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Clinical Science (2002) 103, 511–515 (Printed in Great Britain)
Association of calcium channel blockers and
mortality in haemodialysis patients
Martin TEPEL, Markus VAN DER GIET, Alexander PARK and Walter ZIDEK
Univ.-Klinik Benjamin Franklin, Freie Universita$ t Berlin, Hindenburgdamm 30, D-12200 Berlin, Germany
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Patients with end-stage renal disease show disturbances of calcium metabolism, including
calcification of arterial walls. Such patients show increased mortality, in particular due to
increased cardiovascular-associated deaths. The association of calcium channel blockers and
mortality in patients undergoing haemodialysis was investigated. A total of 188 patients who
were receiving haemodialysis as of July 1998 were followed up for 30 months. Baseline
characteristics, including age, sex, laboratory and clinical data, medication and dialysis
prescription, were obtained. As of December 2000, 51 of the patients (27 %) had died. In the
deceased group, age was significantly higher, body mass index was significantly lower, and
smoking was significantly more frequent compared with the survival group (each P 0.001). The
percentage of patients taking calcium channel blockers was significantly higher in the survival
group. Cox proportional hazard regression analysis showed that haemodialysis patients assigned
calcium channel blocker therapy had a significantly lower risk of mortality [relative risk 0.33
(95 % confidence interval 0.17–0.67) ; P 0.001]. Thus, in haemodialysis patients who were at high
risk of cardiovascular events, administration of calcium channel blockers was associated with
lower mortality.
INTRODUCTION
Total life expectancy for adults with end-stage renal
disease is still less than 10 years, similar to that for other
chronic illnesses [1,2]. The annual mortality among
patients with end-stage renal disease is nearly 25 %.
Cardiovascular disease accounts for approximately half
of the deaths among adults with end-stage renal disease
[3,4]. Cardiovascular disease is frequently seen in patients
with end-stage renal disease, because of the high prevalence of traditional risk factors identified in the general
population, including hypertension, hyperlipidaemia,
diabetes mellitus and smoking. Uraemia-related risk
factors, including increased oxidative stress, microinflammation and salt and water overload have been
considered [5–10]. Malnutrition and inadequate solute
clearance may be critical determinants of the mortality of
patients with end-stage renal disease [11,12].
Calcification of coronary plaques, valves and myocardial tissue, as well as diffuse myocardial fibrosis, are
common pathological findings in uraemic hearts [13].
Elevations of the calciumiphosphate product have been
related to increased mortality in patients with end-stage
renal failure [14]. Block et al. [14] showed an increased
adjusted relative risk of death when the calciumi
phosphate product was greater than 72 mg#\dl#, leading
to an increase in cardiac deaths. An increased calciumi
phosphate product facilitates metastatic calcification of
arterial walls, which produces high arterial tensile stress
[15]. Using electron-beam computed tomography, it was
shown that coronary artery calcification was much more
common in patients with end-stage renal disease compared with healthy subjects [16,17].
In the general population, calcium channel blockers are
effective vasodilators and antihypertensive agents [18].
These drugs (long-acting dihydropyridines, verapamil
Key words : calcium channel blockers, end-stage renal failure, haemodialysis, mortality.
Correspondence : Dr Martin Tepel (e-mail Tepel!zedat.fu-berlin.de).
# 2002 The Biochemical Society and the Medical Research Society
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M. Tepel and others
and diltiazem) have been given preferentially to elderly
patients, or patients with systolic hypertension [19,20].
However, calcium channel blockers may be benefical for
patients with end-stage renal disease because they decrease blood pressure, uraemic calcinosis and pressureinduced calcium entry into vessel walls [21]. Calcium
channel blockers inhibit macrophage proliferation [22].
These drugs have also been shown to reverse elevated
cytosolic calcium concentrations and impaired proliferation in B cells from patients with end-stage renal failure
[23]. Experimental data indicate that calcium channel
blockers protect against calcification of arterial walls in
animal models of calcification of the aorta and coronary
arteries [24,25].
To evaluate prognostic factors with regard to mortality
in patients with end-stage renal disease, we analysed data
from a group of such patients according to their clinical
and biochemical characteristics.
