Vascular Medicine

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 Domröse, MD; Sabine Westphal, MD;
Katrin Borucki, MD; Claus Luley, MD; Klaus H. Neumann, MD; Jutta Dierkes, PhD
Downloaded from http://circ.ahajournals.org/ by guest on February 10, 2017
Background—In 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 Results—This 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; P⫽0.51). 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; P⫽0.13).
Conclusions—Increased 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 Registration—URL: www.anzctr.org.au. Unique identifier: ACTRN12609000911291. URL:
www.cochrane-renal.org. Unique identifier: CRG010600027.
(Circulation. 2010;121:1432-1438.)
Key Words: B vitamins 䡲 cardiovascular diseases 䡲 hemodialysis 䡲 homocysteine 䡲 kidney
䡲 mortality 䡲 prevention
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-
A
lthough a number of prospective observational studies
have shown that hyperhomocysteinemia is associated
with cardiovascular morbidity and mortality,1–3 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.12–14 On average, the homocys-
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, Martinistraße
52, D-20246 Hamburg, Germany. E-mail [email protected]
© 2010 American Heart Association, Inc.
Circulation is available at http://circ.ahajournals.org
DOI: 10.1161/CIRCULATIONAHA.109.904672
1432
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
Downloaded from http://circ.ahajournals.org/ by guest on February 10, 2017
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 (n⫽184), chronic
glomerulonephritis (n⫽140), interstitial nephropathy (n⫽84), polycystic nephropathy (n⫽75), vascular nephropathy (n⫽63), other
reasons (n⫽56), and unknown reasons (n⫽48). 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 (n⫽97), 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
1434
Circulation
March 30, 2010
Results
Compliance, Follow-Up, and Adverse Events
Downloaded from http://circ.ahajournals.org/ by guest on February 10, 2017
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 (n⫽650), 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 O’Brien-Fleming method at an information
rate of 75%, in the final analysis, values of Pⱕ0.044 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 (n⫽97). In the active treatment group,
the median change in homocysteine was ⫺10.4 ␮mol/L
(P⬍0.001), 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 P⬍0.001). 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% (P⫽0.05 for folate and P⬍0.001 for cobalamin). The median homocysteine concentration in the
placebo arm was lowered by 1.8 ␮mol/L compared with
baseline (P⫽0.07).
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; P⫽0.51). Adjustment for prespecified baseline covariates
did not lead to any substantial change in results. An analysis for
Heinz et al
Table 1.
B Vitamins and Mortality in Dialysis Patients
1435
Baseline Characteristics of the Study Participants
Characteristic
Total
(n⫽650)
Placebo
(n⫽323)
Active Treatment
(n⫽327)
Age, y
61⫾13
61⫾13
61⫾13
Male sex, n (%)
379 (58)
