B Vitamins and the Risk of Total Mortality and Cardiovascular Disease in End-Stage

Renal Disease: Results of a Randomized Controlled Trial

Judith Heinz, Siegfried Kropf, Ute Domrse, Sabine Westphal, Katrin Borucki, Claus Luley,
Klaus H. Neumann and Jutta Dierkes
Circulation. 2010;121:1432-1438; originally published online March 15, 2010;
doi: 10.1161/CIRCULATIONAHA.109.904672
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Vascular Medicine
B Vitamins and the Risk of Total Mortality and
Cardiovascular Disease in End-Stage Renal Disease
Results of a Randomized Controlled Trial
Judith Heinz, MSc; Siegfried Kropf, PhD; Ute Domrose, MD; Sabine Westphal, MD;
Katrin Borucki, MD; Claus Luley, MD; Klaus H. Neumann, MD; Jutta Dierkes, PhD
BackgroundIn observational studies, hyperhomocysteinemia has been found to be a risk factor for total mortality and
cardiovascular events in patients with end-stage renal disease. These patients have grossly elevated homocysteine levels
that can be lowered by supplementation with folic acid and vitamin B12. We conducted a randomized clinical trial with
B vitamins to reduce homocysteine levels and therefore cardiovascular events and total mortality.
Methods and ResultsThis randomized, double-blind multicenter study was conducted in 33 dialysis centers in north and
east Germany between July 2002 and July 2008. We randomly assigned 650 patients with end-stage renal disease who
were undergoing hemodialysis to 2 postdialysis treatments: 5 mg folic acid, 50 g vitamin B12, and 20 mg vitamin B6
(active treatment) or 0.2 mg folic acid, 4 g vitamin B12, and 1.0 mg vitamin B6 (placebo) given 3 times per week for
an average of 2 years. The primary outcome was total mortality; the secondary outcome was fatal and nonfatal
cardiovascular events. The primary outcome occurred in 102 patients (31%) receiving the active treatment and in 92
(28%) receiving placebo (hazard ratio, 1.13; 95% confidence interval, 0.85 to 1.50; P0.51). The secondary outcome
occurred in 83 patients (25%) receiving the active treatment and in 98 (30%) receiving placebo (hazard ratio, 0.80; 95%
confidence interval, 0.60 to 1.07; P0.13).
ConclusionsIncreased intake of folic acid, vitamin B12, and vitamin B6 did not reduce total mortality and had no
significant effect on the risk of cardiovascular events in patients with end-stage renal disease.
Clinical Trial RegistrationURL: www.anzctr.org.au. Unique identifier: ACTRN12609000911291. URL:
www.cochrane-renal.org. Unique identifier: CRG010600027.
(Circulation. 2010;121:1432-1438.)
Key Words: B vitamins cardiovascular diseases hemodialysis homocysteine kidney
mortality prevention

lthough a number of prospective observational studies

have shown that hyperhomocysteinemia is associated
with cardiovascular morbidity and mortality,13 clinical studies aimed at lowering homocysteine levels in patients with
cardiovascular disease have yielded disappointing results;
overall, lowering homocysteine by vitamin intervention reduced neither cardiovascular events nor mortality.4 8

Editorial see p 1379

Clinical Perspective on p 1438
As far as cardiovascular disease and homocysteine are
concerned, patients with end-stage renal disease (ESRD) are
of particular interest because they experience high rates of
cardiovascular disease and high rates of mortality9 11 and
exhibit the highest homocysteine concentrations, except for
patients with homocystinuria.1214 On average, the homocys-

teine levels in patients with ESRD are 25 mol/L in those

who take folic acid supplementation or fortification and
35 mol/L in those who do not receive additional vitamins.15 Indeed, similar to the situation in populations without
renal disease, homocysteine is related to cardiovascular
morbidity and mortality in patients with ESRD, as has been
shown in a recent meta-analysis.15 Although the homocysteine levels are much higher in patients with ESRD than in
other population groups, vitamin supplementation has been
shown to be effective in lowering those levels,16,17 although
so far these studies have not been summarized and no
consensus has been reached on the amounts necessary or the
route of administration. In addition, the clinical effect of such
vitamin intervention on cardiovascular disease and mortality
has not been demonstrated in randomized clinical trials in
patients with ESRD without additional vitamin supplementa-

Received August 27, 2009; accepted January 22, 2010.

From the Institute of Clinical Chemistry (J.H., S.W., K.B., C.L., J.D.), Division of Nephrology (U.D., K.H.N.), and Institute of Biometry and Medical
Informatics (S.K.), Magdeburg University Hospital, Magdeburg, Germany.
Correspondence to Judith Heinz, Department of Medical Biometry and Epidemiology, University Medical Center Hamburg-Eppendorf, Martinistrae
52, D-20246 Hamburg, Germany. E-mail j.heinz@uke.de
2010 American Heart Association, Inc.
Circulation is available at http://circ.ahajournals.org

DOI: 10.1161/CIRCULATIONAHA.109.904672

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Heinz et al
tion or fortification. We therefore conducted a randomized
clinical trial to see whether homocysteine-lowering therapy
with folic acid, vitamin B12, and vitamin B6 could reduce total
mortality and cardiovascular events in patients with ESRD
treated with hemodialysis.

