1753
Hypertens Res
Vol.31 (2008) No.9
p.1753-1763
Original Article
A Randomized Trial of the Effect of an Angiotensin II
Receptor Blocker SR47436 (Irbesartan) on 24-Hour
Blood Pressure in Patients with
Essential Hypertension
Yuhei KAWANO1), Yoichi SATO2), and Kaoru YOSHINAGA3)
The aim of this placebo-controlled, double-blind randomized study was to evaluate the duration of the effect
of once-daily administration of irbesartan in patients with essential hypertension. After a placebo run-in
baseline period (of 2–4 weeks), 79 patients were randomized to either irbesartan (one 100 mg tablet per day)
or placebo, for 6 weeks. The primary outcome was the reduction in the mean 24-h blood pressure (BP) as
assessed by ambulatory BP monitoring under standardized conditions. Seventy-six patients completed the
study protocol. In the irbesartan group, the average reductions in 24-h systolic and diastolic BPs were 5.8
and 3.4 mmHg, respectively (95% confidence interval: 3.2–8.4/1.6–5.1 mmHg), and in the placebo group, they
were –1.7 and –0.5 mmHg, respectively (95% confidence interval: –4.3 to 1.0/–1.8 to 0.7 mmHg). There were
statistically significant differences in the average reductions of 24-h BP (7.5/3.9 mmHg, p<0.001), daytime
BP (8.6/4.0 mmHg, p<0.001) and nighttime BP (6.1/3.4 mmHg, p<0.05) as well as casual BP (9.0/5.0 mmHg,
p<0.001). The trough/peak (T /P ) ratios for the systolic and diastolic BPs were 0.84 and 0.78, respectively,
in the irbesartan group. The incidence of adverse events was similar in both groups. The results showed
that irbesartan administered 100 mg once daily was well tolerated in the treatment of essential hypertension
and was effective in producing sustained 24-h BP control. (Hypertens Res 2008; 31: 1753–1763)
Key Words: SR47436, irbesartan, double-blind randomized study, ambulatory blood pressure monitoring,
essential hypertension
Introduction
Hypertension is a major risk factor for cardiovascular dis-
eases (1). The aim of antihypertensive therapy is to lower the
morbidity and mortality from cardiovascular diseases, and a
number of intervention studies have shown that such therapy
is effective (2). Given the long-term objectives of antihyper-
tensive treatment aimed at cardiovascular disease prevention,
it is desirable to use an antihypertensive agent which reliably
controls blood pressure (BP) with few adverse drug reactions
when administered once daily.
Blood pressure can now be measured non-invasively for 24
consecutive hours (3–5). Several studies have shown that the
average BP measured by ambulatory BP monitoring (ABPM)
correlates more strongly with the severity of hypertensive
organ damage than the values measured during outpatient vis-
its (6). In addition, the guidelines for clinical assessment of
antihypertensive drugs in Japan recommend the use of trough/
peak (T/P) ratios based on ABPM measurements to investi-
gate the duration of therapeutic effects (7).
SR47436 (irbesartan) is a non-peptide angiotensin II (AII)
receptor blocker that can be administered orally. Irbesartan
selectively binds to a type 1 AII receptor and lowers BP by
From the 1)Division of Hypertension and Nephrology, National Cardiovascular Center, Suita, Japan; 2)Strategic Development Department, Shionogi &
Co., Ltd., Osaka, Japan; and 3)Miyagi Foundation for the Prevention of Adult Diseases, Sendai, Japan.
Address for Reprints: Yuhei Kawano, M.D., Division of Hypertension and Nephrology, National Cardiovascular Center, 5–7–1 Fujishirodai, Suita 565–
8565, Japan. E-mail: ykawano@hsp.ncvc.go.jp
Received May 7, 2008; Accepted in revised form July 2, 2008.
1754 Hypertens Res Vol. 31, No. 9 (2008)
competing with AII to bind to the receptor. In Japan, single-
dose and repeated-dose studies have been conducted among
healthy male volunteers. Among those with mild to moderate
essential hypertension, two studies of irbesartan have been
conducted: a pilot study and a late phase II clinical study (8).
The results of these studies showed that irbesartan could
safely and effectively lower BP when administered once
daily, and the optimal clinical doses were estimated at 50–100
mg/d.
