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Original Contribution |

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

Rex L. Jamison, MD; Pamela Hartigan, PhD; James S. Kaufman, MD; David S. Goldfarb, MD; Stuart R. Warren, PharmD; Peter D. Guarino, PhD; J. Michael Gaziano, MD; For the Veterans Affairs Site Investigators
[+] Author Affiliations

Author Affiliations: Veterans Affairs (VA) Palo Alto Health Care Systems and Division of Nephrology, Department of Medicine, Stanford University School of Medicine, Stanford, California (Dr Jamison); VA Cooperative Studies Program Coordinating Center, VA Connecticut Healthcare System, West Haven (Drs Hartigan and Guarino); Renal Section, VA Boston Healthcare System and Boston University School of Medicine, Boston, Massachusetts (Dr Kaufman); Nephrology Section, New York Harbor Healthcare System and New York University School of Medicine, New York, New York (Dr Goldfarb); VA Cooperative Studies Program, Clinical Research Pharmacy Coordinating Center and University of New Mexico College of Pharmacy, Albuquerque (Dr Warren); and Massachusetts Veteran's Epidemiology Research and Information (MAVERIC), VA Boston Healthcare System, and Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston (Dr Gaziano).

More Author Information
JAMA. 2007;298(10):1163-1170. doi:10.1001/jama.298.10.1163.
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Published online

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

Figures in this Article

In 1969, McCully1 proposed that high plasma total homocysteine concentration caused severe atherothrombotic disease and death in adolescents with homocystinuria. Folic acid, vitamin B6, and vitamin B12 play critical roles in the metabolism of homocysteine.2 Treatment with large doses of folic acid, pyridoxine hydrochloride (vitamin B6), and cyanocobalamin (vitamin B12) lowered the homocysteine levels and dramatically reduced mortality in these patients.3 In the last 30 years, numerous case-control and prospective studies have extended these findings to the general population and shown that high levels of homocysteine—albeit an order of magnitude lower than those in homocystinuria—are associated with vascular disease.47 On a parallel track, laboratory research has demonstrated that homocysteine causes oxidative stress, injures vascular endothelium, and stimulates formation of thrombi in vitro and in vivo.1,810

Although epidemiologic studies have confirmed the association between homocysteine and cardiovascular risk, interventional studies designed to lower homocysteine levels have not shown a consistent benefit on clinical outcomes. Several randomized controlled trials of lowering homocysteine with folic acid and B vitamins failed to find a reduction of major cardiovascular events or death in a variety of high-risk patients,1113 although a post hoc analysis in one study showed that a subgroup of stroke patients might have benefited from the intervention.14

Patients with chronic kidney disease or end-stage renal disease (ESRD) have higher homocysteine levels than those in the foregoing trials.1517 They have extensive vascular disease, with estimates of annual mortality as high as 20%.1820 The cerebral and cardiovascular complications of the vascular disease, and, in some studies, thrombosis of the vascular access, a common and costly complication in ESRD,21 are correlated with high homocysteine levels.21

The characteristically high homocysteine levels, extensive vascular disease, and high mortality rates make this population particularly suitable to test the benefit of lowering homocysteine. We conducted a randomized controlled trial, sponsored by the Department of Veterans Affairs (VA) Cooperative Studies Program (Homocysteinemia in Kidney and End Stage Renal Disease [HOST]), to determine whether treatment with a combination of high-dose folic acid and vitamins B6 and B12 can reduce mortality and cardiovascular events in patients with advanced chronic kidney disease (ACKD) and ESRD.

Study Design

The details of the HOST study design have been described22 and are summarized here. HOST was a multicenter, randomized, double-blind, placebo-controlled trial to determine whether treatment with folic acid plus pyridoxine and cyanocobalamin to lower plasma total homocysteine levels reduces all-cause mortality and major vascular events in a high-risk population.

Study Population

Participants aged 21 years or older, with ESRD, receiving maintenance hemodialysis or peritoneal dialysis, or with an estimated creatinine clearance of less than or equal to 30 mL/min (to convert creatinine clearance to mL/s, multiply by 0.0167) by the Cockcroft-Gault formula23 (ACKD) were recruited from 36 participating VA medical centers. A plasma homocysteine level of 15 μmol/L or higher was also required. Race and ethnicity were based on patient self-report by using investigator-defined options. Race and ethnicity were assessed because they have been reported to be associated with the prevalence and outcomes of individuals with chronic kidney disease.

The human rights committee at the coordinating center and the institutional review boards of all participating sites approved the study, and all study participants provided written informed consent.

Study Intervention

Participants were randomly assigned to receive a once-daily capsule containing 40 mg of folic acid, 100 mg of pyridoxine hydrochloride, and 2 mg of cyanocobalamin or an identical-appearing placebo capsule. Participants, investigators, laboratory staff, and the Endpoint Adjudication Committee were blinded to treatment assignment. The randomization scheme was stratified by site and disease strata (ESRD vs ACKD) and used a random permuted block design of varying block size. Participants in both groups were allowed to take additional vitamins containing no more than 1 mg of folate, if prescribed by their physicians as part of their general medical care.