Methods
Study Design
The objective of this double-blind, placebo-controlled, randomized
multicenter trial was to see whether therapy with homocysteinelowering B vitamins could reduce total mortality and the risk of
cardiovascular events in patients with ESRD. The trial design and the
baseline data were reported recently.18 The study was conducted in
dialysis centers in north and east Germany between July 2002 and
July 2008. It was coordinated by the Institute of Clinical Chemistry
at the Otto-von-Guericke University in Magdeburg, Germany, and
sponsored by the School of Medicine at that university, Roche
Diagnostics (Mannheim, Germany; laboratory measurements), and
Fresenius Medical Care (Bad Homburg, Germany; study drug and
matching placebo). The sponsors were not involved in the design,
execution, analysis, or reporting of the results of this study. Safety of
the intervention and scientific integrity of the study were supervised
by an independent data and safety monitoring board. The study was
approved by the ethics committees of the School of Medicine of
Otto-von-Guericke University Magdeburg and the appropriate medical associations in the respective federal states of Germany. All
patients gave informed consent.

Study Population
Men and women between 20 and 80 years of age with ESRD treated
for at least 1 month by hemodialysis were enrolled, regardless of
their homocysteine levels. The exclusion criteria were acute coronary events within 6 weeks before randomization, active malignant
tumor, pregnancy, lactation, and addiction to drugs or alcohol.
Patients who had been taking vitamins before recruitment were
included after a washout phase of at least 8 weeks. The patients, who
came from 33 dialysis centers in Germany, had been put on
hemodialysis because of diabetic nephropathy (n184), chronic
glomerulonephritis (n140), interstitial nephropathy (n84), polycystic nephropathy (n75), vascular nephropathy (n63), other
reasons (n56), and unknown reasons (n48). Reason for referral to
hemodialysis was not a criterion for inclusion or exclusion.

Intervention
Patients were randomized to 2 treatment groups. Each patient
received vitamins with an originally assigned code number. The code
numbers were kept within the central pharmacy of the university
hospital. All study investigators, staff, and participants were blinded
to the randomization procedure and treatment assignments.
One tablet contained either 2.5 mg folic acid, 25 g cobalamin,
and 10 mg vitamin B6 (active treatment) or 0.1 mg folic acid, 2 g
cobalamin, and 0.5 mg vitamin B6 (placebo). After each dialysis
session (usually 3 times per week), 2 tablets were taken orally
under the supervision of a nurse. The active treatment and the
placebo tablets were custom made for this study, were outwardly
indistinguishable, and contained 6 other water-soluble vitamins in
similar concentrations, usually in amounts similar to the recommended daily allowance for adults. The exact vitamin content is
given elsewhere.18 The placebo contained vitamins to prevent
vitamin deficiencies in patients assigned to the placebo group on
the one hand and to avoid an influence on homocysteine levels on
the other hand. This approach had been tested in a clinical study
with different multivitamin tablets.19 The amounts of vitamins in
the tablets were controlled annually by an independent pharmaceutical laboratory.

B Vitamins and Mortality in Dialysis Patients

1433

Baseline and Follow-Up Investigations

On entry into the study, demographic and clinical data were
recorded, as well as the use of medication and lifestyle parameters.
A nonfasting blood sample was collected before the first dialysis
session after a weekend for the determination of serum and red blood
cell levels of folate, cobalamin, pyridoxal-5-phosphate (PLP), and
homocysteine. Aliquots of the sample were also used to determine
blood count and clinical chemical, lipid, coagulation, and inflammation parameters. In a subgroup of patients (n97), homocysteine,
serum folate, cobalamin, and PLP were also measured after 6 months
of participation in the study.
Plasma homocysteine was determined in EDTA plasma by highperformance liquid chromatography with fluorescence detection.20
Serum cobalamin and serum folate were analyzed with commercial
test kits (Elecsys Module E170, Roche Diagnostics). PLP was
determined in EDTA plasma by high-performance liquid chromatography (ImmuChrom, Bensheim, Germany). All these laboratory
analyses were performed in the central laboratory of the Magdeburg
University Hospital.
Follow-up visits were arranged once per year for every patient.
The patients medical records were checked for death, major cardiovascular events, hospitalizations, and compliance with the trial
medication. Dropouts resulting from transplantation, change in
dialysis center, or any other reasons were documented. In case of any
uncertainty, the physician in charge of the respective patient was
consulted.

