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Journal of Renin-Angiotensin-Aldosterone
DOI: 10.3317/jraas.2005.014
2005; 6; 84 J Renin Angiotensin Aldosterone Syst
Joel M Neutel, F Wilford Germino and David Smith
Mild-to-Moderate Hypertension
Comparison of Monotherapy with Irbesartan 150 mg or Amlodipine 5 mg for Treatment of
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Abstract
Objective. The primary objective of this
study was to compare the antihypertensive
efficacy of the angiotensin II receptor blocker
irbesartan 150 mg and the calcium channel
blocker amlodipine 5 mg in the treatment of
patients with seated diastolic blood pressure
(DBP) 95–110 mmHg.
Design. Multicentre, randomised, double-blind,
comparative pilot study.
Methods. Subjects were 18–65 years of
age, with DBP 95–110 mmHg, and of non-
African American origin. Following a three-
week, single-blind, placebo lead-in period,
181 subjects were randomised in a 1:1 ratio
to receive once-daily irbesartan 150 mg
(n=89) or amlodipine 5 mg (n=92) for four
weeks. Trough (24±3 hours post-dosing) BP
measurements were obtained at baseline
and at Weeks 2 and 4 under standardised,
controlled conditions. Response was defined as
DBP <90 mmHg or a reduction from baseline
of ≥10 mmHg.
Results. After four weeks of treatment, the
mean (±SE) decrease from baseline in DBP
was 9.4±0.6 mmHg in the irbesartan group
vs. 9.6±0.6 mmHg in the amlodipine group
(p=0.806). The mean decrease from baseline
in seated systolic BP was 12.2±1.0 mmHg in
the irbesartan group vs. 12.0±1.0 mmHg in the
amlodipine group (p=0.885). Overall, 62% of
subjects in the irbesartan group and 63% in the
amlodipine group had a response (p=0.609),
and 54% and 56% of patients (p=0.596),
respectively, had their DBP normalised (<90
mmHg). Adverse events were reported by
21.3% of patients receiving irbesartan and
20.7% receiving amlodipine.
Conclusions. Irbesartan 150 mg demonstrated
comparable efficacy to amlodipine 5 mg, thereby
confirming its value as an antihypertensive
treatment option in non-African American
patients with DBP 95–110 mmHg.
Introduction
Numerous drugs are available for the management
of hypertension, representing several distinct
drug classes and employing diverse mechanisms
of action. Because of the array of therapeutic
choices, matching antihypertensive therapy
Comparison of Monotherapy with Irbesartan 150 mg
or Amlodipine 5 mg for Treatment of Mild-to-Moderate
Hypertension
Joel M Neutel,‡ F Wilford Germino,* David Smith‡
Keywords:
Irbesartan,
Amlodipine,
Ambulatory
BP monitoring
‡Orange County
Research Center,
Tustin, California, USA
*Department of Internal
Medicine,
University of Chicago,
Chicago, Illinois, USA
Correspondence to:
Dr Joel M Neutel
Orange County
Research Center,
14351 Myford Road,
Tustin, CA 92780
Tel: +1 714 550 9990
Fax: +1 714 550 1226
E-mail: jmneutel@aol.
com
Accepted for
Publication
5th September 2005
JRASS 2005;6:84–89
Journal of
the Renin-
Angiotensin-
Aldosterone
System
Including other
Peptidergic Systems
September 2005
Volume 6
Number 2
Paper
to individual patients often presents a clinical
challenge. The choice of agent is based on patient-
related factors as well as drug mechanisms.
These factors include the stage of hypertension,
the presence of comorbid conditions, and the
identification of risk factors for renal disease,
cardiovascular disease, or diabetes mellitus.
In addition, aspects of the treatment regimen
that may affect patient adherence need to be
considered, such as side effects, out-of-pocket
costs, and convenience.1
Calcium channel blockers (CCBs) are an
important class of antihypertensive agents.
As a class, they are well tolerated and are
associated with few side effects.1 Amlodipine,
a dihydropyridine CCB, is currently the most
frequently prescribed branded cardiovascular
agent worldwide and is commonly considered
the ‘gold standard’ antihypertensive treatment
option in terms of efficacy, particularly in
lowering systolic blood pressure (SBP).2 Once-
daily amlodipine is generally well tolerated,
providing statistically significant reductions in BP
over 24 hours.3 The usual initial oral dosage is
5 mg once daily.4
Targeting the renin-angiotensin-aldosterone system
(RAAS) is also an important strategy for lowering
BP.5 Currently, there are three classes of drugs that
inhibit the RAAS: angiotensin-converting enzyme
inhibitors (ACE-Is), angiotensin II receptor
blockers (ARBs), and selective aldosterone
receptor blockers. ACE-Is reduce the formation
of angiotensin (Ang II), whereas ARBs act by
specific blockade of the angiotensin II receptor
subtype 1 (AT1). Selective aldosterone blockers
act at another step of the RAAS, by blocking the
actions of aldosterone.
