Drug Profile

For reprint orders, please contact reprints@expert-reviews.com

Fixed-dose combination
therapy of candesartan cilexetil
and amlodipine besilate for
the treatment of hypertension
in Japan
Expert Rev. Cardiovasc. Ther. 10(5), 577–583 (2012)

Shinji Yasuno*1,
Akira Fujimoto1,
Yasuaki Nakagawa2,
Koichiro Kuwahara2
and Kenji Ueshima1
1
EBM Research Center,
Kyoto University Graduate School of
Medicine, Kyoto, Japan
2
Department of Medicine and Clinical
Science, Kyoto University Graduate
School of Medicine, Kyoto, Japan
*Author for correspondence:
Tel.: +81 75 771 5153
Fax: +81 75 761 2670
syasuno@kuhp.kyoto-u.ac.jp
Hypertension is one of the most prevalent disorders and the largest contributor to global
mortality. The aim of antihypertensive treatment is to reduce the risk of cardiovascular morbidity
and mortality by lowering increased blood pressure (BP) to target levels. Despite progress in
antihypertensive drug development, BP control remains suboptimal. Accumulating evidence
has shown that fixed-dose combination therapy is better in terms of BP control than increasing
the dose of one drug or its corresponding combination. Fixed-dose combinations of an
angiotensin receptor blocker, candesartan cilexetil, and a calcium channel blocker, amlodipine
besilate (candesartan/amlodipine 8/2.5 or 8/5 mg), were approved in Japan for once-daily oral
administration in hypertensive patients. Recent data showed that a fixed-dose combination of
candesartan and amlodipine lowered BP safely and rapidly, providing a potential opportunity to
improve the rate of BP control. Further studies are needed to determine whether this will lead
to improvements in long-term clinical outcomes.
Keywords: amlodipine • candesartan • fixed-dose combination therapy • hypertension

Hypertension is the leading cause of mortal-
ity through its effect on several target organs,
including the brain, heart and kidneys [1,2] . In
the year 2000, the estimated total number of
adults with hypertension was nearly 1 billion
[3] and was nearly 40 million in Japan, which
accounted for approximately 30% of Japan’s
total population [101] . The aim of antihyper-
tensive treatment is not only to lower increased
blood pressure (BP) to target levels but also to
reduce the risk of cardiovascular (CV) morbid-
ity and mortality. Current Japanese guidelines
for the management of hypertension (Japanese
Society of Hypertension Guidelines for the
Management of Hypertension [JSH2009])
recommend a target systolic BP (SBP) and dias-
tolic BP (DBP) of <130/85 mmHg in patients
younger than 65 years, <140/90 mmHg in
those older than 65 years or with cerebro­
vascular disorder, and <130/80 mmHg in
patients with diabetes mellitus, kidney disease
or a history of myocardial infarction [4] . To
achieve these goals, the majority of hyper­tensive
patients, especially those at high CV risk, often
require the combination therapy of two or more
antihypertensive agents [4,5] .
BP was controlled to target level in only
approximately 50 % of patients taking
antihypertensive drugs in Japan, as in the
USA [6,7] . Suboptimal BP control, including
treated but uncontrolled BP, is associated
with an increased risk of CV morbidity and
mortality [8,9] . The important explanations for
suboptimal BP control are therapeutic inertia,
poor adherence and persistence, and associated
conditions such as older age, obesity, diabetes
mellitus and chronic kidney disease [10–12] . Fixed-
dose combination therapy of carefully selected
antihypertensive agents is considered a promising
strategy to improve BP control. In JSH2009,
six combinations of two different classes of
antihypertensive drugs are recommended [4] . With
regard to angiotensin receptor blocker (ARB),
it pairs effectively with calcium channel blocker

www.expert-reviews.com 10.1586/ERC.12.34 © 2012 Expert Reviews Ltd ISSN 1477-9072 577