Trial Outcomes
The primary outcome was total mortality. The secondary outcome
was the occurrence of the first fatal or nonfatal cardiovascular event
(myocardial infarction, unstable angina pectoris, coronary vascularization procedures, sudden cardiac death, stroke, peripheral artery
disease, pulmonary embolism, and thromboses). Shunt thromboses
were not regarded as an end point.
Deaths were confirmed by hospital discharge summaries, autopsy
reports, or the responsible physicians. Causes of death were categorized as cardiac (myocardial infarction, sudden cardiac death, pulmonary edema), vascular (stroke, pulmonary embolism, thromboses,
mesenterial infarction, rupture of an aortic aneurysm), sepsis and
infections, tumors, and other causes (consequences of surgery, fluid
overload and withdrawal from dialysis, cirrhosis of the liver,
cachexia, diabetic complications, accidents, suicides, shunt complications, gastrointestinal bleeding, cerebral hemorrhage, hyperkalemia). In 15 cases, the causes of death could not be established and
were recorded as unknown.
Cardiovascular events were identified by a review of patients
medical records and by consultation with the responsible physicians. Myocardial infarction was diagnosed if at least 2 of the
following criteria had been fulfilled according to standard procedures: clinical status, elevated laboratory parameters (myocardium-specific enzymes, myoglobin), and changes in the ECG.
Catheterization was performed in cases of suspected myocardial
infarction or unstable angina pectoris. Surgical revascularization was
carried out after myocardial infarction, in unstable angina pectoris, or
when clinical signs had been detected by catheterization and the
patients general conditions permitted surgery. Strokes and ischemic
insults were verified by computed tomography. Peripheral artery
disease was diagnosed according to the Fontaine stages or on the
basis of 50% stenoses detected angiographically or sonographically in major arteries and lower limbs. Follow-up and the assigned
treatment were continued in all participants who experienced a
secondary outcome event.

Statistical Analysis
The required number of patients was calculated as 350 per treatment
group on the basis of an annual mortality of 16% and a 30%
mortality reduction as a result of the active treatment. A 1-year
recruitment phase and a study period of 3 years were assumed, with
an annual dropout rate of 10%, 2-sided type I error of 5% (adjusted
for 1 interim analysis), and a type II error of 20%.21 Because of the

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March 30, 2010

Results
Compliance, Follow-Up, and Adverse Events
Between July 2002 and November 2006, a total of 650
patients were included in the trial from 33 dialysis centers in
Germany and were assigned at random to the 2 treatment
arms. The median duration of follow-up was 2.1 years (5th to
95th percentiles, 0.2 to 5.2 years). Of the 650 patients, 107
received a transplant, 75 withdrew from participation during
the trial, and 18 discontinued treatment because of a change
in dialysis center (Figure 1).23
No serious adverse events relating to the study intervention
were reported. Fifteen patients discontinued the treatment
because of intolerance of the vitamins. The disorders reported
included gastrointestinal discomfort, skin rashes, and headaches. Patients who did not continue the therapy until the end
of the study for the reasons mentioned above were included in
the final analysis with data censored at the time of the last
follow-up visit.

Baseline Characteristics

Figure 1. Trial flow diagram according to Consolidated Standards of Reporting Trials (CONSORT) Statement 2001.23

extended recruitment phase and a reduced number of participating

patients (n650), the follow-up period was increased to 6 years. An
interim analysis was carried out by the data and safety monitoring
board in January 2007 after completion of a 2-year follow-up of 75%
of the original number of patients, and they gave no reason to end the
trial before schedule.
All analyses were performed according to the intention-to-treat
principle with the exception that patients who left the study could not
be followed up and were considered censored at that time. As shown
in Figure 1, the proportion of these patients was similar in both
treatment arms. The baseline characteristics of the patients in the 2
treatment arms are described in absolute terms and as percentages,
by means with their SDs when the distribution was approximately
normal, or by medians and 5th to 95th percentiles if it was not and
compared between the 2 arms through the use of the 2 test, t test,
and Mann-Whitney U test.
The effect of the study medication on the plasma levels of
vitamins and homocysteine after 6 months of treatment was checked
in 97 patients by nonparametric tests (Wilcoxon matched-pairs rank
tests and the Mann-Whitney U test). Survival curves were estimated
by the Kaplan-Meier method, and event rates were compared by the
log-rank test. Proportional Cox regression analyses were used to
calculate risk estimates adjusted for further risk factors.
In addition to the analysis of first cardiovascular events, we
carried out an analysis of all cardiovascular events that occurred in
the course of the study. Cardiovascular events that occurred after the
first event were counted for this purpose. For this analysis, the
method suggested by Andersen and Gill22 was used.
All reported P values are 2 sided. After adjustment for 1 interim
analysis according to the OBrien-Fleming method at an information
rate of 75%, in the final analysis, values of P0.044 were taken as
significant for the primary and secondary end points. All statistical
analyses were done with SPSS version 15.0.1.1 for Windows (SPSS
Inc, Chicago, Ill) and SAS version 9.2 for Windows (SAS Institute,
Inc, Cary, NC; PHREG procedure).