Several ARBs are available for the management
of hypertension, either as monotherapy or in
combination with other agents. As a class, the
ARBs have demonstrated efficacy, safety, and
placebo-like tolerability in recommended dosing
regimes.6-10 The fact that their side effect profile is
remarkably benign6,9,10 gives them an advantage
over ACE-Is, which are commonly associated
with a dry cough and the more uncommon risk
of angioedema.8,11,12
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Irbesartan is an effective, long-acting ARB
that provides highly selective, insurmountable
blockade of AT1-receptors and is approved for
the treatment of patients with hypertension
and for the treatment of diabetic nephropathy
in patients with Type 2 diabetes mellitus and
hypertension.13 Clinical trials have shown that
irbesartan, at doses of 75 mg, 150 mg and 300
mg, provides significant dose-related reductions
in BP with once-daily administration in patients
with stage 1 hypertension and the lower limits
of stage 2 hypertension, and has placebo-like
tolerability.7,14,15
Despite the proven efficacy of irbesartan and
other ARBs, there remains a misconception
among some clinicians that these compounds
have reduced BP-lowering efficacy compared
with other well-established antihypertensive
medications, such as amlodipine. This trial aimed
to confirm the comparable efficacy of irbesartan
and amlodipine.
Methods
Study Population
The study enrolled men and women, 18–65
years of age, of non-African American origin,
with seated DBP 95–110 mmHg. Subjects were
recruited from 20 sites in the United States,
including private medical offices, clinical settings
and clinical research centres. All women of
childbearing potential were required to have a
negative pregnancy test (minimum sensitivity
25 IU/L of beta-human chorionic gonadotropin
within 72 hours prior to the start of the study
medication) and to be using an approved method
of contraception.
Subjects were excluded from the study if they had
a history of any of the following: cardiovascular
conditions (angina pectoris, myocardial infarction,
coronary revascularisation within 12 months,
heart failure, obstructive valvular heart disease,
hypertrophic cardiomyopathy, transient ischaemic
attack/cerebrovascular accident, or cardiac
arrhythmias), renal conditions (renovascular
occlusive disease or renal allograft), clinically
important hepatic, metabolic, neurological,
pulmonary, or haematological disorders, known
hypersensitivity to any component of the study
treatments, or severe psychiatric disorder.
African Americans were excluded from the study
based on clinical evidence suggesting that this
subpopulation does not respond as well to beta-
blocker, ACE-I or ARB monotherapy in comparison
with CCB monotherapy.16-19
Study Design
This was a multicentre, randomised, double-
blind, parallel-group study. After an appropriate
tapering of previous antihypertensive therapy
according to manufacturer recommendations,
subjects entered a three-week, single-blind,
placebo lead-in period. Subjects who met eligibility
criteria and had a mean DBP 95–110 mmHg
were randomised in a 1:1 ratio at baseline
(end of the placebo treatment period) to receive
double-blind treatment with irbesartan 150 mg
or amlodipine 5 mg once daily for four weeks.
The randomisation schedule linking the random-
isation number with treatment was computer-
generated by the biostatistics department of
Bristol-Myers Squibb (Princeton, NJ). Trough BP
measurements (taken at 24±3 hours after dosing)
were obtained under standardised, controlled
conditions four times during the placebo lead-in
period and after two and four weeks of active
treatment.
The study was performed in accordance
with Good Clinical Practice guidelines, the
Declaration of Helsinki International Conference
on Harmonization, and requirements of the
United States Food and Drug Administration.
Investigators were required to obtain written
informed consent from all subjects prior to
participation.