METHODS
A total of 188 patients (93 females, 95 males) were
studied. They had been receiving haemodialysis for at
least 1 month in one of three haemodialysis centres as of
July 1998, the start of the study period. The causes
of end-stage renal failure were diabetic nephropathy
in 27 %, nephrosclerosis in 22 %, glomerulonephritis in
17 %, tubulointerstitial diseases in 13 %, polycystic
nephropathy and other diseases in 13 %, and unknown in
8 %. By the end of the study period (December 2000), 51
patients (27 %) had died. The causes of death were
classified as cardiovascular, infection and cancer. Cardiovascular death was defined as fatal myocardial infarction (death occurring within 24 h of entering hospital
for myocardial infarction) or death due to cardiovascular
disease. Death occurring outside hospital for which no
other cause was assigned was regarded as sudden death,
and was included in the definition of cardiovasculardisease-related death. No patients were lost to follow-up.
All medical records were reviewed by one of us (A.P.),
and the following data were obtained : date of birth, sex,
laboratory and clinical data, medications, dialysis prescription, and status as of December 2000. Laboratory
values were obtained before routine haemodialysis in
July 1998. Laboratory and clinical data included body
mass index (calculated as body weight\height# ; kg\m#),
systolic and diastolic blood pressure, total protein, serum
cholesterol, serum triacylglycerol, blood urea nitrogen,
serum creatinine, serum calcium, serum phosphate, serum
potassium, parathyroid hormone and serum ferritin. Data
on the duration of haemodialysis at inclusion (months),
the duration of haemodialysis treatment per session (h),
and use of a high-flux or low-flux dialysis membrane
were obtained. Data on the use of angiotensin-converting
enzyme inhibitors, β-blockers, calcium channel blockers
# 2002 The Biochemical Society and the Medical Research Society
and erythropoietin were obtained. Patients were allocated
to a special medication group only when the medication
was maintained for more than half of the observation
period. Patient informed consent and ethical approval
were obtained for the study.
Statistical analyses were done with SPSS for Windows,
release 8.0.0 (SPSS Inc.) and GraphPad Prism 3.0
(GraphPad Software). Dichotomous baseline characteristics were compared between groups by use of
Fisher’s exact test, and continuous baseline characteristics
by use of the Wilcoxon rank-sum test. A P value of
0.01 was taken to indicate significance. All statistical
tests were two sided. Cox proportional hazards regression analysis was used to look for interactions
between groups and the co-variates age, sex, diabetes
mellitus, smoking, body mass index, systolic and diastolic
blood pressure, duration of haemodialysis at inclusion,
use of high-flux dialyser, haemoglobin, leucocyte count,
platelet count, total protein, serum cholesterol, triacylglycerols, blood urea nitrogen, serum creatinine, serum
potassium, calciumiphosphate product, parathyroid
hormone, serum ferritin, and use of angiotensinconverting enzyme inhibitors, β-blockers, calcium channel blockers and erythropoietin. In a stepwise forward
regression analysis, variables with a P value of 0.05 or
more were removed from the analysis, and variables with
a P value of 0.01 or less were retained. Adjusted hazard
rate ratios (RR) were calculated as the antilogarithm of
the β coefficient of the Cox proportional hazards
regression analysis. The 95 % confidence interval for
the adjusted rate ratio estimates were obtained using the
antilogarithm ( βp1.96istandard error of β). Data are
expressed as meanspS.D.
RESULTS
The clinical and biochemical characteristics of the
patients that died and those that survived are shown in
Table 1. In the 51 patients who died, the cause of death
was cardiovascular in 72 %, infection in 24 % and cancer
in 4 %. In the deceased group, age was significantly
higher and body mass index was significantly lower
compared with the survival group. The percentage of
smokers was significantly higher in the deceased group.
The percentage of patients taking calcium channel
blockers was significantly higher in the survival group
(Fisher’s exact test ; P 0.001).
