Journal of the American Medical Association. 2007 Sep 12;298(10):1163-70.
Jamison RL, Hartigan P, Kaufman JS, Goldfarb DS, Warren SR, Guarino PD, Gaziano JM; Veterans Affairs Site Investigators.
Significance:
Folic acid supplementation does not yield a cardiovascular benefit in patients with hyperhomocysteinemia and kidney disease.
Hyperhomocysteinemia is linked to cardiovascular disease, and patients with chronic kidney disease have the second highest homocysteine levels after patients with homocystinuria.
This study shows that giving high dose folic acid reduces levels of homocysteine but does not affect mortality rates. The result is similar to studies of patients with vascular disease (HOPE-2) and myocardial infarction (NORVIT) published last year. There does not appear to be any remaining rationale for screening for hyperhomocysteinemia at this time.
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 < or =30 mL/min) (n = 1305) or end-stage renal disease (n = 751) and high homocysteine levels (> or = 15 micromol/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 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.
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.
PMID: 17848650
