3606 Nephrol Dial Transplant (2008) 23: 3605–3612 M. Tepel et al.

doi: 10.1093/ndt/gfn304
started Advance
on 01 October 2002 and 29
Access publication ended
May on 30 March 2004.
2008 were assigned in a 1:1 ratio to receive amlodipine or
The trial was registered with ClinicalTrials.gov (number placebo. The study medication was provided in externally
NCT00124969). indistinguishable tablets (appearance, form, colour, smell
Original Article and taste). To ensure allocation concealment, sequentially
numbered containers were used.
Patients
We prospectively studied 251 patients with chronic kidney
Effect of amlodipine on cardiovascular events in hypertensive
disease stage 5 on haemodialysis treatment (159 malesBaseline data collection
haemodialysis patients
and 92 females) with a median age of 61 years (25%
percentile − 75% percentile, 47–69). All of the patients Patient history was raised using a standardized question-
were routinely dialyzed for 4–5 h three times weekly us-naire and comprised personal histories, smoking habits,
ing biocompatible membranes with no dialyzer reuse. The cause of kidney disease judged by clinical appraisal, months
Martin
dialysates used Tepel 1 , Werner Hopfenmueller
were bicarbonate based. All of the pa- of haemodialysis
2 , Alexandra Scholze treatment, pre-existing
1 , Alexandra Maiercardiovascular
1 and Walter dis-
Zidek
tients were ambulatory
1 and free of acute intercurrent ill- ease (i.e. history of myocardial infarction, need for coronary
ness. Haemodialysis
1
treatment was conducted in ambu-angioplasty or coronary bypass surgery, ischaemic stroke,
Medizinische Klinik Nephrologie and 2 Medizinischeperipheral
latory dialysis centres according to established treatmentStatistik und Biometrie,
vascular Charit´
disease Campus
with the needBenjamin Franklin, Berlin,
for amputation
Germanye
guidelines. The participating centres are given in the Ap-or angioplasty), presence of diabetes mellitus and current
pendix. Patients were recruited from 47 centres, represent- medication including angiotensin-converting enzyme in-
ing ∼2000 patients. The trial protocol was approved by all
Abstract hibitors,causes
ß-blockers, lipid-lowering
for increased morbidityagents
and ormortality
erythropoi- in these
involvedBackground.
ethics committees and the trial was undertaken
Hypertensive haemodialysis patients may be etin. Blood pressure was always measured
patients. Several traditional risk factors includingpre-dialysis af-hyper-
in accordance
at a high with the
risk forDeclaration
cardiovascularof Helsinki.
events.Specifi-
This study terwasa rest period diabetes
tension,
un- of 10 minmellitus
of recumbency.
and smokingBloodcan samples
be observed in
cally, the ethical implications
dertaken of the inclusion
to ascertain whether of a placebo
the calcium channelwere drawn before
patients
blocker with the patients’
chronic regular
kidney haemodialysis
disease. Furthermore, ses-
group were taken into
amlodipine account
reduces and considered
mortality acceptable.
and cardiovascular sion.
events Haemoglobin,
uraemia-related
in serum creatinine,
factors includingblood urea nitrogen,
oxidative stress and dis-
All patients
these gave written,
high-risk informed consent.
patients. serum calcium,
turbances serum phosphate, parathyroid
of calcium–phosphate metabolismhormone,have been as-
Methods. We evaluated the effects of amlodipineserum on car- cholesterol
sociated with andincreased
serum triglycerides
cardiovascular weredisease
routinely[5,6]. In the
diovascular events in 251 hypertensive haemodialysis analysed. general population, calcium channel blockers are effective
pa-
tients in an investigator-designed, prospective, random-vasodilators and antihypertensive agents [7]. In prospective
Inclusion criteria
ized, double-blind, placebo-controlled, multicenter trial. studies in hypertensive patients, an amlodipine-based regi-
One hundred and twenty-three patients were randomly as- men prevented more cardiovascular events than an atenolol-
The study included patients with chronic kidney disease
signed to amlodipine (10 mg once daily) and 128Outcomes based regimen [8]. Furthermore, hypertensive patients re-
to placebo.
stage 5 with presently existing arterial hypertension or with
The primary endpoint was mortality from any cause. Theceiving amlodipine had a significantly lower incidence of
a history of arterial hypertension, i.e. resting blood pressure Patientsmyocardial
were followed for 30 compared
months. Data were continu-
secondary endpoint was a composite variable consisting of infarction to patients receiving val-
≥140/90 mmHg or antihypertensive medication. Patients ously evaluated and recorded every
mortality from any cause or cardiovascular event. Analy- sartan [9]. These studies may6 give
months. The evidence
indirect primary that
with chronic kidney disease stage 5 had been undergoing endpoint was the time from calcium randomization
sis was by intention-to-treat. The trial was registered the
with dihydropyridine channeltoblocker
mortality from
could reduce
maintenance haemodialysis for a minimum of 3 months.any cause. The post hoc secondary endpoint was the time
ClinicalTrials.gov (number NCT00124969). macrovascular complications in hypertensive patients with
