The Journal of International Medical Research

2011; 39: 1420 1426

1420
Effects of an Angiotensin 2 Receptor
Blocker plus Diuretic Combination Drug
in Chronic Heart Failure Complicated by
Hypertension
O SUZUKI
1
, H ISHII
2
AND S KOBAYASHI
1
1
Division of Cardiovascular Disease, Inazawa City Hospital, Inazawa City, Aichi, Japan;
2
Division of Cardiovascular Disease, Nagoya University Hospital, Nagoya City, Aichi, Japan
The effects of 24 weeks treatment with an
angiotensin 2 receptor blocker (ARB)/
diuretic combination drug were
investigated in an open-label study of 61
patients with stabilized chronic heart
failure. Reninangiotensinaldosterone
system inhibitors were replaced with a
tablet containing hydrochlorothiazide
6.25 mg plus candesartan 8 mg,
administered orally, once daily, in patients
with systolic blood pressure (SBP)
140 mmHg or diastolic blood pressure
(DBP) 90 mmHg while under optimal
treatment. Both SBP and DBP declined
significantly during the ARB/diuretic
combination treatment. Diuretics
administered previously were
discontinued during the study period in 15
patients, decreasing the number of drugs
being taken. During ARB/diuretic
combination treatment, the blood urea
nitrogen level worsened but no significant
changes were noted in potassium or
estimated glomerular filtration rate,
which had been a matter of concern.
Additionally, the level of brain natriuretic
peptide, an indicator of the severity of
heart failure, was improved, indicating
effectiveness and safety of the
ARB/diuretic combination drug.
KEY WORDS: ANGIOTENSIN RECEPTOR BLOCKERS; CANDESARTAN; DIURETICS; HYDROCHLOROTHIAZIDE;
COMBINATION DRUG; HEART FAILURE; LABORATORY VALUES; COMPLIANCE
Introduction
Diseases that cause heart failure include
ischaemic heart disease, hypertension,
valvular disease and cardiomyopathy.
1 3
There have been few epidemiological studies
of the incidence and causes of heart failure
in the general population in Japan. In the
Framingham Study,
4
5143 subjects in the
USA were followed for a mean of 14.1 years;
heart failure developed during this study in
392 subjects and hypertension was observed
in 91% of the participants.
4
He et al.
5
reported that the risk of heart failure was 1.4
times greater in hypertensive patients,
compared with normotensive patients in an
observational study involving men and
women in the USA. These reports suggest
that hypertension is a risk factor that is
closely related to the development of heart
failure.
For these reasons, hypotensive treatment
is essential for the prevention of heart
1421
O Suzuki, H Ishii, S Kobayashi
ARB/diuretic combination for chronic heart failure with hypertension
failure. The types of hypotensive drug that
are effective for the prevention of heart
failure include angiotensin-converting
enzyme (ACE) inhibitors, angiotensin 2
receptor blockers (ARB), -adrenergic
antagonists (-blockers) and diuretics.
6,7
Based on the evidence obtained in these
studies, reninangiotensinaldosterone
(RAA) system inhibitors and diuretics are
considered beneficial hypotensive drugs for
the prevention of heart failure.
6,7
Hypotensive treatment after the
development of heart failure is also closely
related to prognosis. It is, however, difficult
to investigate the advantages of hypotensive
treatment because blood pressure falls as the
severity of heart failure increases.
8 10
Drugs that improve the prognosis of
patients with heart failure have also been
investigated in large-scale clinical studies.
Such drugs include ACE inhibitors, ARBs, -
blockers, diuretics and aldosterone
antagonists.
11 13
In Japan, drugs that act on
the RAA system (and inhibit left ventricular
hypertrophy and atrial fibrillation
accompanying diastolic failure) are used in
many cases, because diastolic failure often
occurs in elderly patients with heart
failure.
14,15
In particular, the ARB
candesartan is widely used in clinical
practice because its indication for chronic
heart failure has been approved in Japan
and it does not cause coughing.
16,17
To prevent the aggravation of heart
failure and maintain the patients
haemodynamic status, the administration of
loop diuretics and antialdosterone diuretics
to alleviate congestion has been considered
advisable.