 Drug Profile Yasuno, Fujimoto, Nakagawa, Kuwahara & Ueshima
(CCB) or diuretics. Currently, four fixed-dose combinations of
ARBs with CCBs (candesartan/amlodipine, valsartan/amlodipine,
olmesartan/azelnidipine and telmisartan/amlodipine) are available
in Japan. The differences among four fixed-dose combinations of
ARBs with CCBs are beyond the scope of this article. This article
reviews fixed-dose combination therapy with ARB candesartan
cilexetil and CCB amlodipine besilate in Japan, which are the
most frequently prescribed antihypertensive drugs in each class.
Rationale for the use of fixed-dose combination
therapy
Fixed-dose combination therapy has some advantages compared
with monotherapy or combination therapy with its corresponding
drugs in the management of hypertension [13,14] . First, combi-
nation therapy with drugs having distinct and complementary
mechanisms can lower BP more effectively than monotherapy,
because hypertension is a complex multifactorial condition com-
prising multiple pathways. In a recent meta-analysis of 10,969
patients from 42 trials, combining two drugs from different
classes (thiazides, β-blockers, angiotensin-converting enzyme
inhibitors [ACE-Is] and CCBs) was found to be approximately
five-times more effective in lowering BP than increasing the dose
of one drug [15] . Second, combination therapy can minimize
adverse effects compared with monotherapy. Because most anti-
hypertensive drugs have dose-dependent side effects [16] , increas-
ing a dose of one drug to achieve the target BP may be more
frequently associated with the risk of adverse events than combi-
nation therapy with standard doses. Furthermore, one component
of combination therapy can counterbalance the tendency of the
other to produce adverse effects [17] . Finally, fixed-dose combina-
tion therapy can improve adherence and persistence, which are
factors associated with uncontrolled high BP compared with its
corresponding combination. Recently, Fung et al. reported that
the number of prescribed antihypertensive drugs was negatively
associated with adherence and BP control [18] . In their meta-
analysis, Gupta et al. showed that fixed-combination therapy
of two antihypertensive agents is associated with a significant
improvement in adherence compared with its corresponding
free-drug combinations [19] . These results indicate that reduc-
tion of pill burden and simplification of the treatment regimen
can facilitate adherence. Furthermore, the reduced drug cost may
also improve adherence and persistence, because the drug cost of
a fixed-dose combination of two antihypertensive drugs is less
expensive than that of its corresponding drug combinations,
at least in Japan. Accordingly, a fixed-combination therapy is a
potential option in the treatment of hypertension.
Evidence of candesartan & amlodipine in Japanese
hypertensive patients
A large number of clinical trials have shown that both candesar-
tan and amlodipine have efficacy and excellent tolerability in the
treatment of hypertension with or without comorbidities [20–30] ,
indicating that they are suitable for use in combination therapy.
Among them, the CASE-J trial was a clinical trial directly com-
paring the effect of candesartan with that of amlodipine on the
578
incidence of CV morbidity and mortality in 4728 Japanese high-
risk hypertensive patients [20] . BP after 3 years of treatment was
lower than 140/80 mmHg in both groups, and the mean num-
ber of antihypertensive drugs used, including allocated drugs,
was less than two in both groups after 3 years of treatment. For
a mean follow-up period of 3.2 years, there was no difference
in the incidence of CV events between the two groups (hazard
ratio [HR]: 1.01; 95% CI: 0.79–1.28; p = 0.969). The CASE-J
Extension (CASE-J Ex) was an observational study designed to
evaluate the long-term effects of candesartan and amlodipine,
incorporating an additional 3-year follow-up of the CASE-J trial
[31] . More than 80% of patients in both groups continued taking
their allocated drug throughout the extended follow-up period.
During the extended follow-up period, BP was continuously
controlled to a level as low as approximately 135/75 mmHg in
both groups. At the end of the CASE-J Ex, the mean number
of antihypertensive drugs used, including the allocated drugs,