The study included men and women. The study includedfrom randomization to the first event, which was a compos-
Results. The median age of patients was 61 years chronic kidney disease. However, no prospective study has
patients 18 years and older. ite median
variable
(25% percentile − 75% percentile, 47–69), and the beenconsisting
performed ofto
mortality
addressfrom that any cause, cardiac
hypothesis in these high-
follow-up was 19 months (8–30). Fifteen (12%) ofevent the 123including myocardial
risk patients. To date, infarction, need for coronary
a few retrospective cohort studies are
patients assigned to amlodipine and 22 (17%) ofangioplasty the 128 or coronary
available. bypass retrospective
Our previous surgery, ischaemic stroke,
study indicated that
Exclusion criteriaassigned to placebo had a primary endpoint
patients peripheral vascular
calcium
[hazard channeldisease with the
blockers need for amputation
significantly reduced mortality in
ratio 0.65 were
(95% persistent
CI 0.34–1.23); P = 0.19]. Nineteen or angioplasty.
(15%) patientsOnly withone event
chronic per patient
kidney disease was included
stage in
5 on haemodial-
Exclusion criteria hypotension with systolic
the analysis of the secondary endpoint. Non-fatal myocar-analysis
of the 123 haemodialysis patients assigned to amlodipine ysis treatment
blood pressure of <90 mmHg, history of high-grade aor-dial infarction was defined according to the appraisal of[10]. Furthermore, a retrospective
and 32
tic stenosis, (25%)
history ofof the 128
severe haemodialysis
heart failure accordingpatients assigned
to the of to
data from United States Renal Data System Dialysis
placebo reached theclassification
secondary composite the attending
Morbidity physician as the presence
and Mortality of at least
Wave II showed thattwo
theof use of
New York Heart Association stages III endpoint
and IV,the
[hazard
following criteria: chest pain of typical duration and
ratio 0.53 (95% CI 0.31–0.93); P =
acute myocardial infarction within the last 4 weeks, known0.03]. calcium channel blockers was associated with a 21% lower
Conclusion. Amlodipine safely reduces systolic intensity,
blood increased
risk cardiac enzyme
of total mortality concentrations
in haemodialysis (at [11].
patients least Our
allergy to amlodipine, and severe disorders of liver function,
twice the upper limit ofwas normal) and diagnostic
pregnancypressure
or breastand feeding.
it may have a beneficial
In patients effect on cardiovas-
who presently re- aim, therefore, to ascertain whetherelectrocar-
the dihydropyridine
cular outcomes in hypertensive haemodialysis diographical
patients. calcium changes.
channel Causes
blocker of amlodipine
death during the follow-up
reduces mortality and
ceived any dihydropyridine calcium channel blockers, these were classified as cardiovascular including sudden death,
drugs were withdrawn after giving informed consent andinfection, cardiovascular events in hypertensive patients with chronic
cancer or other cause.
5. Death occurring outside
prior to randomization to the study medication. If these hospitalkidney disease stage
for which no other cause was assigned was re-
drugs could not be withdrawn according to the appraisalgarded of as sudden death and was included in the definition
the attending
Keywords:physician,
calcium these patients
channel werecardiovascular
blocker; excluded. Pa- risk;
of cardiovascular death. Deaths were classified by the treat-
tients who did not
chronic givedisease
kidney consent were excluded. Concomi- ing physician independently of the endpoint analysis. Data
tant medication including angiotensin-converting enzyme on mortality were obtained for all patients. Patients who un-
inhibitors, beta (ß) blockers, lipid-lowering agents or ery-derwent kidney transplantation during the follow-up were
Methods
thropoietin was permitted as recommended by the attending censored on the day of transplantation. No patient was lost
The mortality rate in hypertensive patients with to
physician. chronic
the follow-up.
kidney
Patients with disease
chronic is substantially
kidney disease higher
stage 5thanon in the gen- Study protocol
Adverse events and prespecified safety parameters were
eral population
haemodialysis treatment [1–4].
wereAccelerated cardiovascular
randomly assigned disease
eithermonitored Thethroughout
effects of amlodipine
the study. Aon hypotensive
mortality and episode
cardiovascular
andamlodipine
to receive increased (10 macrovascular
mg once daily) complications
or placebo.are A the
wasleading
defined
events as inanhypertensive
event with patients
patientsexperiencing
with chronic clin- kidney disease
computer-generated randomization list was prepared cen- ical symptoms
stage 5associated
on haemodialysiswith reduction
treatmentof blood
were investigated
pressure in
trally guaranteeing
Correspondence that
andin studyrequests
offprint centres to:patients were
Martin Tepel, as-
Medizinis-
during the an investigator-designed,
haemodialysis treatment. prospective, randomized, double-
signed tocheone
Klinik
ofNephrologie,
both treatmentCharit´groups.
Campus Benjamin Franklin, Hinden-e
Eligible patients blind, placebo-controlled, multicentre trial. The total trial
burgdamm 30, 12200 Berlin, Germany. Fax: +49-30-8445-4235; E-mail:
martin.tepel@charite.de duration of the trial was planned for 4 years. Recruitment