Baseline and Follow-up Evaluations

At entry, demographic, clinical, and laboratory data, including plasma homocysteine and serum folic acid and vitamins B6 and B12 levels, were obtained and participants were given a 3-month supply of study drug. Participants returned to the local sites for evaluation at 3 months. A fasting blood sample was collected for homocysteine and folic acid determination. Participants were asked about hospitalizations, medication adherence, study outcomes, and adverse events during the past 3 months and were given a new 3-month supply of study drug. All subsequent quarterly follow-up evaluations were conducted by telephone (or, if necessary, by mail or e-mail) by study coordinators located at 2 centers. The central study coordinators attempted to verify all study-related outcome events reported by the participants by searching the VA electronic records or by requesting records for non-VA hospitalizations. The participants received a quarterly supply of study capsules by mail from the VA Cooperative Studies Program Clinical Research Pharmacy. To assess adherence, participants were asked to return the bottle with unused capsules when they received a new bottle. In a representative substudy of 358 participants from 6 participating sites, blood samples were obtained annually for homocysteine, folic acid, vitamin B6, and vitamin B12 determinations. The sites were selected according to number of participants (3 smaller and 3 larger sites) and were geographically dispersed.

Trial Outcomes

The primary study outcome was time to death from any cause. Secondary outcomes included time to myocardial infarction (MI), stroke, amputation of all or part of a lower extremity, and a composite of these 3 plus all-cause mortality. In addition, we assessed time to thrombosis of arteriovenous access (fistula or graft) in hemodialysis patients and time to initiation of dialysis in ACKD patients. All participants continued to be followed up and to receive their assigned treatment after a secondary outcome event.

Deaths were confirmed by hospital discharge summary, autopsy report, Medicare End Stage Renal Disease Death Notification, or death certificate. Deaths were also tracked with the Beneficiary Identification and Records Locator Subsystem, a VA data file used to record death benefits and dates.24 Fatal and nonfatal events were ascertained through self-reporting by participants in response to specific queries during quarterly follow-up contacts and by review of the patient's VA medical record. Myocardial infarction was diagnosed when 2 of the following 3 criteria were met: typical symptoms, increased cardiac enzyme levels, and diagnostic electrocardiographic changes.25 Stroke was defined as rapid onset of a persistent neurologic deficit attributed to an obstruction in the arterial system of the brain, providing the deficit was not known to be a result of cerebral hemorrhage, trauma, tumor, infection, or other nonthrombotic causes.26 Thrombosis events were collected only for vascular accesses that were actually being used for dialysis and did not include events that occurred before dialysis initiation or that resulted in failure of access maturation.

An independent review committee, blinded to treatment assignment, adjudicated all secondary outcome events: MIs, strokes, and thromboses of the vascular access. Discharge summaries, neurologic examinations, imaging results, cardiac enzyme reports, and electrocardiograms were obtained to verify hospitalization, diagnosis, and outcomes. Only definite or probable events were included in the analysis. An independent data and safety monitoring board monitored the study for safety and scientific integrity.

Laboratory Analyses

Plasma homocysteine level was determined with the Fluorescence Polarization Immunoassay/Abbott Axsym in kits provided by Abbott Laboratories (Abbott Park, Illinois).27 The determination of serum concentrations of folic acid and vitamin B12 (Bayer Direct Chemiluminescence Method [immunoassay]; Bayer Advia Centaur/Bayer Diagnostics, Tarrytown, New York) and vitamin B6 (Alpco REA; RKVB6, Salem, New Hampshire) was performed in a central chemistry laboratory.

Statistical Analysis

The study was designed to enroll 2006 patients, with a median follow-up of 5 years to detect a relative risk reduction in time to event for the primary outcome of 17%, with 80% power, given a loss rate of approximately 1% per year, an annual event rate of 10.3% in the placebo group, and a 2-sided type I error of .05. The target number of events was 820.

All analyses were performed according to intention to treat. Participants who withdrew consent from all follow-up contacts and medical record reviews were included in the primary end point analysis but were censored from secondary outcome analyses at withdrawal. Survival curves for the 2 groups were estimated according to the Kaplan-Meier procedure and compared with the log-rank statistic. The hazard ratios (vitamins relative to placebo) for all primary and secondary outcomes were calculated with the Cox proportional hazards regression model, adjusted for strata (ACKD vs ESRD). Cox models were also used to evaluate the treatment effect on the primary outcome in the prespecified subgroups of age, race, diabetes history, cardiac disease history, renal disease strata, and baseline homocysteine levels. Treatment × subgroup interactions were performed to test for homogeneity. Additional sensitivity analyses of the treatment effect adjusted for baseline covariates were conducted to evaluate the stability of the study conclusions. All reported P values are 2-sided and unadjusted for multiple comparisons. P ≤ .05 was considered significant. SAS version 8.2 was used for all analyses (SAS Institute Inc, Cary, North Carolina).

Between September 2001 and October 2003, of the 2473 patients who consented for screening laboratory tests, 2056 participants—751 with ESRD and 1305 with ACKD—were randomized to the vitamin treatment (1032) or placebo groups (1024) (Figure 1). In May 2006, the data and safety monitoring board recommended that the study be stopped because the required number of primary end points had been reached. Patient contacts were completed August 31, 2006. The median length of follow-up was 3.2 years. Of the 2056 randomized participants, 169 (8.2%) withdrew from regular telephone follow-up but continued to allow medical record review, and 66 (3.2%) withdrew consent from follow-up contacts and medical record review.

Figure 1. Flow of Participants in the Study
Graphic Jump Location

To convert creatinine clearance to mL/s, multiply values by 0.0167. ESRD indicates end-stage renal disease; ACKD, advanced chronic kidney disease.