18,19
Such combinations were
found to be effective in patients with heart
failure in the Randomized Aldactone
Evaluation Study.
20,21
Night-time
hypertension associated with cardiac
dysfunction occurs in many patients who
are, therefore, often given low-dose thiazide
diuretics.
22
Combination drugs that include low-dose
thiazide diuretics and an ARB have recently
been introduced in Japan and are
increasingly being used for hypertension in
clinical cases. Adverse effects are not of
serious concern because these combination
drugs contain small amounts of thiazide,
and hypokalaemia is improved by the
ARB.
23
Thus, their clinical application in
conditions other than hypertension is likely
in the future.
24,25
A thiazide diuretic/
candesartan combination tablet, ECARD

HD (candesartan 8 mg plus hydrochloro -

thiazide 6.25 mg, administered orally, once
daily; Takeda Pharmaceutical Company,
Osaka, Japan) may be of use in heart failure.
Candesartan has long been widely approved
for the treatment of heart failure, although
no evidence confirming the effectiveness of
this specific ARB/diuretic combination in this
indication has been obtained.
The present study evaluated the effects of
the candesartan 8 mg plus
hydrochlorothiazide 6.25 mg combination
tablet, administered orally, once daily, in
patients with stabilized chronic heart failure,
in whom RAA system inhibitors (such as
ARBs) and loop and potassium-retaining
diuretics had been administered with
insufficient hypotensive effect. This study
also investigated whether this ARB/diuretic
combination permitted a reduction in the
overall dose of diuretics that was
administered.
Patients and methods
PATIENTS
This study included consecutive patients with
stabilized chronic heart failure who
displayed diastolic dysfunction on
echocardiography, who visited the
outpatient clinic of Inazawa City Hospital,
1422
O Suzuki, H Ishii, S Kobayashi
ARB/diuretic combination for chronic heart failure with hypertension
Inazawa City, Aichi, Japan, between April
and July 2010. Patients who had a medical
history of admission for heart failure in the
previous 12 20 months, and a systolic
blood pressure (SBP) or diastolic blood
pressure (DBP) of 140 mmHg or
90 mmHg, respectively, measured at home
during treatment with ARBs, calcium
antagonists and diuretics, were included in
the study.
The study was approved by the Ethics
Committee of Inazawa City Hospital and all
patients provided written consent before
enrolment.
TREATMENT AND INVESTIGATIONS
The effects of replacing RAA system
inhibitors with the candesartan 8 mg plus
hydrochlorothiazide 6.25 mg combination
tablet, administered orally, once daily, and
the possibility of reducing the use of
diuretics, were investigated in this open-label
study. Patients received the ARB/diuretic
combination tablet for a 24-week period,
starting between April and July, when the
seasonal variation in the incidence of heart
failure is most marked. Patients discontinued
diuretics when their blood urea nitrogen
(BUN) showed a slight deterioration or if they
complained of any side-effects (e.g. excessive
step-down).
Blood pressure (SBP and DBP) and blood
test values (brain natriuretic peptide [BNP],
BUN, estimated glomerular filtration rate
[eGFR] and potassium levels) were measured
in the hospital before the initiation of
treatment and at home 24 weeks after
therapy initiation, using standard
procedures. Blood pressure was measured
using an automated digital blood pressure
monitor (HEM-1000; Omron, Tokyo, Japan).
eGFR was calculated as follows: eGFR(male)
= (194 serum creatinine [Scr])
1.094

age
0.287
; eGFR(female) = eGFR(male)
0.739. Pre- and post-treatment results were
compared.
STATISTICAL ANALYSES
Statistical analyses were carried out using
the Mini StatMate software package, version
1.1 (Advanced Technology for Medicine &
Science, Tokyo, Japan). All measured values
are presented as mean SD. The differences
in measured parameters before and at the
end of the 24-week treatment period were
analysed using a paired t-test. A P-value
< 0.05 was considered to be statistically
significant.
Results
Thirty-two male and 29 female patients with
chronic heart failure were enrolled in the
study. The characteristics of the patients are
detailed in Table 1.