C The Author [2008].

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Amlodipine and cardiovascular events 3607

Statistical analysis Table 1. Baseline characteristics of hypertensive patients with chronic

kidney disease stage 5 on haemodialysis treatment
Our planned study sample size of 356 patients was based on
the assumptions of a 40% mortality in the placebo group, a Amlodipine group Placebo group
total trial duration of 4 years and a follow-up for each patient (n = 123) (n = 128)
for 30 months. A time-to-event analysis was planned, and
thus the study had 80% power to detect a 14% reduction Age (years) 60 (45–68) 62 (48–68)
in the hazard ratio with a type I error of 0.05. Because the Male n (%) 78 (63%) 81 (63%)
Body mass index (kg/m2 ) 25.4 (22.6–28.9) 26.1 (23.4–28.7)
total trial duration was planned for 4 years, and to ensure Renal disease n (%)
sufficient duration of exposure, i.e. until the last patient Diabetic nephropathy
19 (15%) 26 (20%)
recruited had been followed up for 30 months, recruitment Nephrosclerosis 17 (14%) 26 (20%)
ended on 30 March 2004 although the enrolment rate was Chronic glomerulonephritis 39 (32%) 38 (30%)
slower than planned and mortality rate was much lower than Polycystic kidney disease and 30 (24%) 20 (16%)
interstitial nephritis
that expected from our earlier study [10]. Other/unknown
Continuous data including age, months of haemodialysis Months of haemodialysis 18 (15%) 18 (14%)
treatment and biochemical data are reported as medianSystolic blood pressure 28 (12–48) 23 (13–43)
140 (128–160) 141 (130–160)
(25% percentile − 75% percentile). The non-parametric (mmHg)
Mann–Whitney test was used to detect differences in con- Diastolic blood pressure
(mmHg) 80 (70–80) 80 (70–83)
tinuous variables between the treatment groups. Frequency Present smoker n (%)
counts were calculated for categorical data such as gender, Disease prevalence at baseline24 (20%) 27 (21%)
specific medications and diagnostic classifications. Differ- n (%)
ences in these categorical variables between the treatment Diabetes mellitus
groups were analysed by Fisher’s exact test. All time-to-Cardiovascular
Haemoglobin (g/dL)
disease 33 (27%) 40 (31%)
38 (31%) 44 (34%)
event analyses were performed using the Mantel–Haenszel Serum creatinine (mg/dL) 11.9 (11.0–12.7) 11.6 (10.7–12.4)
log-rank test. The hazard ratio and its 95% confidence Blood urea (mg/dL) 10.0 (7.5–11.3) 9.0 (7.0–11.3)
interval are given. All analyses were based on the intention-Total protein (g/dL) 137 (113–174) 142 (110–166)
to-treat principle. No interim analyses were done. The Serum calcium (mmol/L) 6.7 (6.3–7.1) 6.8 (6.3–7.1)
Serum phosphate (mmol/L) 2.3 (2.2–2.5) 2.3 (2.2–2.5)
association of baseline characteristics including age, gen- Parathyroid hormone (pg/mL) 2.0 (1.7–2.6) 2.0 (1.6–2.4)
der, smoking, presence of diabetes mellitus, medications Serum triglycerides (mg/dL) 188 (88–336) 216 (99–320)
(angiotensin-converting enzyme inhibitors, ß-blockers, Serum cholesterol (mg/dL) 175 (128–243) 158 (114–264)
