Effect of homocysteine lowering on mortality and vascular disease in advanced chronic kidney disease and end-stage renal disease: a randomized controlled trial.
BACKGROUND
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.


METHODS
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 < or =30 mL/min) (n = 1305) or end-stage renal disease (n = 751) and high homocysteine levels (> or = 15 micromol/L).


METHODS
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.


METHODS
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 micromol/L in the vitamin group and 24.2 micromol/L in the placebo group. It was lowered 6.3 micromol/L (25.8%; P < .001) in the vitamin group and 0.4 micromol/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.


CONCLUSIONS
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.


BACKGROUND
clinicaltrials.gov Identifier: NCT00032435.
Jamison
Rex L
RL
Veterans Affairs Palo Alto Health Care Systems and Division of Nephrology, Department of Medicine, Stanford University School of Medicine, Stanford, California 94304, USA. rjamison@stanford.edu
Hartigan
Pamela
P
Kaufman
James S
JS
Goldfarb
David S
DS
Warren
Stuart R
SR
Guarino
Peter D
PD
Gaziano
J Michael
JM
D000368:Aged; D002423:Cause of Death; D004311:Double-Blind Method; D005260:Female; D005492:Folic Acid / Q000008:administration & dosage / Q000627:therapeutic use*; D006710:Homocysteine / Q000097:blood*; D006801:Humans; D053208:Kaplan-Meier Estimate; D007676:Kidney Failure, Chronic / Q000097:blood* / Q000150:complications* / Q000401:mortality; D008297:Male; D008875:Middle Aged; D016016:Proportional Hazards Models; D011736:Pyridoxine / Q000008:administration & dosage / Q000627:therapeutic use; D051436:Renal Insufficiency, Chronic / Q000097:blood* / Q000150:complications* / Q000401:mortality; D014652:Vascular Diseases / Q000209:etiology* / Q000401:mortality / Q000517:prevention & control*; D014805:Vitamin B 12 / Q000008:administration & dosage / Q000627:therapeutic use; D014803:Vitamin B Complex / Q000008:administration & dosage / Q000627:therapeutic use*
D006710:Homocysteine; D014803:Vitamin B Complex; D005492:Folic Acid; D011736:Pyridoxine; D014805:Vitamin B 12