There were no significant differences between the
groups with regard to systolic and diastolic blood
pressure, duration of haemodialysis at inclusion, duration
of haemodialysis treatment per session, use of high-flux
dialysers, haemoglobin, leucocyte count, platelet count,
total protein, serum cholesterol, triacylglycerols, blood
urea nitrogen, serum creatinine, serum potassium,
calciumiphosphate product, parathyroid hormone or
Calcium channel blocker in haemodialysis patients
Table 1 Clinical and biochemical characteristics at the start
of the study of patients with end-stage renal failure
Data are meanspS.D. Dichotomous baseline characteristics were compared by use
of Fisher’s exact test, and continuous baseline characteristics were compared by
use of the Wilcoxon rank-sum test. n.s., not significant.
Characteristic
Age (years)
Male/female (n)
Diabetes mellitus (%)
Smoker (%)
Body mass index (kg/m2)
Systolic blood pressure (mmHg)
Diastolic blood pressure (mmHg)
Duration of haemodialysis
at inclusion (months)
Duration of haemodialysis
treatment (h per session)
High-flux dialyser (%)
Haemoglobin (g/dl)
Leucocytes (g/l)
Platelets (g/l)
Total protein (g/dl)
Serum cholesterol (mg/dl)
Triacylglycerol (mg/dl)
Blood urea nitrogen (mg/dl)
Serum creatinine (mg/dl)
Serum potassium (mmol/l)
Calciumiphosphate product
(mg2/dl2)
Parathyroid hormone (pmol/l)
Serum ferritin (ng/ml)
Angiotensin-converting enzyme
inhibitors (%)
β-Blockers (%)
Calcium channel blockers (%)
Erythropoietin therapy (%)
Died
(n l 51)
Survived
(n l 137)
70p11
27/24
55
43
22p3
138p16
75p8
42p61
62p15
69/68
38
18
24p4
140p17
78p8
47p53
4.2p0.5
4.4p0.5
n.s.
69
11.2p1.2
8.8p3.2
232p99
6.6p0.6
191p55
203p131
66p16
8.2p2.4
5.5p0.8
56p19
82
11.0p1.1
7.8p2.5
218p74
6.7p0.5
203p47
218p146
65p17
8.6p2.6
5.4p0.8
54p19
n.s.
n.s.
n.s.
n.s.
n.s.
n.s.
n.s.
n.s.
n.s.
n.s.
n.s.
P value
0.001
n.s.
n.s
0.001
0.001
n.s.
n.s.
n.s.
13p7
585p708
31
17p11
547p449
40
n.s.
n.s.
n.s.
25
20
78
29
47
84
n.s.
Figure 1
Patient survival
Survival proportions were calculated according to Kaplan-Meier. Groups of patients
with end-stage renal failure with and without calcium channel blockers (CCB) were
analysed. χ2 l 11.50 ; P 0.001.
Figure 2
Risk ratios for patient survival
Cox proportional hazards regression analysis was used to look for interactions
between groups and selected co-variates. Data are mean and 95 % confidence
interval (CI). BMI, body mass index ; CCB, calcium channel blockers.
0.001
n.s.
serum ferritin. The percentages of patients taking
angiotensin-converting enzyme inhibitor (Fisher’s exact
test ; P l 0.31), β-blocker (P l 0.72) or erythropoietin
therapy (P l 0.39) were not significantly different between the groups.
The effect of calcium channel blockers on patient
survival is shown in Figure 1. In haemodialysis patients
the administration of calcium channel blockers was
associated with significantly prolonged patient survival.
Cox proportional hazard regression analysis showed that
age and smoking were significantly related to mortality in
patients with end-stage renal failure. The relative risk of
death was significantly lower in patients with a higher
body mass index. Among patients with end-stage renal
failure assigned to calcium channel blocker therapy, there
was a significant reduction in mortality of 67 % (Figure
2). A total of 74 haemodialysis patients received calcium
channel blockers. Long-lasting dihydropyridine-type
calcium channel blockers were taken by 82 %, verapamiltype by 16 %, and diltiazem-type by 2 %.
DISCUSSION
The main finding of the present study is that increased
age, a lower body mass index and smoking are independent risk factors for death in haemodialysis
patients, whereas the use of calcium channel blockers was
associated with a significant reduction in mortality of
67 %.
