David Goldfarb and colleagues conclude lowering homocysteine won't help patients with serious kidney disease
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
[Dr. Goldfarb, NYU School of Medicine, Division of Nephrology of the Department of Medicine, along with other authors, is credited with contributing to the study concept and design; acquisition of data; analysis and interpretation of data; drafting of the manuscript; critical revision of the manuscript for important intellectual content; administrative, technical or material support; and study supervision.]
Dr. David Goldfarb and colleagues performed a randomized controlled trial of high dose folic acid for high homocysteine levels in patients with kidney disease. There was no effect of homocysteine lowering to prevent heart attacks, strokes, amputations or progression of chronic kidney disease. In combination with other negative studies reported in the last year of folic acid supplementation in patients who did not have kidney disease, there is now no clear indication for supplementation of B vitamins to lower homocysteine.
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