The present study investigated the duration of the anti-
hypertensive effect of irbesartan using ABPM. The effect of
once-daily administration of 100 mg of irbesartan was evalu-
ated in a placebo-controlled, double-blind randomized study.
Methods
The present study was conducted according to the “Good
Clinical Practice for Trials on Drugs (GCP)” ordinance of
Japan (Pharmaceutical Affairs Law, Article 14, Section 3 and
Article 80, Sections 2-1, 4 and 5) established in accordance
with the Declaration of Helsinki. The study was also
approved by the institutional review board of each participat-
Fig. 1. Flowchart depicting the inclusion and exclusion of study subjects.
Enrolled patients
n = 94
Discontinuation/
withdrawal during
baseline period
n = 14
Drug allocation
Not treated/tests not
performed
Irbesartan 100 mg
Placebo n = 0
n = 1
Irbesartan 100 mg
Placebo n = 0
n = 0
Irbesartan 100 mg
Placebo n = 0
n = 0
Irbesartan 100 mg
Placebo n = 0
n = 0
Irbesartan 100 mg
Placebo n = 2
n = 1
GCP non-compliance
Non-qualifying cases
Progressed to
treatment period
Excluded Excluded
Safety analysis set 24-h bloodpressure analysis set Efficacy analysis set
Irbesartan 100 mg
Placebo n = 40
n = 40
Irbesartan 100 mg
Placebo n = 40
n = 39
Irbesartan 100 mg
Placebo n = 38
n = 38Irbesartan 100 mg
Placebo n = 40
n = 39 Irbesartan 100 mg
Placebo n = 40
n = 39
Kawano et al: ABPM Study of Irbesartan in Hypertension Patients 1755
ing medical institution.
Subjects
Eligible subjects were patients with essential hypertension
who visited one of the ten medical institutions listed in the
Appendix between August 2001 and June 2002. Prior to the
start of the baseline period, the investigators used a GCP-
compliant consent form to explain the details of the present
study to the subjects, and informed consent was obtained in
writing from all subjects.
Inclusion criteria at the start of the recruitment were as fol-
lows: 1) age from 25 to 79 years, 2) men or postmenopausal
women, 3) outpatients with essential hypertension, 4)
untreated with antihypertensive agents or, if treated, willing to
forgo current medication during the 4-week placebo run-in
baseline period and the 6-week main study period. Inclusion
criteria at the start of the study period were as follows: 1) sta-
ble sitting BP in the last two measurements during the base-
line period, 2) sitting systolic BP of 150 mmHg or above and
diastolic BP of 95 mmHg or above, or systolic BP of 160
mmHg or above and diastolic BP of 90 mmHg or above, 3) sit-
ting diastolic BP of less than 120 mmHg, 4) mean 24-h sys-
tolic BP of 130 mmHg or above, or diastolic BP of 80 mmHg
or above. The reason we used several criteria for casual BP
was that we wanted to include only patients with definite sys-
tolic-diastolic hypertension. Patients with secondary or malig-
nant hypertension, cardiovascular diseases such as stroke,
myocardial infarction and heart failure, renal failure or liver
dysfunction, and patients judged unsuitable for participation
by the investigator were excluded from the present study.
A total of 94 subjects were enrolled in the present study
(Fig. 1). Of these patients, 14 discontinued or withdrew dur-
ing the baseline period. Hence, drug allocation was performed
in 80 patients (irbesartan group: n=40; placebo group:
n=40). One patient in the irbesartan group was excluded from
the study because the proper allocated drug was not adminis-
tered. Consequently, 79 patients (irbesartan group: n=39;
placebo group: n=40) progressed to the treatment period, and
their data were used for the evaluation of safety and efficacy.
During the treatment period, GCP compliance guidelines
were upheld for all 79 patients. Ambulatory BP monitoring
was not properly performed in three patients (irbesartan
group: n=1; placebo group: n=2); therefore, for the analysis
of 24-h BP, we used data from the remaining 76 patients
(irbesartan group: n=38; placebo group: n=38).
Based on the findings of another ABPM study of irbesartan
(9), it was estimated that the mean difference in the reduction
in mean 24-h BP between the irbesartan group and placebo
group would be 5.0 mmHg with a SD of 6.0 mmHg. Using
these values, the required number of subjects to detect a dif-
ference between the two groups was estimated to be 23 per
group (power of test: 80%, α=0.05, two-sided). Therefore,
the target number of cases was set at 30 subjects per group
(total number of subjects: 60), allowing for dropouts and
withdrawals.
