What effect does folic acid supplementation (with or without additional B vitamin supplementation) have on risk of CVD among persons with or without pre-existing vascular disease?

Strong evidence demonstrates that folic acid supplementation with or without additional B vitamins in adult men and women with pre-existing vascular disease, does not appear to reduce risk of cardiovascular disease, and may increase risk slightly.

Four large randomized placebo controlled trials (CT) and one meta-analysis study examined the relationship between folic acid supplementation and risk of cardiovascular disease (CVD) in adults with pre-existing vascular disease.

Albert et al (2008) (positive quality) conducted an CT as part of an ongoing antioxidant vitamin trail with health professionals in the US. Women aged 40 and older were randomized to either placebo or a supplement containing folic acid (2.5mg), vitamin B₁₂ (mg) and vitamin B₆ (50mg). All women had a history of CVD or three or more coronary risk factors (average age. 62.8 years). The average follow-up was 7.3 years. The primary outcome was composite of myocardial infarction, stroke, coronary revascularization or CVD mortality. Again, despite significant homocysteine lowering, the folic acid, B₁₂ and B₆ vitamin supplement did not reduce cardiovascular events (RR 1.03; 95% CI: 0.90 to 1.19; P=0.65). The authors noted that a limitation of the study was that the research subjects were health professionals and at low risk for folate deficiency. In addition, all subjects were exposed to universal folate fortification of grain at the time the study. Therefore, one cannot rule out the benefit of folate supplementation in a folate-deficient population.

Ebbing et al (2008) (positive quality) conducted an CT in Norway as part of the Western Norway B-Vitamin Intervention Trial. Men and women aged 18 or older from two hospitals in western Norway who where undergoing coronary artery angiography for suspected CVD or aortic valve stenosis were included in the trial. A total of 3,096 patients were randomized (mean age 61.7 years, 20.5% female). A total of 2,121 patients completed the trial. The researchers used a 2 x 2 factorial design. Patients were randomized to a placebo or one of three different daily supplements: 1) Folic acid (0.8mg), plus vitamin B₁₂ (0.4mg) and B₆ (40mg); 2) Folic acid (0.8mg), plus B₁₂ (0.4mg); vitamin B₆ (40mg). The median follow-up was 38 months. The primary outcome was a composite of all-cause death, non-fatal acute myocardial infarction (MI), acute hospitalization or unstable angina pectoris, and non-fatal thromboembolic stroke. Mean plasma homocysteine concentration decreased by 30% after one year of treatment. Despite these reductions, overall there was no effect of the treatment with folic acid and vitamin B₁₂ or vitamin B₆ on total mortality or cardiovascular events. If anything there was a slight but significant increase in risk using post-hoc overall survival analysis of the composite primary endpoint in the group receiving folic acid plus vitamin B₁₂ (HR, 1.43; 95% CI: 1.03 to 1.75; P=03) compared to placebo.

Ray et al (2007) (positive quality) conducted a placebo-controlled clinical trial using data from the Heart Outcomes Prevention Evaluation 2 (HOPE-2), a large (N=5,522), five-year randomized study, to determine whether decreasing homocysteine levels alters the risk for symptomatic venous thromboembolism. The vitamin therapy group received a daily supplement containing 2.5mg of folic acid, 50mg of vitamin B₆, and mg of vitamin B₁₂. The incidence rate of venous thromboembolism was the same in the vitamin therapy group and the placebo group (0.35 per 100 person-years; hazard ratio (HR), 1.01; 95% CI: 0.66, 1.53). Vitamin therapy did not reduce the risk for deep venous thrombosis (HR, 1.04; 95% CI: 0.63, 1.72), pulmonary embolism (HR, 1.14; 95% CI: 0.57, 2.28), or unprovoked venous thromboembolism (HR, 1.21; 95% CI: 0.66, 2.23). Decreasing homocysteine levels with folic acid and vitamins B₆ and B₁₂ did not reduce the risk for symptomatic venous thromboembolism.