erythropoietin and lipid-lowering agents), pre-existing Medications n (%) 171 (148–201) 176 (150–216)
cardiovascular disease, systolic and diastolic blood Angiotensin-converting
enzyme inhibitors
pressureandallocationtoamlodip- ß-blockers 79 (64%) 81 (63%)
inetotheprimaryendpoint(mortality) Erythropoietin
or the secondary combined endpoint was tested us- Lipid-lowering agents 67 (54%) 79 (62%)
ing the Cox proportional hazard model. In a stepwise 108 (88%) 108 (84%)
forward Cox-regression analysis, variables with a P-value 53 (43%) 50 (39%)
of 0.05 or less were retained. The effect of amlodipine
on systolic blood pressure during the study period was Continuous data are shown as median (25% percentile − 75% percentile).
Body mass index was calculated as the weight in kilograms divided by
compared to placebo using two-way ANOVA. Analyses the square of the height in metres. There were no significant differences
were performed with GraphPad prism software (version between the two groups.
5.0, GraphPad Software, San Diego, CA, USA) or SPSS
software (release 8.0.0, SPSS Inc., Chicago, IL, USA). All
statistical tests were two sided. Two-sided P-values <0.05
haemodialysis for a minimum of 3 months three times
were considered to indicate statistical significance.
weekly in ambulatory centres. The median duration of
haemodialysis at the study entry was 27 months (12–46
months). The cause of chronic kidney disease stage 5
was diabetic nephropathy in 45 cases (18%), nephroscle-
rosis in 43 cases (17%), chronic glomerulonephritis in
77 cases (31%), polycystic kidney disease and intersti-
Results tial nephritis in 50 cases (20%), and other/unknown in 36
cases (14%). Forty-one patients (13%) underwent kidney
transplantation during the follow-up and were censored
We investigated the effects of amlodipine on mortality on the day of transplantation. One hundred twenty-three
and cardiovascular events in hypertensive patients withpatients were randomly assigned to receive amlodipine
chronic kidney disease stage 5 on haemodialysis treat- (10 mg once daily) and 128 patients were randomly as-
ment in an investigator-designed, prospective, randomized, signed to receive placebo. All patients commenced study
double-blind, placebo-controlled, multicentre trial. Figuremedication
1 and all received their intended treatment.
shows the flowchart of the study. The study was con- The baseline demographic, clinical and laboratory char-
ducted using 251 patients with chronic kidney disease acteristics of the patients with chronic kidney disease stage
stage 5 on haemodialysis treatment [159 males, 92 fe- 5 are described in Table 1. The two groups of patients were
males; median age, 61 years (25% percentile − 75% per- well matched with respect to baseline characteristics and
centile, 47–69 years); systolic blood pressure 140 mmHgconcomitant therapy. There were no differences in baseline
(130–160 mmHg) and diastolic blood pressure 80 mmHgcharacteristics (age, gender, body mass index, renal disease,
(70–82 mmHg)] who had been undergoing maintenance
3608 M. Tepel et al.

