Effect of Homocysteine Lowering on Mortality and Vascular Disease in Advanced Chronic Kidney Disease and End-stage Renal Disease
A 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
- 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).
- Corresponding Author: Rex L. Jamison, MD, MB3 Room 305, M/C HOST 151, Veterans Affairs Palo Alto Health Care System, 3801 Miranda Ave, Palo Alto, CA 94304 (rjamison{at}stanford.edu).
Abstract
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