189 (59)
190 (58)
Body mass index, kg/m2
27⫾5
27⫾5
27⫾5
Diabetes mellitus, n (%)
262 (40)
123 (38)
139 (43)
5.7 (4.9–7.8)
5.7 (4.7–7.7)
5.8 (4.9–7.9)
576 (89)
278 (86)*
298 (91)*
Systolic BP, mm Hg
135 (100–170)
130 (95–180)
136 (102–169)
Diastolic BP, mm Hg
80 (60–90)
80 (60–90)
80 (60–90)
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 (%)
Downloaded from http://circ.ahajournals.org/ by guest on February 10, 2017
Dialysis-related parameters
Time since dialysis, mo
32 (5–166)
31 (5–152)
32 (5–171)
Time on dialysis, h/wk
13.5 (9.0–16.5)
13.5 (9.0–16.5)
12.5 (9.0–16.5)
Erythropoietin, n (%)
530 (82)
269 (83)
261 (80)
Prestudy vitamins, n (%)
193 (30)
96 (30)
97 (30)
29.0 (14.1–63.3)
28.2 (13.0–62.0)
30.0 (14.9–65.3)
Laboratory measurements
Homocysteine, ␮mol/L
Folate, nmol/L
14.1 (6.6–75.6)
13.8 (6.8–67.5)
14.3 (6.3–84.1)
RBC folate, nmol/L
1758 (707–7399)
1859 (706–7128)
1716 (704–7605)
Cobalamin, pmol/L
344 (154–932)
351 (167–908)
334 (148–994)
PLP, nmol/L
22.9 (6.6–192.8)
23.7 (7.3–187.2)
21.4 (5.5–197.4)
Creatinine, ␮mol/L
Albumin, g/L
CRP, mg/L
CRP ⬎5 mg/L, n (%)
809⫾273
795⫾290
823⫾256
38.8 (33.1–43.6)
38.6 (33.1–44.0)
39.0 (33.1–43.4)
5.9 (0.7–42.7)
5.7 (0.6–40.0)
6.2 (0.6–49.3)
355 (55)
171 (53)
184 (56)
Total cholesterol, mmol/L
4.9 (3.2–7.2)
4.9 (3.1–6.9)
4.9 (3.3–7.3)
HDL cholesterol, mmol/L
0.9 (0.5–1.5)
0.9 (0.5–1.5)
0.9 (0.5–1.6)
LDL cholesterol, mmol/L
2.9 (1.5–4.8)
2.8 (1.4–4.8)
2.9 (1.6–4.8)
Triglycerides, mmol/L
2.3 (0.9–6.1)
2.3 (0.9–5.9)
2.3 (0.9–6.7)
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 mean⫾SD, medians (5th to 95th percentiles), or numbers and percentages as appropriate.
*P⫽0.04 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; P⫽0.13). 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; P⫽0.10; 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-
1436
Circulation
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 (n⫽37)
28.8 (14.1–68.2)
22.3 (9.8–54.1)
0.07
Active treatment (n⫽59)
28.7 (16.5–69.4)
18.8 (7.2–33.6)
⬍0.001
P (placebo vs treatment)†
0.49
⫺1.8 (⫺42.3–15.05)
⫺10.4 (⫺35.8–2.5)
0.03
0.001
Folate, nmol/L
Placebo (n⫽37)
11.8 (5.7–61.4)
15.0 (8.2–83.6)
Active treatment (n⫽54)
12.7 (5.7–118.5)
81.8 (34.0–117.4)
0.05
3.0 (⫺22.9–16.4)
⬍0.001
66.4 (⫺2.0–105.8)
P (placebo vs treatment)†
0.35
⬍0.001
Placebo (n⫽38)
288 (140–690)
399 (227–731)
⬍0.001
125 (⫺158–372)
Active treatment (n⫽58)
279 (72–999)
407 (163–1058)
⬍0.001
100 (⫺225–459)
⬍0.001
Cobalamin, pmol/L
P (placebo vs treatment)†
Downloaded from http://circ.ahajournals.org/ by guest on February 10, 2017
0.45
0.87
0.36
Placebo (n⫽38)
20.6 (9.9–135.5)
22.1 (8.0–284.0)
0.53
0.4 (⫺58.0–218.7)
Active treatment (n⫽57)
26.0 (8.8–333.6)
80.5 (14.1–305.7)
⬍0.001
58.4 (⫺238.9–259.3)
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
(n⫽327), n (%)
Placebo
(n⫽323), n (%)
Crude HR
(95% CI)
P
Adjusted* HR
(95% CI)
P
102 (31)
92 (28)
1.13 (0.85–1.50)
0.51
1.14 (0.85–1.52)
0.37
83 (25)
98 (30)
0.80 (0.60–1.07)
0.13
0.79 (0.59–1.07)
0.13
Primary outcome
Total mortality
Secondary outcome
Cardiovascular events
Category of causes of mortality
Cardiac causes