Observation Methods
Efficacy
A complete medical examination was performed
at the screening visit and after four weeks of
active treatment. Blood pressure and heart rate
were measured during scheduled office visits at
screening, at four visits during the placebo lead-
in period, and on days 1, 14 and 28 of the four-
week active treatment period. All measurements
were obtained using a calibrated mercury
sphygmomanometer under controlled conditions
using the same (dominant) arm and cuff size
at each visit. Mean seated BP was determined
at each visit from three separate measurements
obtained at least 1 minute apart after a 10-minute
period of rest in the seated position. If any of
the three readings was not within 8 mmHg of
the other two, an additional two BP readings
were obtained for the calculation. Study staff
were specifically trained to perform standardised
BP and heart rate measurements to minimise
variability due to measurement technique. Clinic
visits were scheduled between 6 am and 10 am,
and subjects were instructed to postpone taking
their study drug until after their BP had been
measured. Subjects were also required to abstain
from drinking alcoholic or caffeinated beverages
for at least six hours before, and from smoking
for three hours before BP measurements were
obtained.
Safety
Safety and tolerability were evaluated at each clinic
visit by assessing adverse events (defined as a new
or worsening illness, sign, symptom, or clinically
significant laboratory test abnormality during the
course of treatment, whether attributable to study
drug or not), routine laboratory parameters, and
electrocardiograms. Fasting laboratory values
(haematology, serum chemistry, blood urea
nitrogen, and alanine aminotransferase) were
obtained at baseline and at Week 4.
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Journal of
the Renin-
Angiotensin-
Aldosterone
System
Including other
Peptidergic Systems
September 2005
Volume 6
Number 2
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Outcome Measures
The primary efficacy measure was the change
from baseline in mean trough seated DBP
after four weeks of active treatment. Secondary
outcome measures included the change from
baseline in mean trough seated SBP at Week 4,
therapeutic response at Week 4 based on the
proportion of subjects with normalised seated
DBP (DBP <90 mmHg), and the proportion of
responders (subjects with normalised seated DBP
or who experienced a ≥10 mmHg reduction from
baseline in DBP).
Analytical Methods
Sample Size
A sample size of 70 evaluable subjects per treatment
group was required to provide a precision of ±2.5
mmHg for estimating the difference between
groups with 95% confidence, assuming a standard
deviation of 7.5 mmHg, for the change from
baseline in mean trough seated DBP. To allow for
attrition of approximately 10%, a minimum of 156
subjects were required for randomisation.
Data Sets
Safety analyses were performed on the data from
all randomised subjects who received at least
one dose of study medication; efficacy analyses
were performed on all evaluable subjects with
valid data. Data for all efficacy analyses were
summarised for the baseline, Week 2, Week 4 and
endpoint evaluations. An endpoint was defined as
the last measurement obtained during the double-
blind treatment period. Randomised subjects with
protocol violations were excluded from all efficacy
analyses. The exception was subjects whose only
protocol violation was missing a visit for BP or
heart rate measurement (scheduled visit ±3 days),
and for which all other valid measurements were
included.
Statistical Analyses
Statistical analyses were performed on the data
from Weeks 2 and 4 and from endpoint, to assess
the change from baseline in trough DBP and SBP
and to assess therapeutic response. Summaries
of the mean change from baseline to Week 4
in DBP were calculated for specific subgroups
defined by age (<50 years or ≥50 years), gender,
and baseline DBP (<100 mmHg or ≥100 mmHg).
Data were summarised by treatment group for the
proportion of subjects with normalised BP and
the proportion of responders at Weeks 2 and 4.
Treatments were compared using Cochran-Mantel-
Haenszel tests, stratified by site. Data from two
study sites, each having fewer than two subjects
per treatment group for BP values at Week 4,
were combined for analysis.
Analysis of covariance (ANCOVA) was used to
compare the treatment groups with regard to
changes from baseline in trough DBP and SBP at
Week 2, Week 4, and at endpoint. The ANCOVA
model included terms for treatment and treatment
site as main effects and for baseline value as a
covariate. Comparisons of the mean changes from
baseline for the two groups were based on the
difference between the adjusted mean changes
and the associated 95% confidence intervals
(CIs).
Safety Evaluations
Data from all randomised subjects who received at
least one dose of study medication were included
in the safety analysis.
Results
Patients
A total of 238 subjects were enrolled in the study,
181 subjects were randomised (irbesartan n=89;
amlodipine n=92) and 176 subjects (irbesartan
n=86; amlodipine n=90) completed the four-
week, double-blind study period. Five subjects
left the study prematurely (3/89 [3%] subjects in
the irbesartan group and 2/92 [2%] subjects in the
amlodipine group). Data sets were analysed for
all randomised subjects (n=181) and for subjects
with valid data (n=178). The results of both data
sets were similar.