The clinical and demographic characteristics of the patients

are presented in Table 1. The baseline characteristics in the
placebo and active treatment groups were generally well
balanced. Significant differences were found only in the
percentage of patients with hypertension, including patients
receiving antihypertensive therapy. There were no differences
in the total blood pressure values between the treatment
groups. With respect to age, sex, distribution, and prevalence
of diabetes mellitus, the randomized patients were comparable to the entire dialysis population in Germany.24

Effect of Vitamin Supplementation on Plasma

Homocysteine and B Vitamin Levels
The effects of vitamin supplementation on plasma concentrations of homocysteine, folate, cobalamin, and PLP are presented in Table 2. These measurements had been carried out
for efficacy control on biochemical parameters after 6 months
in a subset of patients (n97). In the active treatment group,
the median change in homocysteine was 10.4 mol/L
(P0.001), which corresponds to a 35% decrease in the
baseline level. The median values of folate, cobalamin, and
PLP all increased in the active treatment group: folate, 5-fold;
PLP, 2-fold; and cobalamin, 30% (all P0.001). The
placebo group had been receiving a low-dose preparation of
the same vitamins, and this was associated with an insignificant increase in PLP (5%) and in both folate and cobalamin by 30% (P0.05 for folate and P0.001 for cobalamin). The median homocysteine concentration in the
placebo arm was lowered by 1.8 mol/L compared with
baseline (P0.07).

Primary Outcome: Total Mortality

Of the 650 randomized patients, 194 died during the study
period as a result of all causes, 102 (31%) in the active treatment
group, and 92 (28%) in the placebo group (Table 3 and Figure
2A). The treatment therefore had no effect on total mortality
(hazard ratio [HR], 1.13; 95% confidence interval [CI], 0.85 to
1.50; P0.51). Adjustment for prespecified baseline covariates
did not lead to any substantial change in results. An analysis for

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Heinz et al
Table 1.

B Vitamins and Mortality in Dialysis Patients

1435

Baseline Characteristics of the Study Participants

Characteristic

Total
(n650)

Placebo
(n323)

Active Treatment
(n327)

Age, y

6113

6113

6113

Male sex, n (%)

379 (58)

189 (59)

190 (58)

Body mass index, kg/m2

275

275

275

Diabetes mellitus, n (%)

262 (40)

123 (38)

139 (43)

5.7 (4.97.8)

5.7 (4.77.7)

5.8 (4.97.9)

576 (89)

278 (86)*

298 (91)*

Systolic BP, mm Hg

135 (100170)

130 (95180)

136 (102169)

Diastolic BP, mm Hg

80 (6090)

80 (6090)

80 (6090)

History of CVD, n (%)

312 (48)

149 (46)

163 (50)

Smoking status, n (%)

619

307

312

Never

278 (45)

133 (43)

145 (46)

Former

237 (38)

122 (40)

115 (37)

Current

104 (17)

52 (17)

52 (17)

HbA1c
Hypertension, n (%)

Dialysis-related parameters
Time since dialysis, mo

32 (5166)

31 (5152)

32 (5171)

Time on dialysis, h/wk

13.5 (9.016.5)

13.5 (9.016.5)

12.5 (9.016.5)

Erythropoietin, n (%)

530 (82)

269 (83)

261 (80)

Prestudy vitamins, n (%)

193 (30)

96 (30)

97 (30)

29.0 (14.163.3)

28.2 (13.062.0)

30.0 (14.965.3)

Laboratory measurements
Homocysteine, mol/L
Folate, nmol/L

14.1 (6.675.6)

13.8 (6.867.5)

14.3 (6.384.1)

RBC folate, nmol/L

1758 (7077399)

1859 (7067128)

1716 (7047605)

Cobalamin, pmol/L

344 (154932)

351 (167908)

334 (148994)

PLP, nmol/L

22.9 (6.6192.8)

23.7 (7.3187.2)

21.4 (5.5197.4)

Creatinine, mol/L
Albumin, g/L
CRP, mg/L
CRP 5 mg/L, n (%)

809273

795290

823256

38.8 (33.143.6)

38.6 (33.144.0)

39.0 (33.143.4)

5.9 (0.742.7)

5.7 (0.640.0)

6.2 (0.649.3)

355 (55)

171 (53)

184 (56)

Total cholesterol, mmol/L

4.9 (3.27.2)

4.9 (3.16.9)

4.9 (3.37.3)

HDL cholesterol, mmol/L

0.9 (0.51.5)

0.9 (0.51.5)

0.9 (0.51.6)

LDL cholesterol, mmol/L

2.9 (1.54.8)

2.8 (1.44.8)

2.9 (1.64.8)

Triglycerides, mmol/L

2.3 (0.96.1)

2.3 (0.95.9)

2.3 (0.96.7)

HbA1c indicates hemoglobin A1c; BP, blood pressure; CVD, cardiovascular disease; RBC, red blood cell; PLP,
pyridoxal-5-phosphate; CRP, C-reactive protein; HDL, high-density lipoprotein; and LDL, low-density lipoprotein. Data are
given as meanSD, medians (5th to 95th percentiles), or numbers and percentages as appropriate.
*P0.04 for the comparison with placebo.

specific causes of mortality did not bring to light any significant

effects for particular causes (Table 3).

Secondary Outcome: First Fatal and Nonfatal

Cardiovascular Events
The secondary outcome occurred in 83 patients (25%)
in the active treatment and in 98 (30%) in the placebo
group. The treatment had no significant effect on fatal and
nonfatal cardiovascular events (HR, 0.80; 95% CI, 0.60 to
1.07; P0.13). After adjustment for the baseline covariates, the results remained unaltered (Table 3 and Figure
2B). The numbers of events and HRs specified for individual events are listed in Table 3. Only symptoms of
unstable angina pectoris were significantly reduced by the
active treatment.