was also less than two in both groups. Just as in the CASE-J
trial, no statistically significant difference was noted in the
incidence of primary CV events during the mean follow-up
period of 4.5 years (HR: 0.95; 95% CI: 0.77–1.18; p = 0.650).
With regard to safety parameters, serious adverse events were
reported by the investigators in 211 patients (9.0%) taking cande-
sartan and 233 (10.0%) taking amlodipine during the follow-up
period of the CASE-J trial and CASE-J Ex. The top five most
frequent serious adverse events were malignant neoplastic disease
(candesartan: 2.9%; amlodipine: 3.6%; p = 0.155), pneumonia
(candesartan: 0.8%; amlodipine: 1.0%; p = 0.348), aggravation
of diabetes (candesartan: 0.6%; amlodipine: 0.8%; p = 0.284),
chest pain (­candesartan: 0.5%; amlodipine: 0.6%; p = 0.543) and
bone fracture (candesartan: 0.5%; amlodipine: 0.5%; p = 0.830).
These results indicate that candesartan and amlodipine are
equally efficient in terms of the prevention against CV morbid-
ity and mortality and maintain their antihypertensive effects and
tolerability during long-term administration in Japanese high-risk
hypertensive patients.
Other clinical trials in Japan, specifically, the HIJ-CREATE trial,
compared the effects of candesartan-based therapy with those of
non-ARB-based standard therapy, including ACE-I, on major
adverse CV events (MACEs) in 2049 Japanese hypertensive
patients with angiographically documented coronary artery
disease [23] . There was no significant risk reduction of MACEs
between the candesartan-and non-ARB-based therapy (HR: 0.89;
95% CI: 0.76–1.06; p = 0.19). The number of adverse events
were 798 (77.9%) in the candesartan-based therapy group and
808 (78.8%) in the non-ARB-based standard therapy group
(p = 0.621). In the prespecified adverse events, the incidence of
cough and anemia was lower in the candesartan-based therapy
than in the non-ARB-based standard therapy group (cough: 3.0 vs
16.1%, p = 0.001; and anemia: 0.7 vs 2.6%, p = 0.001, respectively).
Study drug discontinuation was decided by attending physicians
because an adverse event arose more frequently in the non-
ARB-based standard therapy group than in the candesartan
group (12.2 vs 5.7%; p < 0.001). Recently, a subanalysis of
HIJ-CREATE comparing the effects on MACEs of amlodipine
Expert Rev. Cardiovasc. Ther. 10(5), (2012)
 Candesartan cilexetil & amlodipine besilate for the treatment of hypertension in Japan
plus candesartan with those of amlodipine plus non-ARB-based
therapy in 388 patients treated with amlodipine at baseline has
been reported [32] . This showed that treatment with amlodipine
and candesartan reduced the risk of MACEs by 39% compared
with that with amlodipine and non-ARB-based standard
therapy, which included 62.4% use of ACE-I. This suggests
the possible advantage of the combination of candesartan and
amlodipine in Japanese hypertensive patients with coronary artery
disease.
Pharmacologic properties of fixed-dose
combination of candesartan & amlodipine
The ARB candesartan selectively blocks the binding of angioten-
sin II to angiotensin type 1 receptors in vascular smooth muscle
cells. Candesartan cilexetil is the esterified prodrug of candesar-
tan. Oral bioavailability is approximately 40%, and absorbed
candesartan cilexetil is completely metabolized to candesartan.
Candesartan is mainly cleared by the kidney and, to a smaller
extent, by the biliary or intestinal route [33] . The CCB amlodi-
pine inhibits the transmembrane influx of calcium ions into
vascular smooth muscle cells by blocking L-type Ca 2+ channels.
Oral bioavailability is 64%, and absorbed amlodipine is exten-
sively metabolized to inactive metabolites (~90%) in the liver.
Amlodipine is eliminated mainly in the urine as parent drug
(10%) or metabolites (60%) [34,35] . The data of pharmaco­k inetics
of fixed-dose combination of candesartan and amlodipine are
published by the Pharmaceutical and Medical Devices Agency in
Japan. The pharmacokinetics after single oral administration of
a fixed-dose combination of 8 mg candesartan and 5 mg amlodi-
pine in 12 healthy men are shown in Table 1. The pharmaco­kinetics
of candesartan and amlodipine when coadministered orally are
not different from those of candesartan or amlodipine when
