Journal
JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION
Volume 302, Issue 19, Pages 2119-2126Publisher
AMER MEDICAL ASSOC
DOI: 10.1001/jama.2009.1622
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Funding
- Advanced Research Program and Research Council of Norway
- Norwegian Foundation for Health and Rehabilitation
- Norwegian Council on Cardiovascular Disease
- Norwegian Heart and Lung Patient Organization
- Norwegian Red Cross
- Northern Norway Regional Health Authority
- Western Norway Regional Health Authority
- Norwegian Ministry of Health and Care Services
- University of Tromso, Tromso, Norway
- University of Bergen, Bergen, Norway
- Department of Heart Disease at Haukeland University Hospital, Bergen, Norway
- Foundation to Promote Research Into Functional Vitamin B12 Deficiency, Bergen, Norway
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Context Recently, concern has been raised about the safety of folic acid, particularly in relation to cancer risk. Objective To evaluate effects of treatment with B vitamins on cancer outcomes and all-cause mortality in 2 randomized controlled trials. Design, Setting, and Participants Combined analysis and extended follow-up of participants from 2 randomized, double-blind, placebo-controlled clinical trials (Norwegian Vitamin Trial and Western Norway B Vitamin Intervention Trial). A total of 6837 patients with ischemic heart disease were treated with B vitamins or placebo between 1998 and 2005, and were followed up through December 31, 2007. Interventions Oral treatment with folic acid (0.8 mg/d) plus vitamin B-12 (0.4 mg/d) and vitamin B-6 (40 mg/d) (n=1708); folic acid (0.8 mg/d) plus vitamin B-12 (0.4 mg/d) (n=1703); vitamin B-6 alone (40 mg/d) (n=1705); or placebo (n=1721). Main Outcome Measures Cancer incidence, cancer mortality, and all-cause mortality. Results During study treatment, median serum folate concentration increased more than 6-fold among participants given folic acid. After a median 39 months of treatment and an additional 38 months of posttrial observational follow-up, 341 participants (10.0%) who received folic acid plus vitamin B-12 vs 288 participants (8.4%) who did not receive such treatment were diagnosed with cancer (hazard ratio [HR], 1.21; 95% confidence interval [CI], 1.03-1.41; P=.02). A total of 136 (4.0%) who received folic acid plus vitamin B-12 vs 100 (2.9%) who did not receive such treatment died from cancer (HR, 1.38; 95% CI, 1.07-1.79; P=.01). A total of 548 patients (16.1%) who received folic acid plus vitamin B-12 vs 473 (13.8%) who did not receive such treatment died from any cause (HR, 1.18; 95% CI, 1.04-1.33; P=.01). Results were mainly driven by increased lung cancer incidence in participants who received folic acid plus vitamin B-12. Vitamin B-6 treatment was not associated with any significant effects. Conclusion Treatment with folic acid plus vitamin B-12 was associated with increased cancer outcomes and all-cause mortality in patients with ischemic heart disease in Norway, where there is no folic acid fortification of foods. Trial Registration clinicaltrials.gov Identifier: NCT00671346 JAMA. 2009; 302(19): 2119-2126
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