Rationale and design of the Folic Acid for Vascular Outcome Reduction In Transplantation (FAVORIT) trial

Article Outline

• Abstract
• Methods
  • Study subjects
  • Recruitment and follow-up
  • Modifications to study methods
  • High- and low-dose vitamins
  • Randomization assignment
  • End points
  • Estimation of power and sample size
  • Analysis plan
• Results
• Discussion
• Appendix A. Principal investigators and NIH project scientists
• Appendix B. Data and safety monitoring board members
• References
• Copyright

Background

Patients with chronic kidney disease, including kidney transplant recipients, are at high risk for cardiovascular disease (CVD). In addition to the constellation of traditional CVD risk factors in chronic kidney disease, elevated total homocysteine (tHcy) is notably more prevalent among the general population. The Folic Acid for Vascular Outcome Reduction In Transplantation (FAVORIT) trial is designed to evaluate whether lowering tHcy using vitamin supplementation reduces CVD events in renal transplant recipients.

Methods

FAVORIT is a multicenter double-blind randomized controlled clinical trial. Participants are clinically stable renal transplant recipients who are 6 months or longer posttransplant with elevated tHcy. Patients are randomized to a multivitamin that includes either a high-dose or low-dose of folic acid (5 or 0 mg), vitamin B₆ (50 or 1.4 mg), and vitamin B₁₂ (1000 or 2 μg). The primary end point is a composite of incident or recurrent CVD outcomes, that is, coronary heart, cerebrovascular, or abdominal aortic/lower extremity arterial events. A sample size of 4000 is estimated to provide 87% power to detect a 20% treatment effect. Recruitment is expected to continue until July 2006, with follow-up through June 2010.

Results

From August 2002 through December 2004, 2234 of the target 4000 patients were enrolled. In accordance with trial design, mean (SD) screening tHcy was elevated (17.4 ± 6.2 μmol/L), and mean (SD) estimated creatinine clearance was consistent with stable renal function (58.0 ± 18.6 mL/min). Evaluating baseline results to date, 42% of the randomized participants had a history of diabetes mellitus, and 21% had prevalent CVD.

Conclusions

The FAVORIT trial is designed with sufficient power and follow-up time to detect a clinically relevant change in CVD risk between renal transplant recipients receiving a high or low tHcy-lowering folic acid multivitamin. Preliminary screening and baseline data support the trial's objectives.

Patients with chronic kidney disease (CKD) are at very high risk for cardiovascular disease (CVD). Among patients with kidney failure treated with dialysis, the cardiovascular mortality rate is up to 10 times that of the general age-matched population.¹, ² The excess risk of CVD in patients with CKD is due in part to a higher prevalence of established arteriosclerotic risk factors, including older age, hypertension, diabetes, dyslipidemia, and physical inactivity. However, these established risk factors do not account for the multifold increase observed in event rates.³ Unique risk factors related to CKD likely also contribute to this excess CVD risk.² These unique or novel risk factors include elevated homocysteine levels.⁴ Homozygous genetic disorders⁵, ⁶, ⁷ resulting in marked hyperhomocysteinemia (total homocysteine [tHcy] levels, 100-500 μmol/L) are clearly associated with atherothrombotic events early in life,⁸ and tHcy-lowering treatment appears to reduce the incidence of these outcomes among these patients.⁸, ⁹ In addition, pooled data from prospective observational studies suggest that mild to moderate hyperhomocysteinemia (tHcy levels, 12-99 μmol/L)¹⁰ may also be a significant risk factor for arteriosclerotic CVD among the general population.¹¹ However, there are no randomized, controlled clinical trials which have found that tHcy-lowering treatment reduces CVD outcomes.¹² This may be because of the impact of cereal grain flour fortification with folic acid¹³, ¹⁴ on plasma tHcy levels within the general population. This fortification may have confounded the results from some trials conducted in the United States.

Mild to moderate hyperhomocysteinemia has been shown to be an independent risk factor for CVD outcomes in prospective observational studies on patients with CKD, including kidney transplant recipients.¹⁴, ¹⁵, ¹⁶, ¹⁷, ¹⁸ An additional prospective study by Winkelmayer et al¹⁹ reported that tHcy levels above 12 μmol/L were associated with increased risks for total mortality and allograft loss in kidney transplant recipients. Based on these observational studies, it is reasonable to hypothesize that lowering tHcy levels in patients with CKD may reduce their burden of CVD outcomes. Kidney transplant recipients are a suitable population for testing this hypothesis because they have a high rate of both incident and recurrent CVD² and continue to have an excess prevalence of hyperhomocysteinemia despite the fortification of cereal grain flour with folic acid.²⁰ Importantly, these patients are able to “normalize” their tHcy levels with combined folic acid, vitamin B₁₂, and vitamin B₆ treatment.²¹, ²² In contrast, among patients with kidney failure,²³ tHcy levels remain elevated with vitamin therapy, albeit at a lower level.

