research Into Functional Vitamin B12 Deficiency, Bergen, Norway, and Alpharma Inc, Copenhagen, Denmark.

Role of the Sponsors: The main sponsors were nonprofit organizations with no participating role in the trial. Alpharma Inc provided the study capsules, generated the randomization sequence, and concealed the randomization code free of charge and rendered a limited grant to finance the initial phase of the trial. However, Alpharma Inc had no role in the design or implementation of the trial, had no access to study data, and did not participate in data analysis or interpretation or in the preparation, review, or approval of the manuscript.

Additional Contributions: We thank the recruiting physicians, study nurses, laboratory personnel, and other coworkers at Haukeland University Hospital and Stavanger University Hospital. We especially thank study nurse Janne Dyngeland, Department of Heart Disease, Haukeland University Hospital, and chief engineer Gry Kvalheim, Section for Pharmacology, Institute of Medicine, University of Bergen and Haukeland University Hospital, for excellent coordinating work, both of whom were compensated. Finally, we thank all participants for their time and motivation.

Boushey CJ, Beresford SA, Omenn GS, Motulsky AG. A quantitative assessment of plasma homocysteine as a risk factor for vascular disease: probable benefits of increasing folic acid intakes.  JAMA. 1995;274(13):1049-1057
PubMed   |  Link to Article
Refsum H, Ueland PM, Nygård O, Vollset SE. Homocysteine and cardiovascular disease.  Annu Rev Med. 1998;49:31-62
PubMed   |  Link to Article
Nygård O, Nordrehaug JE, Refsum H, Ueland PM, Farstad M, Vollset SE. Plasma homocysteine levels and mortality in patients with coronary artery disease.  N Engl J Med. 1997;337(4):230-236
PubMed   |  Link to Article
Nygård O, Ueland PM, Refsum H, Nordrehaug JE, Vollset SE. Plasma total homocysteine: a risk factor for mortality in aortic stenosis patients [abstract].  Neth J Med. 1998;52:S29-S30
Rimm EB, Willett WC, Hu FB,  et al.  Folate and vitamin B6 from diet and supplements in relation to risk of coronary heart disease among women.  JAMA. 1998;279(5):359-364
PubMed   |  Link to Article
Robinson K, Arheart K, Refsum H,  et al; European COMAC Group.  Low circulating folate and vitamin B6 concentrations: risk factors for stroke, peripheral vascular disease, and coronary artery disease.  Circulation. 1998;97(5):437-443
PubMed   |  Link to Article
Clarke R, Armitage J, Lewington S, Collins R. Homocysteine-lowering trials for prevention of vascular disease: protocol for a collaborative meta-analysis.  Clin Chem Lab Med. 2007;45(12):1575-1581
PubMed   |  Link to Article
Bazzano LA, Reynolds K, Holder KN, He J. Effect of folic acid supplementation on risk of cardiovascular diseases: a meta-analysis of randomized controlled trials.  JAMA. 2006;296(22):2720-2726
PubMed   |  Link to Article
Jamison RL, Hartigan P, Kaufman JS,  et al.  Effect of homocysteine lowering on mortality and vascular disease in advanced chronic kidney disease and end-stage renal disease: a randomized controlled trial.  JAMA. 2007;298(10):1163-1170
PubMed   |  Link to Article
Albert CM, Cook NR, Gaziano JM,  et al.  Effect of folic acid and B vitamins on risk of cardiovascular events and total mortality among women at high risk for cardiovascular disease: a randomized trial.  JAMA. 2008;299(17):2027-2036
PubMed   |  Link to Article
Schnyder G, Roffi M, Flammer Y, Pin R, Hess OM. Effect of homocysteine-lowering therapy with folic acid, vitamin B12, and vitamin B6 on clinical outcome after percutaneous coronary intervention: the Swiss Heart study: a randomized controlled trial.  JAMA. 2002;288(8):973-979