administered orally separately.
Fixed-dose combinations of candesartan and amlodipine
(candesartan/amlodipine 8/2.5 or 8/5 mg) were approved by the
Ministry of Health, Labor and Welfare in Japan in April 2010 for
once-daily oral administration in patients with hypertension who
have responded inadequately to either drug as monotherapy, or
who are receiving separate tablets as combination therapy.
Efficacy & tolerability of fixed-dose combination
of candesartan & amlodipine
According to the product information from Takeda Pharmaceutical
Co., Ltd. (Osaka, Japan; written in Japanese), a double-blind
randomized trial was conducted at the time of application for
approval of fixed-dose combination of candesartan and amlodi-
pine. Subjects were Japanese hypertensive patients older than
20 years whose SBP and DBP were 140–179 and 90–109 mmHg,
respectively, at the sitting position during 4 weeks of the run-in
period. The primary end point was the change in trough DBP at
the sitting position from baseline to 12 weeks after treatment with
a fixed-dose combination of candesartan 8 mg and amlodipine
5 mg, candesartan 8 mg alone or amlodipine 5 mg alone. The
secondary end point was the change in trough SBP at the sit-
ting position from baseline to 12 weeks after treatment. BP was
www.expert-reviews.com
Drug Profile
recorded at weeks 2, 4, 8 and 12. As shown in Figures 1A & 1B, the
BP-lowering effect of a fixed-dose combination of candesartan
8 mg and amlodipine 5 mg was superior to that of candesartan
8 mg or amlodipine 5 mg monotherapy, and its superiority was
observed as early as 2 weeks after treatment. In addition, the pro-
portion of patients achieving the BP target (<130/85 mmHg) at
12 weeks after treatment was significantly greater in those receiving
a fixed-dose combination of candesartan 8 mg and amlodipine
5 mg than those receiving candesartan 8 mg or amlodipine 5 mg
monotherapy (Figure 2). The proportions of patients reaching the
BP goal were 18.0, 24.2 and 53.5% for monotherapeutic cande-
sartan 8 mg, monotherapeutic amlodipine 5 mg and candesartan
8 mg/amlodipine 5 mg, respectively.
According to the product information from Takeda
Pharmaceutical Co., Ltd., drug-related adverse effects of a fixed-
dose combination of candesartan and amlodipine, including
abnormality of laboratory tests, occurred in 35 (11.6%) out of
302 Japanese hypertensive patients enrolled in two clinical stud-
ies for 12 and 52 weeks of follow-up. The common drug-related
adverse effects were dizziness (12/302 [4.0%]) and hypotension
(3/302 [1.0%]). Peripheral edema is a common side effect of
CCBs but was not reported in these studies. It is thought that the
mechanism of peripheral edema induced by CCBs is increased
capillary pressure in peripheral tissues resulting from a decrease in
arteriolar resistance without a similar effect on venous resistance
[36,37]. Interestingly, it was reported that the incidence of periph-
eral edema was significantly lower with combination therapy with
amlodipine plus valsartan than with amlodipine monotherapy
[38], suggesting that peripheral edema may be ameliorated by
coadministration of ARB through lowering capillary pressure
by decreasing venous resistance with ARB. The aforementioned
report regarding the drug-related adverse effects of a fixed-dose
combination of candesartan and amlodipine was based on a
small population and a short duration of follow-up. The post­
marketing surveillance to examine the efficacy and safety in
Japanese h ­ ypertensive patients is in process.
Conclusion
This article reviewed the rationale of the use of fixed-dose
combination therapy in the management of hypertension.
A fixed-dose combination of candesartan and amlodipine can
lower BP safely and rapidly, providing a potential opportunity
for achieving better BP control. Further studies are needed to
Table 1. The pharmacokinetics of candesartan and
amlodipine after oral coadministration.
Parameter Candesartan Amlodipine
Cmax (ng/ml) 78.9 ± 29.6 3.5 ± 0.7
Tmax (h) 4.8 ± 0.8 4.9 ± 0.3
AUC (ng·h/ml) 1117.1 ± 205.7 120.3 ± 28.5
T1/2 (h) 16.3 ± 9.2 37.3 ± 6.3
Data are shown as mean ± standard deviation.
Cmax: Maximum drug concentration; T1/2: Half-life period; Tmax: Maximum drug
concentration time.
579
 Drug Profile Yasuno, Fujimoto, Nakagawa, Kuwahara & Ueshima