Investigational Drugs
Irbesartan (100 mg) tablets and placebo tablets, indistinguish-
able in appearance, were used. The tablets were randomly dis-
tributed within each of the 30 blocks used; each block
consisted of four patients (two in the irbesartan group and two
in the placebo group).
Administration of the Drugs
During the baseline run-in period, one placebo tablet was
administered once daily after breakfast for 2 weeks to patients
with untreated essential hypertension and for 4 weeks to
patients who stopped antihypertensive therapy before enroll-
ing (Fig. 2). During the treatment period, one tablet (either
100 mg of irbesartan or placebo) was administered once daily
after breakfast for 6 weeks.
Fig. 2. Study timeline. *Lengthened by up to 2 weeks depending on patient circumstances. **Shortened or lengthened by 1 week
depending on patient circumstances.
Irbesartan 100 mg group (100 mg tablet once-daily)
Placebo
Placebo group (once-daily administration of a placebo tablet)
-4 -2 0 2 4 6 weeks
Baseline period* (2-4 weeks) Treatment period** (6 weeks)
ABPM
(in hospital)
ABPM
(in hospital)
1756 Hypertens Res Vol. 31, No. 9 (2008)
Use of other antihypertensive drugs was prohibited during
the baseline and treatment periods. Use of the following drugs
was also prohibited unless necessary: psychotropic agents,
anti-anxiety drugs, sedatives, hypnotic agents, analgesics,
central acting muscle relaxants, phenothiazine antihista-
mines, or phosphodiesterase-5 inhibitors.
Measurements
Casual BP and pulse rate were measured at 2-week intervals
in a sitting position after sufficient rest. A tablet of irbesartan
or placebo was taken before the measurement. Casual BP was
measured twice, and the average values were used for analy-
sis. At the end of the baseline period and at the end of the
treatment period, casual BP was also measured in the supine,
and standing positions.
At the end of the baseline period and at the end of the treat-
ment period, ABPM was carried out for 26 consecutive hours
in the hospital using a portable automatic sphygmomanome-
ter (TM-2421; A&D Co., Ltd., Tokyo, Japan) at 15-min inter-
vals during the day (6:00–21:00) and at 30-min intervals at
night (21:00–6:00). The same sphygmomanometer was used
for each patient. During ABPM, the investigational drug was
administered at 10 AM. The patients were instructed to relax
the upper arm as a cuff was fastened in place and to remain in
a sitting position while BP was monitored at peak (3–6 h after
administration) and trough (23–24 h after administration)
hours. The patients were also instructed to record daily activ-
ities, such as the times of meals, sleeping and getting up.
At the end of the baseline period and at the end of the treat-
ment period (or at discontinuation of treatment), the follow-
ing tests were conducted: hematology, blood chemistry,
urinalysis, chest X-ray, electrocardiography, and funduscopy
(if possible).
Table 1. Characteristics of the Study Population
Item Irbesartan 100 mg group Placebo group Total
Total number of subjects 38 (100.0) 38 (100.0) 76 (100.0)
Gender
Male 28 (73.7) 25 (65.8) 53 (69.7)
Female 10 (26.3) 13 (34.2) 23 (30.3)
Age (years) 58.9±8.3 58.8±9.4 58.9±8.8
Body weight (kg) 66.5±13.4 64.6±10.9 65.5±12.2
Height (cm) 162.1±7.6 161.0±8.3 161.5±7.9
Complications
No 9 (23.7) 7 (18.4) 16 (21.1)
Yes 29 (76.3) 31 (81.6) 60 (78.9)
WHO-ISH 1993 Guidelines
Stage I 13 (34.2) 15 (39.5) 28 (36.8)
Stage II 25 (65.8) 22 (57.9) 47 (61.8)
Stage III 0 (0.0) 1 (2.6) 1 (1.3)
History of antihypertensive therapy
No past history 8 (21.1) 11 (28.9) 19 (25.0)
Drug taken in the past 9 (23.7) 9 (23.7) 18 (23.7)
Drug taken until just before the study 21 (55.3) 18 (47.4) 39 (51.3)
Data are mean±SD or n (%).