Baseline Characteristics

The treatment and control groups were well balanced in baseline characteristics (Table 1). The mean (SD) estimated creatinine clearance of participants with ACKD was 21.6 (6.9) mL/min by the Cockcroft-Gault method, and the estimated glomerular filtration rate was 18.3 (6.3) mL/min per 1.73 m2 by the Modification of Diet in Renal Disease abbreviated equation.28

Effect of Intervention on Plasma Homocysteine and B Vitamin Levels

The median plasma homocysteine and folate levels at baseline and 3 months are presented in Table 2. The mean (SD) plasma homocysteine levels at baseline were 24.0 (7.7) and 24.2 (9.8) μmol/L for treatment and placebo groups, respectively. The mean homocysteine level was reduced by 6.2 μmol/L (25.8%) in the treatment group at 3 months (P < .001); values for 36% (332) of the patients in the treatment group decreased into the normal range (< 15 μmol/L). The mean decrease in homocysteine level of 0.4 μmol/L (1.7%) in the placebo group at 3 months was not significant (P = .14). There was a dramatic increase in the level of serum folic acid between baseline and 3 months in the treatment group but little change at 3 months in the placebo group (Table 2). In the cohort of 358 patients who had annual determinations of serum folic acid and plasma homocysteine levels, the effect of active treatment on homocysteine and folic acid at 3 months was maintained throughout the first 3 years of the study (the median follow-up time) (Table 3).

Table Graphic Jump LocationTable 2. Plasma Levels of Total Homocysteine and Folate at Baseline and 3 Months
Table Graphic Jump LocationTable 3. Plasma Total Homocysteine and Folate at Baseline and Annually in Substudy Population
Primary End Point

Treatment had no effect on all-cause mortality (hazard ratio, 1.04; 95% confidence interval [CI], 0.91-1.18) (Figure 2; Table 4). There were 884 deaths: 448 (43.4%) in the treatment group and 436 (42.6%) in the placebo group. The cumulative 3-year mortality rate was 36.3% in the treatment group and 34.6% in the placebo group, with a mortality rate at 1 year of 11.8% vs 10.0%, respectively. After adjusting for the prespecified baseline covariates of age, race, smoking status, history of diabetes or cardiovascular disease, homocysteine, low-density lipoprotein cholesterol, and albumin, the effect of treatment was virtually unchanged (hazard ratio, 1.06; 95% CI, 0.92-1.22).

Figure 2. Kaplan-Meier Estimates of Survival
Graphic Jump Location

There were a total of 884 deaths.

Table Graphic Jump LocationTable 4. Primary and Secondary Outcomes
Secondary End Points, Subgroups, and Adverse Events

Treatment had no effect on any of the major vascular events that comprise the secondary end points, the composite end point, the need to start maintenance dialysis, or thrombosis of the vascular access (Table 4). Vascular access thrombosis occurred in 73 of the 336 patients (22%) with fistulae and 101 of the 221 patients (46%) with grafts at baseline. All-cause mortality did not differ significantly between the treatment and placebo groups in any of the subgroups examined (Figure 3). The hazard ratio of treatment vs placebo for ACKD participants was 1.04 (95% CI, 0.88-1.23) and for ESRD participants, 1.04 (95% CI, 0.83-1.28) (P = .93). The mortality rates for the ACKD participants were 43.1% (placebo) vs 43.8% (treatment); for ESRD participants, 41.7% vs 42.7%, respectively.

Figure 3. Hazard Ratios for All-Cause Mortality by Subgroups
Graphic Jump Location

CI indicates confidence interval; ESRD, end-stage renal disease; ACKD, advanced chronic kidney disease. The sizes of the data markers relate to subgroup sample size.

There was no significant difference in the number and types of adverse events, including serious adverse events, between the treatment and control groups. There were no statistically significant differences between the treatment groups for any of the potential adverse effects of the vitamins that were specifically queried, including gastrointestinal and dermatological events, headache, paresthesia, and fatigue, or for any self-reported adverse events, or hospital admissions.

Adherence

Among patients assigned to the vitamin treatment group, 90.3% reported taking study medication at 1 year, 87.6% at 2 years, and 85.3% at 3 years. In the placebo group, the figures were similar: 90.7% at 1 year, 87.2% at 2 years, and 86.5% at 3 years. A total of 73% in the treatment group and 74% in the placebo group reported never stopping their study medication. Counts of capsules in the returned bottles (77% of those dispensed) revealed that 90% of study capsules were taken by patients in both treatment and placebo groups.

Patients with chronic kidney disease have a high risk for complications of atherosclerosis, including increased mortality. Although traditional risk factors such as hypertension are more prevalent in this population, there has been increasing emphasis on the role of nontraditional risk factors such as anemia, hyperparathyroidism, and hyperhomocysteinemia.29 The association of elevated homocysteine levels with risk of cardiovascular disease has drawn attention because of the nearly universal elevation of homocysteine in patients with chronic kidney disease to levels higher than that of any other patient population except those with homocystinuria, the epidemiologic correlation between homocysteine and cardiovascular risk in the chronic kidney disease population,1517 and the finding that ingestion of folic acid plus pyridoxine and cyanocobalamin lowers homocysteine levels in these patients.16,30

The results of our trial, however, indicate that although administration of large daily doses of folic acid plus pyridoxine and cyanocobalamin to patients with ACKD or ESRD lowered plasma homocysteine levels, it did not improve survival during a median of 3.2 years of follow-up. Furthermore, there was no significant decrease in the incidence of cardiovascular events or, in hemodialysis patients, the rate of thrombosis of the vascular access, a common event requiring hospitalization in these patients.21

Recent reports of several large randomized trials in lower-risk patients without kidney disease, in whom smaller doses of vitamins were used and smaller reductions in homocysteine levels were observed, have failed to show a benefit of vitamin supplementation: the Vitamin Intervention for Stroke Prevention,13 the Heart Outcomes Prevention Evaluation (HOPE-2) study,12 and the Norwegian Vitamin (NORVIT) trial.11 Patients with kidney disease have higher plasma homocysteine levels and a higher risk for cardiovascular events than patients included in the previously cited trials. There have been a limited number of trials of homocysteine lowering in dialysis patients, but these trials were small and therefore underpowered to detect a clinically significant effect on mortality.3133 In our trial, however, which used large doses of vitamins, resulting in a change in homocysteine levels twice that reported in previous trials,1113 and was adequately powered to detect a relative risk reduction in mortality of 17%, we failed to find a benefit of vitamin supplementation. In contrast to the NORVIT study, we did not observe an increased risk of vascular events in the treatment group.11

