Age- and Sex-Related Differences in Efficacy With an Angiotensin II
Receptor Blocker and a Calcium Channel Blocker in Asian Hypertensive
Patients
Kazuomi Kario, MD, PhD; Satoshi Hoshide, MD, PhD
From the Division of Cardiovascular Medicine, Departments of Medicine and Sleep and Circadian Cardiology, Jichi Medical University, School of
Medicine, Shimotsuke, Tochigi, Japan
Overseas guidelines to manage hypertension recommend
selecting different drugs depending on age, but no studies
have investigated the relationship between drug selection
and age- and sex-related differences, although such information
may help to reduce the risk of cardiovascular
mortality. The Azilsartan Circadian and Sleep Pressure––
the First Study (ACS1) trial was a multicentered, randomized,
open-label, two-parallel group study comparing the
effects of an angiotensin II receptor blocker (azilsartan) and
a calcium channel blocker (amlodipine). The present study is
a post hoc analysis of ACS1 to investigate age- and sexrelated
differences in the antihypertensive effects between
azilsartan and amlodipine. Azilsartan significantly reduced
diastolic blood pressure in male patients younger than
60 years compared with amlodipine, but amlodipine significantly
reduced systolic blood pressure in female patients
60 years and older compared with azilsartan. A randomized
controlled trial to evaluate cardiovascular outcomes will
demonstrate whether a diastolic blood pressure–lowering
effect with azilsartan is significantly effective in male patients
younger than 60 years. J Clin Hypertens (Greenwich).
2015:1–7. ª 2015 Wiley Periodicals, Inc.
For the treatment of hypertension to decrease the risk of
cardiovascular events, the Eighth Joint National Committee
(JNC 8) recommends target blood pressure (BP)
goals of <150/90 mm Hg for persons 60 years and older
and a BP goal of <140/90 mm Hg for those younger
than 60 years.1 Although the American Society of
Hypertension (ASH) and the International Society of
Hypertension (ISH) guidelines recommend a target BP
goal <140/90 mm Hg regardless of age, as for drug
selection, an angiotensin II receptor blocker (ARB) or
angiotensin-converting enzyme inhibitor is recommended
as the first-line drug in patients younger than
60 years, while a calcium channel blocker (CCB) or
thiazide diuretic is recommended in patients 60 years
and older.2 The 2014 Japanese Society of Hypertension
(JSH) guidelines, however, recommend a target BP goal
of 140/90 mm Hg for all ages.3
It has recently been reported that regarding the
relationship between cardiovascular events and diastolic
BP (DBP) and systolic BP (SBP), one standard deviation
(SD) increase (13.5 mm Hg) in SBP raises the risk of
total mortality (hazard ratio
, 1.19; 95% con-
fideince interval [CI], 1.08–1.30]) and cardiovascular
mortality (HR, 1.51; 95% CI, 1.34–1.70) in patients of
50 years and older. In patients younger than 50 years,
however, one SD increase (8.2 mm Hg) in DBP, not
SBP, raises the risk of total mortality (HR, 2.05; 95%
CI, 1.26–3.33) and cardiovascular mortality (HR, 4.07;
95% CI, 1.60–10.4).4 Another study on the relationship
between DBP/SBP and cardiovascular events in patients
younger than 50 years also reported that only SBP is
associated with an increased risk of cardiovascular
mortality in women, while both SBP and DBP are
associated with a higher risk of cardiovascular mortality,
independent of each other, in men. In men, the HR
for the risk of cardiovascular mortality by isolated
diastolic hypertension (IDH) (HR, 1.68; 95% CI, 1.29–
2.17]) was similar to that of systolic diastolic hypertension
(SDH) (HR, 1.77; 95% CI, 1.49–2.09), which
showed a higher risk than isolated systolic hypertension
(ISH) (HR, 1.23; 95% CI, 1.03–1.46).5 These recent
reports indicate that proper management of DBP in
younger male patients results in reduced risk of death
caused by cardiovascular events and suggest that it is
necessary to consider a differential approach to BP
management based on age and sex to reduce the risk of
death caused by cardiovascular events. However, there
have been no reports at present that antihypertensive
drug therapy is effective for younger male patients with
ISH, and further investigation is warranted.6,7 To the
best of our knowledge, there are also no reports on the
effectiveness of antihypertensive drug therapy for
patients with IDH.