Assessed for eligibility

(n=251)

Excluded (n=0)

Not meeting inclusion criteria (n=0)

Enrollment
Refused to participate (n=0)
Randomization Other reasons (n=0)

Allocated to amlodipine (n=123) Allocated to placebo (n=128)

Received allocated amlodipine Received allocated placebo (n=128)
(n=123) Did not receive allocated amlodipine
Allocation
Did not receive allocated amlodipine (n=0)
(n=0)

Lost to follow-up (n=0) Lost to follow-up (n=0)

Kidney transplantation (n=23)
Discontinued amlodipine because of
adverse events (n=8)
Discontinued amlodipine because
of non-compliance (n=29)
Discontinued amlodipine because
of relocation (n=3)
Death (n=15)
Subjects at risk at study end (n=45)
Kidney transplantation (n=18)
Follow-up Discontinued placebo because of
adverse events (n=12)
Discontinued placebo because
of non-compliance (n=30)
Discontinued placebo because
of relocation (n=1)
Death (n=22)
Subjects at risk at study end (n=45)

Analyzed (n=123) Analyzed (n=128)

Analysis
Excluded from analysis (n=0 ) Excluded from analysis (n=0)

Fig. 1. The flowchart of the study trial.

months of haemodialysis, systolic and diastolic blood pres-

reached in 37 out of 251 patients (15%). Causes of death
sure, smoking status, biochemical data and medications) were classified as cardiovascular including sudden death
between the groups. In particular, haemoglobin concen-(26 patients; 70%), infection (7 patients; 19%) and cancer
trations, serum calcium, serum phosphate and parathy- (4 patients; 11%). A total of 15 (12%) of the 123 haemodial-
roid hormone were not significantly different between the ysis patients assigned to amlodipine, and 22 (17%) of the
two groups. As indicated by the body mass index, total 128 haemodialysis patients assigned to placebo had a pri-
protein and serum cholesterol, the nutritional status wasmary endpoint. Figure 2 shows Kaplan–Meier estimates of
not significantly different between the two groups. Use the proportion of patients reaching the primary endpoint.
of angiotensin-converting enzyme inhibitors, ß-blockers,Fewer patients in the amlodipine group than in the placebo
erythropoietin and lipid-lowering agents was not signifi- group reached the primary endpoint, though this finding
cantly different between the two groups. Furthermore, the was not significant [hazard ratio 0.65 (95% CI 0.34–1.23);
prevalence of diabetes mellitus [amlodipine, 33 patientsP = 0.19].
(27%); placebo, 40 patients (31%)] and of cardiovascular The association of baseline characteristics including
disease [amlodipine, 38 patients (31%); placebo, 44 patients
age, gender, smoking, presence of diabetes mellitus,
(34%)] was similar in both groups. medications (angiotensin-converting enzyme inhibitors,
ß-blockers, erythropoietin and lipid-lowering agents), pre-
existing cardiovascular disease, systolic and diastolic blood
pressure and allocation to amlodipine to the primary end-
Primary endpoint (mortality) point was tested using a multivariate analysis. Age [hazard
ratio 1.06 (95% CI 1.02–1.08); P < 0.01], systolic blood
During the follow-up (median, 19 months; 8–30 months)
the primary endpoint, i.e. mortality of all causes, was
Amlodipine and cardiovascular events 3609

Proportion
50 Placebo (22 events) Proportion
50 Placebo (32 events)
of events
Amlodipine (15 events) of events
Amlodipine (19 events)
(%)40 (%)
40 HR 0.53 [95% CI 0.31-0.93]
HR 0.65 [95% CI 0.34-1.23] 30 p=0.03
30 p=0.19

20 20

10 10

0 0
0612182430 0612182430
Time from randomisation (months) Time from randomisation (months)

Subjects at risk Subjects at risk

Placebo128 106 81 65 53 45 Placebo128 106 76 60 45 37
Amlodipine 123 107 88 69 60 45 Amlodipine 123 107 88 67 57 42