The primary objective of the Folic Acid for Vascular Outcome Reduction In Transplantation (FAVORIT) trial is to determine whether lowering tHcy levels in patients with CKD will reduce their risk of CVD. The primary hypothesis is that, in stable kidney transplant recipients, treatment with a multivitamin containing high doses of folic acid (5.0 mg), vitamin B₆ (pyridoxine, 50 mg), and vitamin B₁₂ (cyanocobalamin, 1.0 mg) will reduce the rate of pooled arteriosclerotic CVD events relative to treatment with a “low-dose” multivitamin devoid of folic acid and with estimated average requirement amounts of vitamins B₆ (1.4 mg) and B₁₂ (2.0 μg). The primary end point is pooled from both clinical events and invasive procedures for cardiovascular, peripheral vascular, or renovascular disease. The secondary hypotheses being evaluated are (1) treatment with the high-dose multivitamin reduces the rate of total mortality relative to treatment with the low-dose multivitamin; (2) among participants with baseline diabetes, treatment with the high-dose multivitamin reduces the rate of pooled arteriosclerotic CVD events relative to treatment with the low-dose multivitamin; and (3) treatment with the high-dose multivitamin reduces the rate of decline in (a) kidney function and (b) the rate of allograft failure requiring initiation of chronic dialysis relative to treatment with the low-dose multivitamin. This paper describes the rationale and design of the FAVORIT trial and the baseline characteristics of the study participants recruited to date.

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Methods 

The trial is conducted by an Operations Center, Data Coordinating Center, Central Laboratory, and clinical sites (see Appendix A). Institutional review board approval is maintained by all sites. Study enrollment commenced in August 2002 at 3 sites, with 17 additional sites becoming active during the next 14 months. Recruitment of 4000 participants was expected to require 24 to 30 months, and a 5-year follow-up of each patient was planned. An independent Data and Safety Monitoring Board, appointed by the National Institute of Diabetes and Digestive and Kidney Diseases (see Appendix B for members of the Board), meets regularly to review trial data for evidence of adverse or beneficial treatment results and to consider whether the trial as it is currently being conducted will be able to answer the primary hypothesis.

Study subjects 

The fundamental eligibility criteria are that patients 35 to 75 years of age have clinically stable kidney function posttransplantation and elevated tHcy levels. Stable kidney function is ascertained by chart review to establish that the patient's current allograft has been functioning for at least 6-months posttransplantation and there is no evidence of renal allograft dysfunction or deterioration. All enrolled participants have a creatinine-based estimate of glomerular filtration rate²⁴ of 30 mL/min or greater and elevated tHcy (≥12.0 μmol/L for men or ≥11.0 μmol/L for women) based on central laboratory analysis of screening specimens. The complete set of inclusion and exclusion criteria is summarized in Table I. Written informed consent is obtained from all study participants.

Table I. FAVORIT eligibility criteria

Inclusion criteria
Transplant	6 m or more post–kidney transplant
Ccr rate	≥30 mL/min for men or ≥25 mL/min for women (unisex cut point ≥30 mL/min before July 2005)
tHcy	≥12.0 μmol/L for men or ≥11.0 μmol/L for women
Adherence	Informed consent
	Cognitive function adequate for patient to give accurate information
	Adequate transportation facilities
	Geographically accessibility for follow-up
	Within 120 days of screening
Age	35 to 75 y at time of randomization
Exclusion criteria
Concomitant illnesses or medical conditions	Presence of cancer, end-stage congestive heart failure, liver, or pulmonary disease, progressive human immunodeficiency virus or other chronic wasting illness, which in the opinion of the study physician would limit the life expectancy of the patient to less than 2 years or prevent evaluation of recurrent or de novo CVD, other conditions that prevent reliable participation in the study, such as refractory depression, severe cognitive impairment, or alcoholism or other substance abuse, history of solid organ transplant other than the kidney or pancreas
Fecundity	Pregnant or lactating women or women of childbearing potential not practicing birth control
CVD risk modified	Less than 3 m post–acute myocardial infarction or stroke, or less than 3 months post–coronary artery, renal artery, or lower extremity artery percutaneous transluminal coronary angioplasty, or lower extremity amputation; less than 6 m post–coronary artery bypass graft surgery, abdominal aortic aneurysm; participation in another clinical trial specifically involving CVD risk factor management