PubMed   |  Link to Article
Lange H, Suryapranata H, De Luca G,  et al.  Folate therapy and in-stent restenosis after coronary stenting.  N Engl J Med. 2004;350(26):2673-2681
PubMed   |  Link to Article
Eichholzer M, Tonz O, Zimmermann R. Folic acid: a public-health challenge.  Lancet. 2006;367(9519):1352-1361
PubMed   |  Link to Article
Yang Q, Botto LD, Erickson JD,  et al.  Improvement in stroke mortality in Canada and the United States, 1990 to 2002.  Circulation. 2006;113(10):1335-1343
PubMed   |  Link to Article
Bleie Ø, Refsum H, Ueland PM,  et al.  Changes in basal and postmethionine load concentrations of total homocysteine and cystathionine after B vitamin intervention.  Am J Clin Nutr. 2004;80(3):641-648
PubMed
Bleie Ø, Semb AG, Grundt H,  et al.  Homocysteine-lowering therapy does not affect inflammatory markers of atherosclerosis in patients with stable coronary artery disease.  J Intern Med. 2007;262(2):244-253
PubMed   |  Link to Article
Joint European Society of Cardiology/American College of Cardiology Committee.  Myocardial infarction redefined-a consensus document of The Joint European Society of Cardiology/American College of Cardiology Committee for the redefinition of myocardial infarction.  Eur Heart J. 2000;21(18):1502-1513
PubMed   |  Link to Article
Cannon CP, Battler A, Brindis RG,  et al.  American College of Cardiology key data elements and definitions for measuring the clinical management and outcomes of patients with acute coronary syndromes: a report of the American College of Cardiology Task Force on Clinical Data Standards (Acute Coronary Syndromes Writing Committee).  J Am Coll Cardiol. 2001;38(7):2114-2130
PubMed   |  Link to Article
National Kidney Disease Education Program.  GFR calculators for adults (for patients 18 and older). http://www.nkdep.nih.gov/professionals/gfr_calculators/index.htm. Accessed November 16, 2007
Kelleher BP, Broin SD. Microbiological assay for vitamin B12 performed in 96-well microtitre plates.  J Clin Pathol. 1991;44(7):592-595
PubMed   |  Link to Article
O’Broin S, Kelleher B. Microbiological assay on microtitre plates of folate in serum and red cells.  J Clin Pathol. 1992;45(4):344-347
PubMed   |  Link to Article
Midttun O, Hustad S, Solheim E, Schneede J, Ueland PM. Multianalyte quantification of vitamin B6 and B2 species in the nanomolar range in human plasma by liquid chromatography-tandem mass spectrometry.  Clin Chem. 2005;51(7):1206-1216
PubMed   |  Link to Article
Windelberg A, Arseth O, Kvalheim G, Ueland PM. Automated assay for the determination of methylmalonic acid, total homocysteine, and related amino acids in human serum or plasma by means of methylchloroformate derivatization and gas chromatography-mass spectrometry.  Clin Chem. 2005;51(11):2103-2109
PubMed   |  Link to Article
Bønaa KH, Njolstad I, Ueland PM,  et al.  Homocysteine lowering and cardiovascular events after acute myocardial infarction.  N Engl J Med. 2006;354(15):1578-1588
PubMed   |  Link to Article
Lonn E, Yusuf S, Arnold MJ,  et al.  Homocysteine lowering with folic acid and B vitamins in vascular disease.  N Engl J Med. 2006;354(15):1567-1577
PubMed   |  Link to Article
Lenzen MJ, Boersma E, Bertrand ME,  et al.  Management and outcome of patients with established coronary artery disease: the Euro Heart Survey on coronary revascularization.  Eur Heart J. 2005;26(12):1169-1179
PubMed   |  Link to Article
