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Effect of Homocysteine Lowering on Mortality and Vascular Disease in Advanced Chronic Kidney Disease and End-stage Renal DiseaseA Randomized Controlled Trial
Rex L. Jamison, MD;
Pamela Hartigan, PhD;
James S. Kaufman, MD;
David S. Goldfarb, MD;
Stuart R. Warren, PharmD;
Peter D. Guarino, PhD;
J. Michael Gaziano, MD; For the Veterans Affairs Site Investigators
JAMA. 2007;298:1163-1170.
Context High plasma homocysteine levels are a risk factor for mortality and vascular disease in observational studies of patients with chronic kidney disease. Folic acid and B vitamins decrease homocysteine levels in this population but whether they lower mortality is unknown.
Objective To determine whether high doses of folic acid and B vitamins administered daily reduce mortality in patients with chronic kidney disease.
Design, Setting, and Participants Double-blind randomized controlled trial (2001-2006) in 36 US Department of Veterans Affairs medical centers. Median follow-up was 3.2 years for 2056 participants aged 21 years or older with advanced chronic kidney disease (estimated creatinine clearance  30 mL/min) (n = 1305) or end-stage renal disease (n = 751) and high homocysteine levels ( 15 µmol/L).
Intervention Participants received a daily capsule containing 40 mg of folic acid, 100 mg of pyridoxine hydrochloride (vitamin B6), and 2 mg of cyanocobalamin (vitamin B12) or a placebo.
Main Outcome Measures The primary outcome was all-cause mortality. Secondary outcomes included myocardial infarction (MI), stroke, amputation of all or part of a lower extremity, a composite of these 3 plus all-cause mortality, time to initiation of dialysis, and time to thrombosis of arteriovenous access in hemodialysis patients.
Results Mean baseline homocysteine level was 24.0 µmol/L in the vitamin group and 24.2 µmol/L in the placebo group. It was lowered 6.3 µmol/L (25.8%; P < .001) in the vitamin group and 0.4 µmol/L (1.7%; P = .14) in the placebo group at 3 months, but there was no significant effect on mortality (448 vitamin group deaths vs 436 placebo group deaths) (hazard ratio [HR], 1.04; 95% CI, 0.91-1.18). No significant effects were demonstrated for secondary outcomes or adverse events: there were 129 MIs in the vitamin group vs 150 for placebo (HR, 0.86; 95% CI, 0.67-1.08), 37 strokes in the vitamin group vs 41 for placebo (HR, 0.90; 95% CI, 0.58-1.40), and 60 amputations in the vitamin group vs 53 for placebo (HR, 1.14; 95% CI, 0.79-1.64). In addition, the composite of MI, stroke, and amputations plus mortality (P = .85), time to dialysis (P = .38), and time to thrombosis in hemodialysis patients (P = .97) did not differ between the vitamin and placebo groups.
Conclusion Treatment with high doses of folic acid and B vitamins did not improve survival or reduce the incidence of vascular disease in patients with advanced chronic kidney disease or end-stage renal disease.
Trial Registration clinicaltrials.gov Identifier: NCT00032435
Author Affiliations: Veterans Affairs (VA) Palo Alto Health Care Systems and Division of Nephrology, Department of Medicine, Stanford University School of Medicine, Stanford, California (Dr Jamison); VA Cooperative Studies Program Coordinating Center, VA Connecticut Healthcare System, West Haven (Drs Hartigan and Guarino); Renal Section, VA Boston Healthcare System and Boston University School of Medicine, Boston, Massachusetts (Dr Kaufman); Nephrology Section, New York Harbor Healthcare System and New York University School of Medicine, New York, New York (Dr Goldfarb); VA Cooperative Studies Program, Clinical Research Pharmacy Coordinating Center and University of New Mexico College of Pharmacy, Albuquerque (Dr Warren); and Massachusetts Veteran's Epidemiology Research and Information (MAVERIC), VA Boston Healthcare System, and Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston (Dr Gaziano).
RELATED LETTERS
Homocysteine Lowering and Severe Kidney Disease
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Homocysteine Lowering and Severe Kidney Disease—Reply
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