Blood pressure and blood constituent
variables before and at the end of the 24-
week treatment period are shown in Table 2.
Switching to the combination drug
candesartan 8 mg plus hydrochlorothiazide
6.25 mg, administered orally, once daily
significantly reduced SBP and DBP at the end
of the treatment period (P < 0.001 for both).
Three patients dropped out because of
excessive blood pressure reductions and were
switched back to the previously administered
RAA system inhibitors.
As shown in Table 2, the mean level of
BNP decreased during the 24-week treatment
period, showing a significant improvement
compared with the before-treatment level (P
< 0.001). The mean BUN level increased
significantly during treatment (P < 0.01), but
the potassium level and eGFR showed no
significant change during treatment. Three
patients exhibited excessive step-down.
Loop diuretic treatment was discontinued
in 15 patients during the 24-week treatment
period, significantly decreasing the mean
1423
O Suzuki, H Ishii, S Kobayashi
ARB/diuretic combination for chronic heart failure with hypertension
number of drugs being taken per patient
(P < 0.001, Table 2).
Discussion
The present study indicated that the
ARB/diuretic combination tablet, candesartan
8 mg plus hydrochlorothiazide 6.25 mg,
administered orally, once daily, was safe and
effective for patients with stabilized chronic
heart failure. In these patients, RAA system
inhibitors (such as ARB and ACE inhibitors)
were replaced with the combination tablet,
starting between April and July, when the
seasonal variation in the incidence of heart
failure is most marked. During this period,
SBP and DBP decreased by approximately 40
and 20 mmHg, respectively, showing that the
ARB/diuretic combination tablet had a
marked hypotensive effect. The level of BNP,
an indicator of the severity of heart failure,
also decreased.
Although further investigation of the
necessity for active blood pressure reduction
in patients with heart failure is required, the
results reported here help to support the
safety and efficacy of the candesartan 8 mg
plus hydrochlorothiazide 6.25 mg
combination tablet, administered orally,
once daily, in such patients.
The worsening of BUN seen in some
patients in this study may have been due to
the addition of thiazide to the loop diuretics
that were already being administered.
26
Patients heart failure symptoms remained
stable and no patient had to be admitted to
hospital after being switched to the
ARB/diuretic combination tablet, even if
they had a prior medical history of
hospitalization. The number of diuretic
treatments was reduced because of the
worsening of BUN in some patients, resulting
in a significant reduction in the pill burden
for these individuals.
The overall number of drugs used during
the study period was reduced. It has
previously been shown that reducing the pill
burden improves patient compliance.
27,28
Furthermore, improvements in blood
pressure as a result of better patient
compliance have also been reported.
29,30
In
the present study, a marked hypotensive
Male gender 32 (52.4)
Age (years) 68.1 10.9
Risk factors for heart disease
NYHA class II 27 (44.3)
NYHA class III 31 (50.8)
NYHA class IV 1 (1.6)
Left ventricular ejection 54 7.4
fraction, %
Heart rate, beats/min 79.2 12.5
Medical history
Coronary artery bypass graft 12 (19.7)
Aortic valve replacement 7 (11.5)
Pacemaker 7 (11.5)
Old myocardial infarction 18 (29.5)
Cardiac valvular disease 13 (21.3)
Hypertrophic cardiomyopathy 1 (1.6)
Emphysema-associated left 1 (1.6)
and right heart failure
Diabetes mellitus 17 (27.9)
Brain infarction 9 (14.8)
Angina pectoris 13 (21.3)
Urinary bladder carcinoma 3 (4.9)
Gastric ulcer 1 (1.6)
Colorectal cancer 1 (1.6)
Renal failure 4 (6.6)
Anaemia 2 (3.3)
Aortic dissection 1 (1.6)
Lung cancer 1 (1.6)
Asthma 1 (1.6)
Previous smoker 6 (10.8)
Data presented as mean SD or n (%) of patients.
NYHA, New York Heart Association.