Recruitment and follow-up 

Patients are screened for the trial during one of their regular posttransplant follow-up examinations. Approximately 6 weeks before this, a prescreening takes place to identify patients that appear to meet eligibility criteria. Individuals are contacted by telephone, the trial is described, and informed consent for prescreening is obtained as specified by the applicable Institutional Review Board. Specific eligibility requirements are queried, and anyone otherwise eligible who reports taking a vitamin supplement containing folic acid, vitamin B₆, or vitamin B₁₂ is asked to abstain from taking these supplements at least 4 weeks before the screening visit.

The screening visit begins with the informed consent process for screening, baseline, and follow-up contacts. Eligibility criteria are verified, and random blood specimens (plasma, buffy coat, red blood cells, and serum) are collected for central analysis of tHcy and creatinine and for specimen banking. Based on the central laboratory determinations, participants meeting eligibility cut points for creatinine clearance (Ccr) and tHcy are scheduled for the baseline (randomization) visit.

Because up to 120 days may have elapsed since screening, the eligibility criteria are rechecked just before randomization. Participants meeting all the criteria and who are within 120 days of their screening visit are randomly allocated medications with 1 of 16 possible vitamin codes (8 codes correspond to high-dose vitamins, and 8 codes correspond to low-dose vitamins). Data on regular medication use during the past month, blood pressure, height, weight, and medical history are collected. Personal identifying information is recorded to enable future linkage with other databases (eg, National Death Index, United Network for Organ Sharing databases, and the United States Renal Data System [USRDS]). Blood specimens are obtained to assess tHcy,²⁰ folate, pyridoxal-5′-phosphate, total cholesterol, triglycerides, high-density lipoprotein, low-density lipoprotein, creatinine, glucose, and fructosamine, and for specimen banking. Midstream clean catch urine specimens are collected to measure creatinine and albumin, and for banking. As part of the quality assurance program, a small proportion of replicate specimens are collected under blinded identification numbers.

Follow-up contacts occur every 6 months throughout the study, alternating between telephone contacts and clinic visits. Telephone contacts query all interim hospitalizations and outpatient cardiovascular procedures that occurred, assess possible adverse reactions to the study vitamin, and obtain self-reported compliance with the study vitamin and nonstudy use of folic acid, vitamin B₆, or vitamin B₁₂. Annual clinic visit data collection includes this information plus assessments of regular medication use during the past month, blood pressure, height, weight, and medical history. Blood and urine specimen collection and analysis are identical to that in the baseline visit. Pill counts are used to further document compliance. There is one exception to this follow-up schedule. Participants who develop dialysis-dependent kidney failure (end-stage renal disease) adhere to the standard follow-up schedule until their first primary end point occurs. Thereafter, the study vitamin is discontinued, and follow-up consists of mortality surveillance only.

Modifications to study methods 

Slower than anticipated recruitment motivated several modifications to the study protocol. The study enrollment period was extended through January 2007; 10 additional kidney transplant centers were recruited, including a site in Brazil; and, follow-up was shifted to a common end date selected to insure a minimum follow-up time of 48 months.

In spring 2005, study procedures were modified to incorporate a mechanism to reduce the participant burden of needing to make a special visit to complete the baseline examination. The option to combine screening and baseline data collection was added to the protocol. Essentially, the screening visit was expanded to include all of the baseline data collection except for final verification of eligibility and randomization. Patients meeting tHcy and Ccr cut points based on the central laboratory analysis of screening specimens are contacted by telephone to verify the remaining eligibility criteria and, if eligible, are randomized. Vitamins are then sent to the participant by an express delivery service.

The protocol was also modified to incorporate a change to one of the eligibility criteria. Relative to male screenees, a larger proportion of women screened for the trial were ineligible based on Ccr. In July 2005, after 937 women were randomized, the trial implemented a sex-specific Ccr eligibility cut point (≥25 mL/min for women and ≥30 mL/min for men), in recognition of lower mean normal Ccr levels in women compared with men.