What might account for the failure of the treatment in our study? Possibly the underlying burden of disease was too great for a measurable benefit from lowering homocysteine. A trial of statins in diabetic dialysis patients failed to show a mortality benefit despite lowering low-density lipoprotein cholesterol,34 suggesting that even the reduction of some traditional risk factors may not be beneficial in this high-risk population. It may be that although homocysteine levels were substantially reduced, amelioration of the consequences of hyperhomocysteinemia requires lowering to normal levels, an effect that was achieved in only one-third of our participants, despite administration of the highest vitamin doses among homocysteine-lowering studies reported to date.35 Loscalzo,10 commenting on the results of the NORVIT and HOPE-2 trials, has suggested that vitamin therapy may have had adverse effects that offset its homocysteine-lowering benefit.

The disparity between our findings and the epidemiologic literature showing an association between moderate increases in homocysteine and atherothrombotic disease could reflect an unrecognized adverse effect of the folic acid or vitamins but in all probability reflects the inherent limitations of observational studies. It has been suggested that homocysteine marks the existence of vascular disease rather than causes it6,1013,32; yet in homocystinuria, vitamin therapy has an impressive benefit on mortality and cardiovascular events.3 It may be that the relationship between homocysteine and vascular injury is nonlinear or that the potential for amelioration of the vascular injury is too slight in patients without homocystinuria to be detectable, particularly in patients with many other risk factors.

There are several limitations of this study. First, the population was nearly all male. The relationship between homocysteine and vascular disease and the response to vitamin therapy is similar in men and women.2,5,36 The homocysteine levels and extent of vascular disease in the veterans in this trial are similar to those reported in nonveteran men and women with ACKD or ESRD16,18,32,33; we would therefore not expect that the enrollment of a predominantly male population accounts for our null results. Second, to achieve adequate power we enrolled both ACKD and ESRD patients. Jungers et al16 reported an association of homocysteine and cardiovascular disease in chronic kidney disease similar to that in ESRD. In our study, homocysteine levels and prevalence of cardiovascular disease in the ACKD and ESRD strata were remarkably similar, as was the homocysteine-lowering effect of the vitamins. The proportion of participants who died during the study in the 2 groups was nearly identical. Although our study was not powered to examine these 2 strata separately, subgroup analyses did not show any difference in the treatment effect across strata. Third, follow-up contacts after the return visit at 3 months were not in person; thus, adherence and ascertainment of outcomes might have been incomplete. Previous studies have shown, however, that death can be reliably ascertained from death registries and patients' electronic records within the VA health care system.24 Secondary outcomes of cardiovascular events may be less complete, but there is no a priori reason to expect differential ascertainment in the randomized groups.

In conclusion, treatment with high doses of folic acid and B vitamins did not reduce mortality or the incidence of cardiovascular events. Our findings do not support the administration of folic acid and B vitamin supplements to prevent vascular injury or improve survival in patients with ACKD or ESRD.

Corresponding Author: Rex L. Jamison, MD, MB3 Room 305, M/C HOST 151, Veterans Affairs Palo Alto Health Care System, 3801 Miranda Ave, Palo Alto, CA 94304 (rjamison@stanford.edu).

Author Contributions: Drs Jamison and Guarino had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Jamison, Hartigan, Kaufman, Goldfarb, Gaziano.

Acquisition of data: Jamison, Hartigan, Kaufman, Warren, Guarino, Gaziano.

Analysis and interpretation of data: Jamison, Hartigan, Kaufman, Goldfarb, Warren, Guarino, Gaziano.

Drafting of the manuscript: Jamison, Kaufman, Goldfarb, Warren, Guarino.

Critical revision of the manuscript for important intellectual content: Jamison, Hartigan, Kaufman, Goldfarb, Warren, Guarino, Gaziano.

Statistical analysis: Hartigan, Guarino.

Obtained funding: Jamison, Gaziano.

Administrative, technical, or material support: Jamison, Hartigan, Kaufman, Goldfarb, Warren, Guarino, Gaziano.

Study supervision: Jamison, Hartigan, Kaufman, Goldfarb, Warren, Gaziano.

Financial Disclosures: Dr Gaziano reported that in the past 5 years he has received investigator-initiated federal funding from the National Institutes of Health and the Department of Veterans Affairs, as well as nonfederal investigator-initiated funding from McNeil Consumer Products, Amgen, and VeroScience. He also reported receiving research support and supplies from BASF, DMS Pharmaceuticals, and Wyeth Pharmaceuticals; receiving honoraria from Bayer and Pfizer for speaking engagements; serving as a consultant for McNeil Consumer Products, Wyeth Pharmaceuticals, and Bayer; and serving as an expert witness for Merck, Nutraquest, and GlaxoSmithKline. No other authors reported financial disclosures.

HOST Study Participants: Writing Group: R. Jamison, J. M. Gaziano, D. S. Goldfarb, P. Guarino, P. Hartigan, J. Kaufman, S. Warren.

Executive Committee: R. Jamison (chair), J. M. Gaziano (cochair), R. Cxypoliski, S. Fortmann, D. S. Goldfarb, P. Guarino, P. Hartigan, M. Helmuth, J. Kaufman, K. McCully, K. Robinson, S. Warren, and P. Peduzzi (ex officio).