37 (11)
32 (10)
1.18 (0.73–1.89)
0.50
1.26 (0.77–2.06)
0.36
Vascular causes
6 (2)
10 (3)
0.61 (0.22–1.68)
0.34
0.51 (0.18–1.42)
0.20
28 (9)
22 (7)
1.30 (0.74–2.27)
0.36
1.19 (0.67–2.10)
0.55
8 (2)
7 (2)
1.17 (0.43–3.23)
0.76
1.44 (0.50–4.17)
0.50
14 (4)
15 (5)
0.95 (0.46–1.97)
0.89
1.00 (0.48–2.11)
0.99
9 (3)
6 (2)
1.56 (0.56–4.39)
0.40
1.74 (0.61–4.98)
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 (0.57–1.99)
0.86
1.00 (0.53–1.88)
Coronary vascularization procedures
8 (2)
18 (6)
0.44 (0.19–1.02)
0.06
0.44 (0.19–1.03)
0.06
Unstable angina pectoris
5 (2)
15 (5)
0.32 (0.12–0.89)
0.03
0.32 (0.12–0.89)
0.03
Sudden cardiac death
22 (7)
24 (7)
0.93 (0.52–1.66)
0.81
1.04 (0.57–1.91)
0.89
Stroke (nonfatal and fatal)
11 (3)
15 (5)
0.74 (0.34–1.62)
0.45
0.73 (0.33–1.60)
0.43
Peripheral artery disease
26 (8)
34 (11)
0.74 (0.45–1.24)
0.26
0.77 (0.46–1.31)
0.34
7 (2)
6 (2)
1.16 (0.39–3.44)
0.79
1.14 (0.37–3.48)
0.82
Pulmonary embolism and thromboses
*Cox regression analysis adjusted for age, sex, diabetes mellitus, hypertension, time on dialysis, C-reactive protein, and albumin.
Heinz et al
Downloaded from http://circ.ahajournals.org/ by guest on February 10, 2017
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).
1438
Circulation
March 30, 2010
Disclosures
None.
References
Downloaded from http://circ.ahajournals.org/ by guest on February 10, 2017
1. Vollset SE, Refsum H, Tverdal A, Nygård O, Nordrehaug JE, Tell GS,
Ueland PM. Plasma total homocysteine and cardiovascular and noncardiovascular mortality: the Hordaland Homocysteine Study. Am J Clin
Nutr. 2001;74:130 –136.
2. Boushey CJ, Beresford SA, Omenn GS, Motulsky AG. A quantitative
assessment of plasma homocysteine as a risk factor for vascular disease.
JAMA. 1995;274:1049 –1057.
3. Homocysteine Studies Collaboration. Homocysteine and risk of ischemic
heart disease and stroke: a meta-analysis. JAMA. 2002;288:2015–2022.
4. Baker F, Picton D, Blackwood S, Hunt J, Erskine M, Dyas M. Blinded
comparison of folic acid and placebo in patients with ischemic heart
disease: an outcome trial. Circulation. 2002;106:3642. Abstract.
5. Toole JF, Malinow MR, Chambless LE, Spence JD, Pettigrew LC,
Howard VJ, Sides EG, Wang CH, Stampfer M. 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.
6. Bønaa KH, Njølstad I, Ueland PM, Schirmer H, Tverdal A, Steigen T,
Wang H, Nordrehaug JE, Arnesen E, Rasmussen K, for the NORVIT
Trial Investigators. Homocysteine lowering and cardiovascular events
after acute myocardial infarction. N Engl J Med. 2006;354:1578 –1588.
7. Ebbing M, Bleie Ø, Ueland PM, Nordrehaug JE, Nilsen DW, Vollset SE,
Refsum H, Pedersen EK, Nygård O. Mortality and cardiovascular events
in patients treated with homocysteine-lowering B vitamins after coronary
angiography: a randomized controlled trial. JAMA. 2008;300:795– 804.
8. Lonn E, Yusuf S, Arnold MJ, Sheridan P, Pogue J, Micks M, McQueen
MJ, Probstfield J, Fodor G, Held C, Genest J Jr, for the Heart Outcomes
Prevention Evaluation (HOPE) 2 Investigators. Homocysteine lowering
with folic acid and B vitamins in vascular disease. N Engl J Med.
