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
Excluded (n=0)
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)
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