Events Adjudication Committee: D. Forman, T. Gaziano, T. Kurth, D. Mesler.

Data and Safety Monitoring Board: N. Levinsky (chair) [deceased], J. Kopple (chair), B. Brown Jr [deceased], A. Cheung, K. Detre [deceased], T. Greene, M. Klag, A. Motulsky, T. Hostetter, P. Ridker.

VA Cooperative Studies Human Rights Committee, West Haven, Connecticut: R. Marottoli (chair), H. Allore, D. Beckwith, W. Farrell, R. Feldman, R. Mehta, J. Neiderman, E. Perry, S. Kasl, M. Zeman.

VA Principal Investigators, Coinvestigators, and Coordinators: Ann Arbor: E. Young, K. Belanger; Bay Pines: R. Lopez, N. Grunsten; Birmingham: P. Sanders, MD, D. Killian, N. Shanklin; Boston: J. Kaufman, E. Dibbs; Bronx: E. Langhoff, D. Tyrrell; West Haven: S. Crowley, A. Piexoto, A. DeLorenzo, C. Joncas; Cleveland: R. T. Miller, K. Kaelin, M. Markulin; Dallas: D. Dev, D. Coussirat, A. Sajgure; Dayton: M. Saklayen, H. Neff, S. Shook; Denver: M. Chonchol, M. Levi, L. Clegg, A. Singleton; Detroit: D. Abu-Hamdan, L. Bey-Knight, K. King, E. Jones, Washington, DC: C. Palant, H. Sheriff, C. Simmons, J. Sinks; Gainesville: C. Wingo, B. McAllister, J. Sallustio, N. Smith; Hines: S. Popli, P. Linnerud, A. Zuluaga; Houston: G. Dolson, G. Tasby; Indianapolis: R. Agarwal, R. Lewis, D. Jasinski, N. Sachs, D. Veneck; Jackson: S. Ur Rehman, A. Basu, K. Ingram; Charleston: R. Paul, J. Raymond, K. Holmes; Kansas City: T. Wiegmann, J. Abdallah, A. Nagaria, D. Smith, A. Renft, T. Finnigan; Richmond: G. Feldman, S. Schmid; Memphis: C. Cooke, B. Wall, R. Patterson; Miami: G. Contreras, E. Jaimes, G. O'Brien; Minneapolis: K. Ma, J. Rust, S. Otterness; New Orleans: V. Batuman, C. Kulivan; New York: D. S. Goldfarb, M. Shea, F. Modersitzki; Northport: T. Dixon, E. Pastoriza, L. Titus; Palo Alto: R. Jamison, I. Cook, M. Anderson; Pittsburgh: P. Palevsky, P. Salai; Portland: S. Anderson, J. Walczyk; Seattle: A. Lindner, C. Stehman-Breen, E. Pascual, J. Nugent-Carney; San Diego: S. Thomson, S. Mullaney, J. Dingsdale; San Juan: C. Rosado, C. Azcona-Vilchez; Syracuse: S. Betcher, C. Rewakowski; West Palm Beach: D. Cohen, G. Flanagin, J. Steffe; Buffalo: J. Lohr, N. Fucile, L. Yohe; Milwaukee: S. Blumenthal, D. Schmidt.

Study Chair's Office, VA Palo Alto Healthcare System, Palo Alto, California: R. Jamison (study chair), M. Helmuth, G. Georgette, T. Shannon, H. Johnson, M. Martin.

VA Medical Center, Boston, Massachusetts: J. Gaziano (study cochair), R. Cxypoliski, N. Best, N. Pastore, D. Jones, A. Rayne, Z. Castrillon.

VA Cooperative Studies Program Coordinating Center, VA Connecticut Healthcare System, West Haven: P. Peduzzi (director), M. Antonelli (associate director of operations), L. Durant, E. Jobes, S. Joyner, M. Perry, E. Petrokaitis, S. Zellner.

VA Cooperative Studies Program Clinical Research Pharmacy Coordinating Center, Albuquerque, New Mexico: M. Sather (director), M. Chavez, J. Day, D. Garnand, S. Jenkins, M. Nicholson, D. Raisch, T. Sutton.

Massachusetts Veterans Epidemiology Research and Information Center, West Roxbury: M. Brophy, D. Humphries, D. Govan, L. Carlton, J. Wang.

VA Office of Research and Development, Clinical Science R&D, Washington, DC: T. J. O’Leary (director), G. D. Huang (deputy director, Cooperative Studies Program).

Funding/Support:This work was supported by the Cooperative Studies Program, Department of Veterans Affairs Office of Research and Development. The VA Palo Alto Health Care System received payment from PamLab for performing chemical analyses, including the salary of a research technician and for supplies. Abbott Laboratories donated the homocysteine analytic kits.

Role of the Sponsors: The Cooperative Studies Program, Department of Veterans Affairs Office of Research and Development, approved the manuscript for submission but was not involved in the design of the study or the collection, management, analysis, or interpretation of the data. Neither PamLab nor Abbott Laboratories was involved in the design or conduct of the study; the collection, management, analysis, and interpretation of the data; or review or approval of the manuscript.

Additional Contributions: We thank Ron Van Groningen, BS, VA Palo Alto HCS Chemistry Laboratory, for supervising the chemical analyses; and Philip Lavori, PhD, VA Palo Alto Cooperative Studies Program Coordinating Center, and Department of Health Research and Policy, Stanford University; David Tong, MD, California Pacific Medical Center Stroke Center, San Francisco; Paul Jungers, MD, Department of Nephrology, Necker Hospital, Paris, France; and Gere Sunder-Plassmann, MD, Klinische Abteilung fur Nephrologie und Dialyse, Universitatsklinik fur Innere Medizin III, University of Vienna, Vienna, Austria, for helpful advice and information. None of these individuals received compensation for their contributions.