were often needed in the trials designed to examine the effect

of single drugs and in clinical practice [4,5] . In recent years, our
Trough SBP at sitting position (mmHg)

160 interest has shifted to determine which combination therapy is

CA 8 mg preferable to reduce the CV risks. Recently, four combinations of
AM 5 mg ARB or ACE-I with CCB or diuretic are classified as preferred in
150 CA 8 mg/AM 5 mg
the American Society of Hypertension position paper, in which
using only preferred or acceptable two-drug combinations is
*
140
* * * ­recommended [13] .
Both fixed-dose combinations of ARBs with CCBs and those
*
* * * with diuretics are now available in Japan. Which combination
130 is preferable to control BP and suppress the incidence of CV
events? In a landmark study, the ACCOMPLISH trial exam-
ined the effects on CV morbidity and mortality of combination
120 therapy of ACE-I benazepril with CCB amlodipine or diuretic
Baseline 2 4 8 12 hydrochlorothiazide in high-risk hypertensive patients [25]. BP
Weeks control (<140/90 mmHg) was achieved by 75.4% of patients
in the benazepril–amlodipine group and by 72.4% of those in
Trough DBP at sitting position (mmHg)

100 the benazepril–hydrochlorothiazide group with high tolerabil-

CA 8 mg
AM 5 mg ity, indicating that both combination therapies have a strong
CA 8 mg/AM 5 mg BP-lowering effect. Notably, compared with the combination
90 *
therapy of benazepril–hydrochlorothiazide, the combination of
*
*
* benazepril–amlodipine reduced the absolute risk by 2.2% and
* * *
the relative risk by 19.6% in the primary composite end point,
*
including CV death and CV events, with a small difference in BP
80 favoring the benazepril–amlodipine combination. Furthermore,
in a prespecified secondary analysis of the ACCOMPLISH trial,
combination of benazepril–amlodipine was superior to that of
benazepril–hydrochlorothiazide in terms of prevention against
70
progression of chronic kidney disease [40]. The ACCOMPLISH
Baseline 2 4 8 12
investigators interpreted these findings as benefits of combina-
Weeks
tion therapy (benazepril–amlodipine), which were not due to a
small difference in clinic SBP between the treatment arms favoring
Figure 1. Time course of trough blood pressure at the
sitting position from baseline to 2, 4, 6, 8 and 12 weeks benazepril plus amlodipine, but rather due to intrinsic proper-
with candesartan monotherapy, amlodipine monotherapy ties (metabolic or hemodynamic) of its combination, because a
and a fixed-dose combination therapy of candesartan
monotherapy and amlodipine monotherapy. (A) Systolic
blood pressure. (B) Diastolic blood pressure. 80
*p < 0.05 versus fixed-dose combination therapy of CA and AM. p < 0.001
AM: Amlodipine monotherapy; CA: Candesartan monotherapy; 70
DBP: Diastolic blood pressure; SBP: Systolic blood pressure. p < 0.001
60
Data taken from Takeda Pharmaceuticals Co., Ltd.
50
determine whether this will result in improvements in long-term %
40
clinical outcomes.
30
Expert commentary 20
Up until the early 2000s, we have mainly focused on the clari-
10
fication and differentiation of effects of antihypertensive agents
on the incidence of CV events in addition to their BP-lowering 0
effects in head-to-head randomized clinical trials [20,26,28–30] . CA 8 mg AM 5 mg CA 8 mg/AM 5 mg
A recent meta-analysis of 147 randomized trials showed that Treatment
all the classes of antihypertensive drugs have a similar effect in Figure 2. The proportion of patients achieving the blood
reducing the incidences of coronary heart disease and stroke for pressure target (<130/85 mmHg) at 12 weeks after
a given reduction in BP, reaffirming the importance of lower- treatment.
ing BP irrespective of the class of antihypertensive drugs [39] . AM: Amlodipine monotherapy; CA: Candesartan monotherapy.
To achieve the target BP, however, other antihypertensive drugs Data taken from Takeda Pharmaceuticals Co., Ltd.

580 Expert Rev. Cardiovasc. Ther. 10(5), (2012)

 Candesartan cilexetil & amlodipine besilate for the treatment of hypertension in Japan Drug Profile

subanalysis of the ACCOMPLISH trial disclosed that 24-h ambu-
latory BP control was similar in both groups [41]. Because the
ACCOMPLISH participants had a high prevalence of CV disease
and diabetes mellitus, and more than 80% had a concentration
of urine albumin in the normal or microalbuminuria range, the
generalizability of these findings to the broader population, such
as low-risk patients or patients with overt proteinuria, may be
limited. Moreover, a definitive conclusion cannot be drawn from
the results of one clinical trial. The COLM study – a prospec-
tive, randomized, open-label trial – is ongoing to compare the
effects on CV morbidity and mortality of a combination of ARB
olmesartan and dihydropyridine CCB with those of a combina-
tion of olmesartan and low-dose thiazide diuretic in more than
4000 Japanese elderly hypertensive patients [42]. The trial will
provide additional information regarding the efficacy and safety
of combination therapy of ARB and CCB in the treatment of
hypertension.
Five-year view
Hypertension is an independent and important risk factor for CV
morbidity and mortality. Its prevalence is high and is predicted
to increase worldwide. We have a number of different classes
of antihypertensive drugs, but BP control remains suboptimal.
Fixed-dose combination therapy of carefully selected antihyper-
tensive agents is considered a promising strategy to improve BP
control. Accordingly, the frequency of use of fixed-dose combi-
nation therapy will increase over the next 5 years. In parallel,
we need to determine when to initiate it (first- or second-line),
although it is not yet approved for the first-line treatment in
Japan, and whether we should choose specific combinations based
on ­individual patient considerations such as age and comorbid
conditions.
‍Financial & competing interests disclosure
K Kuwahara and K Ueshima have received honoraria for lectures from
both Takeda Pharmaceutical Co., Ltd. and Pfizer, Japan. The authors
have no other relevant affiliations or financial involvement with any
organization or entity with a financial interest in or financial conflict
with the subject matter or materials discussed in the manuscript apart
from those disclosed.
No writing assistance was utilized in the production of this
manuscript.‍