2006;354:1567–1577.
9. Foley RN, Parfrey PS, Sarnak MJ. Epidemiology of cardiovascular
disease in chronic renal disease. J Am Soc Nephrol. 1998;9:S16 –S23.
10. Ikizler TA. Epidemiology of vascular disease in renal failure. Blood Purif.
2002;20:6 –10.
11. Kundhal K, Lok CE. Clinical epidemiology of cardiovascular disease in
chronic kidney disease. Nephron Clin Pract. 2005;101:c47– c52.
12. Dierkes J, Domröse U, Westphal S, Ambrosch A, Bosselmann HP,
Neumann KH, Luley C. Cardiac troponin T predicts mortality in patients
with end-stage renal disease. Circulation. 2000;102:1964 –1969.
13. Bostom AG, Shemin D, Lapane KL, Miller JW, Sutherland P, Nadeau M,
Seyoum E, Hartman W, Prior R, Wilson PW, Selhub J. Hyperhomocysteinemia and traditional cardiovascular disease risk factors in end-stage
renal disease patients on dialysis: a case-control study. Atherosclerosis.
1995;114:93–103.
14. McCully KS. Homocysteine and vascular disease. Nat Med. 1996;2:
386 –389.
15. Heinz J, Kropf S, Luley C, Dierkes J. Homocysteine as a risk factor for
cardiovascular disease in patients treated by dialysis: a meta-analysis.
Am J Kidney Dis. 2009;54:478 – 489.
16. Sunder-Plassmann G, Födinger M, Buchmayer H, Papagiannopoulos M,
Wojcik J, Kletzmayr J, Enzenberger B, Janata O, Winkelmayer WC, Paul
G, Auinger M, Barnas U, Hörl WH. Effect of high dose folic acid therapy
on hyperhomocysteinemia in hemodialysis patients: results of the Vienna
multicenter study. J Am Soc Nephrol. 2000;11:1106 –1116.
17. Dierkes J, Domröse U, Ambrosch A, Bosselmann HP, Neumann KH,
Luley C. Response of hyperhomocysteinemia to folic acid supplementation in patients with end-stage renal disease. Clin Nephrol. 1999;51:
108 –115.
18. Heinz J, Domröse U, Luley C, Westphal S, Kropf S, Neumann KH,
Dierkes J. Influence of a supplementation with vitamins on cardiovascular
morbidity and mortality in patients with end-stage renal disease: design
and baseline data of a randomized clinical trial. Clin Nephrol. 2009;71:
363–365.
19. Dierkes J, Domröse U, Bosselmann KP, Neumann KH, Luley C. Homocysteine lowering effect of different multivitamin preparations in patients
with end-stage renal disease. J Ren Nutr. 2001;11:67–72.
20. Vester B, Rasmussen K. High performance liquid chromatography
method for rapid and accurate determination of homocysteine in plasma
and serum. Eur J Clin Chem Clin Biochem. 1991;29:549 –554.
21. O’Brien PC, Fleming TR. A multiple testing procedure for clinical trials.
Biometrics. 1979;35:549 –556.
22. Andersen PK, Gill RD. Cox’s regression model counting process: a large
sample study. Ann Stat. 1982;10:1100 –1120.
23. Moher D, Schulz KF, Altman DG. The CONSORT statement: revised
recommendations for improving the quality of reports of parallel-group
randomised trials. Lancet. 2001;357:1191–1194.
24. Frei U, Schober-Halstenberg. Nierenersatztherapie in Deutschland:
Bericht über Dialysebehandlung und Nierentransplantation in Deutschland 2006/2007. QuaSi-Niere gGmbH 2008.
25. Zoungas S, McGrath BP, Branley P, Kerr PG, Muske C, Wolfe R,
Atkins RC, Nicholls K, Fraenkel M, Hutchison BG, Walker R, McNeil
JJ. Cardiovascular morbidity and mortality in the Atherosclerosis and
Folic Acid Supplementation Trial (ASFAST) in chronic renal failure:
a multicenter, randomized, controlled trial. J Am Coll Cardiol. 2006;
47:1108 –1116.