Fig. 2. Kaplan–Meier curve of time to the primary endpoint. The primary

Fig. 3. Kaplan–Meier curve of time to the secondary endpoint. The sec-
endpoint was mortality from any cause. ondary endpoint was a composite variable consisting of mortality from
any cause, cardiac event including myocardial infarction, need for coro-
nary angioplasty or coronary bypass surgery, ischaemic stroke, peripheral
pressure [hazard ratio 1.02 (95% CI 1.00–1.04); P = 0.02], vascular disease with the need for amputation or angioplasty.
pre-existing cardiovascular disease [hazard ratio 2.38 (95%
CI 1.10–5.11); P = 0.03] and smoking [hazard ratio 2.60
(95% CI 1.01–6.73); P = 0.05] were associated with the
after adjustment for the other baseline characteristics. Pre-
primary endpoint. The other baseline characteristics and
existing cardiovascular disease predicted the occurrence
allocation to amlodipine did not contribute significantly to
of the secondary composite endpoint [hazard ratio 3.34
the overall results.
(95% CI 1.91–5.86); P < 0.01]. The other baseline char-
acteristics did not contribute significantly to the overall
results.
Secondary composite endpoint We also analysed subclasses of patients to evaluate the
underlying mechanisms of the observed effects. In patients
During the follow-up, the secondary endpoint, which was
who had received any dihydropyridine calcium channel
a composite variable consisting of mortality from any
blockers, these drugs were withdrawn after giving informed
cause, cardiac event including myocardial infarction, need
consent and prior to randomization to the study medication.
for coronary angioplasty or coronary bypass surgery, is-
Ninety-one patients had been treated with calcium channel
chaemic stroke and peripheral vascular disease with the
blockers before the start of the study. After randomiza-
need for amputation or angioplasty, was reached in 51 out of
tion, 42 patients received amlodipine, whereas 49 patients
251 patients (20%). There were 33 deaths from any cause
received placebo. Five (12%) out of 42 patients receiv-
and 18 cardiovascular events. It should be noted that four
ing amlodipine, but 15 (31%) out of 49 patients receiv-
patients who already had a cardiovascular event died during
ing placebo had a cardiovascular event [relative risk 0.39
the subsequent follow-up, but only the time to the first event
(95% CI 0.15–0.98); P = 0.04]. One hundred and sixty hy-
was considered for the secondary composite endpoint.
pertensive patients on haemodialysis had not been treated
Cardiovascular events were classified as cardiac event
with calcium channel blockers before the start of the
(11 patients; 61%), stroke (2 patients; 11%) and amputation
study. After randomization, 80 patients received amlodip-
(5 patients; 28%).
ine, whereas 80 patients received placebo. Thirteen (16%)
A total of 19 (15%) of the 123 haemodialysis patients
out of 80 patients receiving amlodipine, but 18 (23%) out
assigned to amlodipine and 32 (25%) of the 128 haemodial-
of 80 patients receiving placebo had a cardiovascular event
ysis patients assigned to placebo reached the secondary
[relative risk 0.72 (95% CI 0.38–1.37); P = 0.42].
end-
The course of systolic and diastolic blood pressure dur-
point. Figure 3 shows Kaplan–Meier estimates of the pro-
ing the study is shown in Figure 4. Two-way ANOVA
portion of patients reaching the secondary endpoint. Fewer
showed a significant reduction of systolic blood pres-
patients in the amlodipine group than in the placebo group
sure by amlodipine during the study period (P < 0.01)
reached the secondary endpoint [hazard ratio 0.53 (95% CI
from 140 mmHg (128–160 mmHg) to 130 mmHg (120–
0.31–0.93); P = 0.03]. The difference was significant. The
147 mmHg), whereas systolic blood pressure was un-
patients in the amlodipine group had a risk of reaching the
changed in the placebo group (141 mmHg, 130–
secondary endpoint that was 47% lower compared to the
160 mmHg; and 140 mmHg, 130–150 mmHg). Diastolic
placebo group.
blood pressure did not change during the study period in
The association of baseline characteristics including
either group (P > 0.05).
age, gender, smoking, presence of diabetes mellitus,
Hypotensive episodes, i.e. patients experiencing clinical
medications (angiotensin-converting enzyme inhibitors,
symptoms associated with the reduction of blood pressure