Key issues
• Hypertension is an independent and important risk factor for cardiovascular morbidity and mortality.
• In the year 2000, the estimated total number of adults with hypertension was nearly 40 million in Japan, which accounted for
approximately 30% of Japan’s total population.
• To achieve the target blood pressure, the majority of hypertensive patients, especially those at high cardiovascular risk, often require
combination therapy of two or more antihypertensive agents.
• A large number of clinical trials have shown that both candesartan and amlodipine have efficacy and excellent tolerability in the
treatment of hypertension with or without comorbidities, indicating that they are suitable for use in combination therapy.
• The blood pressure-lowering effects of fixed-dose combination of candesartan 8 mg and amlodipine 5 mg are superior to those of
candesartan 8 mg or amlodipine 5 mg monotherapy.
• Fixed-dose combination of candesartan and amlodipine is safe and well tolerated, and the common drug-related adverse effects were
dizziness and hypotension.

4 Ogihara T, Kikuchi K, Matsuoka H et al.; hypertensive patients in Japan: First Report

References
Papers of special note have been highlighted as:
• of interest
•• of considerable interest
1 Ezzati M, Lopez AD, Rodgers A, Vander
Hoorn S, Murray CJ; Comparative Risk
Assessment Collaborating Group. Selected
major risk factors and global and regional
burden of disease. Lancet 360(9343),
1347–1360 (2002).
2 Cohuet G, Struijker-Boudier H.
Mechanisms of target organ damage
caused by hypertension: therapeutic
potential. Pharmacol. Ther. 111(1), 81–98
(2006).
3 Kearney PM, Whelton M, Reynolds K,
Muntner P, Whelton PK, He J. Global
burden of hypertension: analysis of
worldwide data. Lancet 365(9455),
217–223 (2005).
Japanese Society of Hypertension
Committee. The Japanese Society of
Hypertension Guidelines for the
Management of Hypertension (JSH 2009).
Hypertens. Res. 32(1), 3–107 (2009).
•• Japanese guidelines for the management
of hypertension.
Calhoun DA, Jones D, Textor S et al.
5
Resistant hypertension: diagnosis,
evaluation, and treatment. A scientific
statement from the American Heart
Association Professional Education
Committee of the Council for High Blood
Pressure Research. Hypertension 51(6),
1403–1419 (2008).
6 Ohkubo T, Obara T, Funahashi J et al.;
J-HOME Study Group. Control of blood
pressure as measured at home and office,
and comparison with physicians’
assessment of control among treated
of the Japan Home versus Office Blood
Pressure Measurement Evaluation
(J-HOME) study. Hypertens. Res. 27(10),
755–763 (2004).
7 Egan BM, Zhao Y, Axon RN. US trends in
prevalence, awareness, treatment, and
control of hypertension, 1988–2008. JAMA
303(20), 2043–2050 (2010).
8 Staessen JA, Wang JG, Thijs L.
Cardiovascular protection and blood
pressure reduction: a meta-analysis. Lancet
358(9290), 1305–1315 (2001).
9 Lewington S, Clarke R, Qizilbash N, Peto
R, Collins R; Prospective Studies
Collaboration. Age-specific relevance of
usual blood pressure to vascular
mortality: a meta-analysis of individual
data for one million adults in 61
prospective studies. Lancet 360(9349),
1903–1913 (2002).