Additional Analysis: Multiple

Cardiovascular Events
The total number of cardiovascular events was 234 (181 first
events and 53 subsequent events). The rate per 100 patientyears was 13.7 in the active treatment group and 17.1 in the
placebo group. The HR adjusted for multiple covariates was
0.79 (95% CI, 0.59 to 1.05; P0.10; data not shown).

Discussion
The association of high homocysteine levels with the risk of
mortality and cardiovascular disease is an attractive explanation for the elevated risk in hemodialysis patients because
almost every patient exhibits elevated homocysteine levels.
Patients with ESRD show the highest homocysteine concen-

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March 30, 2010

Table 2. Plasma Levels of Total Homocysteine, Serum Levels of Folate, Serum Levels of Cobalamin, and Plasma
Levels of PLP at Baseline and After 6 Months in a Subgroup of 97 Patients
Baseline

At 6 mo

P, Baseline vs 6 mo*

Changes During 6 mo

Total homocysteine, mol/L

Placebo (n37)

28.8 (14.168.2)

22.3 (9.854.1)

0.07

Active treatment (n59)

28.7 (16.569.4)

18.8 (7.233.6)

0.001

P (placebo vs treatment)

0.49

1.8 (42.315.05)
10.4 (35.82.5)

0.03

0.001

Folate, nmol/L
Placebo (n37)

11.8 (5.761.4)

15.0 (8.283.6)

Active treatment (n54)

12.7 (5.7118.5)

81.8 (34.0117.4)

0.05

3.0 (22.916.4)

0.001

66.4 (2.0105.8)

P (placebo vs treatment)

0.35

0.001

Placebo (n38)

288 (140690)

399 (227731)

0.001

125 (158372)

Active treatment (n58)

279 (72999)

407 (1631058)

0.001

100 (225459)

0.001

Cobalamin, pmol/L

P (placebo vs treatment)

0.45

0.87

0.36

Placebo (n38)

20.6 (9.9135.5)

22.1 (8.0284.0)

0.53

0.4 (58.0218.7)

Active treatment (n57)

26.0 (8.8333.6)

80.5 (14.1305.7)

0.001

58.4 (238.9259.3)

P (placebo vs treatment)

0.35

0.001

PLP, nmol/L

0.001

Data are given as medians (5th to 95th percentiles).

*Wilcoxon matched-pairs rank test for repeated measurements.
Mann-Whitney U test.

homocysteine can be lowered by supplementation with folic

acid, vitamin B12, and vitamin B6. It was therefore reasonable
to embark on a randomized controlled trial with the aim of
reducing homocysteine by vitamin supplementation and thus
also reducing cardiovascular risk and mortality.

trations compared with any other patient group except those

with homocystinuria.14 Numerous studies have shown that in
these patients there is an association between homocysteine
on the one hand and cardiovascular events and mortality on
the other hand (see the summary by Heinz et al15), and that

Table 3. Primary and Secondary Outcomes in the Treatment Groups, Respective Causes of Mortality, Individual Cardiovascular End
Points, and the Corresponding HRs With 95% CIs
Active Treatment
(n327), n (%)

Placebo
(n323), n (%)

Crude HR
(95% CI)

Adjusted* HR
(95% CI)

102 (31)

92 (28)

1.13 (0.851.50)

0.51

1.14 (0.851.52)

0.37

83 (25)

98 (30)

0.80 (0.601.07)

0.13

0.79 (0.591.07)

0.13

Primary outcome
Total mortality
Secondary outcome
Cardiovascular events
Category of causes of mortality
Cardiac causes

37 (11)

32 (10)

1.18 (0.731.89)

0.50

1.26 (0.772.06)

0.36

Vascular causes

6 (2)

10 (3)

0.61 (0.221.68)

0.34

0.51 (0.181.42)

0.20

28 (9)

22 (7)

1.30 (0.742.27)

0.36

1.19 (0.672.10)

0.55

8 (2)

7 (2)

1.17 (0.433.23)

0.76

1.44 (0.504.17)

0.50

14 (4)

15 (5)

0.95 (0.461.97)

0.89

1.00 (0.482.11)

0.99

9 (3)

6 (2)

1.56 (0.564.39)

0.40

1.74 (0.614.98)

0.31
0.99

Sepsis and infections

Tumors
Other causes
Unknown
Individual cardiovascular events
Myocardial infarction (nonfatal and fatal)

20 (6)

19 (6)

1.06 (0.571.99)

0.86

1.00 (0.531.88)

Coronary vascularization procedures

8 (2)

18 (6)

0.44 (0.191.02)

0.06

0.44 (0.191.03)

0.06

Unstable angina pectoris

5 (2)

15 (5)

0.32 (0.120.89)

0.03

0.32 (0.120.89)

0.03

Sudden cardiac death

22 (7)

24 (7)

0.93 (0.521.66)

0.81

1.04 (0.571.91)

0.89

Stroke (nonfatal and fatal)

11 (3)

15 (5)

0.74 (0.341.62)

0.45

0.73 (0.331.60)

0.43

Peripheral artery disease

26 (8)

34 (11)

0.74 (0.451.24)

0.26

0.77 (0.461.31)

0.34

7 (2)

6 (2)

1.16 (0.393.44)

0.79

1.14 (0.373.48)

0.82

Pulmonary embolism and thromboses

*Cox regression analysis adjusted for age, sex, diabetes mellitus, hypertension, time on dialysis, C-reactive protein, and albumin.