High- and low-dose vitamins 

The formulation of the high- and low-dose vitamins is provided in Table II. The high- and low-dose tablets are similar in appearance and smell but differ in the concentrations of folic acid, vitamin B₆, and vitamin B₁₂. Study participants, clinical site investigators, and study coordinators are masked to treatment assignment. Typically, 4 100-pill bottles are dispensed to the participant at the randomization contact and at each subsequent annual clinic visit. Participants are instructed to take 1 tablet daily, preferably at a regular time.

Table II. High- and low-dose vitamin formulations

Randomization assignment 

Randomization is by permuted block,²⁵ stratified by clinical site. Two different block sizes are used. The first 2 blocks within each stratum are constrained to be the smaller block size; subsequent block sizes are randomly selected. This strategy facilitates balance within and across clinical sites, even as recruitment is just beginning. Randomization is usually accomplished through the data management system. If the system is unavailable, a back-up procedure enables the site to complete the randomization through the Data Coordinating Center. Using either procedure, the date of randomization is the date the bottle code is assigned to a specific participant.

End points 

The primary end point is recurrent or incident arteriosclerotic CVD as defined by (1) CVD death, (2) myocardial infarction, (3) resuscitated sudden death, (4) stroke, (5) coronary artery revascularization, (6) lower extremity revascularization or, for severe arterial disease, amputation above the ankle, (7) carotid endarterectomy or angioplasty, (8) abdominal aortic aneurysm repair, or (9) renal artery revascularization. The first 4 components of the pooled end point are reviewed and adjudicated by a Clinical Endpoints Committee. The latter 5 procedural components of the pooled end point are identified through case report forms completed from medical records. Unstable angina cases and urgent coronary revascularization procedures are also reviewed by the Clinical Endpoints Committee for myocardial infarction.

Secondary end points consist of all cause mortality, allograft failure as defined by need for chronic dialysis, individual and relevant combinations of the components of the primary end point, and the number of these end points that occur as a function of follow-up time.

Estimation of power and sample size 

Projected CVD event rates were based upon specific estimates (personal communication) produced from the USRDS database.²⁶ A cohort of 12,358 kidney transplant recipients aged 35 to 75 years with at least 6 months of stable allograft function as of January 1, 1995 was constructed from the USRDS database. Five-year incidence densities for the pooled (first) occurrence of nonfatal or fatal CVD events (ie, myocardial infarction; stroke [atherothrombotic or hemorrhagic]; abdominal or thoracic aortic aneurysm repair; revascularization for coronary artery, carotid arterial, renal arterial, or lower extremity arterial disease; lower extremity amputation above the ankle), stratified by diabetic status, were calculated. The 5-year pooled event rates in the nondiabetic and diabetic USRDS samples were 13.6% and 35.2%, respectively. A survey of the original proposed FAVORIT sites indicated that approximately 35% of the kidney transplant patients meeting basic eligibility criteria are diabetic. Power calculations assumed this population mixture and binomial distributions in each, and further that 5% of each treatment group takes no study vitamins, 5% of each study group takes an over-the-counter vitamin preparation, and that 10% of participants will be administratively censored because of development of end-stage renal disease requiring chronic dialysis. Based on these assumptions, a sample size of 4000 has 83% power to detect a 19% treatment effect, and 87% power to detect a 20% treatment effect. These power estimates are similar to those produced by the nQuery Advisor software package²⁷ based on a log-rank test and ignoring the population mixture.

Analysis plan 

Two interim efficacy analyses are planned during the trial for consideration by the Data and Safety Monitoring Board. These analyses will use a Lan-DeMets boundary²⁸ and will be performed when approximately one third and two thirds of the expected number of events are accrued. Conditional power as proposed by Halperin et al²⁹ will be considered if the difference between treatments is small.

The statistical analysis for testing the primary hypothesis will compare the 2 groups on time from randomization to first primary outcome using a log-rank test, censoring participants at 3 months after allograft failure requiring chronic maintenance dialysis. A secondary analysis is planned to evaluate this hypothesis that will be an intention-to-treat analysis, with no censoring after allograft failure. The rationale for censoring participants requiring chronic dialysis in the primary analysis is that homocysteine levels and CVD risk rise after allograft failure, and dialysis patients are routinely prescribed folic acid and B vitamin supplementation, but supplementation has little effect on homocysteine levels in these patients. Thus, FAVORIT investigators concluded that inclusion of data on CVD events after onset of allograft failure may confound interpretation of the main trial. Power calculations took this into consideration as described above.