26. Jamison RL, Hartigan P, Kaufman JS, Goldfarb DS, Warren SR, Guarino
PD, Gaziano JM, for the Veterans Affairs Site Investigators. Effect of
homocysteine lowering on mortality and vascular disease in advanced
chronic kidney disease and end-stage renal disease: a randomized controlled trial. JAMA. 2007;298:1163–1170.
27. Wanner C, Krane V, März W, Olschewski M, Mann JF, Ruf G, Ritz E,
for the German Diabetes and Dialysis Study Investigators. Atorvastatin in
patients with type 2 diabetes mellitus undergoing hemodialysis. N Engl
J Med. 2005;353:238 –248.
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;
P⫽0.51) or cardiovascular morbidity (hazard ratio, 0.80; 95% confidence interval, 0.60 to 1.07; P⫽0.13). 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.
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 Domröse, Sabine Westphal, Katrin Borucki, Claus Luley,
Klaus H. Neumann and Jutta Dierkes
Downloaded from http://circ.ahajournals.org/ by guest on February 10, 2017
Circulation. 2010;121:1432-1438; originally published online March 15, 2010;
doi: 10.1161/CIRCULATIONAHA.109.904672
Circulation is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
Copyright © 2010 American Heart Association, Inc. All rights reserved.
Print ISSN: 0009-7322. Online ISSN: 1524-4539
The online version of this article, along with updated information and services, is located on the
World Wide Web at:
http://circ.ahajournals.org/content/121/12/1432
Data Supplement (unedited) at:
http://circ.ahajournals.org/content/suppl/2013/10/17/CIRCULATIONAHA.109.904672.DC1
Permissions: Requests for permissions to reproduce figures, tables, or portions of articles originally published
in Circulation can be obtained via RightsLink, a service of the Copyright Clearance Center, not the Editorial
Office. Once the online version of the published article for which permission is being requested is located,
click Request Permissions in the middle column of the Web page under Services. Further information about
this process is available in the Permissions and Rights Question and Answer document.
Reprints: Information about reprints can be found online at:
http://www.lww.com/reprints
Subscriptions: Information about subscribing to Circulation is online at:
http://circ.ahajournals.org//subscriptions/
Page 72
Résumés d’articles
Antécédents parentaux d’accident vasculaire cérébral
et risque d’AVC encouru par les enfants
L’Etude 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
Contexte—Les données sur le lien existant entre les antécédents parentaux d’accident vasculaire cérébral (AVC) et le risque de
survenue d’un tel événement chez les enfants sont étonnamment divergentes, cela tenant en grande partie à l’hétérogénéité des
protocoles d’études et à l’absence d’informations validées, contrairement au statut des ascendants en matière d’AVC pour lequel
on dispose de données historiques.
Méthodes et résultats—Nous avons mené une étude en milieu communautaire pour savoir si la survenue d’un AVC chez un parent
(documentée sur un mode prospectif) avait eu ou non pour effet d’accroître le risque encouru par ses enfants de présenter un tel
accident ; pour ce faire, parmi les participants à l’étude de Framingham sur la descendance, nous avons constitué une cohorte de
3 443 individus initialement sans antécédent d’AVC (53 % de femmes ; âge moyen : 48 ± 14 ans) mais dont un parent avait été
victime d’un tel événement (avant l’âge de 65 ans) et qui s’étaient prêtés aux premier, troisième, cinquième et/ou septième
examens prévus, ces sujets ayant été suivis pendant 8 ans après le bilan initial. Sur plus de 11 029 périodes d’observation
individualisée (soit 77 534 années-patients), nous avons recensé 106 AVC parentaux survenus avant l’âge de 65 ans et 128 ayant
frappé la descendance (respectivement 74 et 106 de ces accidents ayant été de type ischémique). Par l’emploi de modèles de Cox
multivariés ajustés pour l’âge, le sexe, la place dans la fratrie et les facteurs de risque d’AVC initialement présents, nous avons
établi que la survenue, chez un ascendant, d’un quelconque type d’AVC et, notamment, d’un accident d’origine ischémique avait
concouru à augmenter le risque de survenue du même type d’AVC chez les enfants (rapport de risques : 2,79 ; intervalle de
confiance [IC] à 95 % : 1,68 à 4,66 ; p <0,001 pour l’analyse portant sur les AVC de tous types ; rapport de risques : 3,15 ; IC à
95 % : 1,69 à 5,88 ; p <0,001 pour l’analyse portant sur les AVC de type ischémique). La corrélation s’est montrée valide, que
l’antécédent d’AVC ait été enregistré chez la mère ou chez le père.