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Heinz et al

Figure 2. Primary end point of total mortality (A) and secondary

end point of fatal and nonfatal cardiovascular events (B).
Kaplan-Meier estimates of survival in the active treatment group
vs placebo group. Solid line indicates active treatment; dashed
line, placebo.

The results of our study, however, do not support the idea

that vitamin supplementation with folic acid, vitamin B12, and
vitamin B6 can generally reduce cardiovascular events and
mortality in patients with ESRD. Although this result is rather
disappointing at first glance, some important points must be
noted. First, the patients in the placebo group received a
low-dose vitamin supplement with the aim of avoiding
vitamin deficiencies in this group, which would then have
been treated by the physicians in charge. Preliminary studies
had suggested that this low-dose supplement would not have
any influence on the homocysteine levels and vitamin levels.19 However, we did not observe a significant difference in
the cobalamin levels between the treatment groups.
Second, we could have expected this result if we had
known the results from other trials that have been published
since the beginning of our study in 2002. It should be
mentioned that the results of the present trial are in line with the
results of other trials in this population group, the Atherosclerosis and Folic Acid Supplementation Trial (ASFAST) and the
Homocysteine Trial (HOST).25,26 The HRs for cardiovascular
events were 0.87 (95% CI, 0.58 to 1.32) in 315 patients in the
ASFAST trial and 0.86 (95% CI, 0.67 to 1.08) for myocardial

B Vitamins and Mortality in Dialysis Patients

1437

infarction and 0.90 (95% CI, 0.58 to 1.40) for stroke in 2056
patients with ESRD or chronic kidney disease in HOST. In a
recent meta-analysis, we calculated for a 5-mol/L increase
in homocysteine an increase in risk of 9% for cardiovascular
events in patients with ESRD.15 If we apply this result to the
homocysteine levels obtained at 6 months in our study (Table
2), then a small, insignificant reduction in cardiovascular
disease events is plausible.
Concerning mortality, the results of our study are comparable to the results of HOST. We did not observe any effect
on specific causes of death. Regarding cardiovascular events,
analysis of specific events showed a significant reduction in
unstable angina pectoris and fewer vascularization procedures (Table 3). Because this is a post hoc analysis, the results
must be considered carefully.
The results of the present study and of other controlled
randomized trials in patients with (end-stage) renal disease
suggest that B vitamins do not have an effect on total
mortality in this population.25,26 However, there is a consistent between-trial reduction in relative risk of cardiovascular
disease, on the order of 10%. The trials conducted so far,
including ours, have been too small to establish a significant
effect of this magnitude. Doing so would require a trial with
2700 patients in each treatment group. It is not likely that an
investigation on this scale will ever be conducted to prove
this statement. The traditional approaches that have been
successful in cardiovascular disease risk reduction in patients
without renal disease are, however, ineffective in patients
with ESRD.27
A major criticism of vitamin supplementation trials in
patients without renal disease is that homocysteine is normal
or nearly normal in these patients. The median baseline
homocysteine level in our study was 28 mol/L, about twice
the value of the homocysteine levels in these trials. Whether
a similar effect would be observed in patients without renal
disease but with homocysteine levels of this magnitude
remains unknown.

Conclusions
Active treatment with folic acid, vitamin B12, and vitamin B6
did not significantly reduce total mortality and cardiovascular
risk in patients with ESRD. Our findings do not support the
administration of high-dose vitamin supplements in this total
population. However, in accordance with other studies with B
vitamins in patients with chronic kidney failure, a smaller
protective effect of the vitamins on cardiovascular events is
possible.

Acknowledgments
We are indebted to all participating dialysis patients, physicians, and
dialysis staff. None of these people received any compensation for
their contribution.

Sources of Funding
This work was funded by the School of Medicine of Otto-von-Guericke
University Magdeburg; Roche Diagnostics, Mannheim, Germany (laboratory measurements); and Fresenius Medical Care, Bad Homburg,
Germany (study drug and matching placebo).

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Circulation

March 30, 2010

Disclosures
None.

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CLINICAL PERSPECTIVE
We studied the effect of homocysteine-lowering treatment with B vitamins in patients with end-stage renal disease in a
randomized controlled trial. After each dialysis session, patients received either a high-dose vitamin supplement (active
treatment: 5 mg folic acid, 50 g vitamin B12, and 20 mg vitamin B6) or a low-dose vitamin supplement to avoid vitamin
deficiencies (control: 0.2 mg folic acid, 4 g vitamin B12, and 1 mg vitamin B6). Homocysteine concentrations were
significantly lowered in the group receiving high amounts of vitamins. Patients were followed up for a median period of
25 months. The vitamin treatment did not affect total mortality (hazard ratio, 1.13; 95% confidence interval, 0.85 to 1.50;
P0.51) or cardiovascular morbidity (hazard ratio, 0.80; 95% confidence interval, 0.60 to 1.07; P0.13). Adjustment for
other risk factors did not change these results substantially. In this randomized clinical trial, a significant clinical benefit
of additional amounts of B vitamins for lowering of homocysteine concentrations was not shown. The results are in
accordance with other trials that used B vitamins in patients with renal disease.