Breeman A, Hordijk-Trion M, Lenzen M,  et al.  Treatment decisions in stable coronary artery disease: insights from the Euro Heart Survey on Coronary Revascularization.  J Thorac Cardiovasc Surg. 2006;132(5):1001-1009
PubMed   |  Link to Article
Casas JP, Bautista LE, Smeeth L, Sharma P, Hingorani AD. Homocysteine and stroke: evidence on a causal link from mendelian randomisation.  Lancet. 2005;365(9455):224-232
PubMed
Lewis SJ, Ebrahim S, Davey Smith G. Meta-analysis of MTHFR 677C→T polymorphism and coronary heart disease: does totality of evidence support causal role for homocysteine and preventive potential of folate?  BMJ. 2005;331(7524):1053
PubMed   |  Link to Article
Zee RYL, Mora S, Cheng S,  et al.  Homocysteine, 5,10-methylenetetrahydrofolate reductase 677C→T polymorphism, nutrient intake, and incident cardiovascular disease in 24 968 initially healthy women.  Clin Chem. 2007;53(5):845-851
PubMed   |  Link to Article
Hansson GK. Inflammation, atherosclerosis, and coronary artery disease.  N Engl J Med. 2005;352(16):1685-1695
PubMed   |  Link to Article
Dusitanond P, Eikelboom JW, Hankey GJ,  et al.  Homocysteine-lowering treatment with folic acid, cobalamin, and pyridoxine does not reduce blood markers of inflammation, endothelial dysfunction, or hypercoagulability in patients with previous transient ischemic attack or stroke: a randomized substudy of the VITATOPS trial.  Stroke. 2005;36(1):144-146
PubMed   |  Link to Article
Durga J, van Tits LJ, Schouten EG, Kok FJ, Verhoef P. Effect of lowering of homocysteine levels on inflammatory markers: a randomized controlled trial.  Arch Intern Med. 2005;165(12):1388-1394
PubMed   |  Link to Article
Friso S, Jacques PF, Wilson PW, Rosenberg IH, Selhub J. Low circulating vitamin B(6) is associated with elevation of the inflammation marker C-reactive protein independently of plasma homocysteine levels.  Circulation. 2001;103(23):2788-2791
PubMed   |  Link to Article
Friso S, Girelli D, Martinelli N,  et al.  Low plasma vitamin B-6 concentrations and modulation of coronary artery disease risk.  Am J Clin Nutr. 2004;79(6):992-998
PubMed
Dierkes J, Weikert C, Klipstein-Grobusch K,  et al.  Plasma pyridoxal-5-phosphate and future risk of myocardial infarction in the European Prospective Investigation into Cancer and Nutrition Potsdam cohort.  Am J Clin Nutr. 2007;86(1):214-220
PubMed
Loscalzo J. Homocysteine trials-clear outcomes for complex reasons.  N Engl J Med. 2006;354(15):1629-1632
PubMed   |  Link to Article
Cole BF, Baron JA, Sandler RS,  et al.  Folic acid for the prevention of colorectal adenomas: a randomized clinical trial.  JAMA. 2007;297(21):2351-2359
PubMed   |  Link to Article
Logan RF, Grainge MJ, Shepherd VC, Armitage NC, Muir KR. Aspirin and folic acid for the prevention of recurrent colorectal adenomas.  Gastroenterology. 2008;134(1):29-38
PubMed   |  Link to Article
Mason JB, Dickstein A, Jacques PF,  et al.  A temporal association between folic acid fortification and an increase in colorectal cancer rates may be illuminating important biological principles: a hypothesis.  Cancer Epidemiol Biomarkers Prev. 2007;16(7):1325-1329
PubMed   |  Link to Article
Ulrich CM. Folate and cancer prevention: a closer look at a complex picture.  Am J Clin Nutr. 2007;86(2):271-273
PubMed
Wang X, Qin X, Demirtas H,  et al.  Efficacy of folic acid supplementation in stroke prevention: a meta-analysis.  Lancet. 2007;369(9576):1876-1882
PubMed   |  Link to Article
Spence JD. Homocysteine-lowering therapy: a role in stroke prevention?  Lancet Neurol. 2007;6(9):830-838
PubMed   |  Link to Article