Conclusions—La survenue documentée d’un AVC chez l’un des parents avant l’âge de 65 ans a concouru à tripler le risque
d’accident du même type chez les enfants. Cette augmentation du risque a persisté après ajustement tenant compte des facteurs
conventionnels de risque d’AVC. Les antécédents parentaux validés d’AVC pourraient dès lors se révéler cliniquement utiles
pour évaluer le degré d’exposition d’un individu donné au risque d’AVC. (Traduit de l’anglais : Parental Occurrence of Stroke
and Risk of Stroke in Their Children The Framingham Study. Circulation. 2010;121:1304–1312.)
Mots clés : épidémiologie 䊏 hérédité 䊏 ischémie 䊏 accident vasculaire cérébral
Influence de la supplémentation en vitamines B sur la mortalité
globale et le risque d’événements cardiovasculaires dans
l’insuffisance rénale terminale
Résultats d’un essai randomisé et contrôlé
Judith Heinz, MSc ; Siegfried Kropf, PhD ; Ute Domröse, MD ; Sabine Westphal, MD ;
Katrin Borucki, MD ; Claus Luley, MD ; Klaus H. Neumann, MD ; Jutta Dierkes, PhD
Contexte—Des études observationnelles ont montré que l’hyperhomocystéinémie contribue à augmenter la mortalité globale et le
risque d’événements cardiovasculaires chez les patients atteints d’insuffisance rénale terminale. Ces individus présentent des
taux d’homocystéine extrêmement élevés, qu’il est possible de réduire par une supplémentation en acide folique et en vitamine
B12. Nous avons donc entrepris un essai clinique randomisé visant à abaisser l’homocystéinémie par l’apport de vitamines B afin
de vérifier si cela avait pour effet de diminuer l’incidence des événements cardiovasculaires et la mortalité globale.
© 2011 Lippincott Williams & Wilkins
Circulation est disponible sur http://circ.ahajournals.org
72
16:33:15:11:10
Page 72
Page 73
Résumés d’articles
73
Méthodes et résultats—Cette étude multicentrique randomisée et en double aveugle a été menée dans 33 centres d’hémodialyse
d’Allemagne du Nord et de l’Est entre juillet 2002 et juillet 2008. Nous avons randomisé 650 patients hémodialysés au stade
d’insuffisance rénale terminale de manière à constituer deux groupes de traitement qui ont respectivement reçu, 3 fois par
semaine pendant une durée moyenne de 2 ans, 5 mg d’acide folique, 50 µg de vitamine B12 et 20 mg de vitamine B6 (groupe de
traitement actif) ou 0,2 mg d’acide folique, 4 µg de vitamine B12 et 1,0 mg de vitamine B6 (groupe placebo). Le critère de
jugement principal a été la mortalité globale, le critère secondaire ayant été le taux d’événements cardiovasculaires fatals et non
fatals. L’événement cible principal est survenu chez 102 (31 %) des patients qui avaient reçu le traitement actif et chez 92 (28 %)
de ceux auxquels le placebo avait été assigné (rapport de risques : 1,13 ; intervalle de confiance [IC] à 95 % : 0,85 à 1,50 ;
p = 0,51). L’événement cible secondaire s’est 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 à 95 % : 0,60 à 1,07 ; p = 0,13).