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Boushey CJ, Beresford SA, Omenn GS, Motulsky AG. A quantitative assessment of plasma homocysteine as a risk factor for vascular disease: probable benefits of increasing folic acid intakes.  JAMA. 1995;274(13):1049-1057
PubMed   |  Link to Article
Eikelboom JW, Lonn E, Genest J Jr, Hankey G, Yusuf S. Homocyst(e)ine and cardiovascular disease: a critical review of the epidemiologic evidence.  Ann Intern Med. 1999;131(5):363-375
PubMed   |  Link to Article
Nygård O, Nordrehaug JE, Refsum H, Ueland PM, Farstad M, Vollset SE. Plasma homocysteine levels and mortality in patients with coronary artery disease.  N Engl J Med. 1997;337(4):230-236
PubMed   |  Link to Article
Hofmann MA, Lalla E, Lu Y.  et al.  Hyperhomocysteinemia enhances vascular inflammation and accelerates atherosclerosis in a murine model.  J Clin Invest. 2001;107(6):675-683
PubMed   |  Link to Article
Lentz SR, Rodionov RN, Dayal S. Hyperhomocysteinemia, endothelial dysfunction, and cardiovascular risk: the potential role of ADMA.  Atheroscler Suppl. 2003;4(4):61-65
PubMed   |  Link to Article
Loscalzo J. Homocysteine trials: clear outcomes for complex reasons.  N Engl J Med. 2006;354(15):1629-1632
PubMed   |  Link to Article
Bønaa KH, Njolstad I, Ueland PM.  et al.  Homocysteine lowering and cardiovascular events after acute myocardial infarction.  N Engl J Med. 2006;354(15):1578-1588
PubMed   |  Link to Article
Lonn E, Yusuf S, Arnold MJ.  et al.  Homocysteine lowering with folic acid and B vitamins in vascular disease.  N Engl J Med. 2006;354(15):1567-1577
PubMed   |  Link to Article
Toole JF, Malinow MR, Chambless LE.  et al.  Lowering homocysteine in patients with ischemic stroke to prevent recurrent stroke, myocardial infarction, and death: the Vitamin Intervention for Stroke Prevention (VISP) randomized controlled trial.  JAMA. 2004;291(5):565-575
PubMed   |  Link to Article
Spence JD, Bang H, Chambless LE, Stampfer MJ. Vitamin Intervention For Stroke Prevention Trial: an efficacy analysis.  Stroke. 2005;36(11):2404-2409
PubMed   |  Link to Article
Bostom AG, Shemin D, Verhoef P.  et al.  Elevated fasting total plasma homocysteine levels and cardiovascular disease outcomes in maintenance dialysis patients: a prospective study.  Arterioscler Thromb Vasc Biol. 1997;17(11):2554-2558
PubMed   |  Link to Article
Jungers P, Joly D, Massy Z.  et al.  Sustained reduction of hyperhomocysteinaemia with folic acid supplementation in predialysis patients.  Nephrol Dial Transplant. 1999;14(12):2903-2906
PubMed   |  Link to Article
Robinson K, Gupta A, Dennis V.  et al.  Hyperhomocysteinemia confers an independent increased risk of atherosclerosis in end-stage renal disease and is closely linked to plasma folate and pyridoxine concentrations.  Circulation. 1996;94(11):2743-2748
PubMed   |  Link to Article
Go AS, Chertow GM, Fan D, McCulloch CE, Hsu CY. Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization.  N Engl J Med. 2004;351(13):1296-1305
PubMed   |  Link to Article
Longenecker JC, Coresh J, Powe NR.  et al.  Traditional cardiovascular disease risk factors in dialysis patients compared with the general population: the CHOICE Study.  J Am Soc Nephrol. 2002;13(7):1918-1927
PubMed   |  Link to Article
US Renal Data System.  USRDS 2004 Annual Data Report: Atlas of End-Stage Renal Disease in the United States. Bethesda, MD: National Institute of Diabetes and Digestive and Kidney Diseases; 2004
Shemin D, Lapane KL, Bausserman L.  et al.  Plasma total homocysteine and hemodialysis access thrombosis:  J Am Soc Nephrol. 1999;10(5):1095-1099
PubMed
Jamison RL, Hartigan P, Gaziano JM.  et al.  Design and statistical issues in the Homocysteinemia in Kidney and End Stage Renal Disease (HOST) Study.  Clin Trials. 2004;1(5):451-460
PubMed   |  Link to Article
Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine.  Nephron. 1976;16(1):31-41
PubMed   |  Link to Article
Peduzzi P, Hatch HT, Johnson G.  et al.  Coordinating center follow-up in the Veterans Administration Cooperative Study of Coronary Artery Bypass Surgery.  Control Clin Trials. 1987;8(3):190-201
PubMed   |  Link to Article
Ryan TJ, Anderson JL, Antman EM.  et al.  ACC/AHA guidelines for the management of patients with acute myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on Management of Acute Myocardial Infarction).  J Am Coll Cardiol. 1996;28(5):1328-1428
PubMed   |  Link to Article
Wahlgren N. Stroke scales. In: Ginsberg M, Bogousslavsky J, eds. Cerebrovascular Disease: Pathophysiology, Diagnosis and Management. Malden, MA: Blackwell Science; 1997:1208-1220
Shipchandler MT, Moore EG. Rapid, fully automated measurement of plasma homocyst(e)ine with the Abbott IMx analyzer.  Clin Chem. 1995;41(7):991-994
PubMed
National Kidney Foundation.  K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification.  Am J Kidney Dis. 2002;39(2):(suppl 1)  S1-S266
PubMed   |  Link to Article
Muntner P, He J, Astor BC, Folsom AR, Coresh J. Traditional and nontraditional risk factors predict coronary heart disease in chronic kidney disease: results from the Atherosclerosis Risk in Communities study.  J Am Soc Nephrol. 2005;16(2):529-538
PubMed   |  Link to Article
Bostom AG, Shemin D, Lapane KL.  et al.  High dose-B-vitamin treatment of hyperhomocysteinemia in dialysis patients.  Kidney Int. 1996;49(1):147-152
PubMed   |  Link to Article
Righetti M, Ferrario GM, Milani S.  et al.  Effects of folic acid treatment on homocysteine levels and vascular disease in hemodialysis patients.  Med Sci Monit. 2003;9(4):PI19-PI24
PubMed
Wrone EM, Hornberger JM, Zehnder JL.  et al.  Randomized trial of folic acid for prevention of cardiovascular events in end-stage renal disease.  J Am Soc Nephrol. 2004;15(2):420-426
PubMed   |  Link to Article
Zoungas S, McGrath BP, Branley P.  et al.  Cardiovascular morbidity and mortality in the Atherosclerosis and Folic Acid Supplementation Trial (ASFAST) in chronic renal failure.  J Am Coll Cardiol. 2006;47(6):1108-1116
PubMed   |  Link to Article
Wanner C, Krane V, Marz W.  et al.  Atorvastatin in patients with type 2 diabetes mellitus undergoing hemodialysis.  N Engl J Med. 2005;353(3):238-248
PubMed   |  Link to Article
Bostom AG, Culleton BF. Hyperhomocysteinemia in chronic renal disease.  J Am Soc Nephrol. 1999;10(4):891-900
PubMed
Homocysteine Lowering Trialists' Collaboration.  Lowering blood homocysteine with folic acid based supplements: meta-analysis of randomised trials.  BMJ. 1998;316(7135):894-898
PubMed   |  Link to Article