Figures

Place holder to copy figure label and caption
Figure 1. Flow of Participants Through the Trial
Graphic Jump Location
Place holder to copy figure label and caption
Figure 2. Mean Circulating B Vitamin and Total Homocysteine Levels at Baseline and During Follow-up
Graphic Jump Location

Mean concentration of B vitamins and total homocysteine in serum or plasma. Error bars represent 95% confidence intervals. Data for the final study visit (median, 38.4 months) are the final data points shown in each graph. Samples for determination of serum folate, serum cobalamin, and plasma total homocysteine were available for 3083 participants at baseline, 2765 participants at 1 month, 2704 participants at 12 months, and 2557 participants at the end of the intervention. Samples for determination of plasma pyridoxal phosphate were available for 3054 participants at baseline, 2726 participants at 1 month, 2665 participants at 12 months, and 2533 participants at the end of the intervention.

Place holder to copy figure label and caption
Figure 3. Kaplan-Meier Curves for the Composite Primary End Point in the Folic Acid vs Non–Folic Acid Groups and the Vitamin B6 vs Non–Vitamin B6 Groups
Graphic Jump Location

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

Place holder to copy figure label and caption
Figure 4. Kaplan-Meier Curves for the Composite Primary End Point in the 4 Intervention Groups
Graphic Jump Location

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

Tables

Table Graphic Jump LocationTable 1. Baseline Participant Characteristics
Table Graphic Jump LocationTable 2. Conventional Treatments Following Baseline Angiography
Table Graphic Jump LocationTable 3. Primary and Secondary End-Point Events and Cox Proportional Hazards for End Points