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Rsums darticles
Antcdents parentaux daccident vasculaire crbral
et risque dAVC encouru par les enfants
LEtude de Framingham
Sudha Seshadri, MD ; Alexa Beiser, PhD ; Aleksandra Pikula, MD ; Jayandra J. Himali, MSc ;
Margaret Kelly-Hayes, DEd, RN ; Stephanie Debette, MD, PhD ; Anita L. DeStefano, PhD ;
Jose R. Romero, MD ; Carlos S. Kase, MD ; Philip A. Wolf, MD
ContexteLes donnes sur le lien existant entre les antcdents parentaux daccident vasculaire crbral (AVC) et le risque de
survenue dun tel vnement chez les enfants sont tonnamment divergentes, cela tenant en grande partie lhtrognit des
protocoles dtudes et labsence dinformations valides, contrairement au statut des ascendants en matire dAVC pour lequel
on dispose de donnes historiques.
Mthodes et rsultatsNous avons men une tude en milieu communautaire pour savoir si la survenue dun AVC chez un parent
(documente sur un mode prospectif) avait eu ou non pour effet daccrotre le risque encouru par ses enfants de prsenter un tel
accident ; pour ce faire, parmi les participants ltude de Framingham sur la descendance, nous avons constitu une cohorte de
3 443 individus initialement sans antcdent dAVC (53 % de femmes ; ge moyen : 48 14 ans) mais dont un parent avait t
victime dun tel vnement (avant lge de 65 ans) et qui staient prts aux premier, troisime, cinquime et/ou septime
examens prvus, ces sujets ayant t suivis pendant 8 ans aprs le bilan initial. Sur plus de 11 029 priodes dobservation
individualise (soit 77 534 annes-patients), nous avons recens 106 AVC parentaux survenus avant lge de 65 ans et 128 ayant
frapp la descendance (respectivement 74 et 106 de ces accidents ayant t de type ischmique). Par lemploi de modles de Cox
multivaris ajusts pour lge, le sexe, la place dans la fratrie et les facteurs de risque dAVC initialement prsents, nous avons
tabli que la survenue, chez un ascendant, dun quelconque type dAVC et, notamment, dun accident dorigine ischmique avait
concouru augmenter le risque de survenue du mme type dAVC chez les enfants (rapport de risques : 2,79 ; intervalle de
confiance [IC] 95 % : 1,68 4,66 ; p <0,001 pour lanalyse portant sur les AVC de tous types ; rapport de risques : 3,15 ; IC
95 % : 1,69 5,88 ; p <0,001 pour lanalyse portant sur les AVC de type ischmique). La corrlation sest montre valide, que
lantcdent dAVC ait t enregistr chez la mre ou chez le pre.
ConclusionsLa survenue documente dun AVC chez lun des parents avant lge de 65 ans a concouru tripler le risque
daccident du mme type chez les enfants. Cette augmentation du risque a persist aprs ajustement tenant compte des facteurs
conventionnels de risque dAVC. Les antcdents parentaux valids dAVC pourraient ds lors se rvler cliniquement utiles
pour valuer le degr dexposition dun individu donn au risque dAVC. (Traduit de langlais : Parental Occurrence of Stroke
and Risk of Stroke in Their Children The Framingham Study. Circulation. 2010;121:13041312.)

Mots cls : pidmiologie hrdit ischmie accident vasculaire crbral

Influence de la supplmentation en vitamines B sur la mortalit

globale et le risque dvnements cardiovasculaires dans
linsuffisance rnale terminale
Rsultats dun essai randomis et contrl
Judith Heinz, MSc ; Siegfried Kropf, PhD ; Ute Domrse, MD ; Sabine Westphal, MD ;
Katrin Borucki, MD ; Claus Luley, MD ; Klaus H. Neumann, MD ; Jutta Dierkes, PhD
ContexteDes tudes observationnelles ont montr que lhyperhomocystinmie contribue augmenter la mortalit globale et le
risque dvnements cardiovasculaires chez les patients atteints dinsuffisance rnale terminale. Ces individus prsentent des
taux dhomocystine extrmement levs, quil est possible de rduire par une supplmentation en acide folique et en vitamine
B12. Nous avons donc entrepris un essai clinique randomis visant abaisser lhomocystinmie par lapport de vitamines B afin
de vrifier si cela avait pour effet de diminuer lincidence des vnements cardiovasculaires et la mortalit globale.