The Kaplan-Meier method will be used to estimate treatment-specific survival curves and to test for differences at specific times. In secondary analyses, proportional hazard models will be used to adjust for other prognostic variables such as initial, and where appropriate “time-dependent,” blood pressure, cigarette smoking, diabetes, lipoprotein levels, and creatinine-based kidney function. The same analysis methods will be applied to secondary outcomes (eg, individual components of the pooled primary outcome). Subgroup analyses will also be done by sex, age group, and race and by tHcy levels at the randomization visit.

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Results 

Study enrollment is expected to continue until January 2007. Through December 31, 2004, the study screened 4233 patients, of which 2777 (66%) met both tHcy and Ccr eligibility cut points. The proportion meeting the sex-specific tHcy cut points was similar (69% of males and 70% of females), but proportionately fewer females met the Ccr cut point (93%) than males (98%). Of 2234 participants randomized through December 31, 2004, 64% are male.³⁰ The distribution of the trial participants tHcy concentrations is not normal, the mean and SD being 16.6 ± 6.0 μmol/L (females) and 17.9 ± 6.2 μmol/L (males), and geometric mean being 15.9 μmol/L (females) and 17.2 μmol/L (males). tHcy concentrations ranged from 11 to 85 μmol/L (median, 15) in females and from 12 to 98 μmol/L (median, 16) in males. A greater proportion of participants are diabetic (42%), this was more than what was expected based on original estimates from USRDS data. The median (interquartile range) time from kidney transplant to randomization is 4.2 years (1.9-7.7 years).

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Discussion 

The FAVORIT trial has several design features that enhance its ability to address the question of whether lowering homocysteine can reduce the risk of CVD among patients with CKD. The planned sample size is the largest to date for a trial with our objective, the planned follow-up time is the longest, and preliminary screening data suggest baseline homocysteine levels are higher than in most trials starting after mandatory folic acid supplementation in the food grain flours. At screening, FAVORIT participants have a mean tHcy level of 17.5 μmol/L in comparison with baseline levels of 11.2-13.4 μmol/L³¹, ³², ³³ in 3 recently completed trials.

Results from 4 completed randomized controlled clinical trials evaluating tHcy lowering for the possible prevention of arteriosclerotic CVD outcomes have now been published.³¹, ³², ³³, ³⁴ Of the studies, 3 examined large nonrenal populations,³¹, ³², ³³ and 1 evaluated dialysis-dependent kidney failure.³⁴ All trials reported no benefit. In both the Vitamin Intervention for Stroke Prevention secondary stroke prevention trial³³ and the Cambridge Heart Antioxidant Study-2 (CHAOS-2) study for the prevention of recurrent arteriosclerotic CVD,³¹ widespread availability of folic acid fortified foodstuffs (with or without government-mandated flour fortification policies) appears to have decreased the expected prevalence of mild hyperhomocysteinemia, and tHcy-lowering treatment effects of high dose, folic acid-based treatment regimens. Specifically, regarding potential “background” effects on treatment, tHcy-lowering therapy reduced tHcy levels on average by only 15% comparing active versus placebo-treated groups in both these trials. Lowering tHcy failed to reduce the primary CVD outcomes in either study (recurrent stroke in Vitamin Intervention for Stroke Prevention; a composite of nonfatal myocardial infarction, CVD death, or unplanned revascularization in Cambridge Heart Antioxidant Study-2 [CHAOS-2]). In the recently completed Norwegian Vitamin Trial (NORVIT) study of 3749 men and women³² who had experienced an acute myocardial infarction within 7 days of randomization, despite achieving a substantial reduction in tHcy levels relative to placebo (ie, 13.0-9.6 μmol/L in the folic acid/ vitamin B₁₂ group vs no change in the placebo group, and the maintenance of 4.5 μmol/L between groups difference throughout the trial period), active treatment did not reduce the primary CVD end point (fatal or nonfatal myocardial infarction or fatal or nonfatal stroke) during 3.5 years of follow-up.