According to previous studies, increased age is an
important predictor of mortality in patients with endstage renal failure [5,12]. As confirmed in our present
study, a low baseline body mass index has already been
established as an independent risk factor for mortality in
patients with end-stage renal failure [26].
Studies on the effects of calcium channel blockers on
# 2002 The Biochemical Society and the Medical Research Society
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M. Tepel and others
mortality in patients with end-stage renal disease are
sparse in the literature. However, benefical effects of
calcium channel blocker administration have been
reported in the general population. The SYST-EUR trial
[27], comparing nitrendipine with placebo in a prospective randomized trial, showed reductions in stroke
and major cardiovascular events in the nitrendipine
group. The PREVENT study [28], which was carried out
in patients with coronary heart disease, looked at
amlodipine versus placebo. An overview of placebocontrolled trials of calcium channel blockers in the
general population [18], including the SYST-EUR trial
and the PREVENT study, showed that, among patients
assigned calcium channel blocker-based therapy, there
were significant decreases in stroke, major cardiovascular
events and cardiovascular death. However, there were no
significant reductions in coronary heart disease, heart
failure or total mortality, but the 95 % confidence
intervals did not exclude moderate advantages for
patients assigned calcium channel blocker therapy [18].
In hypertensive patients, long-acting calcium channel
blockers and diuretics have been reported to be equally
effective in preventing overall cardiovascular complications [29,30]. That was found for both dihydropyridine
(nifedipine) or non-dihydropyridine (diltiazem) calcium
channel blockers. Recently, Motro and Shemesh [31]
reported that the calcium channel blocker nifedipine
slows the progression of coronary calcification in hypertensive patients when compared with the effect of
diuretics.
Concern has been aroused about short-acting dihydropyridine derivatives, since they may increase the risk of
cardiovascular events in patients with coronary heart
disease or Type II (non-insulin-dependent) diabetes
mellitus and hypertension [32,33]. A recent meta-analysis
of randomized controlled trials in the general population
suggested that, compared with other types of antihypertensive drugs, patients assigned calcium channel
blocker therapy had a significantly higher risk of acute
myocardial infarction, congestive heart failure and major
cardiovascular events. However, no significant difference
could be observed for all-cause mortality [34].
Disturbances of calcium metabolism are more frequent
in patients with end-stage renal disease than in the general
population. Morbidity resulting from atherosclerotic
lesions, ischaemic heart disease and cardiomyopathy is
high. There are several lines of evidence that abnormalities of serum calcium, or calciumiphosphate product, contribute to the risk of cardiovascular death in
patients with end-stage renal disease [14,15,17]. Compared with the general population, the administration of
calcium channel blockers may be more beneficial in
patients with end-stage renal disease, because these drugs
interfere directly with disturbed calcium metabolism.
There are some limitations concerning the present
study. Retrospective studies might be influenced by
# 2002 The Biochemical Society and the Medical Research Society
treatment selection bias and problems with different comorbidities. Therefore retrospective analysis of data can
generate hypotheses that should be tested in prospective
studies. In our analysis we controlled for many known
factors that may influence mortality in haemodialysis
patients. We showed that calcium channel blockers
significantly reduced mortality in patients with end-stage
renal failure. Calcium channel blockers are commonly
prescribed for hypertension, a condition that increases
cardiovascular mortality. One would therefore imagine
that prescription of calcium channel blockers indicates
patients with increased risk. It should be noted that our
analysis did not show similar results for other antihypertensive drugs, e.g. angiotensin-converting enzyme
antagonists or β-blockers. In our present study, after
controlling for known risk factors and potential confounders, calcium antagonists were found to reduce
mortality in patients with end-stage renal failure. Further
prospective studies are needed to confirm these results
and to allow the formulation of therapeutic recommendations.
In a very recently published study [35], data from
United States Renal Data System Dialysis Morbidity and
Mortality Wave II were also analysed according to use of
calcium channel blockers. The analysis showed that the
use of a calcium channel blocker was associated with a
21 % lower risk of total mortality in dialysis patients,
confirming the results of our present study.
In conclusion, we have shown that increased age, a
lower body mass index and smoking are significant
predictors of death in patients with end-stage renal
disease, whereas the use of calcium channel blockers was
associated with a significant reduction of mortality.