Conclusions—L’augmentation des apports en acide folique et en vitamines B12 et B6 n’a pas diminué la mortalité globale et n’a pas
eu d’influence significative sur le risque d’événements cardiovasculaires chez les patients atteints d’insuffisance rénale terminale.
Registre des Essais cliniques—URL : www.anzctr.org.au. Identifiant unique : ACTRN12609000911291. URL : www.cochranerenal.org. Identifiant unique : CRG010600027.
(Traduit de l’anglais : B Vitamins and the Risk of Total Mortality and Cardiovascular Disease in End-Stage Renal Disease Results
of a Randomized Controlled Trial. Circulation. 2010;121:1432–1438.)
Mots clés : vitamines B 䊏 maladies cardiovasculaires 䊏 hémodialyse 䊏
homocystéine 䊏 rein 䊏 mortalité 䊏 prévention
Incidence, facteurs prédictifs et implications pronostiques
de l’hospitalisation pour saignement différé après
intervention coronaire percutanée chez les
patients âgés 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-François Marquis, MD ; Jack V. Tu, MD, PhD
Contexte—Les données recueillies sur les complications hémorragiques des interventions coronaires percutanées (ICP) émanent
essentiellement d’essais randomisés qui étaient axés sur les saignements survenus pendant l’hospitalisation. De ce fait, on ne
connaît pas avec précision l’incidence des hémorragies postopératoires différées, les facteurs indépendants qui les favorisent ni
leur importance pronostique en pratique clinique.
Méthodes et résultats—Notre étude a porté sur 22 798 patients âgés de plus de 65 ans qui avaient fait l’objet d’une ICP entre le 1er
décembre 2003 et le 31 mars 2007 en Ontario (Canada). Nous avons eu recours à des modèles de risques proportionnels de Cox
pour établir les facteurs corrélés avec la survenue d’un saignement différé (défini comme ayant motivé l’hospitalisation du
patient postérieurement à celle au cours de laquelle l’ICP avait été pratiquée) et estimer le risque de décès ou d’infarctus du
myocarde associé à un tel saignement. Nous avons observé que 2,5 % des patients avaient été hospitalisés pour un événement
hémorragique dans l’année ayant suivi l’ICP, 56 % des épisodes ayant eu pour siège la sphère digestive. Le facteur ayant le plus
significativement majoré le risque de saignement différé a été l’administration postopératoire de warfarine (rapport de risques
[RR] : 3,12). Les autres facteurs de risque significatifs ont été l’âge (RR : 1,41 par tranche de 10 ans), le sexe masculin
(RR : 1,24), le cancer (RR : 1,80), les antécédents hémorragiques (RR : 2,42), l’insuffisance rénale chronique (RR : 1,93)
et la prise d’anti-inflammatoires non stéroïdiens (RR : 1,73). Après ajustement en fonction des covariables initiales, il est
apparu que l’hospitalisation pour épisode hémorragique avait concouru à augmenter significativement le risque de décès
ou d’infarctus du myocarde à un an (RR : 2,39 ; IC à 95 % : 1,93 à 2,97) ainsi que la mortalité globale (RR : 3,38 ;
IC à 95 % : 2,60 à 4,40).
Conclusions—L’hospitalisation motivée par la survenue d’un saignement différé après ICP contribue à accroître fortement le
risque de décès ou d’infarctus du myocarde. C’est la prescription d’une trithérapie anticoagulante (aspirine, thiénopyridine
et warfarine) qui est à l’origine du risque d’événement hémorragique différé le plus élevé. (Traduit de l’anglais : Incidence,
Predictors, and Prognostic Implications of Hospitalization for Late Bleeding After Percutaneous Coronary Intervention for
Patients Older Than 65 Years. Circ Cardiovase Interv. 2010;3:140–147.)
Mots clés : saignement 䊏 intervention coronaire percutanée 䊏 mortalité 䊏 anticoagulants oraux
16:33:15:11:10
Page 73