Wrone et al³⁴ also reported that high-dose folic acid-based treatment failed to reduce the pooled outcome of CVD events or mortality among end stage renal disease patients on hemodialysis. Although the end-stage renal disease subjects undergoing chronic dialysis enrolled by Wrone et al³⁴ had notably elevated baseline tHcy levels (mean, 31-35 μmol/L), mean on treatment tHcy levels remained substantially elevated (ie, above 20 μmol/L) in all their treated subjects, despite receiving up to 15 mg/d of folic acid. Thus, consistent with earlier published data,²³, ³⁵ in none of the treatment groups, including those receiving 15 mg/d of folic acid, were more than 10% of the treated patients' tHcy levels maintained below 15 μmol/L, let alone normalized to less than 12 μmol/L.

Recently reported trials have certainly provided sobering information about the potential benefits of treating elevated tHcy levels to reduce CVD risk. The findings from these trials also reinforce the uniqueness of the FAVORIT cohort. Previous research demonstrates the excess prevalence of hyperhomocysteinemia in the era of folic acid–fortified cereal grain flour and the ability to safely and successfully normalize tHcy levels in 50% or more of kidney transplant recipients with combined folic acid, vitamin B₁₂, and vitamin B₆ treatment, as opposed to 10% (or fewer) of patients with end-stage renal disease undergoing maintenance dialysis.²² Results from FAVORIT, combined with the results from completed³¹, ³², ³³, ³⁴ and ongoing¹² randomized clinical trials, will yield additional important information on the efficacy and safety of tHcy-lowering treatment for the potential reduction of arteriosclerotic outcomes.

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Appendix A. Principal investigators and NIH project scientists 

Operations Center: Andrew G. Bostom, MD, MS (Rhode Island Hospital, Providence, RI); Data Coordinating Center: Myra A. Carpenter, PhD (University of North Carolina, Chapel Hill, NC); Central Laboratory: Jacob Selhub, PhD (Jean Mayer USDA Human Nutrition Research Center on Aging, Boston, MA); Clinical Endpoints Core: Marc A. Pfeffer, MD, PhD (Brigham and Women's Hospital, Boston, MA); NIH Project Scientists: John W. Kusek, PhD (National Institute of Diabetes and Digestive and Kidney Diseases), and Rebecca Costello, PhD (Office of Dietary Supplements); Renal Transplant Clinical Sites: Deborah B. Adey, MD (*University of California, San Francisco, CA), Paul Bolin, Jr, MD (East Carolina University, Greenville, NC), Andrew G. Bostom, MD, MS (*Rhode Island Hospital, Providence, RI), Barbara Bresnahan, MD (*Medical College of Wisconsin, Milwaukee, WI), Suphamai Bunnapradist, MD (*Cedars-Sinai Health System, Los Angeles, CA), Edward Cole, MD, FRCPC (*Toronto General Hospital, Toronto, Ontario), David J. Conti, MD (*Albany Medical Center, Albany, NY), Fernando G. Cosio, MD (Mayo Clinic, Rochester, MN), Gabriel Danovitch, MD (*University of California, Los Angeles, CA), Alfredo Fabrega, MD (Banner Good Samaritan Transplant Services, Phoenix, Ariz), Lorenzo Gallon, MD (Northwestern University, Chicago, IL), Andrew House, MD, FRCPC (*London Health Sciences Center, London, Ontario), Lawrence Hunsicker, MD (*University of Iowa, Iowa City, IA), Bertram Kasiske, MD (*Hennepin County Medical Center, Minneapolis, MN), Clifton E. Kew, II, MD (*University of Alabama, Birmingham, AL), Matt Koch, MD (*Washington University, St. Louis, MO), M.S. Anil Kumar, MD (Hahnemann University Hospital, Philadelphia, PA), Mariana Markell, MD (*SUNY Downstate Medical Center, Brooklyn, NY), Arthur Matas, MD (University of Minnesota, Minneapolis, MN), Douglas Norman, MD (*Oregon Health Sciences University, Portland, OR), Timothy O'Connor, MD (Southern Illinois University, Springfield, IL), Akinlolu O. Ojo, MD (*University of Michigan, Ann Arbor, MI), Alvaro Pacheco-Silva, MD, PhD (Hospital do Rim e Hipertensão, São Paulo, Brazil), Todd Pesavento, MD (*Ohio State University, Columbus, OH), John Pirsch, MD (*University of Wisconsin, Madison, WI), Ajay K. Singh, MD (Brigham and Women's Hospital, Boston, MA), Stephen R. Smith, MD, MHS (*Duke University, Durham, NC), John Vella, MD, FACP, FRCP (Maine Medical Center, Portland, ME), Matthew Weir, MD (*University of Maryland, Baltimore, MD), Muhammad Yaqub, MD (*Indiana University, Indianapolis, IN).