REFERENCES
1
2
3
4
5
6
7
8
Mallick, N. P. and Gokal, R. (1999) Haemodialysis.
Lancet 353, 737–742
Pastan, S. and Bailey, J. (1998) Dialysis therapy. N. Engl.
J. Med. 338, 1428–1437
Parfrey, P. S. (2000) Cardiac disease in dialysis patients :
diagnosis, burden of disease, prognosis, risk factors and
management. Nephrol. Dial. Transplant. 15 (Suppl. 5),
58–68
Locatelli, F., Marcelli, D., Conte, F. et al. (2000)
Cardiovascular disease in chronic renal failure : the
challenge continues. Nephrol. Dial. Transplant. 15 (Suppl.
5), 69–80
Goldwasser, P., Mittman, N., Antignani, A. et al. (1993)
Predictors of mortality in hemodialysis patients. J. Am.
Soc. Neprol. 3, 1613–1622
Charra, B., Calemard, E. and Laurent, G. (1996)
Importance of treatment time and blood pressure control
in achieving long-term survival on dialysis. Am. J.
Nephrol. 16, 35–44
Bianchi, G. (2000) Hypertension in chronic renal failure
and end-stage renal disease patients treated with
hemodialysis or peritoneal dialysis. Nephrol. Dial.
Transplant. 15 (Suppl. 5), 105–110
Tepel, M., Echelmeyer, M., Orie, N. N. and Zidek, W.
(2000) Increased intracellular reactive oxygen species in
patients with end-stage chronic renal failure : effect of
hemodialysis. Kidney Int. 58, 867–872
Calcium channel blocker in haemodialysis patients
9
10
11
12
13
14
15
16
17
18
19
20
21
22
Baigent, C., Burbury, K. and Wheeler, D. (2000)
Premature cardiovascular disease in chronic renal failure.
Lancet 356, 147–152
Herzog, C. A., Ma, J. Z. and Collins, A. J. (1998) Poor
long-term survival after acute myocardial infarction
among patients on long-term dialysis. N. Engl. J. Med.
339, 799–805
Owen, W. F., Lew, N. L., Liu, Y., Lowrie, E. G. and
Lazarus, J. M. (1993) The urea reduction ratio and serum
albumin concentration as predictors of mortality in
patients undergoing hemodialysis. N. Engl. J. Med. 329,
1001–1006
Iseki, K., Kawazoe, N. and Fukiyama, K. (1993) Serum
albumin is a strong predictor of death in chronic dialysis
patients. Kidney Int. 44, 115–119
Amann, K., Gross, M. L., London, G. M. and Ritz, E.
(1999) Hyperphosphataemia – a silent killer of patients
with renal failure. Nephrol. Dial. Transplant. 14,
2085–2087
Block, G. A., Hulbert-Shearon, T. E., Levin, N. W. and
Port, F. K. (1998) Association of serum phosphorus and
calcium x phosphate product with mortality risk in
chronic hemodialysis patients : a national study. Am. J.
Kidney Dis. 31, 607–617
Marchais, S. J., Metivier, F., Guerin, A. P. and London,
G. M. (1999) Association of hyperphosphataemia with
haemodynamic disturbances in end-stage renal disease.
Nephrol. Dial. Transplant. 14, 2178–2183
Braun, J., Oldendorf, M., Moshage, W., Heidler, R.,
Zeitler, E. and Luft, F. C. (1996) Electron beam
computed tomography in the evaluation of cardiac
calcification in chronic dialysis patients. Am. J. Kidney
Dis. 27, 394–401
Goodman, W. G., Goldin, J., Kuizon, B. D. et al. (2000)
Coronary-artery calcification in young adults with endstage renal disease who are undergoing dialysis. N. Engl.