The summaries of demographic characteristics
for all randomised subjects demonstrated no
apparent differences between the two groups at
baseline (Table 1). The majority of subjects were
men (63%), Caucasian (87%), and the mean age
was 51 years. At baseline, mean (±SD) seated
DBP was 99.7±3.6 mmHg and mean seated SBP
was 150.1±12.6 mmHg.
Reduction in Blood Pressure at
Trough
The primary efficacy measure of adjusted change
from baseline in mean (±SE) trough DBP at Week
4 was -9.4±0.6 mmHg in the irbesartan group and
-9.6±0.6 mmHg in the amlodipine group (Table 2).
The difference in reduction in mean DBP between
the two treatment groups was 0.2 mmHg (95% CI:
-1.5, 1.9; p=0.806). Final mean (±SD) trough DBP
was 90.1±6.9 mmHg in the irbesartan group and
89.9±6.6 mmHg in the amlodipine group.
The adjusted change from baseline in mean (±SE)
trough SBP at Week 4 was -12.2±1.0 mmHg in
the irbesartan group and -12.0±1.0 mmHg in the
amlodipine group (Table 2). The difference in
reduction in mean SBP between the two groups
was 0.2 mmHg (95% CI: -3.0, 2.6; p=0.885) (Table
2). Mean (±SD) trough SBP at treatment end was
138.7±13.1 mmHg in the irbesartan group and
137.5±12.7 mmHg in the amlodipine group. There
were no differences in mean heart rate between
the two groups at Week 4 (71.0 beats/minute in
the irbesartan group vs. 72.4 beats/minute in the
amlodipine group).
After two weeks of treatment, mean (±SD) trough
DBP was 90.4±6.5 mmHg in the irbesartan group
and 91.3±5.9 mmHg in the amlodipine group.
The adjusted change from baseline in mean (±SE)
trough DBP at Week 2 was -9.1±0.6 mmHg in
the irbesartan group and -8.4±0.6 mmHg in the
Paper
Journal of
the Renin-
Angiotensin-
Aldosterone
System
Including other
Peptidergic Systems
September 2005
Volume 6
Number 2
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amlodipine group. The difference in reduction in
mean DBP between the two treatment groups at
Week 2 was 0.7 mmHg (p=0.402). Mean (±SD)
trough SBP at Week 2 was 139.3±13.3 mmHg
in the irbesartan group vs. 139.9±13.5 mmHg in
the amlodipine group; the adjusted change from
baseline in mean (±SE) SBP was -11.5±1.0 mmHg
in the irbesartan group and -9.7±1.0 mmHg in the
amlodipine group. The difference in reduction in
mean SBP between the two treatment groups at
Week 2 was 1.7 mmHg in favour of irbesartan
(95% CI: -4.5, 1.0; p=0.217).
Subgroup Analyses
The treatment effect on the change from baseline
in trough DBP at Week 4 in patient subgroups,
as defined by age, gender, and baseline DBP,
is shown in Table 3. The mean changes from
baseline in DBP were of a similar magnitude in
each treatment group for patients <50 years of
age versus ≥50 years, for men and women, and
for patients with baseline DBP <100 mmHg versus
≥100 mmHg.
Therapeutic Response
At Week 4, the percentage of subjects with
normalised seated DBP (DBP <90 mmHg) was 54%
in the irbesartan group and 56% in the amlodipine
group (p=0.596) (Table 2). The proportion of
responders (subjects with normalised DBP or
who experienced a ≥10 mmHg reduction from
baseline in DBP) was 62% in the irbesartan group
versus 63% in the amlodipine group (p=0.609)
(Table 2).
Adverse Events
All 181 patients randomised were evaluated
for safety. Adverse events were experienced by
19 (21.3%) patients in the irbesartan treatment
group and 19 (20.7%) patients in the amlodipine
treatment group during the four-week double-
blind treatment period. Dizziness was the most
common adverse event, occurring in five (5.6%) of
patients on irbesartan and one (1.1%) of patients
on amlodipine (Table 4).
Two serious adverse events occurred during
the active treatment period: one patient in the
irbesartan treatment group developed a urethral
calculus, and one patient in the amlodipine
treatment group died from acute alcohol
intoxication. Both events were judged to be
unrelated to the study drug.
Discussion
In the current study, irbesartan 150 mg once daily
reduced mean trough DBP by 9.4 mmHg, which
was comparable to that achieved with amlodipine
5 mg once daily (9.6 mmHg). Importantly, the
Table 1
Demographic and baseline characteristics of all
randomised subjects.
Characteristic Irbesartan Amlodipine Total
150 mg 5 mg