2011 Lippincott Williams & Wilkins

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Rsums darticles

73

Mthodes et rsultatsCette tude multicentrique randomise et en double aveugle a t mene dans 33 centres dhmodialyse
dAllemagne du Nord et de lEst entre juillet 2002 et juillet 2008. Nous avons randomis 650 patients hmodialyss au stade
dinsuffisance rnale terminale de manire constituer deux groupes de traitement qui ont respectivement reu, 3 fois par
semaine pendant une dure moyenne de 2 ans, 5 mg dacide folique, 50 g de vitamine B12 et 20 mg de vitamine B6 (groupe de
traitement actif) ou 0,2 mg dacide folique, 4 g de vitamine B12 et 1,0 mg de vitamine B6 (groupe placebo). Le critre de
jugement principal a t la mortalit globale, le critre secondaire ayant t le taux dvnements cardiovasculaires fatals et non
fatals. Lvnement cible principal est survenu chez 102 (31 %) des patients qui avaient reu le traitement actif et chez 92 (28 %)
de ceux auxquels le placebo avait t assign (rapport de risques : 1,13 ; intervalle de confiance [IC] 95 % : 0,85 1,50 ;
p = 0,51). Lvnement cible secondaire sest produit chez 83 (25 %) des patients du groupe de traitement actif et chez 98 (30 %)
des sujets du groupe placebo (rapport de risques : 0,80 ; IC 95 % : 0,60 1,07 ; p = 0,13).
ConclusionsLaugmentation des apports en acide folique et en vitamines B12 et B6 na pas diminu la mortalit globale et na pas
eu dinfluence significative sur le risque dvnements cardiovasculaires chez les patients atteints dinsuffisance rnale terminale.
Registre des Essais cliniquesURL : www.anzctr.org.au. Identifiant unique : ACTRN12609000911291. URL : www.cochranerenal.org. Identifiant unique : CRG010600027.
(Traduit de langlais : B Vitamins and the Risk of Total Mortality and Cardiovascular Disease in End-Stage Renal Disease Results
of a Randomized Controlled Trial. Circulation. 2010;121:14321438.)

Mots cls : vitamines B maladies cardiovasculaires hmodialyse

homocystine rein mortalit prvention

Incidence, facteurs prdictifs et implications pronostiques

de lhospitalisation pour saignement diffr aprs
intervention coronaire percutane chez les
patients gs de plus de 65 ans
Dennis T. Ko, MD, MSc ; Lingsong Yun, MSc ; Harindra C. Wijeysundera, MD ;
Cynthia A. Jackevicius, PharmD, MSc ; Sunil V. Rao, MD ; Peter C. Austin, PhD ;
Jean-Franois Marquis, MD ; Jack V. Tu, MD, PhD
ContexteLes donnes recueillies sur les complications hmorragiques des interventions coronaires percutanes (ICP) manent
essentiellement dessais randomiss qui taient axs sur les saignements survenus pendant lhospitalisation. De ce fait, on ne
connat pas avec prcision lincidence des hmorragies postopratoires diffres, les facteurs indpendants qui les favorisent ni
leur importance pronostique en pratique clinique.
Mthodes et rsultatsNotre tude a port sur 22 798 patients gs de plus de 65 ans qui avaient fait lobjet dune ICP entre le 1er
dcembre 2003 et le 31 mars 2007 en Ontario (Canada). Nous avons eu recours des modles de risques proportionnels de Cox
pour tablir les facteurs corrls avec la survenue dun saignement diffr (dfini comme ayant motiv lhospitalisation du
patient postrieurement celle au cours de laquelle lICP avait t pratique) et estimer le risque de dcs ou dinfarctus du
myocarde associ un tel saignement. Nous avons observ que 2,5 % des patients avaient t hospitaliss pour un vnement
hmorragique dans lanne ayant suivi lICP, 56 % des pisodes ayant eu pour sige la sphre digestive. Le facteur ayant le plus
significativement major le risque de saignement diffr a t ladministration postopratoire de warfarine (rapport de risques
[RR] : 3,12). Les autres facteurs de risque significatifs ont t lge (RR : 1,41 par tranche de 10 ans), le sexe masculin
(RR : 1,24), le cancer (RR : 1,80), les antcdents hmorragiques (RR : 2,42), linsuffisance rnale chronique (RR : 1,93)
et la prise danti-inflammatoires non strodiens (RR : 1,73). Aprs ajustement en fonction des covariables initiales, il est
apparu que lhospitalisation pour pisode hmorragique avait concouru augmenter significativement le risque de dcs
ou dinfarctus du myocarde un an (RR : 2,39 ; IC 95 % : 1,93 2,97) ainsi que la mortalit globale (RR : 3,38 ;
IC 95 % : 2,60 4,40).
ConclusionsLhospitalisation motive par la survenue dun saignement diffr aprs ICP contribue accrotre fortement le
risque de dcs ou dinfarctus du myocarde. Cest la prescription dune trithrapie anticoagulante (aspirine, thinopyridine
et warfarine) qui est lorigine du risque dvnement hmorragique diffr le plus lev. (Traduit de langlais : Incidence,
Predictors, and Prognostic Implications of Hospitalization for Late Bleeding After Percutaneous Coronary Intervention for
Patients Older Than 65 Years. Circ Cardiovase Interv. 2010;3:140147.)

Mots cls : saignement intervention coronaire percutane mortalit anticoagulants oraux

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