J. Med. 342, 1478–1483
Blood Pressure Lowering Treatment Trialists’
Collaboration (2000) Effects of ACE inhibitors, calcium
antagonists, and other blood-pressure-lowering drugs :
results of prospectively designed overviews of
randomised trials. Lancet 355, 1955–1964
Conlin, P. R. and Williams, G. H. (1998) Use of calcium
channel blockers in hypertension. Adv. Intern. Med. 43,
533–562
World Health Organization (1999) International Society
of Hypertension guidelines for the management of
hypertension. J. Hypertens. 117, 151–183
Luft, F. C. and Johnston, C. I. (1992) Are calcium
antagonists of value in ameliorating the course of chronic
renal disease ? Kidney Int. 41 (Suppl. 36), S114–S118
Wright, B., Zeidmann, I., Greig, R. and Poste, G. (1985)
Inhibition of macrophage proliferation by calcium
channel blockers and calmodulin antagonists. Cell.
Immunol. 95, 46–53
23
24
25
26
27
28
29
30
31
32
33
34
35
Alexiewicz, J. M., Smogorzewski, M., Akmal, M., Klein,
M. and Massry, S. G. (1996) Nifedipine reverses the
abnormalities in [Ca#+] and proliferation of B cells from
i
dialysis patients. Kidney Int. 50, 1249–1254
Mutoh, S., Nomoto, A., Sekiguchi, C. and Yamaguchi, I.
(1988) Protective action of calcium antagonist,
nilvadipine, against aortic deposition – a pathogenic factor
in atherosclerosis. Atherosclerosis 73, 181–189
Fleckenstein-Gru$ n, G., Thimm, F., Frey, M. and Matyas,
S. (1995) Progression and regression by verapamil of
vitamin D3-induced calcific medial degeneration in
coronary arteries of rats. J. Cardiovasc. Pharmacol. 26,
207–213
Leavey, S. F., Strawderman, R. L., Jones, C. A., Port,
F. K. and Held, P. J. (1998) Simple nutritional indicators
as independent predictors of mortality in hemodialysis
patients. Am. J. Kidney Dis. 29, 997–1006
Staessen, J. A., Fagard, R., Thijs, L. et al. (1997)
Randomised double-blind comparison of placebo and
active treatment for older patients with isolated systolic
hypertension. The Systolic Hypertension in Europe
(Syst-Eur) Trial. Lancet 350, 757–764
Pitt, B., Byington, R. P., Furberg, C. D. et al. (2000)
Effect of amlodipine on the progression of atherosclerosis
and the occurence of clinical events. PREVENT
Investigators. Circulation 102, 1503–1510
Brown, M. J., Palmer, C. R., Castaigne, A. et al. (2000)
Morbidity and mortality in patients randomised to
double-blind treatment with a long-acting calciumchannel blocker or diuretic in the International
Nifedipine GITS study : Intervention as a goal in
hypertension treatment. Lancet 356, 366–372
Hansson, L., Hedner, T., Lund-Johansen, P. et al. (2000)
Randomised trial of effects of calcium antagonists
compared with diuretics and beta-blockers on
cardiovascular morbidity in hypertension : the Nordic
Diltiazem (NORDIL) study. Lancet 356, 359–365
Motro, M. and Shemesh, J. (2001) Calcium channel
blocker nifedipine slows down progression of coronary
calcification in hypertensive patients compared with
diuretics. Hypertension 37, 1410–1413
Furberg, C. D., Psaty, B. M. and Meyer, J. V. (1995)
Nifedipine : dose-related increase in mortality in patients
with coronary heart disease. Circulation 92, 1326–1331
Estacio, R. O., Jeffers, B. W., Hiatt, W. R., Biggerstaff,
S. L., Gifford, N. and Schrier, R. W. (1998) The effect of
nisoldipine as compared with enalapril on cardiovascular
outcomes in patients with non-insulin-dependent diabetes
and hypertension. N. Engl. J. Med. 338, 645–652
Pahor, M., Psaty, B. M., Alderman, M. H. et al. (2000)
Health outcomes associated with calcium antagonists
compared with other first-line antihypertensive therapies :
a meta-analysis of randomised controlled trials. Lancet
356, 1949–1954
Kestenbaum, B., Gillen, D. L., Sherrard, D. J., Seliger, S.,
Ball, A. and Stehman-Breen, C. (2002) Calcium channel
blocker use and mortality among patients with end-stage
renal disease. Kidney Int. 61, 2157–2164
Received 11 April 2002/8 July 2002; accepted 2 September 2002
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