ß-blockers, erythropoietin and lipid-lowering agents), pre-
during the haemodialysis treatment, were not significantly
existing cardiovascular disease, systolic and diastolic blood
different in the amlodipine group, compared to placebo. A
pressure and allocation to amlodipine to the secondary end-
total of 9 (7%) of the 123 haemodialysis patients assigned to
point was tested using a multivariate analysis. Amlodipine
amlodipine and 16 (13%) of the 128 haemodialysis patients
was associated with the secondary composite endpoint with
a hazard ratio of 0.55 [(95% CI 0.31–0.97); P = 0.04] even
3610 Amlodipine and cardiovascular events M. Tepel et al. 3611
systolic
250blood blood pressure
Placebo <140 mmHg compared to
Amlodipine the refer-
these patients
and Maier.
withAnalysis
chronic and
kidney
interpretation
disease stageof data:
5 andTepel,
Systolic
pressure ence group with systolic blood pressure of 160–180 mmHg
respective
Hopfenmueller,
established outcome
Scholze, definitions
Maier and Zidek.
reported
Drafting
in pre-of the
200
[17,18]. Furthermore, the effect of amlodipine might
(mmHg) viousalso
studies
manuscript:
in these
Tepel,
patients
Hopfenmueller
[12–14]. This
andsecondary
Zidek. Critical re-
be attributed to other mechanisms, including reduced composite asym-
vision
endpoint
of the wasmanuscript
significantly
for important
reduced intellectual
by adminis-content:
metric dimethylarginine [19]. tration of
Tepel,
amlodipine.
Hopfenmueller,
The favourable
Scholze,effectMaierofand theZidek.
calcium Statis-
150
channeltical blocker
analysis:
amlodipine
Tepel and shouldHopfenmueller.
be comparedObtained to the re-fund-
100 ported effectsing: Tepel.of other
Administrative,
treatment modalities
technical or inmaterial
patents with support:
Limitations of the study chronic Tepel,
kidney Scholze
disease and
stageMaier.
5. AStudy
recent supervision:
study indicated
Tepel that
and
50 lipid-loweringZidek. drugs had no statistically significant effect
Some
0 6 12 limitations
18 24 30 0 6 12 of our
18 24randomized,
30 double-blind, onprospec-
the composite endpoint of cardiovascular death, non-
Timestudy
tive from randomisation
were that the (months)
enrolment rate was slower fatalthanmyocardial infarction and stroke in diabetic patients
planned, diabetic nephropathy was lower than expected, with chronic Participating centresstage 5 [12].
the kidney disease
150transplantation
Diastolic bloodPlacebo rate was high and the mortality rate
Amlodipine wasDr Vollgraf,
According to the study protocol, patients
pressure lower than expected. For each patient, a follow-up period Dr Hahn, Dortmund; Dr were
Schumann,treatedDrac-
cording Reinhardt,
to the established
Herne; treatment
Dr Bednarz, guidelines
Dr Clasen, and
M¨ >50%
nster;u
(mmHg)
of 30 months was provided. Each patient was followed up
of the patients received angiotensin-converting
Dr Hoffmann, Dr Witta, Hamm; Dr Kriegel, Dr enzyme
100
until the endpoint (mortality) was reached or theinhibitors patientKresse, or ß-blockers.
Lutherstadt Although
Eisleben;the DruseKallerhoff,
of additional Dr Selke,
terminated the study or the patient was transplanted. This
antihypertensive
Bocholt; Dr Fendt, Berlin; Dr Lange, Drstudy
drugs was permitted in the protocol,
Oppermann,
50
is in accordance to the initial study plan. However, thethe causefinal of different
Perleberg; systolicBerlin;
Dr Braun, blood Dr pressure
Bartke,values
Dr Eger, during
Berlin; Dr
analysis showed that the actual median follow-up the time was
course of the study remains unclear. It is
Cleef, Dr Brauner, Berlin; Dr Nielebock, Dr Gosch, Magde- noteworthy
19 months. All these points may have reduced the that power of Dr Striebing,
hypotensive
burg; episodes Dessau;
were observedDr Kron, more frequentlyBerlin;
Dr Leimbach,
0the study to detect a reduction of mortality in the in amlodipine
the placebo group compared to the
Dr Poley, Dr Francke, Seehausen Altmark; Dr amlodipine group
L¨ ders,u
0 6 12 18
group. 24 30factors
These 0 6 12 18may24 30
explain the absence of(13% a signifi-
versus 7%), although that difference did notArnsberg;
reach
Time from randomisation (months) Dr Schrader, Cloppenburg; Dr Bachmann, Dr
cant effect of amlodipine on the primary endpoint. Another
a statistical significance.
Michling, Patients in
Recklinghausen; DrtheBr¨amlodipine group Dort-u