www.expert-reviews.com 581
 Drug Profile Yasuno, Fujimoto, Nakagawa, Kuwahara & Ueshima
10 Messerli FH, Williams B, Ritz E. Essential
hypertension. Lancet 370(9587), 591–603
(2007).
11 Sarafidis PA, Bakris GL. Resistant
hypertension: an overview of evaluation
and treatment. J. Am. Coll. Cardiol. 52(22),
1749–1757 (2008).
12 Egan BM, Zhao Y, Axon RN, Brzezinski
WA, Ferdinand KC. Uncontrolled and
apparent treatment resistant hypertension
in the United States, 1988 to 2008.
Circulation 124(9), 1046–1058 (2011).
13 Gradman AH, Basile JN, Carter BL et al.
Combination therapy in hypertension.
J. Am. Soc. Hypertens. 4(2), 90–98 (2010).
•• American Society of Hypertension
position article on combination therapy
in hypertension.
14 Black HR. Triple fixed-dose combination
therapy: back to the past. Hypertension
54(1), 19–22 (2009).
15 Wald DS, Law M, Morris JK, Bestwick JP,
Wald NJ. Combination therapy versus
monotherapy in reducing blood pressure:
meta-analysis on 11,000 participants from
42 trials. Am. J. Med. 122(3), 290–300
(2009).
16 Law MR, Wald NJ, Morris JK, Jordan RE.
Value of low dose combination treatment
with blood pressure lowering drugs:
analysis of 354 randomised trials. BMJ
326(7404), 1427 (2003).
17 Sica DA. Rationale for fixed-dose
combinations in the treatment of
hypertension: the cycle repeats. Drugs
62(3), 443–462 (2002).
18 Fung V, Huang J, Brand R, Newhouse JP,
Hsu J. Hypertension treatment in a
medicare population: adherence and
systolic blood pressure control. Clin. Ther.
29(5), 972–984 (2007).
19 Gupta AK, Arshad S, Poulter NR.
Compliance, safety, and effectiveness
of fixed-dose combinations of
antihypertensive agents: a
meta-analysis. Hypertension 55(2),
399–407 (2010).
Ogihara T, Nakao K, Fukui T et al.;
20
Candesartan Antihypertensive Survival
Evaluation in Japan Trial Group. Effects of
candesartan compared with amlodipine in
hypertensive patients with high
cardiovascular risks: candesartan
antihypertensive survival evaluation in
Japan trial. Hypertension 51(2), 393–398
(2008).
•• Candesartan Antihypertensive Survival
Evaluation in Japan trial directly
comparing the effect of candesartan
582
and amlodipine on the incidence of
cardiovascular morbidity and mortality.
21 Schrader J, Lüders S, Kulschewski A et al.;
Acute Candesartan Cilexetil Therapy in
Stroke Survivors Study Group. The
ACCESS Study: evaluation of Acute
Candesartan Cilexetil Therapy in
Stroke Survivors. Stroke 34(7), 1699–1703
(2003).
22 Kloner RA, Weinberger M, Pool JL et al.;
Comparison of Candesartan and
Amlodipine for Safety, Tolerability and
Efficacy (CASTLE) Study Investigators.
Comparative effects of candesartan cilexetil
and amlodipine in patients with mild
systemic hypertension. Comparison of
Candesartan and Amlodipine for Safety,
Tolerability and Efficacy (CASTLE) Study
Investigators. Am. J. Cardiol. 87(6),
727–731 (2001).
23 Kasanuki H, Hagiwara N, Hosoda S et al.;
HIJ-CREATE Investigators. Angiotensin II
receptor blocker-based vs. non-angiotensin
II receptor blocker-based therapy in
patients with angiographically documented
coronary artery disease and hypertension:
the Heart Institute of Japan Candesartan
Randomized Trial for Evaluation in
Coronary Artery Disease (HIJ-CREATE).
Eur. Heart J. 30(10), 1203–1212 (2009).
24 Lithell H, Hansson L, Skoog I et al.;
SCOPE Study Group. The Study on
Cognition and Prognosis in the Elderly
(SCOPE): principal results of a randomized
double-blind intervention trial.
J. Hypertens. 21(5), 875–886 (2003).
25 Jamerson K, Weber MA, Bakris GL et al.;
ACCOMPLISH Trial Investigators.
Benazepril plus amlodipine or
hydrochlorothiazide for hypertension in
high-risk patients. N. Engl. J. Med. 359(23),
2417–2428 (2008).
•• Landmark trial of combination therapy in
hypertensive patients.
26 ALLHAT Officers and Coordinators for
the ALLHAT Collaborative Research
Group. The Antihypertensive and
Lipid-Lowering Treatment to Prevent
Heart Attack Trial. Major outcomes in
high-risk hypertensive patients randomized
to angiotensin-converting enzyme inhibitor
or calcium channel blocker vs diuretic: the
antihypertensive and lipid-lowering
treatment to prevent heart attack trial
(ALLHAT). JAMA 288, 2981–2997
(2002).
27 Dahlöf B, Sever PS, Poulter NR et al.;
ASCOT Investigators. Prevention of
cardiovascular events with an
antihypertensive regimen of amlodipine
adding perindopril as required versus
atenolol adding bendroflumethiazide as
required, in the Anglo-Scandinavian
Cardiac Outcomes Trial-Blood Pressure