Table 2. Distribution of Baseline Values
Item
Irbesartan 100 mg group
(n=38)
Placebo group
(n=38)
Total
(n=76)
Mean 24-h BP during baseline period (mmHg)
Systolic BP 145.0±10.9 142.9±10.6 143.9±10.7
Diastolic BP 95.0±8.8 92.0±7.8 93.5±8.4
Casual BP during baseline period (mmHg)
Systolic BP 163.4±11.3 163.7±9.1 163.6±10.2
Diastolic BP 100.0±5.4 99.2±5.7 99.6±5.5
Casual pulse rate during baseline period (beats/min) 73.2±13.1 72.2±11.4 72.7±12.2
Data are mean±SD. BP, blood pressure.
Kawano et al: ABPM Study of Irbesartan in Hypertension Patients 1757
Adverse Events
All subjective symptoms and objective findings or diseases
which newly appeared or which were exacerbated during the
study were noted and the details were recorded. Any abnor-
mal changes in laboratory data were evaluated based on a
comparison of observed values in the baseline and treatment
periods. If possible, follow-up investigations were performed
until recovery.
Overall Safety
To investigate the severity of adverse drug reactions, overall
safety of use was rated on a scale of 1–5: 1, safe (no safety
Fig. 3. Twenty-four-hour blood pressure in the irbesartan and placebo groups. Mean±SD. SBP, systolic blood pressure; DBP,
diastolic blood pressure.
40
80
120
160
200
10 11 12 13 14 15 16 17 18 19 20 21 22 23 0 1 2 3 4 5 6 7 8 9 10
(mmHg) Irbesartan group Baseline period
Treatment period
Time
40
80
120
160
200
10 11 12 13 14 15 16 17 18 19 20 21 22 23 0 1 2 3 4 5 6 7 8 9 10
(mmHg)
Baseline period
Treatment period
Placebo group
Time
Administration
Administration
SBP
DBP
SBP
DBP
1758 Hypertens Res Vol. 31, No. 9 (2008)
problems, i.e., no adverse effects occurred); 2, slightly unsafe
(mild adverse reaction occurred but no special treatment was
needed and treatment was continued); 3, probably unsafe
(dosage reduction or other measures were required); 4, unsafe
(treatment with the investigational drug was, or should have
been, discontinued); 5, no information available. In the event
that treatment was discontinued for some reason, the investi-
gator also evaluated the overall safety of use on the same
scale. Patients for whom an evaluation could not be made for
some reason were classified as “no information available.”
Analysis
The primary objective was to compare the efficacy of 100 mg
irbesartan compared with placebo group on reducing the
mean 24-h BP from ABPM data. The statistical analysis was
conducted using SAS version 6.12 (SAS Japan Inc., Tokyo,
Japan). The differences between groups were evaluated by
Fig. 4. Twenty-four-hour pulse rate in the irbesartan and placebo groups. Mean±SD.
20
40
60
80
100
120
10 11 12 13 14 15 16 17 18 19 20 21 22 23 0 1 2 3 4 5 6 7 8 9 10
(beats/min) Placebo group
Time
Baseline period
Treatment period
20
40
60
80
100
120
10 11 12 13 14 15 16 17 18 19 20 21 22 23 0 1 2 3 4 5 6 7 8 9 10
Administration
Irbesartan 100 mg group Baseline period
Treatment period
Time
(beats/min)
Administration
Kawano et al: ABPM Study of Irbesartan in Hypertension Patients 1759
the t-test. The secondary objectives were to assess some other
measures of antihypertensive effects and the overall safety of
use. The overall safety of use was assessed in an exploratory
manner by tabulating the incidence, calculating descriptive
statistics, and preparing tables and figures. All tests were two-
sided and conducted at the 5% level of significance, unless
otherwise specified.
Values are expressed as mean±SD and 95% confidence
intervals were used. The Clopper-Pearson method was used
to estimate the confidence interval of ratios.
Results
Baseline Characteristics
The patient characteristics, baseline values of BPs and pulse
rate are shown in Tables 1 and 2. There were no significant
differences between the irbesartan and placebo groups. The
mean 24-h BP during the baseline period in the irbesartan
group were 145.0±10.9 mmHg systolic and 95.0±8.8 mmHg
diastolic and 142.9±10.6 mmHg systolic and 92.0±7.8
mmHg diastolic in the placebo group.
