Effect of Homocysteine Lowering on Mortality and Vascular Disease in Advanced Chronic Kidney Disease and End-stage Renal Disease: A Randomized Controlled Trial

• Published in: JAMA : the journal of the American Medical Association Vol. 298; no. 10; pp. 1163 - 1170
• Main Authors: Jamison, Rex L, Hartigan, Pamela, Kaufman, James S, Goldfarb, David S, Warren, Stuart R, Guarino, Peter D, Gaziano, J. Michael, Veterans Affairs Site Investigators, For the
• Format: Journal Article
• Language: English
• Published: Chicago, IL American Medical Association 12.09.2007
• Subjects: Aged; Amino acids; Biological and medical sciences; Cause of Death; Clinical trials; Double-Blind Method; Epidemiology; Female; Folic Acid - administration & dosage; Folic Acid - therapeutic use; General aspects; Homocysteine - blood; Humans; Kaplan-Meier Estimate; Kidney diseases; Kidney Failure, Chronic - blood; Kidney Failure, Chronic - complications; Kidney Failure, Chronic - mortality; Kidneys; Male; Medical sciences; Middle Aged; Mortality; Nephrology. Urinary tract diseases; Proportional Hazards Models; Public health. Hygiene; Public health. Hygiene-occupational medicine; Pyridoxine - administration & dosage; Pyridoxine - therapeutic use; Renal Insufficiency, Chronic - blood; Renal Insufficiency, Chronic - complications; Renal Insufficiency, Chronic - mortality; Urinary system involvement in other diseases. Miscellaneous; Vascular Diseases - etiology; Vascular Diseases - mortality; Vascular Diseases - prevention & control; Vein & artery diseases; Vitamin B; Vitamin B 12 - administration & dosage; Vitamin B 12 - therapeutic use; Vitamin B Complex - administration & dosage; Vitamin B Complex - therapeutic use; Kidney disease; Thiol; Urinary system disease; Mortality; Cardiovascular disease; Terminal stage; Chronic kidney disease; Epidemiology; Sulfur containing aminoacid; Medicine; Vascular disease; Randomization; Homocystein; Renal failure; Clinical trial; Advanced stage
• ISSN: 0098-7484; 1538-3598
• DOI: 10.1001/jama.298.10.1163

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