ckner, Dr Willeke,
limitation
Fig. 4. Systolic (upperof the and
panel) study may (lower
diastolic be that theblood
panel) median duration
developed
pressure of lower
mund; Dr systolic
Riedasch, blood pressure during
Dr Schreiber, Coesfeld; the study
Dr Baus,
during the haemodialysis
study in the placebo before
groupenrolment was moregroup.
and in the amlodipine than Boxes
23 months;
period. The beneficial effects of amlodipine
Dr Schaper, Frankfurt/Oder; Dr Markus, Frankfurt/Oder; to prevent the
show 25%hence, themedian
percentile, resultsand
of 75%
the percentile;
study may not beshow
whiskers representative
secondary
mini- composite endpoint might be attributed to its an- Th.
mum andfor maximum. Two-way ANOVA showed a significant reduction of Dr Wiedemeyer, Dortmund; Dr Braasch, Eberswalde;
incident haemodialysis patients. These pointstihypertensive
may also Lindner,effects.
Dipl.Med. That finding Hennigsdorf;
Rebhan, is in accordance with Dr
Dr Enke,
systolic blood pressure by amlodipine during the study period (P < 0.01),
indicate that the generalizability of the study
whereas systolic blood pressure was unchanged in the placebo group. Di-
findings
results mayfrom
M¨ ller,theZeitz;
VALUE Drtrial showing
R¨ sch, a beneficial
Dr Theunert, effectDr Meyer,uo
Dessau;
be limited.
astolic blood pressure did not change during the study period in either of amlodipine Heidenau; versusDr valsartan
Heinrich, Dr due to low
Adler, blood pressure
Dipl.Med. Schindler,
In summary, the present study shows that amlodipine
group (P > 0.05). [13]. Freiberg; Dr Hans, Dr Neumann, Dresden; Dr Berger, Dr
safely reduces systolic blood pressure and that it may have
It is important
Tendis, Borna;to note Drthat
Schl¨ systolic and diastolic
cker, Wolfenb¨ ttel; blood
Dr Meistring,ou
a beneficial effect on cardiovascular outcomes inpressure hyperten- G¨was not
rlitz; Drsignificantly
Brockmann,different betweenDrthe
Bad Bevensen; twoWismar;o
Haaf,
assigned sive haemodialysis
to placebo patients. Further
had a hypotensive episode studies are groups
[relative needed
risk at tothe
Dr start of
Dressler, Drthe study.Hofgeismar;
Rhode, On the other Drhand,
Lammers,the Dr
0.58 (95% support these findings.
CI 0.27–1.28); P = 0.21]. analysisMeyer, of subclasses
Oldenburg; of patients showed
Dr Florsch¨ a slightly signif-Dr Bunia,u
tz, Schmalkalden;
icant beneficial
Dr Ernst,effect in the
Iserlohn; Dramlodipine group in
Schulz, Hassfurt; Drpatients
Rob, Dr
who hadHennings, been treated L¨ beck; Dr V¨ gele-Dirks, Dr Riedl, earlier
with calcium channel blockers Bayreuth;uo
but not Dr in patients
H¨ gel, Dr who had not been
Wichmann, treated
Bayreuth; Drwith
Blaser,calcium
Dra
Discussion Acknowledgements. We thank all the participating centres channel involved inblockers. These findings may point to a protec-
this clinical trial that helped with the recruitment of patients andclass
Grunewald, Lohr; Dr Jensen, Dr
data effect of calcium channel blockers in hyperten-
Piper, Wiesbaden; Dr Lufft,
tive
collection.
Our findings show Wethatthank Dr Katrin Streffer
amlodipine for skilful help with
non-significantly re- the study. Dr Klause, Rendsburg; Dr Stefovic-Fuchs, Dr Braun, Din-
This study was supported by Pfizer, Karlsruhe, Germany. The study was
sive patients golfing; onallhaemodialysis.
from Germany. However, further studies
duces the primary endpoint, i.e. all-cause mortality, by are needed
designed, managed and coordinated by the principal investigators. The to clarify that point. Furthermore, in the liter-
35% in hypertensive patients
principal investigators wrotewith
the chronic kidney
study protocol, anddisease ature
had full accessthereto allare somewhat discrepant results as to whether
stage 5.data.Although it did not reach
A university-based, statistical
independent significance,
statistician performedtheitthe
elevated systolic blood pressure contributes to mortal-
may, however,
statisticalbe clinically relevant considering the excess ity in patients with chronic kidney disease stage 5. In one
mortality analyses.
in these Thehigh-risk
principal investigators
patients. The wrote the finalend-
primary version of the paper
that was approved by all co-authors. The study sponsor provided study the including
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Received for publication: 7.2.08

Accepted in revised form: 6.5.08