Bonaa et al (2006) (positive quality) conducted a randomized controlled trial (RCT), double-blind, 2 x 2 factorial design evaluated data from men and women 30 to 85 years of age who had had an acute MI from the Norwegian Vitamin (NORVIT) trial. Vitamin B treatments had no significant (NS) effect on the primary end point (risk ratio, 1.08; 95% CI: 0.93, 1.25; P=0.31). Treatment with vitamin B₆ was not associated with any significant benefit with regard to the primary end point [relative risk (RR) of the primary end point, 1.14; 95% CI: 0.98, 1.32; P=0.09]. In the group given folic acid, vitamin B₁₂ and vitamin B₆, there was a trend toward an increased risk (RR, 1.22; 95% CI: 1.00, 1.50; P=0.05). Treatment with B-vitamins did not lower the risk of recurrent cardiovascular disease after acute MI. In this trial, a harmful effect from combined B-vitamin treatment was suggested.

Bazzano et al (2006) (positive quality) was a meta-analysis. The objective of the metal-analysis was to evaluate the effects of folic acid supplementation on risk of CVD and all-cause mortality among adults with pre-existing CVD or renal disease. The researchers only evaluated RCTs. Studies were retrieved by searching Medline from January 1966 to July 2006. Out of a total of 165 studies reviewed, 12 studies met the criteria for inclusion, representing 16,958 men and women. The studies were conducted around the world (two in the US, one in Australia and New Zealand, one in Canada and eight in Europe). Dosage of folic acid supplementation ranged from 0.5mg per day to 15mg per day and study durations ranged from six months to five years. In this metal-analysis, folic acid supplementation did not reduce risk of CVD or all-cause mortality in persons with prior history of disease. The overall RR of outcomes for subjects receiving folic acid supplementation compared to controls were 0.95 (95% CI: 0.88 to 1.03) for CVD, 1.04 (95% CI: 0.92 to 1.17) for coronary heart disease (CHD) and 0.96 (95% CI: 0.88 to 1.04) for all-cause mortality.

These data taken together demonstrate consistent outcomes showing that folic acid supplementation does not reduce risk of CVD in men and women with existing disease. There is some limited evidence that there may be increased risk. For this reason, adults with pre-existing vascular disease should not be encouraged to take a folic acid supplementation. One question that still remains is whether there are any differences in response due to race or ethnicity with folic acid supplementation.

Albert et al, 2008 (positive quality). This RCT (individually randomized) tested whether a combination of 2.5mg of folic acid, 50mg of vitamin B₆ and mg of vitamin B₁₂ lowers risk of CVD among high-risk women with and without CVD. The study participants were from the Women's Antioxidant and Folic Acid Cardiovascular Study (WAFACS), aged 40 years or older, post-menopausal or with no intention of becoming pregnant, and had a reported history of CVD or had at least three cardiac risk factors. The results showed that 796 participants (14.6%) from a total of 5,442, experienced a confirmed CVD event (139 MIs, 148 strokes, 508 coronary revascularization procedures and 190 cardiovascular deaths). There was no difference in the cumulative incidence of the primary combined endpoint in the active vs. placebo treatment groups at any time during study follow-up. In addition, 406 women (14.9%) in the active treatment group and 390 (14.3%) in the placebo group experienced at least one cardiovascular event included in the primary endpoint (226.9 per 10,000 person-years vs. 219.2 per 10,000 person-years). The overall RR was 1.03 (95% CI: 0.90,1.19; P=0.65) after controlling for age and antioxidant treatment assignment. In conclusion, after 7.3 years of treatment and follow-up, a combination pill of folic acid, vitamin B₆ and vitamin B₁₂ did not reduce a combined endpoint of total cardiovascular events among high-risk women.

Bazzano et al, 2006 (positive quality). This meta-analysis study evaluated the effects of folic acid supplementation on risk of CVD and all-cause mortality using a random-effects model. The 12 RCTs represented 16,958 men and women. The overall RR CIs of outcomes for patients treated with folic acid supplementation compared with controls were 0.95 (0.88,1.03) for CVD, 1.04 (0.92,1.17) for CHD, 0.86 (0.71,1.04) for stroke and 0.96 (0.88,1.04) for all-cause mortality. The RR was consistent among participants with pre-existing CVD or renal disease. Folic acid supplementation has not been shown to reduce risk of CVD or all-cause mortality among participants with prior history of vascular disease. Studies included US, Canadian and European subjects.

