Randomized Trial of Folic Acid for Prevention of Cardiovascular Events in End-Stage Renal Disease ELIZABETH M. WRONE,* † JOHN M. HORNBERGER, ‡ JAMES L. ZEHNDER, § LINDA M. MCCANN,* NORMAN S. COPLON,* and STEPHEN P. FORTMANN, † *Satellite Research, Redwood City, California; † Stanford Center for Research in Disease Prevention, Stanford University School of Medicine, Stanford, California; ‡ Acumen, LLC, Burlingame, California; § Department of Pathology, Stanford University School of Medicine, Stanford, California. Abstract. High serum total homocysteine (tHcy) is gaining scrutiny as a risk factor for cardiovascular disease in the general population. The relationship between tHcy and mor- tality and cardiovascular events in patients with end-stage renal disease (ESRD) is unsettled. This randomized trial evaluates the efficacy of high-dose folic acid in preventing events in ESRD. A total of 510 patients on chronic dialysis were ran- domized to 1, 5, or 15 mg of folic acid contained in a renal multivitamin with a median follow-up of 24 mo. Mortality, cardiovascular events, and homocysteine levels were assessed. There were 189 deaths, and 121 patients experienced at least one cardiovascular event. Composite rates of mortality and cardiovascular events among the folic acid groups did not differ (at 24 mo: 43.7% in 1 mg group, 38.6% in 5 mg group, 47.1% in 15 mg group; log-rank P = 0.47). Unexpectedly, high baseline tHcy was associated with lower event rates. From lowest to highest quartile, event rates at 24 mo were 54.5% for Q1, 41.8% for Q2, 41.2% for Q3, and 34.7% for Q4 (log-rank P = 0.033). In contrast to some studies describing tHcy as a risk factor for mortality and cardiovascular events, this study found a reverse relationship between tHcy and events in ESRD patients. Administration of high-dose folic acid did not affect event rates. End-stage renal disease (ESRD) afflicts nearly half a million people in the United States (1) and carries mortality rates from cardiovascular disease that are 10-fold to 100-fold higher than those of the general population (2). In ESRD, mean total homocysteine levels (tHcy) are commonly elevated, and the role of homocysteine as risk factor has been suggested in some small prospective studies (3–5). However, some studies in ESRD have observed an inverse relationship between tHcy and cardiovascular disease (6,7). Homozygosity for the common C677T mutation of methylenetetrahydrofolate reductase (MTHFR) (8), a key enzyme in homocysteine metabolism may also be associated with elevated tHcy levels and cardiovascular disease in ESRD (7,9). Total serum homocysteine (tHcy) is readily reduced with folic acid and vitamin B12 in the general population. In ESRD, higher doses of folic acid appear to be required, and normal levels of homocysteine are not commonly achieved (10). Pa- tients with ESRD are frequently given multivitamin supple- ments to compensate for dialysate losses and dietary restric- tions; however, the optimal amount of folic acid supple- mentation in ESRD for reduction of tHcy has not been established. To explore the relationship between folic acid, homocys- teine, and clinical outcomes, we present the results of a ran- domized trial of folic acid for prevention of cardiovascular morbidity/mortality in patients with ESRD. The primary ques- tion addressed is “does supplementation with a multivitamin containing folic acid in 5-mg or 15-mg doses reduce a com- posite end point of mortality and cardiovascular events over 3 yr compared with standard therapy (1 mg of folic acid)?” Secondarily, “do these higher doses of folic acid prevent vas- cular access clotting?” In addition, we test the hypothesis that high levels of baseline tHcy and the TT genotype of the C677T mutation of MTHFR are associated with an increased inci- dence of cardiovascular events and mortality. Materials and Methods Participants This randomized, double blind, three-arm study of homocysteine reduction was performed at 10 affiliated nonprofit outpatient dialysis facilities in Northern California. At the time of enrollment, approxi- mately 1100 patients received treatment at these outpatient facilities. Patients were recruited by study dietitians at their dialysis units. Written consent was obtained from every patient after a full explana- tion of the study, which was approved by the Administrative Panel on Human Subjects in Medical Research of Stanford University. Adult patients undergoing hemodialysis or peritoneal dialysis and who were able to participate in the consent process were eligible for the study. Patients who were undergoing intradialytic parenteral nutrition, an- ticipating a living-related kidney transplant, receiving an anti-seizure Received April 4, 2003. Accepted October 18, 2003. Correspondence to: Dr. Elizabeth Wrone, Diablo Nephrology Medical Group, 112 La Casa Via, Suite 210, Walnut Creek, CA 94598. Phone: 925-944-0351; Fax: 925-944-1957; Email: ewrone@stanfordalumni.org 1046-6673/1502-0420 Journal of the American Society of Nephrology Copyright © 2004 by the American Society of Nephrology DOI: 10.1097/01.ASN.0000110181.64655.6C J Am Soc Nephrol 15: 420–426, 2004