Background: High levels of homocysteine are associated with cardiovascular disease, but studies examining the cardiovascular benefit of lowering homocysteine levels with folic acid and B vitamins have inconsistent results. The only benefit shown in recent studies was in a subgroup of stroke patients. Because patients with end-stage renal disease (ESRD) have an annual cardiovascular mortality of 20 percent and higher levels of homocysteine than patients in previous studies, Jamison and colleagues conducted a randomized controlled trial to determine whether this high-risk population would benefit from folic acid and B-vitamin supplementation.

The Study: The participants in the Homocysteinemia in Kidney and End Stage Renal Disease trial were 21 years or older, with ESRD requiring regular dialysis or with an estimated creatinine clearance of 30 mL per minute (0.50 mL per second) or less. Eligible patients had a plasma homocysteine level of 2.03 mg per L (15.0 μmol per L) or higher. Participants were randomized to folic acid and B-vitamin supplementation (40 mg folic acid, 100 mg pyridoxine, 2 mg cyanocobalamin) or placebo. Both groups were allowed to take an additional 1 mg or less of folate as part of their routine medical care.

Homocysteine, vitamin B₁₂, vitamin B₆, and folic acid levels were measured at baseline and three months, and at yearly intervals in a representative subgroup of patients. An initial in-person follow-up session was conducted at three months to determine interim health, adverse effects, and medication adherence; subsequently, quarterly follow-up was conducted by telephone, mail, or e-mail.

The primary outcome was time to all-cause mortality. Secondary outcomes were time to myocardial infarction, stroke, and amputation of a lower extremity, and a composite of all secondary outcomes and all-cause mortality. Additional secondary outcomes were time to thrombosis of arte-riovenous access in hemodialysis patients, and time to dialysis initiation in patients with advanced chronic kidney disease.

Results: The 2,056 participants included 751 with ESRD and 1,305 with advanced chronic kidney disease; 1,032 were in the treatment group and 1,024 were in the placebo group. All participants were followed for a median of 3.2 years. At three months, the mean homocysteine level in the treatment group was reduced by 0.84 mg per L (6.2 μmol per L; 25.8 percent). In the placebo group, the mean reduction was nonsignificant at 0.05 mg per L (0.4 μmol per L; 1.7 percent). In more than one third of treated patients, the homocysteine level was reduced to the normal range. Folic acid level increased in the treatment group. These changes persisted throughout the three years of follow-up in the representative subgroup.

All-cause mortality was similar between groups, with death occurring in 43.4 percent of the treatment group and 42.6 percent of the placebo group. Adjustment for covariates did not change the analysis. Additionally, there were no differences in secondary outcomes between groups. Calculation of hazard ratios showed nonsignificant differences for all outcomes. There were no significant differences in adverse events or medication adherence.

Conclusion: Lowering homocysteine levels with folate and B vitamins in patients with chronic kidney disease does not improve outcomes. The authors conclude that although patients with homocystinuria benefit from such supplementation, patients with cardiovascular and end-stage renal disease do not.