TABLE 1:
Characteristics of the 61 patients with
stabilized chronic heart failure
complicated by hypertension who were
enrolled in the present study investigating
the effectiveness and safety of a
candesartan 8 mg plus hydrochloro -
thiazide 6.25 mg combination tablet,
administered orally, once daily
1424
O Suzuki, H Ishii, S Kobayashi
ARB/diuretic combination for chronic heart failure with hypertension
effect was obtained by replacing RAA system
inhibitors with the candesartan 8 mg plus
hydrochlorothiazide 6.25 mg combination
tablet; however, compliance was not
specifically measured in this study, therefore
no firm conclusions can be drawn regarding
compliance, reduction in number of drugs
taken and improvements in blood pressure
from these data.
The present study unexpectedly included
patients who retained adequate systolic
capacity (i.e. left ventricular ejection fraction
of > 40%). Previous large-scale clinical
studies in heart failure mainly involved
patients with systolic heart failure.
31 34
Evidence for the efficacy of hypotensive
drugs for the treatment of diastolic failure is
still inadequate: the Candesartan in Heart
Failure: Assessment of Reduction in Mortality
and Morbidity-Preserved trial
35
is the only
large-scale clinical study in which an
improvement in diastolic failure attributable
to the use of candesartan has been observed.
Replacement of RAA system inhibitors with
candesartan inhibited the aggravation of
heart failure symptoms in the Assessment of
the Response to Candesartan in Heart
Failure in Japan study,
36
and its indication
for chronic heart failure has been approved
in Japan. The subjects in the present study
had chronic heart failure and displayed
diastolic dysfunction on echocardiography.
The Antihypertensive and Lipid-Lowering
Treatment to Prevent Heart Attack Trial
(ALLHAT) and The International Nifedipine
GITS Study: Intervention as a Goal in
Hypertension Treatment (INSIGHT) study
reported inhibitory effects of low-dose
thiazide diuretics on cardiovascular events,
including heart failure, compared with the
effects of ACE inhibitors and calcium
antagonists.
32,34
The ARB/diuretic
combination tablet described here contains
hydrochlorothiazide, and may be
therapeutically useful for maintaining
diastolic function in patients with chronic
heart failure.
The present study investigated the effect of
an ARB/diuretic combination drug on
stabilized chronic heart failure. This study is
important because there is insufficient
evidence regarding the treatment of diastolic
Before After 24 weeks Statistical
Item treatment of treatment significance
b
Systolic blood pressure, mmHg 156.4 13.1 120.8 11.3 P < 0.001
Diastolic blood pressure, mmHg 92.2 8.7 72.1 9.0 P < 0.001
Brain natriuretic protein, pg/ml 153.5 175.6 113.7 138.8 P < 0.001
Potassium, mEq/l 4.2 0.4 4.2 0.4 NS
Blood urea nitrogen, mg/dl 20.2 8.1 22.3 7.6 P < 0.01
Estimated glomerular filtration rate, 61.4 21.2 60.2 18.0 NS
ml/min per 1.73 m
2
No. of drugs used 3.7 0.9 3.1 0.7 P < 0.001
Data presented as mean SD.
a
ECARD

HD tablets, each containing 8 mg of the angiotensin 2 receptor blocker candesartan and 6.25 mg
of the diuretic hydrochlorothiazide. The dosage was one tablet daily, administered orally.
b
Paired t-test.
TABLE 2:
Findings before and after 24 weeks of treatment with a candesartan 8 mg plus
hydrochlorothiazide 6.25 mg combination tablet
a
in 61 patients with stabilized chronic
heart failure
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Received for publication 7 March 2011 Accepted subject to revision 17 March 2011
Revised accepted 5 July 2011
Copyright 2011 Field House Publishing LLP
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Administration of the candesartan 8 mg plus
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Acknowledgements
We are grateful to Takashi Higashi, Masao
Bashomatsu and Hiroshi Sekiyama for
technical assistance.
Conflicts of interest
The authors had no conflicts of interest to
declare in relation to this article.
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Authors address for correspondence
Dr Osamu Suzuki
Division of Cardiovascular Disease, Inazawa City Hospital, 1-1 Gogosho-machi, Inazawa
City, Aichi 492-8146, Japan.
E-mail: hp-med@city.inazawa.aichi.jp
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O Suzuki, H Ishii, S Kobayashi
ARB/diuretic combination for chronic heart failure with hypertension