Homocysteine lowering with folic acid and B vitamins in vascular disease.
What this study found
The combination lowered homocysteine but did not reduce major vascular events overall. The primary outcome occurred in 519 participants (18.8%) in the active group versus 547 (19.8%) with placebo (relative risk 0.95; 95% CI 0.84 to 1.07; P = 0.41). Mean total plasma homocysteine fell from 12.2 to 9.7 μmol per liter in the active group, while it rose from 12.2 to 12.9 μmol per liter with placebo; the between-group difference in change was 3.2 μmol per liter at the end of the study. Stroke was reduced (111 [4.0%] vs 147 [5.3%]; RR 0.75; 95% CI 0.59 to 0.97; P = 0.03), but death from any cause…
- Study & population
- Randomized, placebo-controlled, multicenter trial in adults aged 55 years or older with a history of vascular disease or diabetes plus additional atherosclerotic risk factors.
- Intervention
- The active regimen was a daily oral combined pill containing folic acid 2.5 mg, vitamin B6 50 mg, and vitamin B12 1 mg, given for a mean follow-up of 5 years and compared with matching placebo.
- Key limitation
- The primary vascular outcome was negative despite clear biochemical homocysteine lowering, so the clinical benefit was limited.
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Open PDFOriginal abstract
BACKGROUND In observational studies, lower homocysteine levels are associated with lower rates of coronary heart disease and stroke. Folic acid and vitamins B6 and B12 lower homocysteine levels. We assessed whether supplementation reduced the risk of major cardiovascular events in patients with vascular disease. METHODS We randomly assigned 5522 patients 55 years of age or older who had vascular disease or diabetes to daily treatment either with the combination of 2.5 mg of folic acid, 50 mg of vitamin B6, and 1 mg of vitamin B12 or with placebo for an average of five years. The primary outcome was a composite of death from cardiovascular causes, myocardial infarction, and stroke. RESULTS Mean plasma homocysteine levels decreased by 2.4 micromol per liter (0.3 mg per liter) in the active-treatment group and increased by 0.8 micromol per liter (0.1 mg per liter) in the placebo group. Primary outcome events occurred in 519 patients (18.8 percent) assigned to active therapy and 547 (19.8 percent) assigned to placebo (relative risk, 0.95; 95 percent confidence interval, 0.84 to 1.07; P=0.41). As compared with placebo, active treatment did not significantly decrease the risk of death from cardiovascular causes (relative risk, 0.96; 95 percent confidence interval, 0.81 to 1.13), myocardial infarction (relative risk, 0.98; 95 percent confidence interval, 0.85 to 1.14), or any of the secondary outcomes. Fewer patients assigned to active treatment than to placebo had a stroke (relative risk, 0.75; 95 percent confidence interval, 0.59 to 0.97). More patients in the active-treatment group were hospitalized for unstable angina (relative risk, 1.24; 95 percent confidence interval, 1.04 to 1.49). CONCLUSIONS Supplements combining folic acid and vitamins B6 and B12 did not reduce the risk of major cardiovascular events in patients with vascular disease. (ClinicalTrials.gov number, NCT00106886; Current Controlled Trials number, ISRCTN14017017.).