The results of the Azilsartan Circadian and Sleep
Pressure––the First Study (ACS1), a comparative trial
we conducted to investigate the effects of an ARB
(20 mg azilsartan) and a CCB (5 mg amlodipine) by age
of patients, showed that amlodipine was more effective
than azilsartan in patients 60 years and older.8,9 The
present study was a post hoc analysis of the ACS1 study
to compare and investigate the therapeutic effect of an
Address for correspondence: Kazuomi Kario, MD, PhD, Division of
Cardiovascular Medicine, Department of Medicine, Jichi Medical University,
School of Medicine, 3311-1 Yakushiji, Shimotsuke, Tochigi 329-0498,
Japan
E-mail: kkario@jichi.ac.jp
Manuscript received: August 3, 2015; revised: September 18, 2015;
accepted: September 22, 2015
DOI: 10.1111/jch.12733
The Journal of Clinical Hypertension 1
ORIGINAL PAPER
ARB (azilsartan) and a CCB (amlodipine) by the age and
sex of the patients. We also explored the determinants
of the antihypertensive effects of azilsartan and
amlodipine.
METHODS
Study Design
This study was conducted in accordance with the
principles of the Declaration of Helsinki and Title 45,
U.S. Code of Federal Regulations, Part 46, Protection of
Human Subjects. This study protocol was reviewed and
approved by the institutional review boards of the
participating study sites. All patients provided written
informed consent.
The objective of the study was to compare the effects of
20 mg azilsartan and 5 mg amlodipine in Japanese
patients with stage I or II primary hypertension. The
study design was described in the previous ACS1 study
report (ClinicalTrials.gov ID: NCT01762501).8 Briefly,
after informed consent was obtained, participants underwent
a 2-week washout period. Ambulatory BP monitoring
(ABPM) was then performed at the start of the runin
period. The ABPM device was attached to patients at
an outpatient visit to measure BP continuously, starting at
10 AM (2 hours) for at least 26 hours. BP was measured
every 30 minutes. After the run-in period (1 week),
patients were randomized in a 1:1 ratio using a dynamic
allocation algorithm to orally receive 20 mg of azilsartan
(Takeda Pharmaceutical Company, Ltd, Osaka, Japan)
or 5 mg of amlodipine (Pfizer Japan Inc, Tokyo, Japan)
once daily before or after breakfast in the morning from
week 0. Patients visited the study site every 2 weeks until
the end of the treatment (week 8) and were measured by
ABPM at the end of treatment.
Patients were screened for eligibility according to the
inclusion and exclusion criteria, which are described in
the previous ACS1 study report.8
Statistical Analysis
The differences between the azilsartan and amlodipine
groups (each group included 359 cases) were determined
using the full analysis set of the ACS1 study.9 For
the comparison between the two groups, analysis of
covariance was used with baseline as a covariate for
change from baseline at week 8 in each subgroup, and
chi-square test was used for percentages of patients who
achieved BP goals (control rate). For multivariate
analysis, a stepwise method (both enter and stay,
P=.15) was used for change in BP in each subgroup.
The following values were used as covariates: baseline,
sex (male, female), body mass index (BMI) (<25 or
≥25 kg/m2
), smoking (yes/no), drinking (yes/no), complication
of type 2 diabetes mellitus (yes/no), and
duration of hypertension (<5 or ≥5 years). The tests
were performed with a two-sided significance level of
5%. Analysis was performed using SAS software version
9.4 (SAS Institute, Cary, NC).
RESULTS
Patient Characteristics
Patient characteristics at baseline are shown in Table I.