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Appendix B. Data and safety monitoring board members 

Chairperson: Janet T. Wittes, PhD (Statistics Collaborative, Washington, DC). Members: Charles Herzog, MD (Hennepin County Medical Center, Minneapolis, MN), Rex L. Jamison, MD (Stanford University, Stanford, CA), Paul Levy, ScD (Research Triangle Institute, Research Triangle Park, NC), Robert A. Phillips, PhD (UMASS Memorial Medical Center, Worcester, MA), Ashwini Sehgal, MD (Metrohealth Medical Center, Cleveland, OH), Donald Stablein, PhD (The EMMES Corporation, Rockville, MD), Meir J. Stampfer, MD (Harvard University, Boston, MA), Peter W. Wilson, MD (Medical University of South Carolina, Charleston, SC).

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References 

1. Foley RN, Parfrey PS, Sarnak MJ. Clinical epidemiology of cardiovascular disease in chronic renal disease. Am J Kidney Dis. 1998;32(5 Suppl 3):S112–S119
   • View In Article
   • Full-Text PDF (52 KB)
   • CrossRef
2. Levey AS, Beto JA, Coronado BE, et al. Controlling the epidemic of cardiovascular disease in chronic renal disease: what do we know? What do we need to learn? Where do we go from here? National Kidney Foundation Task Force on Cardiovascular Disease. Am J Kidney Dis. 1998;32:853–906
   • View In Article
   • Full-Text PDF (284 KB)
   • CrossRef
3. Shlipak MG, Fried LF, Cushman M, et al. Cardiovascular mortality risk in chronic kidney disease: comparison of traditional and novel risk factors. JAMA. 2005;293:1737–1745
   • View In Article
   • CrossRef
4. Bostom AG, Culleton BF. Hyperhomocysteinemia in chronic renal disease. J Am Soc Nephrol. 1999;10:891–900
   • View In Article
   • MEDLINE
5. Linnell JC, Bhatt HR. Inherited errors of cobalamin metabolism and their management. Baillieres Clin Haematol. 1995;8:567–601
   • View In Article
   • MEDLINE
   • CrossRef
6. Mudd SH, Levy HL, Skovby F. Disorders of transsulfuration. In:  Scriver CR,  Beaudet AL editor. Metabolic basis of inherited disease. 6th ed. New York: McGraw Hill, Inc; 1989;
   • View In Article
7. Rosenblatt DS. Inherited disorders of folate transport and metabolism. In:  Scriver CR,  Beaudet AL,  Sly WS, et al. editor. Metabolic basis of inherited disease. 6th ed.. New York: McGraw Hill, Inc.; 1989;p. 2049–2064
   • View In Article
8. Mudd SH, Skovby F, Levy HL, et al. The natural history of homocystinuria due to cystathionine beta-synthase deficiency. Am J Hum Genet. 1985;37:1–31
   • View In Article
   • MEDLINE
9. Wilcken DE, Wilcken B. The natural history of vascular disease in homocystinuria and the effects of treatment. J Inherit Metab Dis. 1997;20:295–300
   • View In Article
   • MEDLINE
   • CrossRef
10. Ueland PM, Refsum H, Stabler SP, et al. Total homocysteine in plasma or serum: methods and clinical applications. Clin Chem. 1993;39:1764–1779
    • View In Article
    • MEDLINE
11. Ueland PM, Refsum H, Beresford SA, et al. The controversy over homocysteine and cardiovascular risk. Am J Clin Nutr. 2000;72:324–332
    • View In Article
    • MEDLINE
12. Clarke R. Homocysteine-lowering trials for prevention of heart disease and stroke. Semin Vasc Med. 2005;5:215–222
    • View In Article
    • MEDLINE
    • CrossRef
13. Jacques PF, Selhub J, Bostom AG, et al. The effect of folic acid fortification on plasma folate and total homocysteine concentrations. N Engl J Med. 1999;340:1449–1454
    • View In Article
    • MEDLINE
    • CrossRef
14. Massy ZA, Chadefaux-Vekemans B, Chevalier A, et al. Hyperhomocysteinaemia: a significant risk factor for cardiovascular disease in renal transplant recipients. Nephrol Dial Transplant. 1994;9:1103–1108
    • View In Article
    • MEDLINE
15. 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;17:2554–2558
    • View In Article
    • MEDLINE
    • CrossRef