References

Boushey CJ, Beresford SA, Omenn GS, Motulsky AG. A quantitative assessment of plasma homocysteine as a risk factor for vascular disease: probable benefits of increasing folic acid intakes.  JAMA. 1995;274(13):1049-1057
PubMed   |  Link to Article
Refsum H, Ueland PM, Nygård O, Vollset SE. Homocysteine and cardiovascular disease.  Annu Rev Med. 1998;49:31-62
PubMed   |  Link to Article
Nygård O, Nordrehaug JE, Refsum H, Ueland PM, Farstad M, Vollset SE. Plasma homocysteine levels and mortality in patients with coronary artery disease.  N Engl J Med. 1997;337(4):230-236
PubMed   |  Link to Article
Nygård O, Ueland PM, Refsum H, Nordrehaug JE, Vollset SE. Plasma total homocysteine: a risk factor for mortality in aortic stenosis patients [abstract].  Neth J Med. 1998;52:S29-S30
Rimm EB, Willett WC, Hu FB,  et al.  Folate and vitamin B6 from diet and supplements in relation to risk of coronary heart disease among women.  JAMA. 1998;279(5):359-364
PubMed   |  Link to Article
Robinson K, Arheart K, Refsum H,  et al; European COMAC Group.  Low circulating folate and vitamin B6 concentrations: risk factors for stroke, peripheral vascular disease, and coronary artery disease.  Circulation. 1998;97(5):437-443
PubMed   |  Link to Article
Clarke R, Armitage J, Lewington S, Collins R. Homocysteine-lowering trials for prevention of vascular disease: protocol for a collaborative meta-analysis.  Clin Chem Lab Med. 2007;45(12):1575-1581
PubMed   |  Link to Article
Bazzano LA, Reynolds K, Holder KN, He J. Effect of folic acid supplementation on risk of cardiovascular diseases: a meta-analysis of randomized controlled trials.  JAMA. 2006;296(22):2720-2726
PubMed   |  Link to Article
Jamison RL, Hartigan P, Kaufman JS,  et al.  Effect of homocysteine lowering on mortality and vascular disease in advanced chronic kidney disease and end-stage renal disease: a randomized controlled trial.  JAMA. 2007;298(10):1163-1170
PubMed   |  Link to Article
Albert CM, Cook NR, Gaziano JM,  et al.  Effect of folic acid and B vitamins on risk of cardiovascular events and total mortality among women at high risk for cardiovascular disease: a randomized trial.  JAMA. 2008;299(17):2027-2036
PubMed   |  Link to Article
Schnyder G, Roffi M, Flammer Y, Pin R, Hess OM. Effect of homocysteine-lowering therapy with folic acid, vitamin B12, and vitamin B6 on clinical outcome after percutaneous coronary intervention: the Swiss Heart study: a randomized controlled trial.  JAMA. 2002;288(8):973-979
PubMed   |  Link to Article
Lange H, Suryapranata H, De Luca G,  et al.  Folate therapy and in-stent restenosis after coronary stenting.  N Engl J Med. 2004;350(26):2673-2681
PubMed   |  Link to Article
Eichholzer M, Tonz O, Zimmermann R. Folic acid: a public-health challenge.  Lancet. 2006;367(9519):1352-1361
PubMed   |  Link to Article
Yang Q, Botto LD, Erickson JD,  et al.  Improvement in stroke mortality in Canada and the United States, 1990 to 2002.  Circulation. 2006;113(10):1335-1343
PubMed   |  Link to Article
Bleie Ø, Refsum H, Ueland PM,  et al.  Changes in basal and postmethionine load concentrations of total homocysteine and cystathionine after B vitamin intervention.  Am J Clin Nutr. 2004;80(3):641-648
PubMed
Bleie Ø, Semb AG, Grundt H,  et al.  Homocysteine-lowering therapy does not affect inflammatory markers of atherosclerosis in patients with stable coronary artery disease.  J Intern Med. 2007;262(2):244-253
PubMed   |  Link to Article
Joint European Society of Cardiology/American College of Cardiology Committee.  Myocardial infarction redefined-a consensus document of The Joint European Society of Cardiology/American College of Cardiology Committee for the redefinition of myocardial infarction.  Eur Heart J. 2000;21(18):1502-1513
PubMed   |  Link to Article
Cannon CP, Battler A, Brindis RG,  et al.  American College of Cardiology key data elements and definitions for measuring the clinical management and outcomes of patients with acute coronary syndromes: a report of the American College of Cardiology Task Force on Clinical Data Standards (Acute Coronary Syndromes Writing Committee).  J Am Coll Cardiol. 2001;38(7):2114-2130
PubMed   |  Link to Article
National Kidney Disease Education Program.  GFR calculators for adults (for patients 18 and older). http://www.nkdep.nih.gov/professionals/gfr_calculators/index.htm. Accessed November 16, 2007
Kelleher BP, Broin SD. Microbiological assay for vitamin B12 performed in 96-well microtitre plates.  J Clin Pathol. 1991;44(7):592-595
PubMed   |  Link to Article
O’Broin S, Kelleher B. Microbiological assay on microtitre plates of folate in serum and red cells.  J Clin Pathol. 1992;45(4):344-347
PubMed   |  Link to Article