Both the azilsartan and amlodipine groups consisted of
359 cases, and BP and other patient characteristics at
baseline were similar in both groups (Table I). When
analyzed by age and sex, the baseline BP values of 24-hour
DBP (P=.0256) and awake DBP (P=.0409) in the
amlodipine group were significantly higher than in the
azilsartan group in male patients younger than 60 years.
The average age of female patients was significantly
higher in the azilsartan group (P=.0349) in patients
younger than 60 years. In male patients aged 60 years
and older, the number of smokers was significantly higher
in the azilsartan group (P=.0440), and the values of awake
SBP (P=.0139) and 2-hour SBP after waking (P=.0287)
were significantly higher in the amlodipine group.
Sex-Related Changes in BP in Patients Younger
Than 60 Years
Azilsartan reduced overall BP more than amlodipine in
male patients younger than 60 years (Table II). In
particular, the changes in the azilsartan and amlodipine
groups for 24-hour DBP were 10.5 mm Hg and
8.5 mm Hg (P=.0407), respectively. In addition, the
changes in the azilsartan and amlodipine groups for
awake DBP were 11.3 mm Hg and 8.4 mm Hg
(P=.0057), respectively. Therefore, there was a signifi-
cant difference between the groups. The changes in the
azilsartan and amlodipine groups for clinic DBP were
11.2 mm Hg and 8.5 mm Hg (P=.0550), respectively,
showing a declining trend in the azilsartan group.
In female patients, only 2-hour SBP after waking was
significantly reduced in the amlodipine group
(P=.0031), and no other differences between the azilsartan
and amlodipine groups were observed.
Sex-Related Changes in BP in Patients 60 Years and
Older
In female patients 60 years and older, amlodipine
significantly reduced the overall BP (Table II). Particularly
concerning SBP, amlodipine showed significantly
greater reductions compared with azilsartan. Change in
clinic SBP was 18.5 mm Hg on azilsartan compared
with 24.3 mm Hg on amlodip
รบกวนด้วยค่ะ ด่วนค้ะ TT
Receptor Blocker and a Calcium Channel Blocker in Asian Hypertensive
Patients
Kazuomi Kario, MD, PhD; Satoshi Hoshide, MD, PhD
From the Division of Cardiovascular Medicine, Departments of Medicine and Sleep and Circadian Cardiology, Jichi Medical University, School of
Medicine, Shimotsuke, Tochigi, Japan
Overseas guidelines to manage hypertension recommend
selecting different drugs depending on age, but no studies
have investigated the relationship between drug selection
and age- and sex-related differences, although such information
may help to reduce the risk of cardiovascular
mortality. The Azilsartan Circadian and Sleep Pressure––
the First Study (ACS1) trial was a multicentered, randomized,
open-label, two-parallel group study comparing the
effects of an angiotensin II receptor blocker (azilsartan) and
a calcium channel blocker (amlodipine). The present study is
a post hoc analysis of ACS1 to investigate age- and sexrelated
differences in the antihypertensive effects between
azilsartan and amlodipine. Azilsartan significantly reduced
diastolic blood pressure in male patients younger than
60 years compared with amlodipine, but amlodipine significantly
reduced systolic blood pressure in female patients
60 years and older compared with azilsartan. A randomized
controlled trial to evaluate cardiovascular outcomes will
demonstrate whether a diastolic blood pressure–lowering
effect with azilsartan is significantly effective in male patients
younger than 60 years. J Clin Hypertens (Greenwich).
2015:1–7. ª 2015 Wiley Periodicals, Inc.