Figures

Figure 1. Flow of Participants in the Study
Graphic Jump Location

To convert creatinine clearance to mL/s, multiply values by 0.0167. ESRD indicates end-stage renal disease; ACKD, advanced chronic kidney disease.

Figure 2. Kaplan-Meier Estimates of Survival
Graphic Jump Location

There were a total of 884 deaths.

Figure 3. Hazard Ratios for All-Cause Mortality by Subgroups
Graphic Jump Location

CI indicates confidence interval; ESRD, end-stage renal disease; ACKD, advanced chronic kidney disease. The sizes of the data markers relate to subgroup sample size.

Tables

Table Graphic Jump LocationTable 2. Plasma Levels of Total Homocysteine and Folate at Baseline and 3 Months
Table Graphic Jump LocationTable 3. Plasma Total Homocysteine and Folate at Baseline and Annually in Substudy Population
Table Graphic Jump LocationTable 4. Primary and Secondary Outcomes

References

McCully KS. Vascular pathology of homocysteinemia: implications for the pathogenesis of arteriosclerosis.  Am J Pathol. 1969;56(1):111-128
PubMed
Finkelstein J. Regulation of homocysteine metabolism. In: Carmel R, Jacobsen DW, eds. Homocysteine in Health and Disease. Cambridge, UK: Cambridge University Press; 2001:92-99
Wilcken DE, Wilcken B. The natural history of vascular disease in homocystinuria and the effects of treatment.  J Inherit Metab Dis. 1997;20(2):295-300
PubMed   |  Link to Article
Homocysteine Studies Collaboration.  Homocysteine and risk of ischemic heart disease and stroke: a meta-analysis.  JAMA. 2002;288(16):2015-2022
PubMed   |  Link to Article
Boushey CJ, Beresford SA, Omenn GS, Motulsky AG. A quantitative assessment of plasma homocysteine as a risk factor for vascular disease: probable benefits of increasing folic acid intakes.  JAMA. 1995;274(13):1049-1057
PubMed   |  Link to Article
Eikelboom JW, Lonn E, Genest J Jr, Hankey G, Yusuf S. Homocyst(e)ine and cardiovascular disease: a critical review of the epidemiologic evidence.  Ann Intern Med. 1999;131(5):363-375
PubMed   |  Link to Article
Nygård O, Nordrehaug JE, Refsum H, Ueland PM, Farstad M, Vollset SE. Plasma homocysteine levels and mortality in patients with coronary artery disease.  N Engl J Med. 1997;337(4):230-236
PubMed   |  Link to Article
Hofmann MA, Lalla E, Lu Y.  et al.  Hyperhomocysteinemia enhances vascular inflammation and accelerates atherosclerosis in a murine model.  J Clin Invest. 2001;107(6):675-683
PubMed   |  Link to Article
Lentz SR, Rodionov RN, Dayal S. Hyperhomocysteinemia, endothelial dysfunction, and cardiovascular risk: the potential role of ADMA.  Atheroscler Suppl. 2003;4(4):61-65
PubMed   |  Link to Article
Loscalzo J. Homocysteine trials: clear outcomes for complex reasons.  N Engl J Med. 2006;354(15):1629-1632
PubMed   |  Link to Article
Bønaa KH, Njolstad I, Ueland PM.  et al.  Homocysteine lowering and cardiovascular events after acute myocardial infarction.  N Engl J Med. 2006;354(15):1578-1588
PubMed   |  Link to Article
Lonn E, Yusuf S, Arnold MJ.  et al.  Homocysteine lowering with folic acid and B vitamins in vascular disease.  N Engl J Med. 2006;354(15):1567-1577
PubMed   |  Link to Article
Toole JF, Malinow MR, Chambless LE.  et al.  Lowering homocysteine in patients with ischemic stroke to prevent recurrent stroke, myocardial infarction, and death: the Vitamin Intervention for Stroke Prevention (VISP) randomized controlled trial.  JAMA. 2004;291(5):565-575
PubMed   |  Link to Article
Spence JD, Bang H, Chambless LE, Stampfer MJ. Vitamin Intervention For Stroke Prevention Trial: an efficacy analysis.  Stroke. 2005;36(11):2404-2409
PubMed   |  Link to Article
Bostom AG, Shemin D, Verhoef P.  et al.  Elevated fasting total plasma homocysteine levels and cardiovascular disease outcomes in maintenance dialysis patients: a prospective study.  Arterioscler Thromb Vasc Biol. 1997;17(11):2554-2558
PubMed   |  Link to Article
Jungers P, Joly D, Massy Z.  et al.  Sustained reduction of hyperhomocysteinaemia with folic acid supplementation in predialysis patients.  Nephrol Dial Transplant. 1999;14(12):2903-2906