16. Ducloux D, Motte G, Challier B, et al. Serum total homocysteine and cardiovascular disease occurrence in chronic, stable renal transplant recipients: a prospective study. J Am Soc Nephrol. 2000;11:134–137
    • View In Article
    • MEDLINE
17. Jungers P, Chauveau P, Bandin O, et al. Hyperhomocysteinemia is associated with atherosclerotic occlusive arterial accidents in predialysis chronic renal failure patients. Miner Electrolyte Metab. 1997;23:170–173
    • View In Article
    • MEDLINE
18. Moustapha A, Naso A, Nahlawi M, et al. Prospective study of hyperhomocysteinemia as an adverse cardiovascular risk factor in end-stage renal disease. Circulation. 1998;97:138–141
    • View In Article
    • MEDLINE
19. Winkelmayer WC, Kramar R, Curhan GC, et al. Fasting plasma total homocysteine levels and mortality and allograft loss in kidney transplant recipients: a prospective study. J Am Soc Nephrol. 2005;16:255–260
    • View In Article
    • MEDLINE
    • CrossRef
20. Bostom AG, Gohh RY, Liaugaudas G, et al. Prevalence of mild fasting hyperhomocysteinemia in renal transplant versus coronary artery disease patients after fortification of cereal grain flour with folic acid. Atherosclerosis. 1999;145:221–224
    • View In Article
    • Abstract
    • Full Text
    • Full-Text PDF (67 KB)
    • CrossRef
21. Beaulieu AJ, Gohh RY, Han H, et al. Enhanced reduction of fasting total homocysteine levels with supraphysiological versus standard multivitamin dose folic acid supplementation in renal transplant recipients. Arterioscler Thromb Vasc Biol. 1999;19:2918–2921
    • View In Article
    • MEDLINE
    • CrossRef
22. Bostom AG, Gohh RY, Beaulieu AJ, et al. Treatment of hyperhomocysteinemia in renal transplant recipients. A randomized, placebo-controlled trial. Ann Intern Med. 1997;127:1089–1092
    • View In Article
    • MEDLINE
23. Bostom AG, Shemin D, Gohh RY, et al. Treatment of mild hyperhomocysteinemia in renal transplant recipients versus hemodialysis patients. Transplantation. 2000;69:2128–2131
    • View In Article
    • MEDLINE
    • CrossRef
24. Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron. 1976;16:31–41
    • View In Article
    • MEDLINE
    • CrossRef
25. Piantadosi S. Clinical trials: a methodologic perspective. New York: Wiley; 1997;
    • View In Article
26. Herzog C. The USRDS and its products. United States Renal Data System. Am J Kidney Dis. 1997;30(2 Suppl 1):S21–S39
    • View In Article
    • Full-Text PDF (1829 KB)
    • CrossRef
27. Elashoff JD, nQuery Advisor Version 4.0 User's Guide 2000. Los Angeles: Karger Publishers
    • View In Article
28. Lan KKG, DeMets DL. Discrete sequential boundaries for clinical trials. Biometrika. 1983;70:659–663
    • View In Article
    • CrossRef
29. Halperin M, Lan KK, Ware JH, et al. An aid to data monitoring in long-term clinical trials. Control Clin Trials. 1982;3:311–323
    • View In Article
    • MEDLINE
    • CrossRef
30. SAS Institute . SAS language reference: concepts, version 8. Cary (NC): SAS Institute Inc.; 1999;
    • View In Article
31. Baker F, Picton D, Blackwood S, et al. Blinded comparison of folic acid and placebo in patients with ischemic heart disease: an outcome trial. Circulation. 2002;106:II-741
    • View In Article
32. Bonaa KH. NORVIT: randomised trial of homocysteine-lowering with B-vitamins for secondary prevention of cardiovascular disease after acute myocardial infarction. In: European Society of Cardiology Congress. Stockholm, Sweden. 2005;
    • View In Article
33. 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;291:565–575
    • View In Article
    • CrossRef
34. 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;15:420–426
    • View In Article
    • MEDLINE
    • CrossRef
35. Bostom AG, Shemin D, Gohh RY, et al. Treatment of hyperhomocysteinemia in hemodialysis patients and renal transplant recipients. Kidney Int Suppl. 2001;78:S246–S252
    • View In Article
    • MEDLINE

• * One of 20 initial clinical sites.