Lowering Arm (ASCOT-BPLA): a
multicentre randomised controlled trial.
Lancet 366(9489), 895–906 (2005).
28 Berl T, Hunsicker LG, Lewis JB et al.;
Irbesartan Diabetic Nephropathy Trial.
Collaborative Study Group. Cardiovascular
outcomes in the Irbesartan Diabetic
Nephropathy Trial of patients with
Type 2 diabetes and overt nephropathy.
Ann. Intern. Med. 138(7), 542–549
(2003).
29 Julius S, Kjeldsen SE, Weber M et al.;
VALUE trial group. Outcomes in
hypertensive patients at high cardiovascular
risk treated with regimens based on
valsartan or amlodipine: the VALUE
randomised trial. Lancet 363(9426),
2022–2031 (2004).
30 Narumi H, Takano H, Shindo S et al.;
Valsartan Amlodipine Randomized Trial
Investigators. Effects of valsartan and
amlodipine on cardiorenal protection in
Japanese hypertensive patients: the
Valsartan Amlodipine Randomized
Trial. Hypertens. Res. 34(1), 62–69
(2011).
31 Ogihara T, Ueshima K, Nakao K et al.;
CASE-J Ex Study Group. Long-term
effects of candesartan and amlodipine on
cardiovascular morbidity and mortality in
Japanese high-risk hypertensive patients:
the Candesartan Antihypertensive Survival
Evaluation in Japan Extension Study
(CASE-J Ex). Hypertens. Res. 34(12),
1295–1301 (2011).
• Extension of the CASE-J trial.
32 Yamaguchi J, Hagiwara N, Ogawa H et al.;
HIJ-CREATE Investigators. Effect of
amlodipine + candesartan on
cardiovascular events in hypertensive
patients with coronary artery disease (from
The Heart Institute of Japan Candesartan
Randomized Trial for Evaluation in
Coronary Artery Disease [HIJ-CREATE]
Study). Am. J. Cardiol. 106(6), 819–824
(2010).
• Sub analysis of the HIJ-CREATE study
examining the efficacy of combination of
amlodipine with candesartan in Japanese
hypertensive patients with coronary artery
disease.
33 Gleiter CH, Mörike KE. Clinical
pharmacokinetics of candesartan. Clin.
Pharmacokinet. 41(1), 7–17 (2002).
Expert Rev. Cardiovasc. Ther. 10(5), (2012)
 Candesartan cilexetil & amlodipine besilate for the treatment of hypertension in Japan
34 Faulkner JK, McGibney D, Chasseaud LF,
Perry JL, Taylor IW. The pharmacokinetics
of amlodipine in healthy volunteers after
single intravenous and oral doses and after
14 repeated oral doses given once daily.
Br. J. Clin. Pharmacol. 22(1), 21–25
(1986).
35 Beresford AP, McGibney D, Humphrey
MJ, Macrae PV, Stopher DA. Metabolism
and kinetics of amlodipine in man.
Xenobiotica 18(2), 245–254 (1988).
36 Opie LH. Pharmacological differences
between calcium antagonists. Eur. Heart J.
18 (Suppl. A), A71–A79 (1997).
37 Messerli FH. Evolution of calcium
antagonists: past, present, and future. Clin.
Cardiol. 26(2 Suppl. 2), II12–II16 (2003).
38 Philipp T, Smith TR, Glazer R et al.
Two multicenter, 8-week, randomized,
double-blind, placebo-controlled,
parallel-group studies evaluating the
efficacy and tolerability of amlodipine and
valsartan in combination and as
www.expert-reviews.com
monotherapy in adult patients with mild to
moderate essential hypertension. Clin.
Ther. 29(4), 563–580 (2007).
39 Law MR, Morris JK, Wald NJ. Use of
blood pressure lowering drugs in the
prevention of cardiovascular disease:
meta-analysis of 147 randomised trials in
the context of expectations from
prospective epidemiological studies. BMJ
338, b1665 (2009).
40 Bakris GL, Sarafidis PA, Weir MR et al.;
ACCOMPLISH Trial investigators. Renal
outcomes with different fixed-dose
combination therapies in patients with
hypertension at high risk for cardiovascular
events (ACCOMPLISH): a prespecified
secondary analysis of a randomised
controlled trial. Lancet 375(9721),
1173–1181 (2010).
41 Jamerson KA, Devereux R, Bakris GL et al.
Efficacy and duration of benazepril plus
amlodipine or hydrochlorothiazide on
24-hour ambulatory systolic blood pressure
Drug Profile
control. Hypertension 57(2), 174–179
(2011).
42 Ogihara T, Saruta T, Rakugi H et al.;
COLM study investigators. Rationale, study
design and implementation of the COLM
study: the combination of OLMesartan and
calcium channel blocker or diuretic in
high-risk elderly hypertensive patients.
Hypertens. Res. 32(2), 163–167 (2009).
• Ongoing trial investigating the effect on
cardiovascular morbidity and mortality of
the combination of angiotensin receptor
blocker with calcium channel blocker or
diuretic in high-risk elderly hypertensive
patients.
Website
101 Ministry of Health, Labor and Welfare,
Japan (available in Japanese only).
www.mhlw.go.jp/houdou/2008/04/dl/
h0430-2c.pdf
(Accessed 14 January 2012)
583