Midttun O, Hustad S, Solheim E, Schneede J, Ueland PM. Multianalyte quantification of vitamin B6 and B2 species in the nanomolar range in human plasma by liquid chromatography-tandem mass spectrometry.  Clin Chem. 2005;51(7):1206-1216
PubMed   |  Link to Article
Windelberg A, Arseth O, Kvalheim G, Ueland PM. Automated assay for the determination of methylmalonic acid, total homocysteine, and related amino acids in human serum or plasma by means of methylchloroformate derivatization and gas chromatography-mass spectrometry.  Clin Chem. 2005;51(11):2103-2109
PubMed   |  Link to Article
Bønaa KH, Njolstad I, Ueland PM,  et al.  Homocysteine lowering and cardiovascular events after acute myocardial infarction.  N Engl J Med. 2006;354(15):1578-1588
PubMed   |  Link to Article
Lonn E, Yusuf S, Arnold MJ,  et al.  Homocysteine lowering with folic acid and B vitamins in vascular disease.  N Engl J Med. 2006;354(15):1567-1577
PubMed   |  Link to Article
Lenzen MJ, Boersma E, Bertrand ME,  et al.  Management and outcome of patients with established coronary artery disease: the Euro Heart Survey on coronary revascularization.  Eur Heart J. 2005;26(12):1169-1179
PubMed   |  Link to Article
Breeman A, Hordijk-Trion M, Lenzen M,  et al.  Treatment decisions in stable coronary artery disease: insights from the Euro Heart Survey on Coronary Revascularization.  J Thorac Cardiovasc Surg. 2006;132(5):1001-1009
PubMed   |  Link to Article
Casas JP, Bautista LE, Smeeth L, Sharma P, Hingorani AD. Homocysteine and stroke: evidence on a causal link from mendelian randomisation.  Lancet. 2005;365(9455):224-232
PubMed
Lewis SJ, Ebrahim S, Davey Smith G. Meta-analysis of MTHFR 677C→T polymorphism and coronary heart disease: does totality of evidence support causal role for homocysteine and preventive potential of folate?  BMJ. 2005;331(7524):1053
PubMed   |  Link to Article
Zee RYL, Mora S, Cheng S,  et al.  Homocysteine, 5,10-methylenetetrahydrofolate reductase 677C→T polymorphism, nutrient intake, and incident cardiovascular disease in 24 968 initially healthy women.  Clin Chem. 2007;53(5):845-851
PubMed   |  Link to Article
Hansson GK. Inflammation, atherosclerosis, and coronary artery disease.  N Engl J Med. 2005;352(16):1685-1695
PubMed   |  Link to Article
Dusitanond P, Eikelboom JW, Hankey GJ,  et al.  Homocysteine-lowering treatment with folic acid, cobalamin, and pyridoxine does not reduce blood markers of inflammation, endothelial dysfunction, or hypercoagulability in patients with previous transient ischemic attack or stroke: a randomized substudy of the VITATOPS trial.  Stroke. 2005;36(1):144-146
PubMed   |  Link to Article
Durga J, van Tits LJ, Schouten EG, Kok FJ, Verhoef P. Effect of lowering of homocysteine levels on inflammatory markers: a randomized controlled trial.  Arch Intern Med. 2005;165(12):1388-1394
PubMed   |  Link to Article
Friso S, Jacques PF, Wilson PW, Rosenberg IH, Selhub J. Low circulating vitamin B(6) is associated with elevation of the inflammation marker C-reactive protein independently of plasma homocysteine levels.  Circulation. 2001;103(23):2788-2791
PubMed   |  Link to Article
Friso S, Girelli D, Martinelli N,  et al.  Low plasma vitamin B-6 concentrations and modulation of coronary artery disease risk.  Am J Clin Nutr. 2004;79(6):992-998
PubMed
Dierkes J, Weikert C, Klipstein-Grobusch K,  et al.  Plasma pyridoxal-5-phosphate and future risk of myocardial infarction in the European Prospective Investigation into Cancer and Nutrition Potsdam cohort.  Am J Clin Nutr. 2007;86(1):214-220
PubMed
Loscalzo J. Homocysteine trials-clear outcomes for complex reasons.  N Engl J Med. 2006;354(15):1629-1632
PubMed   |  Link to Article
Cole BF, Baron JA, Sandler RS,  et al.  Folic acid for the prevention of colorectal adenomas: a randomized clinical trial.  JAMA. 2007;297(21):2351-2359
PubMed   |  Link to Article
Logan RF, Grainge MJ, Shepherd VC, Armitage NC, Muir KR. Aspirin and folic acid for the prevention of recurrent colorectal adenomas.  Gastroenterology. 2008;134(1):29-38
PubMed   |  Link to Article
Mason JB, Dickstein A, Jacques PF,  et al.  A temporal association between folic acid fortification and an increase in colorectal cancer rates may be illuminating important biological principles: a hypothesis.  Cancer Epidemiol Biomarkers Prev. 2007;16(7):1325-1329
PubMed   |  Link to Article
Ulrich CM. Folate and cancer prevention: a closer look at a complex picture.  Am J Clin Nutr. 2007;86(2):271-273
PubMed
Wang X, Qin X, Demirtas H,  et al.  Efficacy of folic acid supplementation in stroke prevention: a meta-analysis.  Lancet. 2007;369(9576):1876-1882
PubMed   |  Link to Article
Spence JD. Homocysteine-lowering therapy: a role in stroke prevention?  Lancet Neurol. 2007;6(9):830-838
PubMed   |  Link to Article
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