Bonaa et al, 2006 (positive quality). This RCT, double-blind, 2 x 2 factorial design evaluated data from men and women 30 to 85 years of age who had had an acute MI from the Norwegian Vitamin (NORVIT) trial. Vitamin-B treatments had NS effect on the primary end point (RR, 1.08; 95% CI: 0.93, 1.25; P=0.31). Also, treatment with vitamin B₆ was not associated with any significant benefit with regard to the primary end point (RR of the primary end point, 1.14; 95% CI: 0.98, 1.32; P=0.09). In the group gimetalfolic acid, vitamin B₁₂ and vitamin B₆, there was a trend toward an increased risk (RR, 1.22; 95% CI: 1.00, 1.50; P=0.05). Treatment with B vitamins did not lower the risk of recurrent CVD after acute MI. In this trial a harmful effect from combined B-vitamin treatment was suggested.

Ebbing et al, 2009 (positive quality). This randomized double blind controlled trial assessed the effect of treatment with folic acid and vitamin B₁₂ and the effect of treatment with vitamin B₆ as secondary prevention. Data from the Western Norway B-vitamin intervention Trial (WENBIT) was used; it included men and women 18 years old or older undergoing coronary artery angiography for suspected coronary artery disease (CAD) or aortic valve stenosis from two university hospitals in Western Norway. Intervention treatment consisted of daily oral dose of one of the following: 1) Folic acid, 0.8mg, plus vitamin B₁₂ (cyanocobalamin), 0.4mg and vitamin B₆ (pyridoxine), 40mg; 2) Folic acid, 0.8mg, plus vitamin B₁₂, 0.4mg; 3) Vitamin B₆, 40mg; or 4) Placebo. Mean follow-up was 38 months. Results after one year showed mean serum folate concentration increased seven-fold and mean serum cobalamin concentration increased by 65% in the groups receiving folic acid plus vitamin B₁₂. Mean plasma total homocysteine level was decreased by 30%, from 10.8 (SD, 4.5) μmol per L at baseline to 7.6 (SD, 2.2) μmol per L in the groups receiving folic acid and vitamin B₁₂ (P<0.001). In the final results, 422 participants (13.7% of all) experienced an event in the composite primary end point of death, acute MI (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=0.36). 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=0.75). There were no differences in treatment response for the separate end points of death, total AMI (fatal and non-fatal, including procedure-related), or unstable angina pectoris. The incidence of total stroke (fatal and non-fatal, including hemorrhagic) was NS lower in the groups receiving folic acid. The incidence of acute hospitalization due to angina pectoris was lower in the folic acid groups (HR= 0.82; 95% CI: 0.67,1.00; P=.05). Post-hoc overall survival analysis showed no differences between the groups (P=0.07), 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=0.03) compared with placebo. Daily supplements: 1) Folic acid (0.8mg), plus vitamin B₁₂ (0.4mg) and B₆ (40mg); 2) Folic acid (0.8mg), plus B₁₂ (0.4mg); vitamin B₆ (40mg). The median follow-up was 38 months. The primary outcome was a composite of all-cause death, non-fatal AMI, acute hospitalization or unstable angina pectoris and non-fatal thromboembolic stroke. Mean plasma homocysteine concentration decreased by 30% after one year of treatment. Despite these reductions, overall there was no effect of the treatment with folic acid and vitamin B₁₂ or vitamin B₆ on total mortality or cardiovascular events. If anything, there was a slight but significant increase in risk using post-hoc overall survival analysis of the composite primary end point in the group receiving folic acid plus vitamin B₁₂ (HR=1.43; 95% CI: 1.03,1.75; P=0.03) compared to placebo.

Ray et al, 2007 (positive quality). This placebo-controlled clinical trial used data from the Heart Outcomes Prevention Evaluation 2 (HOPE-2), a large, randomized study, to determine whether decreasing homocysteine levels alters the risk for symptomatic venous thromboembolism. The incidence rate of venous thromboembolism was the same in the vitamin therapy group and the placebo group (0.35 per 100 person-years; HR, 1.01 95% CI: 0.66, 1.53). Vitamin therapy did not reduce the risk for deep venous thrombosis (HR, 1.04; 95% CI: 0.63, 1.72), pulmonary embolism (HR, 1.14; 95% CI: 0.57, 2.28), or unprovoked venous thromboembolism (HR, 1.21; 95% CI: 0.66, 2.23). Decreasing homocysteine levels with folic acid and vitamins B₆ and B₁₂ did not reduce the risk for symptomatic venous thromboembolism.