For the treatment of hypertension to decrease the risk of
cardiovascular events, the Eighth Joint National Committee
(JNC 8) recommends target blood pressure (BP)
goals of <150/90 mm Hg for persons 60 years and older
and a BP goal of <140/90 mm Hg for those younger
than 60 years.1 Although the American Society of
Hypertension (ASH) and the International Society of
Hypertension (ISH) guidelines recommend a target BP
goal <140/90 mm Hg regardless of age, as for drug
selection, an angiotensin II receptor blocker (ARB) or
angiotensin-converting enzyme inhibitor is recommended
as the first-line drug in patients younger than
60 years, while a calcium channel blocker (CCB) or
thiazide diuretic is recommended in patients 60 years
and older.2 The 2014 Japanese Society of Hypertension
(JSH) guidelines, however, recommend a target BP goal
of 140/90 mm Hg for all ages.3
It has recently been reported that regarding the
relationship between cardiovascular events and diastolic
BP (DBP) and systolic BP (SBP), one standard deviation
(SD) increase (13.5 mm Hg) in SBP raises the risk of
total mortality (hazard ratio
, 1.19; 95% con-
fideince interval [CI], 1.08–1.30]) and cardiovascular
mortality (HR, 1.51; 95% CI, 1.34–1.70) in patients of
50 years and older. In patients younger than 50 years,
however, one SD increase (8.2 mm Hg) in DBP, not
SBP, raises the risk of total mortality (HR, 2.05; 95%
CI, 1.26–3.33) and cardiovascular mortality (HR, 4.07;
95% CI, 1.60–10.4).4 Another study on the relationship
between DBP/SBP and cardiovascular events in patients
younger than 50 years also reported that only SBP is
associated with an increased risk of cardiovascular
mortality in women, while both SBP and DBP are
associated with a higher risk of cardiovascular mortality,
independent of each other, in men. In men, the HR
for the risk of cardiovascular mortality by isolated
diastolic hypertension (IDH) (HR, 1.68; 95% CI, 1.29–
2.17]) was similar to that of systolic diastolic hypertension
(SDH) (HR, 1.77; 95% CI, 1.49–2.09), which
showed a higher risk than isolated systolic hypertension
(ISH) (HR, 1.23; 95% CI, 1.03–1.46).5 These recent
reports indicate that proper management of DBP in
younger male patients results in reduced risk of death
caused by cardiovascular events and suggest that it is
necessary to consider a differential approach to BP
management based on age and sex to reduce the risk of
death caused by cardiovascular events. However, there
have been no reports at present that antihypertensive
drug therapy is effective for younger male patients with
ISH, and further investigation is warranted.6,7 To the
best of our knowledge, there are also no reports on the
effectiveness of antihypertensive drug therapy for
patients with IDH.
The results of the Azilsartan Circadian and Sleep
Pressure––the First Study (ACS1), a comparative trial
we conducted to investigate the effects of an ARB
(20 mg azilsartan) and a CCB (5 mg amlodipine) by age
of patients, showed that amlodipine was more effective
than azilsartan in patients 60 years and older.8,9 The
present study was a post hoc analysis of the ACS1 study
to compare and investigate the therapeutic effect of an
Address for correspondence: Kazuomi Kario, MD, PhD, Division of
Cardiovascular Medicine, Department of Medicine, Jichi Medical University,
School of Medicine, 3311-1 Yakushiji, Shimotsuke, Tochigi 329-0498,
Japan
E-mail: kkario@jichi.ac.jp
Manuscript received: August 3, 2015; revised: September 18, 2015;
accepted: September 22, 2015
DOI: 10.1111/jch.12733
The Journal of Clinical Hypertension 1
ORIGINAL PAPER
ARB (azilsartan) and a CCB (amlodipine) by the age and
sex of the patients. We also explored the determinants
of the antihypertensive effects of azilsartan and
amlodipine.
METHODS
Study Design
This study was conducted in accordance with the
principles of the Declaration of Helsinki and Title 45,
U.S. Code of Federal Regulations, Part 46, Protection of
Human Subjects. This study protocol was reviewed and
approved by the institutional review boards of the
participating study sites. All patients provided written
informed consent.