PubMed   |  Link to Article
Robinson K, Gupta A, Dennis V.  et al.  Hyperhomocysteinemia confers an independent increased risk of atherosclerosis in end-stage renal disease and is closely linked to plasma folate and pyridoxine concentrations.  Circulation. 1996;94(11):2743-2748
PubMed   |  Link to Article
Go AS, Chertow GM, Fan D, McCulloch CE, Hsu CY. Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization.  N Engl J Med. 2004;351(13):1296-1305
PubMed   |  Link to Article
Longenecker JC, Coresh J, Powe NR.  et al.  Traditional cardiovascular disease risk factors in dialysis patients compared with the general population: the CHOICE Study.  J Am Soc Nephrol. 2002;13(7):1918-1927
PubMed   |  Link to Article
US Renal Data System.  USRDS 2004 Annual Data Report: Atlas of End-Stage Renal Disease in the United States. Bethesda, MD: National Institute of Diabetes and Digestive and Kidney Diseases; 2004
Shemin D, Lapane KL, Bausserman L.  et al.  Plasma total homocysteine and hemodialysis access thrombosis:  J Am Soc Nephrol. 1999;10(5):1095-1099
PubMed
Jamison RL, Hartigan P, Gaziano JM.  et al.  Design and statistical issues in the Homocysteinemia in Kidney and End Stage Renal Disease (HOST) Study.  Clin Trials. 2004;1(5):451-460
PubMed   |  Link to Article
Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine.  Nephron. 1976;16(1):31-41
PubMed   |  Link to Article
Peduzzi P, Hatch HT, Johnson G.  et al.  Coordinating center follow-up in the Veterans Administration Cooperative Study of Coronary Artery Bypass Surgery.  Control Clin Trials. 1987;8(3):190-201
PubMed   |  Link to Article
Ryan TJ, Anderson JL, Antman EM.  et al.  ACC/AHA guidelines for the management of patients with acute myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on Management of Acute Myocardial Infarction).  J Am Coll Cardiol. 1996;28(5):1328-1428
PubMed   |  Link to Article
Wahlgren N. Stroke scales. In: Ginsberg M, Bogousslavsky J, eds. Cerebrovascular Disease: Pathophysiology, Diagnosis and Management. Malden, MA: Blackwell Science; 1997:1208-1220
Shipchandler MT, Moore EG. Rapid, fully automated measurement of plasma homocyst(e)ine with the Abbott IMx analyzer.  Clin Chem. 1995;41(7):991-994
PubMed
National Kidney Foundation.  K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification.  Am J Kidney Dis. 2002;39(2):(suppl 1)  S1-S266
PubMed   |  Link to Article
Muntner P, He J, Astor BC, Folsom AR, Coresh J. Traditional and nontraditional risk factors predict coronary heart disease in chronic kidney disease: results from the Atherosclerosis Risk in Communities study.  J Am Soc Nephrol. 2005;16(2):529-538
PubMed   |  Link to Article
Bostom AG, Shemin D, Lapane KL.  et al.  High dose-B-vitamin treatment of hyperhomocysteinemia in dialysis patients.  Kidney Int. 1996;49(1):147-152
PubMed   |  Link to Article
Righetti M, Ferrario GM, Milani S.  et al.  Effects of folic acid treatment on homocysteine levels and vascular disease in hemodialysis patients.  Med Sci Monit. 2003;9(4):PI19-PI24
PubMed
Wrone EM, Hornberger JM, Zehnder JL.  et al.  Randomized trial of folic acid for prevention of cardiovascular events in end-stage renal disease.  J Am Soc Nephrol. 2004;15(2):420-426
PubMed   |  Link to Article
Zoungas S, McGrath BP, Branley P.  et al.  Cardiovascular morbidity and mortality in the Atherosclerosis and Folic Acid Supplementation Trial (ASFAST) in chronic renal failure.  J Am Coll Cardiol. 2006;47(6):1108-1116
PubMed   |  Link to Article
Wanner C, Krane V, Marz W.  et al.  Atorvastatin in patients with type 2 diabetes mellitus undergoing hemodialysis.  N Engl J Med. 2005;353(3):238-248
PubMed   |  Link to Article
Bostom AG, Culleton BF. Hyperhomocysteinemia in chronic renal disease.  J Am Soc Nephrol. 1999;10(4):891-900
PubMed
Homocysteine Lowering Trialists' Collaboration.  Lowering blood homocysteine with folic acid based supplements: meta-analysis of randomised trials.  BMJ. 1998;316(7135):894-898
PubMed   |  Link to Article
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