Changes in BP and Pulse Rate during ABPM
Systolic and diastolic BPs and pulse rate, as measured by
ABPM, are shown in Figs. 3 and 4. At all measurement
points, systolic and diastolic BPs during the treatment period
in the irbesartan group were lower than those during the base-
line period. In contrast, no marked differences in systolic and
diastolic BPs were noted between the baseline and treatment
periods for the placebo group. For pulse rate, no marked
changes were observed between the baseline and treatment
periods for either the irbesartan or the placebo group (Fig. 4).
In the irbesartan group, 24-h systolic and diastolic BPs
were significantly reduced whereas the values in the placebo
group were unchanged (Table 3). The differences between the
groups in the mean reduction in BP were 7.5/3.9 mmHg in 24
Table 3. Reductions in 24-h, Daytime and Nighttime BP
Item and time period Group n
Baseline
period
mean
Treatment
period
mean
Reduction Difference between treatment groups
Mean
95% confidence
interval p* Mean
95% confidence
interval
Systolic BP
24 h Irbesartan 38 145.0 139.2 5.8 3.2–8.4 0.0001 7.5 3.8–11.1
Placebo 38 142.9 144.6 −1.7 −4.3–1.0
Daytime (11:00–21:00) Irbesartan 38 150.1 143.8 6.3 3.2–9.5 0.0001 8.6 4.4–12.8
Placebo 38 146.9 149.1 −2.3 −5.1–0.6
Nighttime (0:00–5:00) Irbesartan 38 134.8 129.5 5.3 2.3–8.3 0.0100 6.1 1.5–10.7
Placebo 38 134.8 135.6 −0.8 −4.4–2.7
Diastolic BP
24 h Irbesartan 38 95.0 91.7 3.4 1.6–5.1 0.0004 3.9 1.8–6.0
Placebo 38 92.0 92.5 −0.5 −1.8–0.7
Daytime (11:00–21:00) Irbesartan 38 98.6 95.2 3.4 1.3–5.4 0.0018 3.9 1.5–6.4
Placebo 38 95.0 95.6 −0.6 −2.0–0.8
Nighttime (0:00–5:00) Irbesartan 38 87.7 84.4 3.3 1.2–5.4 0.0218 3.4 0.5–6.2
Placebo 38 86.0 86.1 −0.1 −2.1–2.0
Unit: mmHg. BP, blood pressure. *t-test.
Table 4. T/P ratios as Determined by ABPM
Item Group T value (mmHg)
P value
(mmHg) T/P ratio
Placebo-corrected
T value
(mmHg)
P value
(mmHg) T/P ratio
Systolic BP Irbesartan 100 mg 6.6 7.8 0.84 6.9 9.0 0.77
Placebo −0.3 0.1
Diastolic BP Irbesartan 100 mg 4.3 5.4 0.78 3.7 5.8 0.64
Placebo 0.5 0.5
T, trough; P, peak; ABPM, ambulatory blood pressure monitoring; BP, blood pressure.
1760 Hypertens Res Vol. 31, No. 9 (2008)
h, 8.6/4.0 mmHg in daytime, and 6.1/3.4 mmHg in nighttime.
The reductions in trough systolic and diastolic BPs were
6.6 and 4.3 mmHg, respectively, in the irbesartan group and
−0.3 and 0.5 mmHg, respectively, in the placebo group
(Table 4). The differences in the reductions for both the
trough systolic and diastolic BPs were statistically significant.
Trough and peak values were calculated from the mean
reduction in BP during 24 h. The T/P ratios for systolic and
diastolic BPs in the irbesartan group were 0.84 and 0.78,
respectively (Table 4). Placebo-corrected T/P ratios were also
calculated by taking the mean reduction in trough and peak
BPs and correcting it for the mean reduction in the placebo
group. The placebo-corrected T/P ratios for systolic and dias-
tolic BPs were 0.77 and 0.64, respectively.
Changes in Casual BP and Pulse Rate
Changes in outpatient readings for sitting BP and pulse rate
are shown in Fig. 5. In the irbesartan group, both systolic and
diastolic BPs were significantly decreased at the second week
(by 9.1 and 6.0 mmHg, respectively) of the treatment period,
and remained significantly low up to the sixth week. In the
placebo group, small but significant reductions in BPs were
observed from the fourth week of the treatment. No ma