The objective of the study was to compare the effects of
20 mg azilsartan and 5 mg amlodipine in Japanese
patients with stage I or II primary hypertension. The
study design was described in the previous ACS1 study
report (ClinicalTrials.gov ID: NCT01762501).8 Briefly,
after informed consent was obtained, participants underwent
a 2-week washout period. Ambulatory BP monitoring
(ABPM) was then performed at the start of the runin
period. The ABPM device was attached to patients at
an outpatient visit to measure BP continuously, starting at
10 AM (2 hours) for at least 26 hours. BP was measured
every 30 minutes. After the run-in period (1 week),
patients were randomized in a 1:1 ratio using a dynamic
allocation algorithm to orally receive 20 mg of azilsartan
(Takeda Pharmaceutical Company, Ltd, Osaka, Japan)
or 5 mg of amlodipine (Pfizer Japan Inc, Tokyo, Japan)
once daily before or after breakfast in the morning from
week 0. Patients visited the study site every 2 weeks until
the end of the treatment (week 8) and were measured by
ABPM at the end of treatment.
Patients were screened for eligibility according to the
inclusion and exclusion criteria, which are described in
the previous ACS1 study report.8
Statistical Analysis
The differences between the azilsartan and amlodipine
groups (each group included 359 cases) were determined
using the full analysis set of the ACS1 study.9 For
the comparison between the two groups, analysis of
covariance was used with baseline as a covariate for
change from baseline at week 8 in each subgroup, and
chi-square test was used for percentages of patients who
achieved BP goals (control rate). For multivariate
analysis, a stepwise method (both enter and stay,
P=.15) was used for change in BP in each subgroup.
The following values were used as covariates: baseline,
sex (male, female), body mass index (BMI) (<25 or
≥25 kg/m2
), smoking (yes/no), drinking (yes/no), complication
of type 2 diabetes mellitus (yes/no), and
duration of hypertension (<5 or ≥5 years). The tests
were performed with a two-sided significance level of
5%. Analysis was performed using SAS software version
9.4 (SAS Institute, Cary, NC).
RESULTS
Patient Characteristics
Patient characteristics at baseline are shown in Table I.
Both the azilsartan and amlodipine groups consisted of
359 cases, and BP and other patient characteristics at
baseline were similar in both groups (Table I). When
analyzed by age and sex, the baseline BP values of 24-hour
DBP (P=.0256) and awake DBP (P=.0409) in the
amlodipine group were significantly higher than in the
azilsartan group in male patients younger than 60 years.
The average age of female patients was significantly
higher in the azilsartan group (P=.0349) in patients
younger than 60 years. In male patients aged 60 years
and older, the number of smokers was significantly higher
in the azilsartan group (P=.0440), and the values of awake
SBP (P=.0139) and 2-hour SBP after waking (P=.0287)
were significantly higher in the amlodipine group.
Sex-Related Changes in BP in Patients Younger
Than 60 Years
Azilsartan reduced overall BP more than amlodipine in
male patients younger than 60 years (Table II). In
particular, the changes in the azilsartan and amlodipine
groups for 24-hour DBP were 10.5 mm Hg and
8.5 mm Hg (P=.0407), respectively. In addition, the
changes in the azilsartan and amlodipine groups for
awake DBP were 11.3 mm Hg and 8.4 mm Hg
(P=.0057), respectively. Therefore, there was a signifi-
cant difference between the groups. The changes in the
azilsartan and amlodipine groups for clinic DBP were
11.2 mm Hg and 8.5 mm Hg (P=.0550), respectively,
showing a declining trend in the azilsartan group.
In female patients, only 2-hour SBP after waking was
significantly reduced in the amlodipine group
(P=.0031), and no other differences between the azilsartan
and amlodipine groups were observed.
Sex-Related Changes in BP in Patients 60 Years and
Older
In female patients 60 years and older, amlodipine
significantly reduced the overall BP (Table II). Particularly
concerning SBP, amlodipine showed significantly
greater reductions compared with azilsartan. Change in
clinic SBP was 18.5 mm Hg on azilsartan compared
with 24.3 mm Hg on amlodip